WO2006086609A2

WO2006086609A2 - Inhibitors of tryptase

Info

Publication number: WO2006086609A2
Application number: PCT/US2006/004680
Authority: WO
Inventors: Bernard Hirschbein; Chang Sun Lee; Joane Litvak; Weili Liu; Martin Sendzik; Emma J. Shelton; Jeffrey R. Spencer; David Sperandio; Vincent W-F. Tai; Julia Winslow-Lohman; Robert Yee
Original assignee: Axys Pharmaceuticals, Inc.
Priority date: 2005-02-10
Filing date: 2006-02-09
Publication date: 2006-08-17
Also published as: WO2006086609A3

Abstract

The present invention related to certain inhibitors of tryptase that are inhibitors of tryptase, pharmaceutical composition comprising these compounds and method of treating asthma, allergic rhinitis, and/or Chronic Obstructive Pulmonary Disease utilizing these compounds.

Description

INHIBITORS OF TRYPTASE

BACKGROUND OF THE INVENTION

Cross Reference to Related Applications

The Applicants claim priority under 35 U.S. C. 119(e) to copending Provisional Application No. 60/651,870 filed on February 10, 2005, the disclosure of which is incorporated herein by reference in its entirety.

Field of the Invention

This invention relates to novel methods and compositions for the treatment of diseases associated with tryptase activity by administration of novel tryptase inhibitors.

State of the Art

Tryptase, the predominant protease secreted from human mast cells, is thought to be involved in neuropeptide processing and tissue inflammation. Elevated levels of tryptase have been detected in a number of diseases, including asthma, allergic conjunctivitis, allergic rhinitis, rheumatoid arthritis, multiple sclerosis, interstitial cytitis (Drugs of the Future 1996, 21, 811), and Chronic Obstructive Pulmonary Disease (COPD). In particular, tryptase concentrations are elevated in the bloodstream for several hours following anaphylaxis (Schwartz et al N. Eng. J. Med. 1987, 316, 1622-1626) (Shalit, et al. J. Allergy & Clin. Immunol. 1990, 86, 117-125.), are increased in nasal and lung lavage fluid from atopic subjects following specific antigen challenge (Castells et al. J. Allerg. Clin. Immunol. 1988, 141, 563-568), and are elevated in lung lavage fluid of atopic asthmatics after endobronchial allergen challenge. Smokers often have striking elevations of bronchoalveolar lavage fluid tryptase levels, a finding that provides some support for the hypothesis that release of proteinase from activated mast cells could contribute to lung destruction in smoker's emphysema. (Celenteron et al. Chest 1988, 94, 119-123). Animal studies have shown microvascular leakage subsequent to injection of tryptase (He, et al. Eur J. Pharmacol. 1997, 328, 89-97). hi addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting that it is involved in pulmonary fibrosis and interstitial lung disease (Ross et al. (199I) J. Clin. Invest. 88:493-499).

Asthma is becoming increasingly prevalent, especially in the pediatric population (GINA Workshop Report, Global Strategy for Asthma Management and Prevention -updated April 2002. (Scientific information and recommendations for asthma programs. NIH Publication No. 02-3659)). It is recognized as an inflammatory disorder (Hood et al, Immunology, Benjamin-Cummings, ed., 2^nd ed., 1984) and frequently is characterized by progressive development of hyperresponsiveness of the trachea and bronchi to both irnmunospecific allergens and generalized chemical or physical stimuli. The disease involves multiple biochemical mediators in both its acute and chronic stages. The hyperresponsiveness of asthmatic bronchiolar tissue is believed to be the result of chronic inflammatory reactions, involving a variety of cells and inflammatory mediators (Busse & Lemanske (2001) N Engl. J. Med. 344:350-362) which irritate and damage the epithelium lining the airway wall and promote pathological thickening of the underlying tissue. Bronchial biopsies in patients with only mild asthma have features of inflammation in the airway wall.

Allergic responses to inhaled allergens can initiate the inflammatory sequence. For example, allergens can activate mast cells and basophils, which are present in the epithelium and underlying smooth muscle tissue by binding IgE located on the cell surface. Activated mast cells release a number of preformed or primary chemical mediators (e.g., histamine) of the inflammatory response and generate numerous other secondary mediators of inflammation (e.g., superoxide, lipid derived mediators, etc.) in situ. In addition, several large molecules (e.g., proteoglycans, tryptase, chymase, etc.) are released by degranulation of mast cells.

The release of these preformed mediators from mast cells probably accounts for the early bronchiolar constriction in the asthmatic reaction to air borne allergens. The early phase of the asthmatic reaction peaks approximately fifteen minutes after exposure to allergen and is generally followed by recovery over the ensuing one to two hours. Twenty five to thirty five percent of the patient population experience a further decline in respiratory function which maximizes six to twelve hours after exposure. This late reaction phase is accompanied by a marked increase in the number of inflammatory cells (e.g., eosinophils, neutrophils, lymphocytes, etc.) infiltrating the bronchiolar tissue. The infiltrating cells are attracted to the site by release of mast cell derived chemotactic agents and then become activated during the late reaction phase. The late asthmatic response is believed to be a secondary inflammatory reaction mediated in part by the secretory activity of granulocytes.

Tryptase is implicated in the degradation of vasodilating and bronchorelaxing neuropeptides (Caughey et al. J.Pharmacol. Exp. Ther 1988, 244, 133-137; Franconi et al. J. Pharmacol. Exp. Titer. 1988, 248, 947-951; and Tarn et al. Am. J. Respir. Cell MoI. Biol. 1990, 3, 27-32) and modulation of bronchial responsiveness to histamine (Sekizawa et al. J. Clin. Invest. 1989, 83, 175-179). These findings suggest that tryptase may increase bronchoconstriction in asthma by destroying bronchodilating peptides. Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, which suggests that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Tryptase was also shown to activate PAR-2 (Molino, et al. J. Biol. Chem. 1997, 272, 4043-4049), a tethered ligand G-protein-coupled receptor that is believed to mediate some of the inflammation and hyperreactivity seen in asthma (Schmidlin, et alJ. Immunol. 2002, 169, 5315-5321). Further, administration of tryptase inhibitor protects against development of the late and airway hyperresponsive phases in allergen challenged sheep (Clark et al. Am. J. Respir. Crit. Care Med. 1995, 152, 2076-2083) and inhibits the immediate cutaneous response to intradermal injection of allergen in allergic sheep (Molinari etal. Amer. Physiol. Soc. 1995, 79(6), 1966-1970). Tryptase inhibitor was also found to reduce the acute airway response to allergen in pigs (Dahlback, et al. Clin. & Exp. Allergy 2002, 32, 967-971). Most relevant are results from a clinical trial showing that a tryptase inhibitor reduced allergen-induced late asthmatic response in mild atopic asthmatics (Krishna, et al. J. Allergy Clin. Immunol. 2001, 707, 1039-1045). All of the above-described findings clearly indicate the applicability of tryptase inhibitors as therapeutic agents in treating asthma and other disorders associated with inflammation of the respiratory tract.

Myocardial infarction is associated with an inflammatory response ultimately leading to healing and formation of a scar (Frangogiannis, et. al.Cardiovasc Res 2002, 53, 31-47). Mast cells may regulate this healing process by releasing proteases, particularly tryptase (Somasundaram, et al. J. of Pathol. 2005, 205, 102-111). Tryptase' s activation of the PAR-2 receptor (id.), a receptor that is believed to mediate some of the inflammation seen in healing myocardial infarctions (id.), may be responsible for inducing inflammation and angiogenesis, perhaps partially via induction of angiogenic chemokines.

Tryptase has been observed to cleave gelatinase and fibronectin (J. Cell. Biochem. 1992, 50, 337) which suggests that it may function in the normal regulation of extracellular matrix turnover though a direct proteolytic mechanims. Such activity is important for tissue growth and remodeling, cell migration and wound healing, and probably metastasis as well. Tryptase may also have a role in other pathological conditions where pro-matrix metalloproteinase 3 (MMP-3) is implicated because of tryptase's role in activation of MMP- 3. Once activated, MMP-3 can degrade proteoglycans, fibronectin, laminin, and type IV and type IX collagen. Such conditions include cartilage degradation as well as collagen deposits in such diseases as arthritis, chronic periodontitis, rheumatoid synovium and sclerosis.

Diseases or conditions that may be mediated by tryptase activity include: metastasis of tumor cells, anaphylaxis, mastocytosis, scleroderma, urticaria, atopic dermatitis, bullous pemphigoid, psoriasis, pulmonary fibrosis, interstitial pneumonia, nephritis, hepatic fibrosis, hepatitis, hepatic cirrhosis, Crohn's disease, ulcerative colitis, allergic rhinitis, peptic ulcers, gastric disease induced by non-steroidal inflammatory agents, cardiac infarction, disseminated intravascular coagulation, pancreatitis, multi-organ failure, interstitial lung diseases, gingivitis, peridontitis, viral infections, breast cancer, ocular allergy, bladder cancer, fibrotic lung disease, artherosclerosis, cardiomyopathic disorders, rheumatoid arthritis, and Chronic Obstructive Pulmonary Disease (COPD).

The disclosures of these and other documents referred to throughout this application are incorporated herein by reference.

SUMMARY OF THE INVENTION

In first aspect, this invention is directed to a Compound of Formula I:

I where

A is optionally substituted benzo, optionally substituted pyridino, optionally substituted pyrimidino, optionally substituted pyrazino, or optionally substituted pyridazino;

D is =N-, or =CR⁶- where R⁶ is hydrogen, alkyl, halo, alkylcarbonyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, haloaloxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl;

R¹ is hydrogen, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, or aralkyloxycarbonyl;

R² is hydrogen, alkyl, alkylsulfonyl, alkylphosphonyl, or alkoxyalkyloxyalkyl;

R³ is hydrogen, alkyl, hydroxy, halo, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, R^10aR^10bNC(O)NR^10c- (where R^1Oa, R^1Ob, and R¹⁰° are independently hydrogen, alkyl, or substituted alkyl), R^llaR^{l lb}NC(O)O- (where R^lla and R^{l lb} are independently hydrogen, alkyl, or substituted alkyl), or R^12aOC(O)NR^12b- (where R^12a and R^12b are independently hydrogen, alkyl, or substituted alkyl); and R¹⁰⁰ is a group of formula (Al):

(Al) where

R^4a and R^4b are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, halo, alkoxy, acyl, acyloxy, acylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, -NR^19oC(0)NR^19aR^19b (where R^19a, R^19b, and R^19c are independently hydrogen, alkyl, or substituted alkyl), -OC(O)NR^24aR^24b (where R^24a and R^24b are independently hydrogen, alkyl, or substituted alkyl), or -NR^25bC(O)OR^25a (where R^25a and R are independently hydrogen, alkyl, or substituted alkyl); and where alkyl, alkenyl, and alkynyl, either alone or as part of another group are independently optionally substituted with one, two, three, four, or five halo; and

L is -X^!-Y -Z¹- where X¹ is alkylene, alkenylene, or cycloalkylene and where X¹ is optionally substituted by one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, alkylamino, and dialkylamino; Y¹ is -O-, -NR¹³-, -C(O)-, -C(O)O-, -C(O)NR¹³-, -NR¹³C(O)-, -C(O)NR¹³C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹³-, -NR¹³SO₂-, -OC(O)-, -OC(O)NR¹³-, -NR¹³C(O)O-, or -NR¹³C(O)NR¹⁴- (where R¹³ and R¹⁴ are independently hydrogen, alkyl, or substituted alkyl); and Z¹ is a bond, alkylene, alkenylene, or cycloalkylene;

L is -X - where X is alkylene, alkenylene, or cycloalkylene and is optionally substituted by one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, alkylamino, and dialkylamino;

L is -Y²-Z²- where Y² is -NR¹⁵-, -C(O)-, -C(O)O-, -C(O)NR¹⁵-, -NR¹⁵C(O)-, -C(O)NR¹⁵C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹⁵-, -NR¹⁵SO₂-, -OC(O)-, -OC(O)NR¹⁵-, -NR¹⁵C(O)O-, or -NR¹⁵C(O)NR¹⁶- (where R¹⁵ and R¹⁶ are independently hydrogen, alkyl, or substituted alkyl); and where Z² is alkylene, alkenylene, or cycloalkylene; and

L is -Y³- where Y³ is -NR¹⁷-, -C(O)O-, -C(O)NR¹⁷-, -NR¹⁷C(O)-, -C(O)NR¹⁷C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹⁷-, -NR¹⁷SO₂-, -OC(O)-, -OC(O)NR¹⁷-, -NR¹⁷C(O)O-, or -NR¹⁷C(O)NR¹⁸- (where R¹⁷ and R¹⁸ are independently hydrogen, alkyl, or substituted alkyl); or

L is -X⁵-Y^5a-Z⁵-Y^5b- where X⁵ is alkylene, alkenylene, or cycloalkylene and where X⁵ is optionally substituted by one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, alkylamino, and dialkylamino; Y^5a is -O-, -NR¹³-, -C(O)-, -C(O)O-, -C(O)NR¹³-, -NR¹³C(O)-, -C(O)NR¹³C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹³-, -NR¹³SO₂-, -OC(O)-, -OC(O)NR¹³-, -NR¹³C(O)O-, or -NR¹³C(O)NR¹⁴- (where R¹³ and R¹⁴ are independently hydrogen, alkyl, or substituted alkyl); Z⁵ is a bond, alkylene, alkenylene, or cycloalkylene where the alkylene or alkenylene are optionally substituted with aralkyloxyalkyl; and Y^5b is -C(O)-;

Het is heterocycloalkyl; and

R⁷, R⁸, and R⁹ are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, acylamino, acyloxy, acylaminoalkyloxycarbonyl, alkylthio, alkylsulfonyl, alkoxy, alkoxycarbonyl, alkoxyalkylamino, alkoxyalkylaminocarbonyl, alkoxyalkyloxy, alkoxyalkyloxycarbonyl, amino, alkylamino, dialkylamino, aminoalkyloxy, carboxy, carboxyalkylaminocarbonyl where the "alkyl" is optionally substituted with one or two hydroxy, cyano, cyanoalkylaminocarbonyl, aryl, aryloxy, arylsulfonyl, arylthioalkylcarbonyl, aralkyl where the alkyl is optionally substituted with one or two hydroxy, aralkyloxy, aralkyloxycarbonyl, aralkyloxyaminocarbonyl, aralkyloxycarbonylamino, aralkenyl, cycloalkyl, cycloalkyloxy, cycloalkylaminocarbonyl, cycloalkylalkyl where the "alkyl" is optionally substituted with one or two hydroxy, cycloalkylalkylaminocarbonyl, cycloalkylalkyloxycarbonyl, heteroaryl, heteroarylaminocarbonyl, heteroaralkyl, heteroaralkenyl, heteroaralkyloxy, halo, hydroxy, hydroxyalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, N-hydroxyaminocarbonyl, iV-alkoxyaminocarbonyl, hydroxyalkylaminocarbonyl, dialkylaminoalkyloxycarbonyl, dialkylaminoalkylaminocarbonyl, arylamino, arylaminocarbonyl, alkylsulfonylamino, alkylsulfonylaminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylaminocarbonyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkylalkyloxycarbonyl, optionally substituted heterocycloalkylalkylaminocarbonyl, aminocarbonylamino, N-aryl-iV-(alkylcarbonyl)-amino, N-(alkylsulfonyl)-iV-alkyl-amino, alkoxycarbonylalkylaminocarbonyl where the "alkyl" is optionally substituted with one or two hydroxy, or trialkylsilyl; or any two of R⁷, R⁸, and R⁹ attached to the same carbon atom together with the carbon to which they are attached form indanylene or optionally substituted heterocycloalkylene; and where the alkyl, alkenyl, and alkynyl in R⁷, R⁸, and R⁹, either alone or part of another group (for example, the alkyl within the group "alkoxy" or for example, any alkyl or alkenyl within the group "optionally substituted alkenyl"), independently are optionally substituted with one, two, three, four, or five halo; or

R¹⁰⁰ is a group of formula (A2):

(A2) where

R^4a and R^4b are as defined above;

R⁵ is -Y¹^X^{1 !}-Q¹¹ where Y¹¹ is -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR^26a-, -C(O)NR^26a-, -NR^26aC(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are independently hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, or acyl, where X¹¹ is a bond, alkylene, or alkenylene, (where X¹¹ is optionally substituted with hydroxy, alkoxycarbonyl, carboxy), and where Q¹¹ is heteroaryl, aryl, aryloxy, or cycloalkyl;

R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is alkylene or alkenylene; Y¹² is -NR^26a-, -0-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR²⁶³-, -NR²⁶³C(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are as defined above; X^12b is a bond, alkylene, or alkenylene where X^12b is optionally substituted with one, two, or three groups selected from hydroxy, cyano, halo, heteroaryl, alkylcarbonyl, alkoxycarbonyl, carboxy, -NR^27aR^27b (where R^27a and R^27b are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, heteroaryl, or heteroarylaminocarbonyl), -C(O)NR^28aR^28b (where R^28a and R^28b are independently hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, hydroxy, or heteroaryl), and -NR^29aC(O)OR^29b (where R^29a is hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, or hydroxy, and R^29b is alkyl); and Q¹² is aryl, aryloxy, aralkyloxy, heteroaryl, aralkylaminocarbonyl (where the alkyl is optionally substituted with alkoxycarbonyl or carboxy), cycloalkyl, cycloalkylaminocarbonyl, cycloalkylalkyloxy, -NR^3OaR^3Ob (where R^3Oa is hydrogen or alkyl and R^3Ob is aryl, heteroaryl, or cycloalkylalkyl) or -S(O)_n-R³¹ (where n is 0, 1, or 2 and R³¹ is heteroaryl, cycloalkylalkyl or aralkyl); where the alkyl within any group in Q¹² is optionally substituted with alkoxyalkyl);

R⁵ is -X¹³-Y¹³-Z¹³ where X¹³ is alkylene or alkenylene, where Y¹³ is -NR^26a-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR^26a-, -NR²⁶³C(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR^26aC(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are as defined above, and where Z¹³ is hydrogen, alkyl, or alkenyl (where Z¹³ is optionally substituted with one, two, or three halo, hydroxy, amino, alkoxy, alkoxycarbonyl, carboxy, or alkylcarbonylamino); or

R⁵ is -Y¹⁴-Z¹⁴ where Y¹⁴ is -S(O)-, -NR^26aC(O)-, -C(O)NR²⁶³-, -NR^26aC(O)NR^26b-, -C(O)NR²⁶³C(O)-, -NR²⁶³C(O)O-, -OC(O)NR²⁶³, or -OC(O)-, where R^26a and R^26b are as defiend above, and where Z¹⁴ is alkyl or alkenyl (where Z¹⁴ is optionally substituted with one, two, or three halo, hydroxy, amino, alkoxy, alkoxycarbonyl, carboxy, or alkylcarbonylamino); or

R¹⁰⁰ is a group of formula (A3):

(A3) where

X⁴ is alkylene optionally substituted with one, two, three, four, or five halo;

Y⁴ is -C(O)-, -NR³²C(O)-, -S(O)₂-, or a bond;

Z⁴ is heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, carboxy, aryl, aralkyl, cyano, arylcarbonyl, alkoxy, and hydroxy; or Z⁴ is -NR^50aR^50b where R^5Oa is hydrogen, alkyl, alkoxy, or hydroxy and R^5Ob is -(alkylene)-aryl where the alkylene is optionally substituted with one or two groups selected from halo, alkoxycarbonyl, hydroxy, and carboxy; or a pharmaceutically acceptable salt therof.

In second aspect, this invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient.

In a third aspect, this invention is directed to a method of treating a disease, disorder, or syndrome responsive to the inhibition of tryptase in an animal suffering said disease, disorder, or syndrome, comprising administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I. In a fourth aspect, this invention is directed to a method of treating an immunomediated respiratory disease independently selected from the group consisting of asthma, COPD, and allergic rhinitis, preferably asthma, in an animal which method comprises administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient in combination with one or more compound(s) independently selected from the group consisting of a β-2 adrenoreceptor agonist, corticosteroid, leukotriene antagonist, phosphodiesterase 4 inhibitor, and antihistamine. Preferably, the compound of Formula I and the pharmaceutically acceptable excipient is administered in combination with one or more compound(s) independently selected from salmeterol, fluticasone, budesonide, montelukast, levalbuterol, and roflumilast.

In a fifth aspect, this invention is directed to a method of treating an immunomediated disease independently selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease (IBD) (comprising Crohn's Disease and Ulcerative Colitis), myocardial infarction, and systemic lupus erythematosus (SLE) in an animal which method comprises administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient in combination with one or more anti-inflammatory compound(s). Preferably, the compound of Formula I and the pharmaceutically acceptable excipient is administered in combination with one or more compound(s) independently selected from azathioprine, plaquenil, prednisone, sulfasalazine, methotrexate, Arava, Remicade, and Enbrel.

In a sixth aspect, this invention is directed to an intermediate of Formula II or III:

II where R²⁰ is -X^OH, -X^NHR¹³, -X^C(O)OH, -X'-SH, -X²-LG where LG is a leaving group under alkylating conditions, -C(O)OH, -NHR¹⁵, -NHR¹⁷, -X⁵-NHR¹³, -X⁵-C(O)OH, -NHR^26a, -X^12a-C(O)OH, -X^12a-NHR^26a, -X¹³-C(O)OH, or -X¹³-NHR^26a; and all other groups are as defined in the Summary of the Invention; or

III where R⁷⁵ is -X⁴-C(O)OH, -X⁴-LG where LG is a leaving group under alkylating conditions, or -X⁴-NHR³²; and all other groups are as defined in the Summary of the Invention.

In a seventh aspect, this invention is directed to N-(4-iodo-pyridin-3-yl)- methanesulfonamide.

In a eighth aspect, this invention is directed to a process of preparing a compound of Formula I, in which Y¹ is -C(O)NR¹³- or -NR¹³C(O)- comprising:

(a) reacting an intermediate of Formula II:

II where R²⁰ is -X^R²³; and R²³ is -NHR¹³ or -C(O)OH, with an intermediate of formula R²²C(O)OH or NHR²¹R²², respectively; where R²¹ is R¹³ and R²² is -Z^R²³, wherein R²³ is a moiety of Formula (a):

(a) and each A, R³, R^4a, R^4b X¹, Z¹ R⁷, R⁸, R⁹ and R¹³ are as defined in the Summary of the Invention or R²¹ and R²² together with the nitrogen atom to which they are attached form a moiety of Formula (a); and

(b) optionally separating individual isomers; and

(c) optionally modifying any of the A, D, R¹, R², R³, R^4a, and R^4b groups; or a process of preparing a compound of Formula I, in which Y¹² is -C(O)NR^26a- or

-NR²⁶³C(O)- comprising:

(d) reacting an intermediate of Formula II where R²⁰ is -X^12a-NHR^26a or -X^12a-C(O)OH, with an intermediate of formula Q¹²-X^12b-C(O)OH, or Q¹²-X^12b-NHR^26a, respectively; and (e) optionally separating individual isomers; and

(f) optionally modifying any of the A, D, R¹, R², R³, R^4a, and R^4b groups; or a process of preparing a compound of Formula I, in which Y⁴ is -C(O)- comprising:

(g) reacting an intermediate of Formula III:

III where R⁷⁵ is -C(O)OH and all other groups are as defined in the Summary of the Invention, with an intermediate of formula NHR^50aR^50b or NHR²¹R²² where R²¹ and R²² together with the nitrogen atom to which they are attached form heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, carboxy, aryl, aralkyl, cyano, arylcarbonyl, alkoxy, and hydroxy; (h) optionally separating individual isomers; and (i) optionally modifying any of the A, D, R¹, R², and R³ groups.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations and Definitions:

Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meanings:

"Acyl" means a -C(O)R radical where R is optionally substituted alkyl, optionally substituted alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkylalkyl, as defined herein, e.g., acetyl, benzoyl, trifluoromethylcarbonyl, or 2-methoxyethylcarbonyl, and the like.

"Acylamino" means a -NRR' radical where R is hydrogen, hydroxy, alkyl, or alkoxy and R' is acyl, as defined herein.

"Acylaminoalkyl" means an alkyl radical substituted with at least one, preferably one or two, acylamino group(s), as defined herein.

"Acylaminoalkyloxycarbonyl" means a -C(O)OR radical where R is an acylaminoalkyl group, as defined herein.

"Acyloxy" means an -OR radical where R is acyl, as defined herein, e.g. cyanomethylcarbonyloxy, and the like. "Administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., β-2 adrenoreceptor agonists, corticosteroids, leukotriene antagonists, and/or phosphodiesterase 4 inhibitors, etc.), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.

"Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing one or two double bonds e.g., ethenyl, propenyl (including all isomeric forms), 1-methylpropenyl, butenyl (including all isomeric forms), or pentenyl (including all isomeric forms), and the like.

"Alkenylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms containing at least one, preferably one or two, double bonds e.g., ethen-l,2-diyl, propen-3,3-diyl, propen-1,3- diyl, or 2-methyl-but-2-en-l,4-diyl, and the like.

"Alkoxy" means a radical -OR where R is alkyl as defined herein, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.

"Alkoxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, alkoxy group(s), as defined herein, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, or 3,4-dimethoxybutyl, and the like.

"Alkoxyalkylamino" means an -NR^aR^b where R^a is hydrogen, alkyl, or alkoxyalkyl, as defined herein, and R^b is alkoxyalkyl, as defined herein.

"Alkoxyalkylaminocarbonyl" means the radical -C(O)R where R is alkoxyalkylamino, as defined herein.

"Alkoxyalkyloxy" means a -OR radical where R is alkoxyalkyl, as defined herein.

"Alkoxyalkyloxyalkyl" means an alkyl radical substituted with at least one, preferably one or two, alkoxyalkyloxy group(s), as defined herein.

"Alkoxyalkyloxycarbonyl" means a -C(O)OR radical where R is alkoxyalkyl as defined herein.

"Alkoxyalkyloxycarbonylalkyl" means an alkyl radical substituted with at least one, preferably one or two, alkoxyalkyloxycarbonyl group(s), as defined herein

"Alkoxyaminocarbonyl" means a -C(O)NHR radical where R is alkoxy, as defined herein, e.g. methoxyaminocarobnyl, and the like.

"Alkoxycarbonyl" means a radical -C(O)OR where R is alkyl as defined herein, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, or 2-propoxycarbonyl, n-, iso-, or tert-butoxycarbonyl, and the like.

"Alkoxycarbonylalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, alkoxycarbonyl group(s), as defined herein, e.g., methoxycarbonylmethyl or methoxycarbonylethyl, and the like.

"Alkoxycarbonylalkylaminocarbonyl" means a -C(O)NR^aR^b radical where R^a is alkoxycarbonylalkyl, as defined herein, and R^b is hydrogen, alkyl, as defined herein, or alkoxycarbonylalkyl, as defined herein.

"Alkoxycarbonylalkyloxy" means an -OR radical where R is alkoxycarbonylalkyl, as defined herein.

"Alkoxycarbonylalkyloxyalkyl" means an alkyl radical substituted with at least one, preferably one or two, alkoxycarbonylalkyloxy group(s), as defined herein.

"Alkoxycarbonylamino" means a -NRC(O)OR' radical where R is hydrogen or alkyl, as defined herein, and R' is alkyl, as defined herein, e.g., methoxycarbonylamino, methoxycarbonyl-iV-methylamino or isopropoxycarbonylamino, and the like.

"Alkoxycarbonylaminoalkyl" means an alkyl radical as defined herein substituted with at least one, preferably one or two, alkoxycarbonylamino as defined herein, e.g., 2-(methoxycarbonylamino)ethyl, methoxycarbonyl-iV-methylaminomethyl or 2-(isopropoxycarbonylamino)propyl, and the like.

"Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or pentyl (including all isomeric forms), and the like.

"Alkylamino" means a radical -NHR where R is alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., methylamino, ethylamino, n-, wø-propylamino, n-, iso-, tert-butylamino, or methylamino-N-oxide, and the like.

"Alkylaminoalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, alkylamino group(s), as defined herein.

"Alkylaminoalkylaminocarbonyl" means a -C(O)NR⁵R" radical where R' is hydrogen, alkyl, hydroxy, or alkoxy and R" is alkylaminoalkyl, as defined herein.

"Alkylarninoalkyloxy" means a -OR radical, as defined herein, substituted with at least one, preferably one or two, alkylaminoalkyl group(s), as defined herein. "Alkylaminoalkyloxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, alkylaminoalkyloxy group(s), as defined herein.

"Alkylaminocarbonyl" means a -C(O)R radical where R is alkylamino as defined herein e.g, methylaminocarbonyl or ethylaminocarbonyl, and the like.

"Alkylaminosulfonyl" means a -S(O)₂NHR radical where R is alkyl, as defined herein.

"Alkylcarbonyl" means a -C(O)R radical where R is alkyl as defined herein, e.g., methylcarbonyl, ethylcarbonyl, or 2-propylcarbonyl, and the like.

"Alkylcarbonylamino" means a -NRR' radical, where R is hydrogen or alkyl, as defined herein, and R' is alkylcarbonyl as defined herein, e.g., methylcarbonylamino or ethylcarbonylamino, and the like.

"Alkylcarbonyloxy" means an -OR radical where R is alkylcarbonyl, as defined herein, e.g., methylcarbonyloxy, ethylcarbonyloxy, or n-propylcarbonyloxy, and the like.

"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or as otherwise indicated or a branched saturated divalent hydrocarbon radical of two to six carbon atoms or as otherwise indicated, e.g., methylene, prop-2,2-diyl, eth-l,2-diyl, prop-l,3-diyl, l-methylprop-l,3-diyl, 2-methylprop-l,3-diyl, but-l,4-diyl (including all isomers), or pent-l,5-diyl (including all isomers), and the like. Alkylene may contain the number of carbon atoms indicated. For example the term (alkylene)_1-3 means alkylene containing from 1 carbon atom, i.e., methylene, to 3 carbon atoms, i.e., eth-l,2-diyl, eth-l,l-diyl, prop-l,3-diyl, l-methyleth-l,2-diyl-, 2-methyleth-l,2-diyl, prop-l,l-diyl, and prop-2,2-diyl. The term (alkylene)o means that a bond is intended.

"Alkylphosphonyl" means a -OPO(OR)₂ radical where R is alkyl, as defined herein.

"Alkylsulfinyl" means a -S(O)R radical where R is alkyl as defined herein, e.g., methylsulfinyl, ethylsulfinyl, or propylsulfinyl, and the like.

"Alkylsulfonyl" means a -SO₂R radical where R is alkyl as defined herein, e.g., methylsulfonyl or ethylsulfonyl, and the like.

'W-(alkylsulfonyl)-7V-alkyl-amino" means a -NR^aR^b radical where R^a is an alkyl radical as defined herein and R^b is an alkylsulfonyl radical, as defined herein.

"Alkylsulfonylamino" means an -NHR^a radical, where R^a is alkylsulfonyl, as defined herein, e.g., methylsulfonylamino, and the like.

"Alkylsulfonylaminoalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two alkylsulfonylamino group(s), as defined herein.

"Alkylsulfonylaminocarbonyl" means a -C(O)R radical where R is alkylsulfonylamino, as defined herein.

"Alkylthio" means an -SR radical where R is alkyl as defined herein, e.g., methylthio, ethylthio, propylthio, or butylthio, and the like.

"Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one, preferably one or two, triple bond(s), e.g., ethynyl, propynyl (and all isomeric forms) and butynyl (and all isomeric forms) , and the like.

"Amino" means a -NH₂ radical or an N-oxide derivative, or a protected derivative thereof such as -NH→O, -NHBoc, or -NHCbz, and the like.

"Aminoalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, -NH₂ group(s), e.g., aminomethyl, aminoethyl, or 1,4-diamino- 2-methyl-pentyl, and the like.

"Aminoalkyloxy" means an -OR radical where R is aminoalkyl as defined herein.

"Aminoalkylaminocarbonyl" means a -C(O)NR'R" radical where R' is hydrogen, alkyl, hydroxy, or alkoxy and R" is aminoalkyl, as defined herein.

"Aminocarbonyl" means a -CONH₂ radical_, or an N-oxide derivative, or a protected derivative thereof.

"Aminocarbonylamino" means a -NRC(O)NH₂ where R is hydrogen or alkyl, as defined herein.

"Aralkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, aryl group(s) as defined herein, e.g., benzyl or phenethyl, and the like.

"Aralkyloxy" means an -OR radical where R is aralkyl as defined above, e.g., benzyloxy, and the like.

"Aralkyloxyaminocarbonyl" means a -C(O)NHOR radical where R is aralkyl, as defined herein.

"Aralkyloxycarbonyl" means a -C(O)R radical where R is arakyloxy as defined herein.

"Aralkyloxycarbonylalkyl" means an alkyl radical, as defined herein, substituted with at least one, prefereably one or two, aralkyloxycarbonyl group(s), as defined herein.

"Aralkyloxycarbonylamino" means a -NHR radical where R is aralkyloxycarbonyl, as defined herein.

"Aryl" means a monovalent, monocyclic or fused bicyclic hydrocarbon radical of 6 to 12 ring atoms, wherein the ring comprising a monocyclic radical ring is aromatic and wherein at least one of the fused rings comprising a bicyclic radical is aromatic. Fused bicyclic hydrocarbon radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. More specifically the term aryl includes, but is not limited to, phenyl, naphthyl, indanyl (including, for example, indan-5-yl, or indan-2-yl, and the like) or tetrahydronapthyl (including, for example, tetrahydronapth-1-yl, or tetrahydronapth-2-yl, and the like), and the like. Unless indicated otherwise, aryl may be substituted on any ring with one, two, or three substituents independently selected from the group consisting of acyl, acylamino, acyloxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, alkylthio, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, amino, alkylamino, dialkylamino, nitro, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, cyano, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aminoalkoxy, alkoxyalkyloxy, hydroxyalkyloxy,aminoalkyloxy, alkylcarbonylamino, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, -CONR^PR^V (where R^p is hydrogen, alkyl, hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkylalkyl and R^v is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy), -(alkylene)-SiR_!-₃ (where R is alkyl), -P(O)OR⁵R" (where R' and R" are alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, optionally substitututed heterocycloalkyl, optionally substitututed heterocycloalkylalkyl, heteroaryl, or heteroaralkyl), -P(O)R⁵R" where R' and R" are alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, optionally substitututed heterocycloalkyl, optionally substitututed heterocycloalkylalkyl, heteroaryl, or heteroaralkyl; or R⁵ and R⁵⁵ together with the P to which they are attached form optionally substituted heterocycloalkyl or heteroaryl), -P(O)(OR')(OR") (where R⁵ and R" are alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, optionally substitututed heterocycloalkyl, optionally substitututed heterocycloalkylalkykl, heteroaryl, or heteroaralkyl), optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkylaminocarbonyl, and heteroaryl; or when two substituents are adjacent to each other they can combine to form methylenedioxy group or aryl is pentafluorophenyl. Within the optional substituents on "aryl⁵⁵, any alkyl, alkenyl, or alkynyl, either alone or as part of another group (including, for example, the alkyl in heteroaralkyl and the alkyl in alkoxy), is independently optionally substituted with one, two, three, four, or five halo.

'W-aryl-7V-(alkylcarbonyl)-amino" means a -NR^aR^b radical where R^a is aryl, as defined herein and R^b is alkylcarbonyl, as defined herein.

"Arylamino" means a -NR'R" radical where R' is hydrogen, hydroxy, alkyl, alkenyl, alkoxy, or alkenyloxy and R" is aryl, as defined herein.

"Arylarninoalkyl" means an alkyl radical substituted with -NHR where R is aryl, as defined herein.

"Arylaminocarbonyl" means a -C(O)NHR radical where R is aryl, as defined herein.

"Arylcarbonyl" means a -C(O)R radical where R is aryl as defined herein.

"Arylcarbonylamino" means a the radical -NHC(O)R where are is aryl, as defined herein.

"Aryloxy" means a -OR where R is aryl as defined herein.

"Aryloxyalkyl" means an alkyl radical substituted with aryloxy, as defined herein.

"Arylthioalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, -S-aryl group(s).

"Arylthioalkylcarbonyl" means a -C(O)R radical where R is arylthioalkyl, as defined herein.

"Carboxy" means a -C(O)OH radical.

"Carboxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, -C(O)OH group(s), e.g., carboxymethyl, carboxyethyl, 1-, 2-, or 3-carboxypropyl, and the like.

"Carboxyalkylaminoalkyl" means an alkyl radical substituted with -NHR where R is carboxyalkyl, as defined herein.

"Carboxyalkylaminocarbonyl" means a -C(O)NHR radical where R is carboxyalkyl as defined herein.

"Carboxyalkylcarbonylamino" means an alkyl radical substituted with -NHC(O)R where R is carboxyalkyl, as defined herein.

"Carboxyalkyloxyalkyl" means an alkyl radical substituted with -OR where R is carboxyalkyl, as defined here.

"Chronic bronchitis" clinically means a daily cough with production of sputum for 3 months, two years in a row. In chronic bronchitis, the lining of the airways becomes inflamed and swells leading to narrowing and obstruction of the airways. The inflammation stimulates production of mucous (sputum), which can cause further obstruction of the airways. Obstruction of the airways, especially with mucus, increases the likelihood of bacterial lung infections.

"Chronic Obstructive Pulmonary Disease" or "COPD" is a disease comprising primarily chronic bronchitis and/or emphysema and is characterized by chronic obstruction of the flow of air through the airways and out of the lungs. The obstruction generally is permanent and progressive over time, limiting the ability to exhale. Chronic asthma may also develop into COPD where the lungs have become irreversibly damaged and scarred from repeated, untreated asthma flares. There is frequent overlap among COPD patients. Thus, patients with emphysema may have some of the characteristics of chronic bronchitis. Similarly, patients with chronic bronchitis also may have some of the characteristics of emphysema.

"Composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

"Cyanoalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, cyano group(s), e.g., cyanomethyl, 2-cyanoethyl, or 2-cyanopropyl, and the like.

"Cyanoalkylaminocarbonyl" means a -C(O)NR⁵R" radical where R' is hydrogen, alkyl, hydroxy, or alkoxy and R" is cyanoalkyl as defined herein.

"Cycloalkyl" means a monocyclic or fused bicyclic, saturated or partially unsaturated, monovalent hydrocarbon radical of three to ten carbon ring atoms. Fused bicyclic hydrocarbon radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. More specifically, the term cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthyl (including, but not limited to, decahydronaphth-1-yl or decahydronaphth-2-yl, and the like), or cyclohexenyl and the like. The cycloalkyl ring may be substituted with one, two, or three substituents independently selected from acyl, acyloxy, acylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfmyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, nitro, alkoxyalkyloxy, aminoalkoxy, carboxy, cyano, -P(O)ORR' (where R and R' are independently alkyl, cycloalkyl, aryl, or heteroaryl), -P(O)RR' (where R and R' are independently alkyl, cycloalkyl, aryl, or heteroaryl; or R and R' together with the P to which they are attached form optionally substituted heterocycloalkyl or heteroaryl), aryl, aralkyloxy, and heteroaryl. Within the above optional substitutents, the alkyl, alkenyl, and alkynyl, either alone or as part of another substituent on the cycloalkyl ring, are independently optionally substituted with one, two, three, four, or five halo, e.g. haloalkyl, haloalkoxy, haloalkenyloxy, or haloalkylsulfonyl.

"Cycloalkylalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, cycloalkyl group(s) as defined herein, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, 2-(cyclopropyl)-propyl, or cyclohexylmethyl, and the like.

"Cycloalkylalkyloxycarbonyl" means a -C(O)OR where R is cycloalkylalkyl as defined herein.

"Cycloalkylene" means a monocyclic or fused bicyclic, saturated or partially unsaturated, divalent hydrocarbon radical of three to ten carbon ring atoms. Fused bicyclic hydrocarbon radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. More specifically, the term cycloalkylene includes, but is not limited to, cycloprop- 1,1-diyl, cyclobut-l,3-diyl, cyclopent-l,4-diyl, cyclohex-l,3-diyl, cyclohex-l,4-diyl, or cyclohex-3-en-l,2-diyl, and the like. The cycloalkylene ring may be substituted with one, two, or three substituents independently selected from the group consisting of acyl, acyloxy, acylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, nitro, alkoxyalkyloxy, aminoalkoxy, carboxy, cyano, -P(O)ORR' (where R and R' are independently alkyl, cycloalkyl, aryl, or heteroaryl), -P(O)RR' (where R and R' are independently alkyl, cycloalkyl, aryl, or heteroaryl; or R and R' together with the P to which they are attached form heterocycloalkyl or heteroaryl), aryl, and heteroaryl. Within the above optional substitutents, the alkyl, alkenyl, and alkynyl, either alone or as part of another substituent on the cycloalkyl ring, are independently optionally substituted with one, two, three, four, or five halo, e.g. haloalkyl, haloalkoxy, haloalkenyloxy, or haloalkylsulfonyl .

"Cycloalkylalkylaminocarbonyl" means a -C(O)NHR radical where R is cycloalkylalkyl, as defined herein. "Cycloalkylalkynyl" is an alkynyl radical, as defined herein, substituted with at least one, preferably one or two, cycloalkyl group(s) as defined herein.

"Cycloalkylcarbonyl" means a -C(O)R radical where R is cycloalkyl as defined herein.

"Cycloalkylcarbonylamino" means a -NR^aR^b radical where R^a is cycloalkylcarbonyl, as defined herein and R^b is hydrogen or alkyl, as defined herein.

"Cycloalkylcarbonylaminoalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, cycloalkylcarbonylamino group(s), as defined herein.

"Cycloalkylcarbonyloxy" means a -OC(O)R, where R is cycloalkyl, as defined above, e.g., cyclohexylcarbonyloxy, and the like.

"Cycloalkylcarbonyloxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, prefereably one or two, cycloalkylcarbonyloxy group(s), as defined herein.

"Cycloalkyloxy" means a -OR radical where R is cycloalkyl as defined herein.

"Dialkylamino" means a radical -NRR' where R and R' are independently alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N,iV-methylpropylamino orN,N-methylethylamino, and the like.

"Dialkylarninoalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, dialkylamino group(s), as defined herein.

"Dialkylaminoalkylaminocarbonyl" means the radical -C(O)NHR where R is dialkylamino, as defined herein.

"Dialkylaminoalkyloxy" means a -OR radical where R is dialkylaminoalkyl, as defined herein.

"Dialkylaminoalkyloxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, dialkylaminoalkyloxy group(s), as defined herein.

"Dialkylaminoalkyloxycarbonyl" means a -C(O)R radical where R is dialkylaminoalkyloxy, as defined herein.

"Dialkylaminocarbonyl" means a -C(O)R radical where R is dialkylamino as defined herein, e.g, dimethylaminocarbonyl or methylethylaminocarbonyl, and the like.

"Dialkylaminocarbonylalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, dialkylaminocarbonyl group(s), as defined herein.

"Dialkylaminocarbonylalkyloxy" means an -OR radical where R is dialkylaminocarbonylalkyl, as defined herein. "Dialkylaminocarbonylalkyloxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, dialkylaminocarbonylalkyloxy group(s), as defined herein.

"Dialkylaminosulfonyl" means a -S(O)NR⁵R" where R' and R" are alkyl, as defined herein.

"Emphysema" means a lung condition featuring an abnormal accumulation of air in the lung's alveoli, leading to their enlargement and resulting breakage or damage or formation of scar tissue. Emphysema is associated with smoking cigarettes and also with or worsened by repeated infection of the lungs, such as is seen in chronic bronchitis.

"Halo" means fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.

"Haloalkenyl" means means an alkenyl radical, as defined herein, substituted with at least one, preferably one to five, halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens.

"Haloalkoxy" means a radical -OR where R is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.

"Haloalkoxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two haloalkoxy group(s), as defined herein.

"Haloalkoxycarbonyl" means the radical -C(O)R where R is haloalkyl, as defined herein.

"Haloalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one to five halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens, e.g., -CH₂Cl, -CF₃, -CHF₂, -CF₂CF₃, -CF(CH₃)₃, or -CHFCl, and the like.

"Haloalkylamino" means a -NR^aR^b radical where R^a is haloalkyl, as defined herein, and R^b is hydrogen, alkyl, or haloalkyl, as defined herein, e.g. iV-(trifluoromethyl)- N-(2,2-difluoroethyl)-amino.

"Haloalkylaminoalkyl" means an alkyl radical substituted with haloalkylamino, as defined herein.

"Haloalkylaminocarbonyl" means a -C(O)R radical where R is haloalkylamino, as defined herein.

"Heteroarakenyl" means an alkenyl radical, as defined herein, substituted with at least one, preferably, one or two, heteroaryl group(s), as defined herein.

"Heteroaralkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, heteroaryl group(s) as defined herein, e.g., pyridinylmethyl, furanylmethyl, or chloropyridinylmethyl, and the like.

"Heteroarakynyl" means an alkynyl radical, as defined herein, substituted with at least one, preferably, one or two, heteroaryl group(s), as defined herein

Heteroaralkyloxy" means an -OR radical where R is heteroaralkyl as defined herein e.g., furanylmethyloxy or pyridinylethyloxy, and the like.

"Heteroaryl" means a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing one or more, preferably one, two, three, or four ring heteroatoms independently selected from -O-, -S(O)_n- (n is 0, 1, or 2), -N-, -N(R²⁰⁰)-, -Si(alkyl)₂-, -P(=S)(R²⁰¹)-, and -P(O)(R²⁰¹)-, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or tricyclic radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R²⁰⁰ is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. R²⁰¹ is alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl. Fused bicyclic radical includes bridged ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. In particular, when the point of valency is located on a nitrogen or phosphorous atom, R²⁰⁰ or R²⁰¹, respectively, is absent. More specifically, the term heteroaryl includes, but is not limited to, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyl (including, for example, 2,3-dihydro-lH^"-mdol-2~yl or 2,3-dihydro-li/-indol-5-yl, and the like), pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like), benzopyranyl, thiazolyl, methylenedioxyphenyl (including, for example, methylenedioxyphen-5-yl), and the derivatives thereof, or iV-oxide or a protected derivative thereof. Unless otherwise stated, the heteroaryl ring may be substituted with one, two, or three substituents independently selected from the group consisting of acyl, acylamino, acyloxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, alkenyloxy, alkoxycarbonyl, alkylthio, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aminoalkoxy, optionally substituted heterocycloalkyl, halo, hydroxy, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, optionally substituted phenyl, -CONR^PR^V (where R^p is hydrogen, alkyl, hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkylalkyl and R^v is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy), -(alkylene)_1-3-SiR_1-3 (where R is alkyl), -P(O)ORR' (where R and R' are independently alkyl, cycloalkyl, aryl, or heteroaryl), -P(O)RR' (where R and R' are independently alkyl, cycloalkyl, aryl, or heteroaryl; or R and R' together with the P to which they are attached form optionally heterocycloalkyl or heteroaryl), and heteroaryl substituted with a group independently selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, hydroxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkylcarbonylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylarninocarbonyl, carboxy, and cyano; or when two substituents are adjacent to each other they can combine to form methylenedioxy group. Within R²⁰⁰, R²⁰¹, and the above optional substitutents, the alkyl, alkenyl, and alkynyl, either alone or as part of another substituent on the heteroaryl ring, are independently optionally substituted with one, two, three, four, or five halo, e.g. haloalkyl, haloalkoxy, or haloalkylsulfonyl.

"Heteroarylamino" means a -NR'R" radical where R' is hydrogen, hydroxy, alkyl, alkenyl, alkoxy, or alkenyloxy and R" is heteroaryl, as defined herein.

"Heteroarylaminoalkyl" means an alkyl radical substituted with heteroarylamino, as defined herein.

"Heteroarylaminocarbonyl" means -C(O)NR^aR^b where R^a is hydrogen or alkyl, as defined herein, and R is heteroaryl as defined herein.

"Heteroarylaminocarbonylalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, heteroarylaminocarbonyl group(s), as defined herein.

"Heteroaryloxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, heteroaryloxy group(s) as defined herein, e.g., furanyloxymethyl or pyridinyloxyethyl, and the like.

"Heterocycloalkyl" means a saturated or partially unsaturated monovalent monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated monovalent fused bicyclic group of 5 to 12 ring atoms in which one or more, preferably one, two, three, or four ring heteroatoms independently selected from -0-, -S(O)_n- (n is 0, 1, or 2), -N-, -N(R²⁰⁰)-, -Si(alkyl)₂-, -P(=S)(R²⁰¹)-, and -P(=O)(R²⁰¹)-, the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R²⁰⁰ is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. R²⁰¹ is alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl. Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. In particular, when the point of valency is located on a nitrogen or phosphorous atom, R²⁰⁰ or R²⁰¹, respectivley, is absent. More specifically the term heterocycloalkyl includes, but is not limited to, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, and thiomorpholinyl, and the derivatives thereof and N-oxide, including the N-oxide of piperazin-l,4-diyl, or a protected derivative thereof.

"Hydroxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, hydroxy grouρ(s), provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1 -(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxyproρyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, or l-(hydroxymethyl)-2-hydroxyethyl, and the like.

"Hydroxyalkyloxy" means an -OR radical where R is hydroxyalkyl, as defined herein.

"Hydroxyalkylaminocarbonyl" means a -C(O)NR⁵R" where R' is hydroxyalkyl, as defined herein, and R" is hydrogen, alkyl, or hydroxyalkyl, as defined herein.

"Hydroxyalkyloxyalkyl" means a -OR radical where R is hydroxyalkyloxy, as defined herein.

"N-Hydroxyaminocarbonyl" means a -C(O)NR^aR^b where R^a is hydroxy and R^b is hydrogen or alkyl, as defined herein.

"Hyperresponsiveness" means the late phase bronchoconstriction and airway hyperreactivity associated with chronic asthma. Hyper-responsiveness of asthmatic bronchiolar tissue is believed to result from chronic inflammation reactions, which irritate and damage the epithelium lining the airway wall and promote pathological thickening of the underlying tissue.

"Immunomediated inflammatory disorders" means those diseases associated with mast cell mediator release and susceptible to treatment with a tryptase inhibitor [e.g., immunomediated type hypersensitivity diseases such as asthma, allergic rhinitis, Chronic Obstructive Pulmonary Disease (COPD), urticaria and angioedema, eczematous anaphylaxis, dermatitis such as atopic dermatitis, hyperproliferative skin disease, peptic ulcers, inflammatory bowel disorder, ocular and vernal conjunctivitis, rheumatoid arthritis, SLE, Inflammatory Bowel Disease, including Crone's Disease and Ulcerative Colitis, or inflammatory skin conditions, and the like].

"2,2,-Indanylene" means a divalent radical having the following structure:

and when used in conjunction with any two of R⁷, R⁸, and R⁹ attached to the same carbon ring atom of Het it is intended that any two of R⁷, R⁸, and R⁹ attached to the same carbon ring atom together with the heterocycloalkyl they are attached forms a heterospiroalkyl moiety, e.g., indan-2',4-piperidin-l~yl. Unless indicated otherwise, the indanylene ring may be substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, halo, hydroxy, amino, alkylamino, dialkylamino, nitro, alkylcarbonyl, alkylcarbonylamino, alkoxycarbonyl, alkoxyalkyl, aminoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, hydroxyalkyl, oxo, thioxo, imino, and optionally substituted phenyl.

"Isomer" or "isomers" means compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers" or sometimes "optical isomers". An atom bonded to four nonidentical substituents is termed a "chiral center". A compound with one chiral center has two enantiomeric forms of opposite chirality; and a mixture of both enatiomeric forms in equal amounts is termed racemic. A compound that has one or more chiral centers has 2^11"1 enantiomeric pair(s), where n is the number of chiral centers, unless the compound is meso (i.e. the compound has 2 or more assymetric or chiral centers but which is achiral because it contains an internal plane of symmetry). Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture". When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and ^-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see "Advanced Organic Chemistry," 4th edition, March, Jerry, John Wiley & Sons, New York, 1992). It is understood that the names and illustration used in this Application to describe compounds of Formula I are meant to be encompassed all possible stereoisomers and any mixture, racemic or otherwise, thereof.

"Mercaptoalkylaminocarbonyl" means a -C(O)NR^aR^b radical where R^a is hydrogen or alkyl and R^b is a mercaptoalkyl radical group.

"Mercaptoalkylaminocarbonylalkyl" means an alkyl radical as defined herein substituted with at least one, preferably one or two, mercaptoalkylaminocarbonyl group(s) as defined herein, e.g., iV-(mercaptomethyl)-aminocarbonylethyl oriV-(2-mercapto-n-propyl)- aminocarbonylmethyl, and the like.

"Methylene" means a radical -CH₂- and the term -(methylene)_n- wherein n means the number of methylenes indicated and when n is 0 then a bond is intended.

"Methylenedioxy" means a radical -0-CH₂-O-.

"Optionally substituted" or "may be substituted," when modifying a particular group, means that the group the term modifies may, but does not have to, be substituted. Where the term "optionally substituted" or "may be substituted" is used to modify a particular group, this does not mean, unless otherwise stated, that any other groups not so modified cannot also be optionally substituted. Futhermore, where a group is defined as being substituted by one of a number of enumerated alternative substitutents, it does not mean, unless otherwise stated, that the group cannot be substituted further with one or more substituents not enumerated. For example, "optionally substituted heterocycloalkyl" means that the heterocycloalkyl may but need not be substituted with the enumerated substituents within the definition of "optionally substituted heterocycloalkyl"; and the description includes situations where the heterocycloalkyl group is substituted and situations where the heterocycloalkyl group is not substituted.

"Optionally substituted alkenyl" means an alkenyl radical, as defined herein, substituted with one or more group(s), preferably one, two, or three groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkylcarbonylamino, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, arylamino, aryloxy, hydroxy, hydroxyalkyloxy, heteroarylamino, heteroaryloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, carboxy, carboxyalkyloxy, carboxyalkylamino, carboxyalkylcarbonylamino (where the "alkyl" within "carboxyalkylcarbonylamino" is optionally substituted with one or two amino), alkylcarbonylamino, alkylcarbonyloxy, -S(0)o_-2-alkyl, -S(O)_0-2-alkenyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, -NR^c-Sθ₂-alkyl (where R⁰ is hydrogen, optionally substituted alkyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkoxycarbonylalkylcarbonylamino where the "alkyl" within

"alkoxycarbonylalkylcarbonylamino" is optionally substituted with one or two hydroxy, alkylaminocarbonylamino, dialkylaminocarbonylamino, dialkylaminoalkylcarbonylamino, dialkylaininocarbonylalkyloxy, alkoxyalkyloxy, alkoxyalkyloxycarbonyl, alkoxycarbonylalkyloxy, aralkyloxycarbonyl, optionally substituted heterocycloalkyloxy, and -C(O)NR^aR^b (where R^a is hydrogen, optionally substituted alkyl, alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, or alkenyloxy, and R^b is hydrogen, optionally substituted alkyl, alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, optionally substituted heterocycloalkyl, or heteroaryl, or R^a and R^b together with the nitrogen to which they are attached form optionally substituted heterocycloalkyl).

"Optionally substituted alkyl" means an alkyl radical, as defined herein, substituted with one or more group(s), preferably one, two, or three groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkylcarbonylamino, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, arylamino, aryloxy, hydroxy, hydroxyalkyloxy, heteroarylamino, heteroaryloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, carboxy, carboxyalkyloxy, carboxyalkylamino, carboxyalkylcarbonylamino where the "alkyl" within "carboxyalkylcarbonylamino" is optionally substituted with one or two amino, alkylcarbonylamino, alkylcarbonyloxy, -S(O)_0-2-alkyl, -S(O)_0-2-alkenyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, -NR^c-SO₂-alkyl (where R^c is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkoxycarbonylalkylcarbonylamino where the "alkyl" within

"alkoxycarbonylalkylcarbonylamino" is optionally substituted with one or two hydroxy, alkylaminocarbonylamino, dialkylaminocarbonylamino, dialkylaminoalkylcarbonylamino, dialkylaminocarbonylalkyloxy, alkoxyalkyloxy, alkoxyalkyloxycarbonyl, alkoxycarbonylalkyloxy, aralkyloxycarbonyl, optionally substituted heterocycloalkyloxy, and -C(O)NR^aR^b (where R^a is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, or alkenyloxy, and R^b is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, optionally substituted heterocycloalkyl, or heteroaryl, or R^a and R^b together with the nitrogen to which they are attached form optionally substituted heterocycloalkyl).

"Optionally substituted alkynyl" means an alkynyl radical, as defined herein, substituted with one or more group(s), preferably one, two, or three groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkylcarbonylamino,alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, arylamino, aryloxy, hydroxy, hydroxyalkyloxy, heteroarylamino, heteroaryloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, carboxy, carboxyalkyloxy, carboxyalkylamino, carboxyalkylcarbonylamino where the "alkyl" within "carboxyalkylcarbonylamino" is optionally substituted with one or two amino, alkylcarbonylamino, alkylcarbonyloxy, -S(O)_0-2-alkyl, -S(O)_0-2-alkenyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, -NR^c-SO₂-alkyl (where R^c is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkoxycarbonylalkylcarbonylamino where the "alkyl" within

"alkoxycarbonylalkylcarbonylamino" is optionally substituted with one or two hydroxy, alkylaminocarbonylamino, dialkylaminocarbonylamino, dialkylaminoalkylcarbonylamino, dialkylaminocarbonylalkyloxy, alkoxyalkyloxy, alkoxyalkyloxycarbonyl, alkoxycarbonylalkyloxy, aralkyloxycarbonyl, optionally substituted heterocycloalkyloxy, and -C(O)NR^aR^b (where R^a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, hydroxy, alkoxy, or alkenyloxy, and R^b is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, hydroxy, alkoxy, alkenyloxy, optionally substituted heterocycloalkyl, or heteroaryl, or R^a and R^b together with the nitrogen to which they are attached form optionally substituted heterocycloalkyl).

"Optionally substituted benzo" means a

radical, as represented by the ring labeled A in Formula I, where the points of fusion with the 5-membered ring are indicated by the asterisks and where the benzo ring is optionally substituted with one, two, three, or four substituents independently selected from the group consisting of alkyl, aminocarbonyl, halo, haloalkyl, optionally substituted heterocycloalkyl, cyano, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and heteroaryl. Examples of ring A together with the 5-membered ring to which A is fused include, but are not limited to,

"Optionally substituted heterocycloalkyl" means a saturated or partially unsaturated monovalent monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated monovalent fused bicyclic group of 5 to 12 ring atoms in which one or more, preferably one, two, three, or four ring heteroatoms independently selected from -O-, -S(O)_n- (n is 0, 1, or 2), -N-, -N(R²⁰⁰)-, -Si(alkyl)₂-, -P(=S)(R²⁰¹)-, and -P(=O)(R²⁰¹)-, the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R²⁰⁰ is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. R²⁰¹ is alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl. Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. In particular, when the point of valency is located on a nitrogen or phosphorous atom, R²⁰⁰ or R²⁰¹, respectivley, is absent. More specifically the term optionally substituted heterocycloalkyl includes, but is not limited to, pyrrolidinyl, 2,5-dihydro-li7-pyrrolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, and thiomorpholinyl, and the derivatives thereof and N- oxide or a protected derivative thereof. Unless stated otherwise, the heterocyloalkyl ring is optionally substituted with one, two, or three substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, acyloxy, acylamino, alkoxy, alkenyloxy, alkoxycarbonyl, alkylthio, halo, hydroxy, hydroxyalkyloxy, aminoalkyloxy, alkoxyalkyloxy, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, aminoalkoxy, optionally substituted phenyl, heterocycloalkyl, heteroaryl, -P(O)ORR' (where R and R' are independently alkyl, cycloalkyl, aryl, or heteroaryl), and -P(O)RR' (where R and R' are independently alkyl, cycloalkyl, aryl, or heteroaryl; or R and R' together with the P to which they are attached form heterocycloalkyl or heteroaryl). Within R²⁰⁰, R²⁰¹, and the above optional substitutents, the alkyl, alkenyl, and alkynyl, either alone or as part of another substituent on the heterocycloalkyl ring, are independently optionally substituted with one, two, three, four, or five halo, e.g. haloalkyl, haloalkoxy, or haloalkylsulfonyl.

"Optionally substituted heterocycloalkylalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, optionally substituted heterocycloalkyl group(s) as defined herein, e.g., piperazinylmethyl or morpholinylethyl, and the like.

"Optionally substituted heterocycloalkylalkyloxy" means an -OR radical where R is optionally substituted heterocycloalkylalkyl as defined herein, e.g., tetrahydropyranylmethyloxy, and the like.

"Optionally substituted heterocycloalkyloxy" means an -OR radical where R is optionally substituted heterocycloalkyl as defined herein.

"Optionally substituted heterocycloalkylene" means a saturated or partially unsaturated divalent monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated divalent fused bicyclic group of 5 to 12 ring atoms in which one or more, preferably one, two, three, or four ring heteroatoms independently selected from -O-, -S(O)_n- (n is 0, 1, or 2), -N-, -N(R²⁰⁰)-, -Si(alkyl)₂-, -P(=S)(R²⁰¹)-, and -P(=O)(R²⁰¹)-, the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R²⁰⁰ is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. R²⁰¹ is alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl. Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. In particular, when the point of valency is located on a nitrogen or phosphorous atom, R²⁰⁰ or R²⁰¹, respectivley, is absent. More specifically the term heterocycloalkylene includes, but is not limited to, pyrrolidin-diyl, piperidin-diyl, morpholin-diyl, piperazin-diyl, tetrahydropyran-diyl, 2-oxopiperidin-diyl, and thiomorpholin-diyl, and the derivatives thereof and N-oxide or a protected derivative thereof. Unless stated otherwise, the heterocyloalkylene ring is optionally substituted with one, two, or three substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, acyloxy, acylamino, alkoxy, alkenyloxy, alkoxycarbonyl, alkylthio, halo, hydroxy, hydroxyalkyloxy, aminoalkyloxy, alkoxyalkyloxy, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, aminoalkoxy, optionally substituted phenyl, heterocycloalkyl, heteroaryl, -P(O)ORR' (where R and R' are independently alkyl, cycloalkyl, aryl, or heteroaryl), and -P(O)RR' (where R and R' are independently alkyl, cycloalkyl, aryl, or heteroaryl; or R and R' together with the P to which they are attached form heterocycloalkyl or heteroaryl). Within R²⁰⁰, R²⁰¹, and the above optional substitutents, the alkyl, alkenyl, and alkynyl, either alone or as part of another substituent on the heterocycloalkylene ring, are independently optionally substituted with one, two, three, four, or five halo, e.g. haloalkyl, haloalkoxy, or haloalkylsulfonyl.

"Optionally substituted heterocycloalkyloxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, optionally substituted heterocycloalkyloxy group(s), as defined herein.

"Optionally substituted heterocycloalkylalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, optionally substituted heterocycloalkyl group(s), as defined herein, e.g., piperazinylmethyl or morpholinylethyl, and the like.

"Optionally substituted heterocycloalkylalkylaminocarbonyl" means a the radical -C(O)NHR where R is optionally substituted heterocycloalkylalkyl, as defined herein.

"Optionally substituted heterocycloalkylalkyloxycarbonyl" means a -C(O)R radical where R is optionally substituted heterocycloalkylalkyloxy as defined herein.

"Optionally substituted heterocycloalkylcarbonyl" means a -C(O)R radical where R is optionally substituted heterocycloalkyl as defined herein, e.g. morpholin-4-ylcarbonyl, and the like.

"Optionally substituted heterocycloalkyloxy" means a -OR radical where R is optionally substituted heterocycloalkyl as defined herein.

"Optionally substituted pyrazino" means a radical, as represented by the ring labeled A in Fo:rmula I, where the points of fusion with the 5-membered ring are indicated by the asterisks and where the pyrazino ring is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, aminocarbonyl, halo, haloalkyl, optionally substituted heterocycloalkyl, cyano, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and heteroaryl. Examples of ring A together with the 5-membered ring to which A is fused include, but are not limited to,

"Optionally substituted pyridazino" means a

N Il

N radical, as represented by the ring labeled A in Formula I, where the points of fusion with the 5-membered ring are indicated by the asterisks and where the pyridazino ring is optionally substituted with one or two substituents selected from the group consisting of alkyl, aminocarbonyl, halo, haloalkyl, optionally substituted heterocycloalkyl, cyano, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and heteroaryl. Examples of ring A together with the 5-membered ring to which A is fused include, but are not limited to,

Optionally substituted pyridino" means a

radical, as represented by the ring labeled A in Formula I, where the points of fusion with the 5-membered ring are indicated by the asterisks and where the pyridino ring is optionally substituted with one, two, or three substituents selected from the group consisting of alkyl, aminocarbonyl, halo, haloalkyl, optionally substituted heterocycloalkyl, cyano, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and heteroaryl. Examples of ring A together with the 5-membered ring to which A is fused include, but are not limited to,

"Optionally substituted pyrimidino" means a

radical, as represented by the ring labeled A in Formula I, where the points of fusion with the 5-membered ring are indicated by the asterisks and where the pyrimidino ring is optionally substituted with one or two substituents selected from the group consisting of alkyl, aminocarbonyl, halo, haloalkyl, optionally substituted heterocycloalkyl, cyano, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and heteroaryl. Examples of ring A together with the 5-membered ring to which A is fused include, but are not limited to,

"Optionally substituted phenyl" means a phenyl ring optionally substituted with one, two, or three substituents independently selected from alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, heteroaryl, optionally substituted heterocycloalkyl, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, and carboxy; or optionally substituted with five fluorine atoms.

"Optionally substituted phenylalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, optionally substituted phenyl as defined herein e.g., benzyl or phenylethyl, and the like.

"Optionally substituted phenylcarbonylamino" means a -NR^aC(O)R radical where R is optionally substituted phenyl, as defined herein, and R^a is hydrogen or alkyl.

"Optionally substituted phenyloxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two, -OR radical(s), where R is optionally substituted phenyl, as defined herein.

"Partially unsaturated" describes a group which contains at least one unsaturated bond but does not contain an aromatic ring. For example, partially unsaturated cycloalkylene includes cyclohexenyl group but not indanyl.

A "pharmaceutically acceptable carrier or excipient" means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable carrier/excipient" as used in the specification and claims includes both one and more than one such excipient.

"Substituted," when modifying a particular group, means that the group the term modifies must be substituted. Where the term "substituted" is used to modify a particular group, this does not mean, unless otherwise stated, that any other groups not so modified cannot be substituted. Futhermore, where a group is defined as being substituted by one of a number of enumerated alternative substitutents, it does not mean, unless otherwise stated, that the group cannot be substituted further with one or more substituents not enumerated. For example, the phrase "substituted alkyl" means that the alkyl group referred to must be substituted with one or more of the substituents set forth in the definitions for "substituted alkyl."

"Sulfonylalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably one or two sulfonyl group(s).

"Syncytial viral infection" means an infection by a virus, such as a respiratory syncytial virus, causing the formation of a cellular protoplasmic mass, i.e. syncytia, via infection.

A "therapeutically effective amount" means the amount of a compound of Formula I that, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the animal to be treated.

"Treating" or "treatment" of a disease, disorder, or syndrome includes:

(1) preventing the disease, disorder, or syndrome, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome;

(2) inhibiting the disease, disorder, or syndrome, i.e., arresting or reducing the development of the disease, disorder, or syndrome or its clinical symptoms; or

(3) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome or its clinical symptoms. "Trialkylsilyl" means a the radical -Si(R)₃ where R at each occurrence is independently an alkyl radical, as defined herein.

The present invention also includes the prodrugs of compounds of Formula I. The term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula I when the prodrug is administered to an animal subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo. Prodrugs of compounds of Formula I include compounds wherein a hydroxy, amidino, guanidino, amino, carboxylic, or a similar group is modified. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., AζiV- dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula I), amides (e.g, trifluoroacetylamino, acetylamino, and the like), and the like. Prodrugs of compounds of Formula I are also within the scope of this invention.

The present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula I. For example, when compounds of Formula I contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. Also when compounds of Formula I contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups. A comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1991, the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of Formula I can be prepared by methods well known in the art.

A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17^th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference.

The compounds of the present invention may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. AU chiral, diastereomeric, racemic forms are within the scope of this invention, unless the specific stereochemistry or isomeric form is specifically indicated.

Certain compounds of Formula I can exist as isomers. AU possible isomers are within the scope of this invention. Additionally, as used herein the terms alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl, heteroaryl, heterocycloalkyl are substituted, they include all the positional isomers albeit only a few examples are set forth.

Preferred Embodiments 1. One preferred group of compounds of Formula 1 is where

A is optionally substituted benzo, optionally substituted pyrimidino, or optionally substituted pyridino;

D is =Ν-, or -CR⁶- where R⁶ is hydrogen, halo, or carboxyalkyl;

R is hydrogen;

R³ is hydrogen, halo, or mercaptoalkylaniinocarbonylalkyl; and

R¹⁰⁰ is a group of formula (Al):

(Al) where

R^4a and R^4b are hydrogen;

L is selected from the group consisting of:

-X¹^-Z¹- where X¹ is alkylene; Y¹ is -C(O)-, -C(O)NH-, or -NHC(O)- and Z¹ is a bond, alkylene, or alkenylene;

-X²- where X² is alkylene;

-Y²-Z²- where Y² is -C(O)NH- or -NHC(O)-; and Z² is alkylene; and

-X⁵-Y^5a-Z⁵-Y^5b- where X⁵ is alkylene; Y^5a is -C(O)NH- or -NHC(O)- (where R¹³ is hydrogenl); Z⁵ is alkylene where the alkylene is optionally substituted with aralkyloxyalkyl; and Y⁵Ms -C(O)-;

Het is piperidinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, or 4-oxo-4λ⁵- [l,4]azaphosphinanyl (where the phosphorous atom is substituted with alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl); and

R⁷, R⁸, and R⁹ are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, acyl, acylamino, acylaminoalkyloxycarbonyl, alkoxycarbonyl, alkoxyalkylaminocarbonyl, alkoxyalkyloxycarbonyl, amino, carboxy, carboxyalkylaminocarbonyl (where the "alkyl" is optionally substituted with one or two hydroxy), cyano, cyanoalkylaminocarbonyl, aryl, aryloxy, arylsulfonyl, arylthioalkylcarbonyl, aralkyl (where the alkyl is optionally substituted with one or two hydroxy), aralkyloxy, aralkyloxyaminocarbonyl, aralkyloxycarbonylamino, cycloalkylaminocarbonyl, cycloalkylalkyl (where the "alkyl" is optionally substituted with one or two hydroxy), cycloalkylalkylaminocarbonyl, cycloalkylalkyloxycarbonyl, heteroaryl, heteroarylaminocarbonyl, heteroaralkyl, halo, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, iV-hydroxyaminocarbonyl, iV-alkoxyaminocarbonyl, hydroxyalkylaminocarbonyl, dialkylaminoalkyloxycarbonyl, dialkylaminoalkylaminocarbonyl, arylamino, arylaminocarbonyl, alkylsulfonylamino, alkylsulfonylaminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylaminocarbonyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxycarbonyl, optionally substituted heterocycloalkylalkylaminocarbonyl, aminocarbonylamino, N-aryl-N-(alkylcarbonyl)-amino, or alkoxycarbonylalkylaminocarbonyl (where the "alkyl" is optionally substituted with one or two hydroxy); or any two of R⁷, R⁸, and R⁹ attached to the same carbon atom together with the carbon to which they are attached form indanylene or optionally substituted heterocycloalkylene; and where the alkyl, alkenyl, and alkynyl in R⁷, R⁸, and R⁹, either alone or part of another group (for example, the alkyl within the group "alkoxy" or for example, any alkyl or alkenyl within the group "optionally substituted alkenyl"), independently are optionally substituted with one, two, three, four, or five halo; or R¹⁰⁰ is a group of formula (A2):

(A2) where

R^4a and R^4b are hydrogen;

R⁵ is selected from the group consisting of:

.Y¹LX¹LQ¹¹ where Y¹¹ is -C(O)ΝR^26a-, -NR^26aC(O)-, -NR²⁶³C(O)O-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are independently hydrogen or hydroxy, where X¹¹ is a bond, alkylene, or alkenylene, (where X¹¹ is optionally substituted with hydroxy), and where Q¹¹ is heteroaryl, aryl, aryloxy, or cycloalkyl;

__χ ^12a__γ ¹²__χ1²b_Ql² _{where χ}1²a _{is alkylene;} γl2 j_g .C(O)NH-, -NHC(O)-, _Or

-NHC(O)NH-; X^12b is a bond, alkylene, or alkenylene where X^12b is optionally substituted with one, two, or three groups selected from hydroxy, cyano, halo, heteroaryl, alkoxycarbonyl, carboxy, -NR^27aR^27b (where R^27a and R^27b are independently hydrogen or alkyl), -C(O)NR^28aR^28b (where R^28a and R^28b are independently hydrogen, alkyl, alkoxy, or heteroaryl), and -NHC(O)OR^29b (where R^29b is alkyl); and Q¹² is aryl, aryloxy, aralkyloxy, heteroaryl, aralkylaminocarbonyl (where the alkyl is optionally substituted with alkoxycarbonyl or carboxy), cycloalkyl, cycloalkylaminocarbonyl, cycloalkylalkyloxy, -NR^30aR^30b (where R^3Oa is hydrogen or alkyl and R^3Ob is aryl, heteroaryl, or cycloalkylalkyl) or -S(O)_n-R³¹ (where n is O or 2 and R³¹ is heteroaryl, cycloalkylalkyl or aralkyl); where the alkyl within any group in Q¹² is optionally substituted with alkoxyalkyl); or R¹⁰⁰ is a group of formula (A3):

(A3) where

X⁴ is alkylene;

Y⁴ is -C(O)-;

Z⁴ is heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkylalkyl, alkoxycarbonyl, carboxy, aralkyl, cyano, acyl, and hydroxy; or Z⁴ is -NHR^50b where R^50b is -(alkylene)-aryl where the alkylene is optionally substituted with one or two groups selected from alkoxycarbonyl, hydroxy, and carboxy.

2. A Compound of Formula I:

I where

D is =N- or =CR⁶- where R⁶ is hydrogen, alkyl, halo, alkylcarbonyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, haloaloxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl;

R is hydrogen, alkyl, alkylsulfonyl, alkylphosphonyl, or alkoxyalkyloxyalkyl;

R³ is hydrogen, alkyl, hydroxy, halo, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, R^10aR^10bNC(O)NR^10c- (where R^1Oa, R^10b, and R¹⁰° are independently hydrogen, alkyl, or substituted alkyl), R^{l la}R^llbNC(O)O- (where R^lla and R^llb are independently hydrogen, alkyl, or substituted alkyl), or R^12aOC(O)NR^12b- (where R^12a and R^12b are independently hydrogen, alkyl, or substituted alkyl); and

R¹⁰⁰ is a group of formula (Al):

(Al) where

R^^a and R⁴" are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, halo, alkoxy, acyl, acyloxy, acylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, -NR^19cC(O)NR^19aR^19b (where R^19a, R^19b, and R^19c are independently hydrogen, alkyl, or substituted alkyl), -OC(O)NR^24aR^24b (where R^24a and R^24b are independently hydrogen, alkyl, or substituted alkyl), or -NR^25bC(O)OR^25a (where R^25a and R^25b are independently hydrogen, alkyl, or substituted alkyl); and where alkyl, alkenyl, and alkynyl, either alone or as part of another group are independently optionally substituted with one, two, three, four, or five halo; and

L is -X -Y^J-Z - where X¹ is alkylene, alkenylene, or cycloalkylene and where X¹ is optionally substituted by one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, alkylamino, and dialkylamino; Y¹ is -O-, -NR¹³-, -C(O)-, -C(O)O-, -C(O)NR¹³-, -NR¹³C(O)-, -C(O)NR¹³C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹³-, -NR¹³SO₂-, -OC(O)-, -OC(O)NR¹³-, -NR¹³C(O)O-, or -NR¹³C(O)NR¹⁴- (where R¹³ and R¹⁴ are independently hydrogen, alkyl, or substituted alkyl); and Z¹ is a bond, alkylene, alkenylene, or cycloalkylene;

L is -Y²-Z²- where Y² is -NR¹⁵-, -C(O)-, -C(O)O-, -C(O)NR¹⁵-, -NR¹⁵C(O)-, -C(O)NR¹⁵C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹⁵-, -NR¹⁵SO₂-, -OC(O)-, -OC(O)NR¹⁵-, -NR¹⁵C(O)O-, or -NR¹⁵C(O)NR¹⁶- (where R¹⁵ and R¹⁶ are independently hydrogen, alkyl, or substituted alkyl); and where Z² is alkylene, alkenylene, or cycloalkylene; and L is -Y³- where Y³ is -NR¹⁷-, -C(O)O-, -C(O)NR¹⁷-, -NR¹⁷C(O)-, -C(O)NR¹⁷C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹⁷-, -NR¹⁷SO₂-, -OC(O)-, -OC(O)NR¹⁷-, -NR¹⁷C(O)O-, or -NR¹⁷C(O)NR¹⁸- (where R¹⁷ and R¹⁸ are independently hydrogen, alkyl, or substituted alkyl); or

Het is heterocycloalkyl; and

R⁷, R⁸, and R⁹ are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, acylamino, acyloxy, acylaminoalkyloxycarbonyl, alkylthio, alkylsulfonyl, alkoxy, alkoxycarbonyl, alkoxyalkylamino, alkoxyalkylaminocarbonyl, alkoxyalkyloxy, alkoxyalkyloxycarbonyl, amino, alkylamino, dialkylamino, aminoalkyloxy, carboxy, carboxyalkylaminocarbonyl where the "alkyl" is optionally substituted with one or two hydroxy, cyano, cyanoalkylaminocarbonyl, aryl, aryloxy, arylsulfonyl, arylthioalkylcarbonyl, aralkyl where the alkyl is optionally substituted with one or two hydroxy, aralkyloxy, aralkyloxycarbonyl, aralkyloxyaminocarbonyl, aralkyloxycarbonylamino, aralkenyl, cycloalkyl, cycloalkyloxy, cycloalkylaminocarbonyl, cycloalkylalkyl where the "alkyl" is optionally substituted with one or two hydroxy, cycloalkylalkylaminocarbonyl, cycloalkylalkyloxycarbonyl, heteroaryl, heteroarylaminocarbonyl, heteroaralkyl, heteroaralkenyl, heteroaralkyloxy, halo, hydroxy, hydroxyalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, N-hydroxyaminocarbonyl, N-alkoxyaminocarbonyl, hydroxyalkylaminocarbonyl, dialkylaminoalkyloxycarbonyl, dialkylaminoalkylaminocarbonyl, arylamino, arylaminocarbonyl, alkylsulfonylamino, alkylsulfonylaminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylaminocarbonyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkylalkyloxycarbonyl, optionally substituted heterocycloalkylalkylaminocarbonyl, arninocarbonylamino, N-aryl-N-(alkylcarbonyl)-amino, 7V-(alkylsulfonyl)-iV-alkyl-ainino, alkoxycarbonylalkylaminocarbonyl where the "alkyl" is optionally substituted with one or two hydroxy, or trialkylsilyl; or any two of R⁷, R⁸, and R⁹ attached to the same carbon atom together with the carbon to which they are attached form indanylene or optionally substituted heterocycloalkylene; and where the alkyl, alkenyl, and alkynyl in R⁷, R⁸, and R⁹, either alone or part of another group, independently are optionally substituted with one, two, three, four, or five halo; or a pharmaceutically acceptable salt thereof.

3. A Compound of Formula I:

I where

R² is hydrogen, alkyl, alkylsulfonyl, alkylphosphonyl, or alkoxyalkyloxyalkyl;

R³ is hydrogen, alkyl, hydroxy, halo, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, R^10aR^10bNC(O)NR^10c- (where R^1Oa, R^1Ob, and R^1Oc are independently hydrogen, alkyl, or substituted alkyl), R^llaR^llbNC(O)O- (where R^lla and R^llb are independently hydrogen, alkyl, or substituted alkyl), or R^12aOC(O)NR^12b- (where R^12a and R^12b are independently hydrogen, alkyl, or substituted alkyl); and R¹⁰⁰ is a group of formula (A2):

(A2) where

R^4a and R^4b are as defined above;

R⁵ is -Yⁿ-Xⁿ-Qⁿ where Y¹¹ is -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR^26a-, -C(O)NR^26a-, -NR²⁶³C(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b~, where R^26a and R^26b are independently hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, or acyl, where X¹¹ is a bond, alkylene, or alkenylene, (where X¹¹ is optionally substituted with hydroxy, alkoxycarbonyl, carboxy), and where Q¹¹ is heteroaryl, aryl, aryloxy, or cycloalkyl;

R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is alkylene or alkenylene; Y¹² is -NR²⁶³-, -0-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR²⁶³-, -NR^26aC(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R are as defined above; X is a bond, alkylene, or alkenylene where X is optionally substituted with one, two, or three groups selected from hydroxy, cyano, halo, heteroaryl, alkylcarbonyl, alkoxycarbonyl, carboxy, -NR R (where R and R are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, heteroaryl, or heteroarylaminocarbonyl), -C(O)NR^28aR^28b (where R^28a and R^28b are independently hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, hydroxy, or heteroaryl), and -NR^29aC(O)OR^29b (where R^29a is hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, or hydroxy, and R^29b is alkyl); and Q¹² is aryl, aryloxy, aralkyloxy, heteroaryl, aralkylaminocarbonyl (where the alkyl is optionally substituted with alkoxycarbonyl or carboxy), cycloalkyl, cycloalkylaminocarbonyl, cycloalkylalkyloxy, -NR^30aR^30b (where R^30a is hydrogen or alkyl and R^30b is aryl, heteroaryl, or cycloalkylalkyl) or -S(O)_n-R³¹ (where n is 0, 1, or 2 and R³¹ is heteroaryl, cycloalkylalkyl or aralkyl); where the alkyl within any group in Q¹² is optionally substituted with alkoxyalkyl);

R⁵ is -X¹³-Y¹³-Z¹³ where X¹³ is alkylene or alkenylene, where Y¹³ is -NR²⁶³-, -0-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR²⁶³-, -NR²⁶³C(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are as defined above, and where Z¹³ is hydrogen, alkyl, or alkenyl (where Z¹³ is optionally substituted with one, two, or three halo, hydroxy, amino, alkoxy, alkoxycarbonyl, carboxy, or alkylcarbonylamino); or

R⁵ is -Y¹⁴-Z¹⁴ where Y¹⁴ is -S(O)-, -NR²⁶³C(O)-, -C(O)NR²⁶³-, -NR^26aC(O)NR^26b-, -C(O)NR²⁶³C(O)-, -NR²⁶³C(O)O-, -OC(O)NR²⁶³, or -OC(O)-, where R^26a and R^26b are as defiend above, and where Z¹⁴ is alkyl or alkenyl (where Z¹⁴ is optionally substituted with one, two, or three halo, hydroxy, amino, alkoxy, alkoxycarbonyl, carboxy, or alkylcarbonylamino); or a pharmaceutically acceptable salt thereof.

4. A Compound of Formula I:

I where

R² is hydrogen, alkyl, alkylsulfonyl, alkylphosphonyl, or alkoxyalkyloxyalkyl;

R³ is hydrogen, alkyl, hydroxy, halo, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl, alkylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, R^10aR^10bNC(O)NR^10c- (where R^1Oa, R^1Ob, and R^1Oc are independently hydrogen, alkyl, or substituted alkyl), R^{l la}R^{l lb}NC(O)O- (where R^lla and R^{l lb} are independently hydrogen, alkyl, or substituted alkyl), or R^12aOC(O)NR^12b- (where R^12a and R^12b are independently hydrogen, alkyl, or substituted alkyl); and R¹⁰⁰ is a group of formula (A3):

(A3) where

Y⁴ is -C(O)-, -NR³²C(O)-, -S(O)₂-, or a bond;

Z⁴ is heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, carboxy, aryl, aralkyl, cyano, arylcarbonyl, alkoxy, and hydroxy; or Z⁴ is -NR^5OaR^50b where R^50a is hydrogen, alkyl, alkoxy, or hydroxy and R^50b is -(alkylene)-aryl where the alkylene is optionally substituted with one or two groups selected from halo, alkoxycarbonyl, hydroxy, and carboxy; or a pharmaceutically acceptable salt therof.

5. Another preferred group of compounds of Formula 1 is where A is optionally substituted benzo, optionally substituted pyridino, optionally substituted pyrimidino, optionally substituted pyrazino, or optionally substituted pyridazino. Preferably, A is optionally substituted benzo, optionally substituted pyridino, or optionally substituted pyrimidino. More preferably, A is unsubstituted pyridino or pyridino substituted with halo, amino, aminocarobnyl, or heteroaryl. Even more preferably, A is unsubstituted pyridino or pyridino substituted with chloro, amino, aminocarobnyl, or 5-methyl-[l,2,4]oxadiazol-3-yl. Particularly preferably, A is unsubstituted pyridino. Even more particularly preferably, A is

; preferably, of the even more partiuclarly preferable group

6. Another preferred group of compounds of Formula 1 is where D is =N-, or =CR⁶- where R⁶ is hydrogen, alkyl, halo, alkylcarbonyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, haloaloxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl. Preferably, D is =N- or =CR⁶- where R⁶ is hydrogen, halo, or carboxyalkyl. More preferably, D is =N- or =CH-. Even more preferably, D is =CH-. 7. Another preferred group of compounds of Formula 1 is where R¹ is hydrogen, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, or aralkyloxycarbonyl. Preferably, R¹ is hydrogen or alkylsulfonyl. More preferably, R¹ is hydrogen of methylsulfonyl. Even more preferably, R¹ is hydrogen.

8. Another preferred group of compounds of Formula 1 is where R² is hydrogen, alkyl, alkylsulfonyl, alkylphosphonyl, or alkoxyalkyloxyalkyl. Preferably, R² is hydrogen or alkoxyalkyloxyalkyl. More preferably, R² is hydrogen or -CH₂OCHaCH₂OCH₃. Even more preferably, R² is hydrogen.

9. Another preferred group of compounds of Formula 1 is where R³ is hydrogen, alkyl, hydroxy, halo, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl, alkylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, R^10aR^10bNC(O)NR^10c- (where R^1Oa, R^10b, and R^1Oc are independently hydrogen, alkyl, or substituted alkyl), R^llaR^UbNC(O)O- (where R^lla and R^llb are independently hydrogen, alkyl, or substituted alkyl), or R^12aOC(O)NR^12b- (where R^12a and R^12b are independently hydrogen, alkyl, or substituted alkyl). Preferably, R³ is hydrogen, halo, or mercaptoalkylaminocarbonylalkyl. More preferably, R³ is hydrogen or chloro. Even more preferably, R³ is hydrogen.

10. Another preferred group of compounds of Formula 1 is where R^4a and R^4b are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, halo, alkoxy, acyl, acyloxy, acylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, -NR^19cC(O)NR^19aR^19b (where R^19a, R^19b, and R^19c are independently hydrogen, alkyl, or substituted alkyl), -OC(O)NR^24aR^24b (where R^24a and R^24b are independently hydrogen, alkyl, or substituted alkyl), or -NR^25bC(O)OR^25a (where R^25a and R^25b are independently hydrogen, alkyl, or substituted alkyl); and where alkyl, alkenyl, and alkynyl, either alone or as part of another group are independently optionally substituted with one, two, three, four, or five halo. Preferably, R^4a and R^4b are hydrogen.

11. Another preferred group of compounds of Formula 1 is where R¹⁰⁰ is a group of formula (Al):

(Al) where

R^4a and R^4b are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, halo, alkoxy, acyl, acyloxy, acylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, -NR^19cC(O)NR^19aR^19b (where R^19a, R^19b, and R¹⁹° are independently hydrogen, alkyl, or substituted alkyl), -OC(O)NR^24aR^24b (where R^24a and R^24b are independently hydrogen, alkyl, or substituted alkyl), or -NR^25bC(O)OR^25a (where R^25a and R^25b are independently hydrogen, alkyl, or substituted alkyl); and where alkyl, alkenyl, and alkynyl, either alone or as part of another group are independently optionally substituted with one, two, three, four, or five halo; and

L is -X^Y^Z¹- where X¹ is alkylene, alkenylene, or cycloalkylene and where X¹ is optionally substituted by one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, alkylamino, and dialkylamino; Y¹ is -O-, -NR¹³-, -C(O)-, -C(O)O-, -C(O)NR¹³-, -NR¹³C(O)-, -C(O)NR¹³C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹³-, -NR¹³SO₂-, -OC(O)-, -OC(O)NR¹³-, -NR¹³C(O)O-, or -NR¹³C(O)NR¹⁴- (where R¹³ and R¹⁴ are independently hydrogen, alkyl, or substituted alkyl); and Z¹ is a bond, alkylene, alkenylene, or cycloalkylene;

L is -X²- where X² is alkylene, alkenylene, or cycloalkylene and is optionally substituted by one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, alkylamino, and dialkylamino;

L is -X⁵-Y^5a-Z⁵-Y^5b- where X⁵ is alkylene, alkenylene, or cycloalkylene and where X⁵ is optionally substituted by one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, alkylamino, and dialkylamino; Y^5a is -0-, -NR¹³-, -C(O)-, -C(O)O-, -C(O)NR¹³-, -NR¹³C(O)-, -C(O)NR¹³C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹³-, -NR¹³SO₂-, -OC(O)-, -OC(O)NR¹³-, -NR¹³C(O)O-, or -NR¹³C(O)NR¹⁴- (where R¹³ and R¹⁴ are independently hydrogen, alkyl, or substituted alkyl); Z⁵ is a bond, alkylene, alkenylene, or cycloalkylene where the alkylene or alkenylene are optionally substituted with aralkyloxyalkyl; and Y^5b is -C(O)-;

Het is heterocycloalkyl; and

R ₅ R , and R are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, acylamino, acyloxy, acylaniinoalkyloxycarbonyl, alkylthio, alkylsulfonyl, alkoxy, alkoxycarbonyl, alkoxyalkylamino, alkoxyalkylaminocarbonyl, alkoxyalkyloxy, alkoxyalkyloxycarbonyl, amino, alkylamino, dialkylamino, aminoalkyloxy, carboxy, carboxyalkylaminocarbonyl where the "alkyl" is optionally substituted with one or two hydroxy, cyano, cyanoalkylaminocarbonyl, aryl, aryloxy, arylsulfonyl, arylthioalkylcarbonyl, aralkyl where the alkyl is optionally substituted with one or two hydroxy, aralkyloxy, aralkyloxycarbonyl, aralkyloxyaminocarbonyl, aralkyloxycarbonylamino, aralkenyl, cycloalkyl, cycloalkyloxy, cycloalkylaminocarbonyl, cycloalkylalkyl where the "alkyl" is optionally substituted with one or two hydroxy, cycloalkylalkylaminocarbonyl, cycloalkylalkyloxycarbonyl, heteroaryl, heteroarylaminocarbonyl, heteroaralkyl, heteroaralkenyl, heteroaralkyloxy, halo, hydroxy, hydroxyalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, N-hydroxyaminocarbonyl, N-alkoxyaminocarbonyl, hydroxyalkylaminocarbonyl, dialkylaminoalkyloxycarbonyl, dialkylaminoalkylarninocarbonyl, arylamino, arylaminocarbonyl, alkylsulfonylamino, alkylsulfonylaminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylaminocarbonyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkylalkyloxycarbonyl, optionally substituted W

heterocycloalkylalkylaminocarbonyl, aminocarbonylamino, iV-aryl-iV-(alkylcarbonyl)-ainino, N-(alkylsulfonyl)-iV-alkyl-amino, alkoxycarbonylalkylaminocarbonyl where the "alkyl" is optionally substituted with one or two hydroxy, or trialkylsilyl; or any two of R⁷, R⁸, and R⁹ attached to the same carbon atom together with the carbon to which they are attached form indanylene or optionally substituted heterocycloalkylene; and where the alkyl, alkenyl, and alkynyl in R⁷, R⁸, and R⁹, either alone or part of another group, independently are optionally substituted with one, two, three, four, or five halo.

Preferably, R^4a and R^4b are hydrogen; L is -X^Y'-Z¹- where X¹ is alkylene, Y¹ is -C(O)-, -C(O)NH-, or -NHC(O)-, and Z¹ is a bond, alkylene, or alkenylene; or L is -X²- where X² is alkylene; or L is -Y²-Z²- where Y² is -C(O)NH- or -NHC(O)-; and Z² is alkylene; or L is -X⁵-Y^5a-Z⁵-Y^5b- where X⁵ is alkylene; Y^5a is -C(O)NH- or -NHC(O)-; Z⁵ is alkylene where the alkylene is optionally substituted with aralkyloxyalkyl; and Y^5b is -C(O)-; Het is piperidinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, or 4-oxo-4λ⁵-[l,4]azaphosphinanyl (where the phosphorous atom is substituted with alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl); R⁷ and R⁸ are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, acyl, acylamino, acylaminoalkyloxycarbonyl, alkoxycarbonyl, alkoxyalkylaminocarbonyl, alkoxyalkyloxycarbonyl, amino, carboxy, carboxyalkylaminocarbonyl (where the "alkyl" is optionally substituted with one or two hydroxy), cyano, cyanoalkylaminocarbonyl, aryl, aryloxy, arylsulfonyl, arylthioalkylcarbonyl, aralkyl (where the alkyl is optionally substituted with one or two hydroxy), aralkyloxy, aralkyloxyaminocarbonyl, aralkyloxycarbonylamino, cycloalkylaminocarbonyl, cycloalkylalkyl (where the "alkyl" is optionally substituted with one or two hydroxy), cycloalkylalkylaminocarbonyl, cycloalkylalkyloxycarbonyl, heteroaryl, heteroarylaminocarbonyl, heteroaralkyl, halo, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, N-hydroxyaminocarbonyl, iV-alkoxyaminocarbonyl, hydroxyalkylaminocarbonyl, dialkylaminoalkyloxycarbonyl, dialkylaminoalkylaminocarbonyl, arylamino, arylaminocarbonyl, alkylsulfonylamino, alkylsulfonylaminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylaminocarbonyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxycarbonyl, optionally substituted heterocycloalkylalkylaminocarbonyl, aminocarbonylamino, iV-aryl-N-(alkylcarbonyl)-amino, or alkoxycarbonylalkylaminocarbonyl (where the "alkyl" is optionally substituted with one or two hydroxy); or any two of R⁷, R⁸, and R⁹ attached to the same carbon atom together with the carbon to which they are attached form indanylene or optionally substituted heterocycloalkylene; and where the alkyl, alkenyl, and alkynyl in R⁷, R⁸, and R⁹, either alone or part of another group, independently are optionally substituted with one, two, three, four, or five halo; and R⁹ is hydrogen.

More preferably, R^4a and R^4b are hydrogen; L is -X¹^-Z¹- where X¹ is alkylene, Y¹ is -C(O)- or -C(O)NH-, and Z¹ is a bond or alkylene; Het is piperidinyl, piperazinyl, N-oxide of piperazinyl, pyrrolidinyl, or 4-oxo-4λ⁵-[l,4]azaphosphinanyl (where the phosphorous atom is substituted with alkyl, aralkyl, or cycloalkylalkyl); R⁷ and R⁸ are independently hydrogen, optionally substituted alkyl (preferably alkyl substituted with one or two alkoxyalkyloxycarbonyl, dialkylaminoalkyloxy, hydroxy or carboxy), optionally substituted alkenyl (preferably alkenyl), alkoxycarbonyl, carboxy, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, hydroxy, alkylsulfonylaminocarbonyl, alkoxycarbonylalkylaminocarbonyl, optionally substituted heterocycloalkyl, cycloalkylalkyl, amino, acyl (preferably optionally substituted heterocycloalkylcarbonyl), alkoxyalkyloxycarbonyl, dialkylaminoalkyloxycarbonyl, optionally substituted heterocycloalkylalkyloxycarbonyl, dialkylaminoalkylaminocarbonyl, or cyano; and R⁹ is hydrogen.

Even more preferably, R^4a and R^4b are hydrogen; L is -CH₂C(O)-; Het is piperidinyl, N-oxide of piperazinyl, or 4-oxo-4λ⁵-[l,4]azaphosphinanyl (where the phosphorous atom is substituted with aralkyl or cycloalkylalkyl); R⁷ and R⁸ are independently hydrogen, phenylmethyl, methoxycarbonyl, carboxy, fluorophenylmethyl, fluorophenylmethyl, thienyl, methylsulfonylaminocarbonyl, 2-oxo-l,3-dihydro-benzoimidazol-l-yl, allyl, hydroxy, tetrazolyl, fluorophenylmethyloxy, iV-(methoxycarbonylmethyl)-aminocarbonyl, 5-oxo- 4/7-[l,2,4]oxadiazoryl, amino, pyrrolidinyl carbonyl, 2-(methoxy)-ethyloxycarbonyl, 2-(methoxy)-ethyloxycarbonylmethyl, 2-(N,N-diethylamino)-ethyloxycarbonyl, 2-(morpholin-4-yl)-ethyloxycarbonyl, 2-(N,N-diethylamino)-ethylaminocarbonyl, cyano, 2-(N,N-diethylamino)-ethyloxymethyl, cyclopropylmethyl, or carboxyalkyl where the alkyl is substituted with hydroxy; and R⁹ is hydrogen.

Particularly preferably, R^4a and R^4b are hydrogen; L is -CH₂C(O)-; Het is piperidinyl, N-oxide of piperazinyl, or 4-oxo-4λ⁵-[l,4]azaphosphinanyl (where the phosphorous atom is substituted with fluorophenylalkyl); R⁷ and R⁸ are independently hydrogen, phenylmethyl, methoxycarbonyl, carboxy, 2-fluorophenylmethyl, 3 -fluorophenylmethyl, 4-fluorophenylmethyl, 3,4-difluorophenylmethyl, thien-3-yl, hydroxy, methylsulfonylaminocarbonyl, 2-oxo-l,3-dihydro-benzoimidazol-l-yl, allyl, tetrazolyl, 4-fluorophenylmethyloxy, N-(methoxycarbonylmethyl)-aminocarbonyl, 5-oxo-4H- [l,2,4]oxadiazolyl, amino, pyrrolidinylcarbonyl, 2-(methoxy)-ethyloxycarbonyl, 2-(methoxy)-ethyloxycarbonylmethyl, 2-(ΛζN-diethylamino)-ethyloxycarbonyl, 2-(morpholin-4-yl)-ethyloxycarbonyl, 2-(N,iV-diethylamino)-ethylaminocarbonyl, cyano, 2~(N,N-diemylamino)-ethyloxymethyl, cyclopropylmethyl, 1-carboxy-l-hydroxymethyl; and R⁹ is hydrogen. More preferably, R⁷ and R⁸ are independently hydrogen, 3,4-difluorophenylmethyl, carboxy, cyclopropylmethyl, cyano, or 4-fluorophenylmethyl; and R⁹ is hydrogen.

Even more particularly preferably, -Het(R⁷)(R⁸) is 4-carboxy-

4-(3 ,4-difluorophenylmethyl)-piperidin- 1 -yl, 4-carboxy-4-(cyclopropylmethyl)-piperidin- 1 -yl, 4-cyano-4-(cyclopropylmethyl)-piperidin- 1 -yl, 4-(4-fluorophenylmethyl)-4-oxo- 4λ⁵-[ 1 ,4]azaphosρhinanyl, or 4-(4-fluorophenylmethyl)-4-oxy-piρerazin- 1 -yl.

12. Another preferred group of compounds of Formula 1 is where R¹⁰⁰ is a group of formula (A2):

(A2) where

R^4a and R^4b are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, halo, alkoxy, acyl, acyloxy, acylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkylsulflnyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, -ΝR^19cC(O)ΝR^19aR^19b (where R^19a, R^19b, and R^19c are independently hydrogen, alkyl, or substituted alkyl), -OC(O)NR^24aR^24b (where R^24a and R^24b are independently hydrogen, alkyl, or substituted alkyl), or -NR^25bC(O)OR^25a (where R^25a and R are independently hydrogen, alkyl, or substituted alkyl); and where alkyl, alkenyl, and alkynyl, either alone or as part of another group are independently optionally substituted with one, two, three, four, or five halo; and

R⁵ is -Y^X^Q¹¹ where Y¹¹ is -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR²⁶³-, -NR²⁶³C(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are independently hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, or acyl, where X¹¹ is a bond, alkyl ene, or alkenylene, (where X¹¹ is optionally substituted with hydroxy, alkoxycarbonyl, carboxy), and where Q¹¹ is heteroaryl, aryl, aryloxy, or cycloalkyl;

R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is alkylene or alkenylene; Y¹² is -NR^26a-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR^26a-, -C(O)NR^26a-, -NR^26aC(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are as defined above; X^12b is a bond, alkylene, or alkenylene where X^12b is optionally substituted with one, two, or three groups selected from hydroxy, cyano, halo, heteroaryl, alkylcarbonyl, alkoxycarbonyl, carboxy, -NR R (where R and R are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, heteroaryl, or heteroarylaminocarbonyl), -C(O)NR^28aR^28b (where R^28a and R^28b are independently hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, hydroxy, or heteroaryl), and -NR^29aC(O)OR^29b (where R^29a is hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, or hydroxy, and R^29b is alkyl); and Q¹² is aryl, aryloxy, aralkyloxy, heteroaryl, aralkylaminocarbonyl (where the alkyl is optionally substituted with alkoxycarbonyl or carboxy), cycloalkyl, cycloalkylaminocarbonyl, cycloalkylalkyloxy, -NR^30aR^30b (where R^3Oa is hydrogen or alkyl and R^30b is aryl, heteroaryl, or cycloalkylalkyl) or -S(O)_n-R³¹ (where n is 0, 1, or 2 and R³¹ is heteroaryl, cycloalkylalkyl or aralkyl); where the alkyl within any group in Q¹² is optionally substituted with alkoxyalkyl);

R⁵ is -X¹³-Y¹³-Z¹³ where X¹³ is alkylene or alkenylene, where Y¹³ is -NR^26a-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR²⁶³-, -NR²⁶³C(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R ^a and R^26b are as defined above, and where Z¹³ is hydrogen, alkyl, or alkenyl (where Z¹³ is optionally substituted with one, two, or three halo, hydroxy, amino, alkoxy, alkoxycarbonyl, carboxy, or alkylcarbonylamino); or

R⁵ is -Y¹⁴-Z¹⁴ where Y¹⁴ is -S(O)-, -NR²⁶³C(O)-, -C(O)NR²⁶³-, -NR^26aC(O)NR^26b-, -C(O)NR²⁶³C(O)-, -NR²⁶³C(O)O-, -OC(O)NR²⁶³, or -OC(O)-, where R^26a and R^26b are as defiend above, and where Z¹⁴ is alkyl or alkenyl (where Z¹⁴ is optionally substituted with one, two, or three halo, hydroxy, amino, alkoxy, alkoxycarbonyl, carboxy, or alkylcarbonylamino) .

Preferably, R^4a and R^4b are hydrogen; and

R⁵ is -Y¹¹^-Q¹¹ where Y¹¹ is -C(O)NR²⁶³-, -NR²⁶³C(O)-, -NR²⁶³C(O)O-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are independently hydrogen or hydroxy, where X¹¹ is a bond, alkylene, or alkenylene, (where X¹¹ is optionally substituted with hydroxy), and where Q¹¹ is heteroaryl, aryl, aryloxy, or cycloalkyl; or

R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is alkylene; Y¹² is -C(O)NH-, -NHC(O)-, or -NHC(O)NH-; X^12b is a bond, alkylene, or alkenylene where X^12b is optionally substituted with one, two, or three groups selected from hydroxy, cyano, halo, heteroaryl, alkoxycarbonyl, carboxy, -NR R (where R and R are independently hydrogen or alkyl), -C(O)NR^28aR^28b (where R^28a and R^28b are independently hydrogen, alkyl, alkoxy, or heteroaryl), and -NHC(O)OR^29b (where R^29b is alkyl); and Q¹² is aryl, aryloxy, aralkyloxy, heteroaryl, aralkylaminocarbonyl (where the alkyl is optionally substituted with alkoxycarbonyl or carboxy), cycloalkyl, cycloalkylaminocarbonyl, cycloalkylalkyloxy, -NR^30aR^30b (where R^30a is hydrogen or alkyl and R^30b is aryl, heteroaryl, or cycloalkylalkyl) or -S(O)_n-R³¹ (where n is O or 2 and R³¹ is heteroaryl, cycloalkylalkyl or aralkyl); where the alkyl within any group in Q¹² is optionally substituted with alkoxyalkyl).

More preferably, R^4a and R^4b are hydrogen; and-R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is alkylene, Y is -C(O)NH-, X is alkylene or alkenylene where X is optionally substituted with one or two groups selected from alkoxycarbonyl, carboxy, -C(O)NHR (where R alkyl), and hydroxy; and Q¹² is aryl, aryloxy, aralkyloxy, -S(O)₂-R³¹ (where R³¹ is aryl).

Even more preferably, R^4a and R^4b are hydrogen; and R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is -CH₂-, Y¹² is C(O)NH, X^12b is eth-l,2-diyl optionally substituted with methoxycarbonyl, carboxy, or N-methylaminocarbonyl, or X^12b is buten-diyl optionally substituted with methoxycarbonyl, carboxy, or X^12b is prop-diyl optionally substituted with methoxycarbonyl, carboxy, hydroxy, or X^12b is but-diyl optionally substituted with carboxy, or X^12b is meth-diyl optionally substituted with methoxycarbonyl; and Q¹² is phenylmethyloxy, fluorophenylmethyloxy, phenyl, phenyloxy, indanyl, phenylmethylsulfonyl, chlorophenyl, or methoxyphenyl.

Particularly preferably, R^4a and R^4b are hydrogen; and R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is -CH₂-, Y¹² is C(O)NH, X^12b is -CH₂CH₂-, -CH[C(O)OCH₃]CH₂-, -CH(COOH)CH₂-, -CH[C(O)NHCH₃]CH₂-, -CH(COOH)CH₂-CH=CH-, -CH(COOH)CH₂CH₂-, -CH[C(O)OCH₃]CH₂CH₂-, -CH[C(O)OCH₂CH₃]CH₂-CH=CH-, -CH₂CH(OH)CH₂CH₂-, -CH₂CH(OH)CH₂-, -CH[C(O)OCH₂CH₃]CH₂CH₂-, -CH(CH₂COOH)CH₂CH₂-, -CH[CH₂C(O)OCH₃]CH₂CH₂-, -CH[C(O)OCH₃]-, or -CH(COOH)CH₂CH₂CH₂-; and Q¹² is phenylmethyloxy, 4-fluoroρhenylmethyloxy, phenyl, phenyloxy, indan-1-yl, phenylmethylsulfonyl, 4-chlorophenyl, or 4-methoxyphenyl.

Even more particularly preferably, R^4a and R^4b are hydrogen; and R⁵ is -CH₂C(O)NHCH₂CH₂; and Q¹² is 4-fluorophenylmethyloxy.

13. Another preferred group of compounds of Formula 1 is where R¹⁰⁰ is a group of formula (A3):

(A3) where

Y⁴ is -C(O)-, -NR³²C(O)-, -S(O)₂-, or a bond;

Z⁴ is heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, carboxy, aryl, aralkyl, cyano, arylcarbonyl, alkoxy, and hydroxy; or Z⁴ is -NR^50aR^50b where R^50a is hydrogen, alkyl, alkoxy, or hydroxy and R^50b is -(alkylene)-aryl where the alkylene is optionally substituted with one or two groups selected from halo, alkoxycarbonyl, hydroxy, and carboxy.

Preferably, X⁴ is alkylene; Y⁴ is -C(O)-; and Z⁴ is heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkylalkyl, alkoxycarbonyl, carboxy, aralkyl, cyano, acyl, and hydroxy; or Z⁴ is -NR^50aR^50b where R^50a is hydrogen and R^50b is -(alkylene)-aryl where the alkylene is optionally substituted with one or two groups selected from alkoxycarbonyl, hydroxy, and carboxy.

More preferably, X⁴ is -CH₂-; Y⁴ is -C(O)-; and Z⁴ is piperidinyl, piperazinyl, or 4-oxo-4λ⁵-[l,4]azaphosphinanyl (where the phosphorous atom is substituted with alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl) and where Z⁴ is optionally substituted with one or two cyclopropylmethyl, methoxycarbonyl, carboxy, phenethyl, phenylmethyl, cyano, fluorophenylmethyl, phenylcarbonyl, or hydroxy; or Z⁴ is -NHR^50b where R^5Ob is -(alkylene)-aryl where the alkylene is optionally substituted with one or two groups selected from methoxycarbonyl, ethoxycarbonyl, hydroxy, and carboxy. Even more preferably -(alkylene)-aryl is -CH[C(O)CH₂CH₃]CH₂CH₂CH₂-phenyl, -CH₂CH(OH)CH₂CH₂-phenyl, -CH₂CH₂CH₂CH₂-phenyl, -CH₂CH[C(O)CH₂CH₃]CH₂CH₂-phenyl, or -CH₂CH₂CH₂-phenyl.

Even more preferably, X⁴ is -CH₂-; Y⁴ is -C(O)-; and Z⁴ is piperidinyl substituted with cyano and 4-fluorophenylmethyl.

14. Another preferred group of compounds of Formula 1 is where L is -X^Y'-Z¹- where X¹ is alkylene, alkenylene, or cycloalkylene and where X¹ is optionally substituted by one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, alkylamino, and dialkylamino; Y¹ is -O-, -NR¹³-, -C(O)-, -C(O)O-, -C(O)NR¹³-, -NR¹³C(O)-, -C(O)NR¹³C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹³-, -NR¹³SO₂-, -OC(O)-, -OC(O)NR¹³-, -NR¹³C(O)O-, or -NR¹³C(O)NR¹⁴- (where R¹³ and R¹⁴ are independently hydrogen, alkyl, or substituted alkyl); and Z¹ is a bond, alkylene, alkenylene, or cycloalkylene;

L is -X⁵-Y^5a-Z⁵-Y^5b- where X⁵ is alkylene, alkenylene, or cycloalkylene and where X⁵ is optionally substituted by one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, alkylamino, and dialkylamino; Y^5a is -0-, -NR¹³-, -C(O)-, -C(O)O-, -C(O)NR¹³-, -NR¹³C(O)-, -C(O)NR¹³C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹³-, -NR¹³SO₂-, -OC(O)-, -OC(O)NR¹³-, -NR¹³C(O)O-, or -NR¹³C(O)NR¹⁴- (where R¹³ and R¹⁴ are independently hydrogen, alkyl, or substituted alkyl); Z⁵ is a bond, alkylene, alkenylene, or cycloalkylene where the alkylene or alkenylene are optionally substituted with aralkyloxyalkyl; and Y^5b is -C(O)-.

Preferably, L is -X¹^-Z¹- where X¹ is alkylene, Y¹ is -C(O)-, -C(O)NH-, or -NHC(O)- and Z¹ is a bond, alkylene, or alkenylene; L is -X²- where X² is alkylene; L is -Y²- Z²- where Y² is -C(O)NH- or -NHC(O)-, and Z² is alkylene; or L is -X⁵-Y^5a-Z⁵-Y^5b- where X⁵ is alkylene, Y^5a is -C(O)NH- or -NHC(O)-, Z⁵ is alkylene where the alkylene is optionally substituted with aralkyloxyalkyl, and Y^5b is -C(O)-. More preferably More preferably, L is -CH₂C(O)-, -CH₂C(O)NHCH₂CH₂CH₂-, -CH₂C(O)NH-, -CH₂NHC(O)CH₂-, -CH₂C(O)-, -C(CH₃)₂C(O)-, -CH₂CH₂-, or -NHC(O)CH₂-.

Within the above preferred groups, a more preferred group is that where L is -X¹^-Z¹- where X¹ is alkylene, Y¹ is -C(O)-, -C(O)NH-, or -NHC(O)- and Z¹ is a bond, alkylene, or alkenylene. Even more preferably, L is -CH₂C(O)-.

15. Another preferred group of compounds of Formula 1 is where Het is heterocycloalkyl. Preferably, Het is piperidinyl, piperazinyl, N-oxide of piperazinyl, homopiperazinyl, pyrrolidinyl, or 4-oxo-4λ⁵-[l,4]azaphosphinanyl (where the phosphorous atom is substituted with alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl). More preferably, Het is piperidinyl, N-oxide of piperazinyl, or 4-oxo-4λ⁵-[l,4]azaphosphinanyl (where the phosphorous atom is substituted with aralkyl or cycloalkylalkyl). Even more preferably, Het is piperidinyl.

16. Another preferred group of compounds of Formula 1 is where R⁷, R⁸, and R⁹ are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, acylamino, acyloxy, acylarninoalkyloxycarbonyl, alkylthio, alkylsulfonyl, alkoxy, alkoxycarbonyl, alkoxyalkylamino, alkoxyalkylaminocarbonyl, alkoxyalkyloxy, alkoxyalkyloxycarbonyl, amino, alkylamino, dialkylamino, aminoalkyloxy, carboxy, carboxyalkylaminocarbonyl where the "alkyl" is optionally substituted with one or two hydroxy, cyano, cyanoalkylaminocarbonyl, aryl, aryloxy, arylsulfonyl, arylthioalkylcarbonyl, aralkyl where the alkyl is optionally substituted with one or two hydroxy, aralkyloxy, aralkyloxycarbonyl, aralkyloxyaminocarbonyl, aralkyloxycarbonylamino, aralkenyl, cycloalkyl, cycloalkyloxy, cycloalkylaminocarbonyl, cycloalkylalkyl where the "alkyl" is optionally substituted with one or two hydroxy, cycloalkylalkylaminocarbonyl, cycloalkylalkyloxycarbonyl, heteroaryl, heteroarylaminocarbonyl, heteroaralkyl, heteroaralkenyl, heteroaralkyloxy, halo, hydroxy, hydroxyalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, iV-hydroxyaminocarbonyl, iV-alkoxyaminocarbonyl, hydroxyalkylaminocarbonyl, dialkylaminoalkyloxycarbonyl, dialkylaminoalkylaminocarbonyl, arylamino, arylaminocarbonyl, alkylsulfonylamino, alkylsulfonylaminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylaminocarbonyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkylalkyloxycarbonyl, optionally substituted heterocycloalkylalkylaminocarbonyl, aminocarbonylamino, N-aryl-iV-(alkylcarbonyl)-amino, 7V-(alkylsulfonyl)-N-alkyl-amino, alkoxycarbonylalkylaminocarbonyl where the "alkyl" is optionally substituted with one or two hydroxy, or trialkylsilyl; or any two of R⁷, R⁸, and R⁹ attached to the same carbon atom together with the carbon to which they are attached form indanylene or optionally substituted heterocycloalkylene; and where the alkyl, alkenyl, and alkynyl in R⁷, R⁸, and R⁹, either alone or part of another group, independently are optionally substituted with one, two, three, four, or five halo.

Preferably, R⁷ and R⁸ are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, acyl, acylarnino, acylaminoalkyloxycarbonyl, alkoxycarbonyl, alkoxyalkylaminocarbonyl, alkoxyalkyloxycarbonyl, amino, carboxy, carboxyalkylaminocarbonyl (where the "alkyl" is optionally substituted with one or two hydroxy), cyano, cyanoalkylaminocarbonyl, aryl, aryloxy, arylsulfonyl, arylthioalkylcarbonyl, aralkyl (where the alkyl is optionally substituted with one or two hydroxy), aralkyloxy, aralkyloxyaminocarbonyl, aralkyloxycarbonylamino, cycloalkylaminocarbonyl, cycloalkylalkyl (where the "alkyl" is optionally substituted with one or two hydroxy), cycloalkylalkylaminocarbonyl, cycloalkylalkyloxycarbonyl, heteroaryl, heteroarylaminocarbonyl, heteroaralkyl, halo, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, iV-hydroxyaminocarbonyl, N-alkoxyaminocarbonyl, hydroxyalkylaminocarbonyl, dialkylaminoalkyloxycarbonyl, dialkylaminoalkylaminocarbonyl, arylamino, arylaminocarbonyl, alkylsulfonylamino, alkylsulfonylaminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylaminocarbonyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxycarbonyl, optionally substituted heterocycloalkylalkylaminocarbonyl, aminocarbonylamino, N-aryl-N-(alkylcarbonyl)~amino, or alkoxycarbonylalkylaminocarbonyl (where the "alkyl" is optionally substituted with one or two hydroxy); or any two of R⁷, R⁸, and R⁹ attached to the same carbon atom together with the carbon to which they are attached form indanylene or optionally substituted heterocycloalkylene; and where the alkyl, alkenyl, and alkynyl in R⁷, R⁸, and R⁹, either alone or part of another group, independently are optionally substituted with one, two, three, four, or five halo; and R⁹ is hydrogen.

More preferably, R⁷ and R⁸ are independently hydrogen, optionally substituted alkyl (preferably alkyl substituted with one or two alkoxyalkyloxycarbonyl, dialkylaminoalkyloxy, hydroxy or carboxy), optionally substituted alkenyl (preferably alkenyl), alkoxycarbonyl, carboxy, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, hydroxy, alkylsulfonylaminocarbonyl, alkoxycarbonylalkylaminocarbonyl, optionally substituted heterocycloalkyl, cycloalkylalkyl, amino, acyl (preferably optionally substituted heterocycloalkylcarbonyl), alkoxyalkyloxycarbonyl, dialkylaminoalkyloxycarbonyl, optionally substituted heterocycloalkylalkyloxycarbonyl, dialkylaminoalkylaminocarbonyl, or cyano; and R⁹ is hydrogen.

Even more preferably, R⁷ and R⁸ are independently hydrogen, phenylmethyl, methoxycarbonyl, carboxy, fluorophenylmethyl, difluorophenylmethyl, thienyl, methylsulfonylaminocarbonyl, 2-oxo-l,3-dihydro-benzoimidazol-l-yl, allyl, hydroxy, tetrazolyl, fluorophenylmethyloxy, N-(methoxycarbonylmethyl)-aminocarbonyl, 5-oxo-4H- [l,2,4]oxadiazolyl, amino, pyrrolidinylcarbonyl, 2-(methoxy)-ethyloxycarbonyl, 2-(methoxy)-ethyloxycarbonylmethyl, 2-(i\ζN-diethylamino)-ethyloxycarbonyl, 2-(morpholin-4-yl)-ethyloxycarbonyl, 2-(N,N-diethylamino)-ethylaminocarbonyl, cyano, 2-(ΛζN-diethylamino)-ethyloxymethyl, cyclopropylmethyl, or carboxyalkyl where the alkyl is substituted with hydroxy; and R⁹ is hydrogen.

Particularly preferably, R⁷ and R⁸ are independently hydrogen, phenylmethyl, methoxycarbonyl, carboxy, 2-fluorophenyhnethyl, 3 -fluorophenylmethyl, 4-fluorophenylmethyl, 3,4-difluorophenylmethyl, thien-3-yl, hydroxy, methylsulfonylaminocarbonyl, 2-oxo-l,3-dihydro-benzoimidazol-l~yl, allyl, tetrazolyl, 4-fluorophenylmethyloxy, iV-(methoxycarbonylmethyl)-aminocarbonyl, 5-oxo-4H- [l,2,4]oxadiazolyl, amino, pyrrolidinylcarbonyl, 2-(methoxy)-ethyloxycarbonyl, 2-(methoxy)-ethyloxycarbonylmethyl, 2-(N,iV-diethylamino)-ethyloxycarbonyl, 2-(morpholin-4-yl)-ethyloxycarbonyl,, 2-(N,iV-diethylamino)-ethylaminocarbonyl, cyano, 2-(N,iV-diethylamino)-ethyloxymethyl, cyclopropylmethyl, 1 -carboxy- 1-hydroxymethyl; and R⁹ is hydrogen.

More particularly preferably, R⁷ and R⁸ are independently hydrogen, 3,4-difluorophenylmethyl, carboxy, cyclopropylmethyl, cyano, or 4-fluorophenylmethyl; and R⁹ is hydrogen.

17. Another preferred group of compounds of Formula 1 is where

R⁵ is -Y¹ '-X¹ ^Q¹¹ where Y¹¹ is -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶S -C(O)NR²⁶³-, -NR²⁶³C(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are independently hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, or acyl, where X¹¹ is a bond, alkylene, or alkenylene, (where X¹¹ is optionally substituted with hydroxy, alkoxycarbonyl, carboxy), and where Q¹¹ is heteroaryl, aryl, aryloxy, or cycloalkyl;

R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is alkylene or alkenylene; Y¹² is -NR²⁶³-, -0-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR²⁶³-, -NR^26aC(O)-₅ -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are as defined above; X^12b is a bond, alkylene, or alkenylene where X^12b is optionally substituted with one, two, or three groups selected from hydroxy, cyano, halo, heteroaryl, alkylcarbonyl, alkoxycarbonyl, carboxy, -NR^27aR^27b (where R^27a and R^27b are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, heteroaryl, or heteroarylaminocarbonyl), -C(O)NR^28aR^28b (where R^28a and R^28b are independently hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, hydroxy, or heteroaryl), and -NR^29aC(O)OR^29b (where R^29a is hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, or hydroxy, and R^29b is alkyl); and Q¹² is aryl, aryloxy, aralkyloxy, heteroaryl, aralkylaminocarbonyl (where the alkyl is optionally substituted with alkoxycarbonyl or carboxy), cycloalkyl, cycloalkylaminocarbonyl, cycloalkylalkyloxy, -NR^30aR^30b (where R^30a is hydrogen or alkyl and R^30b is aryl, heteroaryl, or cycloalkylalkyl) or -S(O)_n-R³¹ (where n is 0, 1, or 2 and R³¹ is heteroaryl, cycloalkylalkyl or aralkyl); where the alkyl within any group in Q¹² is optionally substituted with alkoxyalkyl);

R⁵ is -X¹³-Y¹³-Z¹³ where X¹³ is alkylene or alkenylene, where Y¹³ is -NR^26a-, -0-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR²⁶% -NR^26aC(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR^26aC(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are as defined above, and where Z¹³ is hydrogen, alkyl, or alkenyl (where Z¹³ is optionally substituted with one, two, or three halo, hydroxy, amino, alkoxy, alkoxycarbonyl, carboxy, or alkylcarbonylamino); or

Preferably, R⁵ is -Y¹^X¹ '-Q¹ * where Y¹¹ is -C(O)NR²⁶³-, -NR²⁶³C(O)-, -NR²⁶³C(O)O- , or -NR^26aC(O)NR^26b-, where R^26a and R^26b are independently hydrogen or hydroxy, where X¹¹ is a bond, alkylene, or alkenylene, (where X¹¹ is optionally substituted with hydroxy), and where Q¹¹ is heteroaryl, aryl, aryloxy, or cycloalkyl; or R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X¹²³ is alkylene, Y¹² is -C(O)NH-, -NHC(O)-, or -NHC(O)NH-, X^12b is a bond, alkylene, or alkenylene where X^12b is optionally substituted with one, two, or three groups selected from hydroxy, cyano, halo, heteroaryl, alkoxycarbonyl, carboxy, -NR^27aR^27b (where R^27a and R^27b are independently hydrogen or alkyl), -C(O)NR^28aR^28b (where R^28a and R^28b are independently hydrogen, alkyl, alkoxy, or heteroaryl), and -NHC(O)OR^29b (where R^29b is alkyl), and Q¹² is aryl, aryloxy, aralkyloxy, heteroaryl, aralkylaminocarbonyl (where the alkyl is optionally substituted with alkoxycarbonyl or carboxy), cycloalkyl, cycloalkylaminocarbonyl, cycloalkylalkyloxy, -NR^30aR^30b (where R^30a is hydrogen or alkyl and R^30b is aryl, heteroaryl, or cycloalkylalkyl) or -S(O)_n-R³¹ (where n is 0 or 2 and R³¹ is heteroaryl, cycloalkylalkyl or aralkyl) and where the alkyl within any group in Q¹² is optionally substituted with alkoxyalkyl).

More preferably, R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is alkylene, Y¹² is -C(O)NH-, X^12b is alkylene or alkenylene where X^12b is optionally substituted with one or two groups selected from alkoxycarbonyl, carboxy, -C(O)NHR (where R alkyl), and hydroxy; and Q¹² is aryl, aryloxy, aralkyloxy, -S(O)₂-R³¹ (where R³¹ is aryl).

Even more preferably, R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is -CH₂-, Y¹² is C(O)NH,

X is eth-l,2-diyl optionally substituted with methoxycarbonyl, carboxy, or iV-methylaminocarbonyl, or X^12b is buten-diyl optionally substituted with methoxycarbonyl, carboxy, or X^12b is prop-diyl optionally substituted with methoxycarbonyl, carboxy, hydroxy, or X^12b is but-diyl optionally substituted with carboxy, or X^12b is meth-diyl optionally substituted with methoxycarbonyl; and Q¹² is phenylmethyloxy, fluorophenylmethyloxy, phenyl, phenyloxy, indanyl, phenylmethylsulfonyl, chlorophenyl, or methoxyphenyl.

Particularly preferably, R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is -CH₂-, Y¹² is C(O)NH, X^12b is -CH₂CH₂-, -CH[C(O)OCH₃]CH₂-, -CH(COOH)CH₂-, -CH[C(O)NHCH₃]CH₂-, -CH(COOH)CH₂-CH=CH-, -CH(COOH)CH₂CH₂-, -CH[C(O)OCH₃]CH₂CH₂-, -CH[C(O)OCH₂CH₃]CH₂-CH=CH-, -CH₂CH(OH)CH₂CH₂-, -CH₂CH(OH)CH₂-, -CH[C(O)OCH₂CH₃]CH₂CH₂-, -CH(CH₂COOH)CH₂CH₂-, -CH[CH₂C(O)OCH₃]CH₂CH₂-, -CH[C(O)OCH₃]-, or -CH(COOH)CH₂CH₂CH₂-; and Q¹² is phenylmethyloxy, 4-fluorophenylmethyloxy, phenyl, phenyloxy, indan-1-yl, phenylmethylsulfonyl, 4-chlorophenyl, or 4-methoxyphenyl.

Even more particularly preferably, R⁵ is -CH₂C(O)NHCH₂CH₂; and Q¹² is 4-fluorophenylmethyloxy.

18. Another preferred group of compounds of Formula 1 is where Z⁴ is heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, carboxy, aryl, aralkyl, cyano, arylcarbonyl, alkoxy, and hydroxy; or Z⁴ is -NR^50aR^50b where R^5Oa is hydrogen, alkyl, alkoxy, or hydroxy and R^5Ob is -(alkylene)-aryl where the alkylene is optionally substituted with one or two groups selected from halo, alkoxycarbonyl, hydroxy, and carboxy.

Preferably, Z⁴ is heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkylalkyl, alkoxycarbonyl, carboxy, aralkyl, cyano, acyl, and hydroxy; or Z⁴ is -NR^50aR^50b where R^5Oa is hydrogen and R^50b is -(alkylene)-aryl where the alkylene is optionally substituted with one or two groups selected from alkoxycarbonyl, hydroxy, and carboxy.

More preferably, Z⁴ is piperidinyl, piperazinyl, or 4-oxo-4λ⁵-[l,4]azaphosphinanyl (where the phosphorous atom is substituted with alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl) and where Z⁴ is optionally substituted with one or two cyclopropylmethyl, methoxycarbonyl, carboxy, phenethyl, phenylmethyl, cyano, fluorophenylmethyl, phenylcarbonyl, or hydroxy; or Z⁴ is -NHR^50b where R^50b is -(alkylene)-aryl where the alkylene is optionally substituted with one or two groups selected from methoxycarbonyl, ethoxycarbonyl, hydroxy, and carboxy. Even more preferably -(alkylene)-aryl is -CH[C(O)CH₂CH₃]CH₂CH₂CH₂-ρhenyl, -CH₂CH(OH)CH₂CH₂-phenyl, -CH₂CH₂CH₂CH₂- phenyl, -CH₂CH[C(O)CH₂CH₃]CH₂CH₂-phenyl, or -CH₂CH₂CH₂-ρhenyl.

Even more preferably, Z⁴ is piperidinyl substituted with cyano and 4-fluorophenylmethyl.

19. Another preferred group of compounds of Formula 1 is where A is optionally substituted pyridino; D is =CH-; and R¹, R², and R³ are hydrogen.

20. Within the preferred group 2, a more preferred group is that where L is -CH₂C(O)-.

21. Within the preferred group 2, a more preferred group is that wherein Het is piperidinyl where L is attached at the 1 -position and R⁷ and R⁸ are attached at the 4-position or where Het is piperazinyl and L is attached at the 1 -position and R⁷ is attached at the 4-ρosition.

22. Within the preferred group 2, a more preferred group is that where R⁷ is carboxy, R⁸ is aralkyl, and R⁹ is hydrogen; R⁷ is alkoxycarbonyl, R⁸ is aralkyl, and R⁹ is hydrogen; R⁷ is carboxy, R⁸ is heteroaralkyl, and R⁹ is hydrogen; R⁷ is alkoxycarbonyl, R⁸ is cycloalkylalkyl, and R is hydrogen; R is carboxy, R is cycloalkylalkyl, and R is hydrogen; R is cyano, R is cycloalkylalkyl, and R⁹ is hydrogen; or R⁷ and R⁹ are hydrogen and R⁸ is aralkyl.

Preferably, R⁷ is carboxy, R⁸ is aralkyl, and R⁹ is hydrogen; R⁷ is carboxy, R⁸ is cycloalkylalkyl, and R⁹ is hydrogen; R⁷ is cyano, R⁸ is cycloalkylalkyl, and R⁹ is hydrogen; or R⁷ and R⁹ are hydrogen and R⁸ is aralkyl.

Within the above preferred groups in 22, another more preferred group is that where Het is piperidinyl or piperazinyl, and R and R are located at the 4-position of Het and L is located at the 1 -position of Het; and R⁹ is hydrogen.

23. Within the preferred group 3, a more preferred group is that where X^12a is alkylene, preferably -CH₂-; Y¹²- is -C(O)NH-; and X^12b is alkylene optionally substituted with one or two hydroxy, carboxy, or alkoxycarbonyl.

24. Within the preferred group 3, a more preferred group is that where A is \^ * or

25. Within the preferred group 3, a more preferred group is that where

R⁵ is -f'-X"^¹¹ where Y¹¹ is -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR²⁶³-, -NR²⁶³C(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are independently hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, or acyl, where X¹¹ is a bond, alkylene, or alkenylene, (where X¹¹ is optionally substituted with hydroxy, alkoxycarbonyl, carboxy), and where Q¹¹ is heteroaryl, aryl, aryloxy, or cycloalkyl; or

R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is alkylene or alkenylene; Y¹² is -NR^26a-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶S -C(O)NR²⁶³-, -NR^26aC(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are as defined above; X^12b is a bond, alkylene, or alkenylene where X^12b is optionally substituted with one, two, or three groups selected from hydroxy, cyano, halo, heteroaryl, alkylcarbonyl, alkoxycarbonyl, carboxy, -NR^27aR^27b (where R^27a and R^27b are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, heteroaryl, or heteroarylaminocarbonyl), -C(O)NR^28aR^28b (where R^28a and R^28b are independently hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, hydroxy, or heteroaryl), and -NR^29aC(O)OR^29b (where R^29a is hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, or hydroxy, and R^29b is alkyl); and Q¹² is aryl, aryloxy, aralkyloxy, heteroaryl, aralkylaminocarbonyl (where the alkyl is optionally substituted with alkoxycarbonyl or carboxy), cycloalkyl, cycloalkylaminocarbonyl, cycloalkylalkyloxy, -NR^30aR^30b (where R^30a is hydrogen or alkyl and R^30b is aiyl, heteroaryl, or cycloalkylalkyl) or -S(O)_n-R³¹ (where n is 0, 1, or 2 and R³¹ is heteroaryl, cycloalkylalkyl or aralkyl); where the alkyl within any group in Q is optionally substituted with alkoxyalkyl).

Even more preferably, R⁵ is -X^12a-Y¹²-X^12b-Q¹²

26. Within the preferred group 25, a more preferred group is that where Q¹² is aryl, aryloxy, aralkyloxy, or -S(O)₂-R³¹ where R³¹ is aryl. Even more preferably, Q¹² is aryl or aralkyloxy. Particularly preferably, Q¹² is phenyl, phenyloxy, phenylmethyloxy, 4-methoxyphenyl, indanyl, phenylmethylsulfonyl, or 4-chlorophenyl.

27. Within the preferred groups 2 or 3, a more preferrred group is that wherein R^4a and R^4b are hydrogen.

28. Within the the preferred group 4, a more preferred group is that where X⁴ is -CH₂- and Y⁴ is -C(O)-. Even more preferably, Z⁴ is heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, carboxy, aryl, aralkyl, cyano, arylcarbonyl, alkoxy, and hydroxy. Particularly preferably, Z⁴ is heterocycloalkyl substituted with one or two cyano or aralkyl.

*

29. Within the the preferred group 4, a more preferred group is that where A is NL ^* and D is =CH-.

30. Yet another preferred group is that wherein this invention is directed to a method of treating an immunomediated inflammatory disease responsive to the inhibition of tryptase in an animal suffering said disease, comprising administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I. Preferably the immunomediated inflammatory disease is one associated with the respiratory tract, such as asthma, the hyperresponsiveness phase associated with chronic asthma, allergic rhinitis, and Chronic Obstructive Pulmonary Disease (COPD) or is one associated with mast cells, such as conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel disease (IBD), peptic ulcers and various skin conditions, and particularly rheumatoid arthritis.

More preferably, the disease is asthma, allergic rhinitis, COPD, rheumatoid arthritis, or IBD. Even more preferably the disease is asthma or allergic rhinitis. Particularly preferably the disease is asthma.

31. Yet another preferred group is that wherein this invention is directed A method of treating an immunomediated respiratory disease independently selected from the group consisting of asthma, COPD, and allergic rhinitis, in an animal which method comprises administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient in combination with one or more compound(s) independently selected from the group consisting of a β-2 adrenoreceptor agonist, corticosteroid, leukotriene antagonist, phosphodiesterase 4 inhibitor, and antihistamine.

Preferably, the β-2 adrenoreceptor agonist is salmeterol or levalbuterol, the corticosteroid is budesonide or fluticasone, the leukotriene D4 antagonist is montelukast, and the phosphodiesterase 4 inhibitor is roflumilast.

Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups unless stated otherwise. A person of ordinary skill in the art would recognize that certain groups listed above in the preferred embodiments can exist as geometric or stereoisomers. The present invention includes individual stereoisomers and geometric isomers and mixtures thereof.

Representative compounds of Formula I

Selected compounds of the invention are provided in Table 1, having Formula I

where R¹, R², and R³ are hydrogen; D is =CR⁶- where R⁶ is hydrogen; and R¹⁰⁰ is

(Al) where R^4a, R^4b, and R⁹ are hydrogen; L is -X¹^-Z¹- where X¹ is -CH₂-, Y¹ is -C(O)-, and Z¹ is a bond; and all other groups are as defined below: Table 1.

W

and Compounds 1-154 are named:

4-(4-fluoro-ρhenylmethyl)- 1 - {2-[2'-hydroxy-3 ^t-(liJ-ρyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl} -ρiperidine-4-carboxylic acid;

4-(3,4-difluoro-ρhenylmethyl)-l-{2-[2'-hydiOxy-3'-(l_JH-pyrrolo[2,3-c]pyridm-2-yl)- biphenyl-4-yl] -acetyl } -piperidine-4-carboxylic acid;

4-(3-fluoro-phenylmethyl)-l-{2-[2^t-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl} -piperidine-4-carboxylic acid;

N-(4-ρhenylmethyl-l-{2-[2'-hydroxy-3'-(lH^'-ρyrrolo[2_?3-c]ρyridin-2-yl)-biρhenyl- 4-yl]-acetyl}-piperidine-4-carbonyl)-methanesulfonamide;

4-ρhenylmethyl-l-{2-[2^l-hydroxy-3'-(l/i-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperidine-4-carbonitrile;

4-(l//-tetrazol-5-yl)-4-(phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2₅3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine; iV-hydroxy-4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide; methyl 4-ρhenylmethyl- 1 - {2-[2'-hydroxy-3 '-(1 H-pyrrolo[2,3 -c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piρeridine-4-carboxylate;

4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-ρyirolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide;

N-(4,5-dihydro-thiazol-2-yl)-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH--pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide; methyl 4-(3,4-difluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyπOlo[2,3-c]ρyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate; methyl 4-(3-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate; methyl 4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate;

4-ρhenylmethyl-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]- acetyl} -piperidine-4-carboxylic acid;

[(4-(4-fluoro-benzyl)-l-{2-[2^l-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biphenyl- 4-yl] -acetyl } -piperidine-4-carbonyl)-amino] -acetic acid;

4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl} - N-methyl-piperidine-4-carboxamide; methyl l-{2-[2'-hydroxy-3^t-(lH-pyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]-acetyl}- 4-thiophen-3-ylmethyl-piperidine-4-carboxylate;

4-(2-fluoro-phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(1 H-pyrrolo[2,3 -c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidme-4-carboxylic acid; l-{2-[2'-hydroxy-3^l-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]-acetyl}- 4-thiophen-3 -ylmethyl-piperidine-4-carboxylic acid; methyl [(4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carbonyl)-amino]-acetate;

4-(methylcarbonyloxy)-4-(phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine; iV-(2,2,2-trifluoro-ethyl)-4-phenylmethyl- 1 - {2-[2'-hydroxy-3 ⁽-(li7-ρyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl] -acetyl } -piperidine-4-carboxamide;

4-(hydroxy)-4-(4-fluorophenylmethyl)-l-{2-[2'-hydroxy-3^I-(lH-ρyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-(3,4-difluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3^l-(lH-pyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylic acid; N-ρhenylmethyloxy-4-(4-fluoro-ρhenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(lH^"-ρyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl] -acetyl } -piperidine-4-carboxamide;

4-(hydroxy)-4-(phenylmethyl)-l-{2-[2'-hydroxy-3^l-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidine;

4-(4-fluoro-ρhenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)- biρhenyl-4-yl]-acetyl} -piperidine-4-carboxylic acid; methyl 4-(2-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]ρyridin-2- yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate; methyl 4i?-(4-fluoro-phenylmethyloxy)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-pyrrolidine-26'-carboxylate; methyl 4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH^r-pyrrolo[3,2-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate; methyl 4-(3,4-difluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[3,2-c]pyridin- 2-yl)-biphenyl-4-yl] -acetyl } -piρeridine-4-carboxylate;

N-(lH-tetrazol-5-yl)-4-ρhenylmethyl-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin- 2-yl)-biphenyl-4-yl]-acetyl}-ρiρeridine-4-carboxamide; methyl 4-phenylmethyl- 1 - {2-[2'-hydroxy-3 '-(l/J-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-ρiρeridine-4-carboxylate;

4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperidine-4-carboxylic acid;

N^-dimethyl-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(l/f-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide; methyl 4-(2-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[3,2-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate;

N-thiazol-2-yl-4-ρhenylmethyl-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridm-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide;

4-(fluoro)-4-(ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(li/-ρyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine; methyl 4-allyl- 1 - {2-[2'-hydroxy-3 '-(1 H-pyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperidine-4-carboxylate;

4-allyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]-acetyl}- piperidine-4-carboxylic acid;

4-(2-fluoro-ρhenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(1 H-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylic acid; 4-(hydroxy)-4-(phenylmethyl)-l-{2-[2'-hydroxy-3'-(l/i-ρyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine; methyl 4-ρhenylmethyloxy-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl} -pyrrolidine-2-carboxylate;

4-fluoro-4-(phenylmethyl)-l-{2-[2'-hydroxy-3^t-(li7-ρyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidine; iV-dimethyl-4-Phenylmethyl-l-{2-[2^t-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperidine-4-carboxamide;

4-phenylmethyloxy-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl- 4-yl] -acetyl } -pyrrolidine-2-carboxylic acid;

4-amino-4-(phenylmethyl)-l-{2-[2'-hydroxy-3^I-(lH^"-pyrrolo[3₃2-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidine;

4-hydroxy-4-phenyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl- 4-yl]-acetyl} -piperidine;

3 -hydroxy-4-(3-trifluoromethyl-phenyl)- 1 - {2-[2'-hydroxy-3 '-( lH-ρyrrolo[3 ,2- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-hydroxy-4-(4-chlorophenyl)-l-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[3,2-c]pyridm-2-yl)- biphenyl-4-yl] -acetyl} -piperidine;

4-hydroxy-4-(3-trifluoromethyl-phenyl)-l-{2-[2'-hydroxy-3'-(lH^'-pyrrolo[3,2- c]pyridin-2-yl)-biphenyl-4-yl] -acetyl} -piperidine;

4-methyl-4-(methoxycarbonyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperidine;

4-phenylmethyl-4-[(phenylmethyloxy)-carbonylamino]-l-{2-[2'-hydroxy-3'-(liJ- pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-phenylmethyl-2-(ThLydroxymethyl)-l-{2-[2'-hydroxy-3'-(liϊ-pyrrolo[3,2-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperazine; methyl 1 -phenylmethyl-4- {2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine-2-carboxylate; methyl 4-ρhenylmethyl-l-{2-[2^!-hydroxy-3^t-(li7-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine-2-carboxylate; l-ρhenylmethyl-4-{2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperazine-2-carboxylic acid;

4-ρhenylmethyl-l-{2-[2'-hydroxy-3'-(lH^r-ρyrrolo[3,2-c]ρyridin-2-yl)-biphenyl-4-yl]- acetyl}-piperazine-2-carboxylic acid; 4(i?)-(4-fluoro-ρhenylmethyloxy)-l-{2-[2'-hydroxy-3'-(l//-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-pyrrolidine-2(5)-carboxylic acid;

N-(lH-[l,2,4]Mazol-3-yl)-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3- c]ρyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxainide; methyl 4R-(4-fluoro-phenylmethyloxy)-l-{2-[2'-hydroxy-3^I-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-pyrrolidine-2i?-carboxylate; methyl l-phenylmethyl-4-{2-[2^t-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine-2-carboxylate;

4-hydroxy-4-phenyl-l-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl] -acetyl } -piperidine;

4-hydroxy-4-(4-chloroρhenyl)- 1 - {2-[2'-hydroxy-3 '-( lH^"-ρyrrolo[2,3 -c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine;

4-(moφholin-4-ylcarbonyl)-4-(phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl] -acetyl } -piperidine;

N-methoxy-4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide;

4-(5-methyl-[ 1 ,2,4]triazol-3-yl)-4-(4-fluorophenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(IH- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine; l-phenylmethyl-4-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]- acetyl } -piperazine-2-carboxylic acid;

4(i?)-(4-fluoro-phenylmethyloxy)-l-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridm- 2-yl)-biphenyl-4-yl]-acetyl}-pyrrolidine-2(i?)-carboxylic acid;

2-(methoxycarbonyl)-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperazine;

2-carboxy-4-(phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(l/J-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-hydroxy-4-(phenylmethyl)-l-{2-[2'-hydroxy-3^l-(3-chloro-lH-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine; iV-cyclopropylmethyl-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxyamide;

4-(4H-5-oxo-[l,2,4]oxadiazol-3-yl)-4-(phenylmethyl)-l-{2-[2^t-hydroxy-3'-(l//- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine; iV-(2,2,2-trifluoro-ethyl)-4-(4-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3^!-(lH- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide; phenylmethyl (4-(4-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(l/-^'-ρyrrolo[2,3- c]pyridin-2-yl)-biρhenyl-4-yl]-acetyl}-piperidin-4-yl)-acetate;

(4-(4-fluoro-ρhenylmethyl)-l-{2-[2^l-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidin-4-yl)-acetic acid;

N-(4-(4-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3^t-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidin-4-yl)-methanesulfonamide; methyl 4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH^'-imidazo[4,5-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate;

4-hydroxy-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(l/jr-iniidazo[4,5-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine;

(4-(4-fluoro-ρhenylmethyl)- 1 - {2-[2'-hydroxy-3 '-( l/i-ρyrrolo[2,3 -c]ρyridin-2-yl> biphenyl-4-yl]-acetyl}-ρiperidin-4-yl)-urea;

4-(lH-tetrazol-5-yl)-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(3-chloro-lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-(4-fluoro-phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(lH-imidazo[4,5-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperidine-4-carboxylic acid;

4-(4,5-dihydro-thiazol-2-yl)-4-(4-fluoroρhenylmethyl)-l-{2-[2'-hydroxy-3'-(lH- pyrrolo [2,3 -c]pyridin-2-yl)-biphenyl-4-yl] -acetyl } -piperidine;

N-(4-(4-fluoro-phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-( l//-pyrrolo[2,3 -c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidin-4-yl)-acetaniide;

4-(lH^"-[l,2,3]triazol-4-yl)-4-(4-fluorophenylmethyl)-l-{2-[2'-hydroxy-3^t-(l//- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine; iV-cyclopropylmethyl-4-(4-fluoro-phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-( 1 H- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide; phenylmethyl (4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidin-4-yl)-carbamate; methyl 4-cyclopropylmethyl-l-{2-[2^l-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate;

4-cycloproρylmethyl- 1 - {2-[2'-hydroxy-3 '-( 1 H-pyrrolo[2,3 -c]pyridin-2-yl)-biphenyl- 4-yl]-acetyl} -piperidine-4-carboxylic acid;

4-amino-4-phenylmethyl- 1 - {2-[2'-hydroxy-3 '-(l//-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperidine;

4-hydroxy-4-(4-fluorophenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(Ii7-pyrrolo[3,2-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine; 2-diethylamino-ethyl 4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3^l-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate;

N^- dimethyl-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide;

4-(N,N-dimethylaminocarbonyl)-4-plienylmethyl-l-{2-[2'-liydroxy-3'-(li?- imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-(hydroxymethyl)-4-(4-fluorophenylmethyl)-l-{2-[2'-hydroxy-3^!-(lH^"-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piρeridine;

4-(hydroxymethyl)-4-(4-fluorophenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(Ii7-imidazo[4,5- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-(4-fluoro-ρhenylmethyl)- 1 - {2-[2'-hydroxy-3 '-( lH^"-ρyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperidine-4-carbonitrile;

4-(hydroxymethyl)-4-(cycloproρylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-ρiperidine; methyl 4-ρhenylmethyl-l - {2-[2'-hydroxy-3'-(lH-imidazo[4,5-c]ρyridin-2-yl)- biρhenyl-4-yl]-acetyl}-piperidine-4-carboxylate; methyl l-{2-[3'-(5,7-dihydro-4H-ρurin-8-yl)-2'-hydroxy-biρhenyl-4-yl]-acetyl}-4-(4- fluoro-phenylmethyl)-piperidine-4-carboxylate;

4-hydroxy-4-(3-trifluoromethylphenyl)-l-{2-[2'-hydroxy-3'-(li7-imidazo[4,5- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine; methyl 4-cyclopentylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyiτolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate; methyl l-{2-[2^l-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}- 4-isobutyl-piperidine-4-carboxylate;

4-(4-fluoro-phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(1 H-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidin-4-ylmethyl cyclopropanecarboxylate; methyl 4-(3,3-difluoro-allyl)-l-{2-[2^I-hydroxy-3'-(lH-pynOlo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate;

Ν-(4-(4-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidin-4-ylmethyl)-methanesulfonamide;

N-(4-(4-fluoro-ρhenylmethyl)-l-{2-[2^l-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidin-4-ylmethyl)-cyclopropanecarboxamide; methyl 1 - {2-[2'-hydroxy-3 '-( lH-pyrrolo[2,3 -c]pyridin-2-yl)-biphenyl-4-yl]-acetyl} - 4-(2,2,2-trifluoro-ethyl)-piperidine-4-carboxylate; 4-cyano-4-(cyclopropylmethyl)- 1 - {2-[2'-hydroxy-3 '-(17f-pyrrolo[2,3 -c]pyridin-2-yl)- biρhenyl-4-yl] -acetyl } -piperidine;

4-(aminocarbonyl)-4-(cyclopropylmethyl)-l-{2-[2'-hydroxy-3'-(li7-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-(N,N-dimethylamioncarbonyl)-4-(cyclopropylmethyl)-l-{2-[2'-hydroxy-3'-(lH- pyrrolo[2,3 -c]pyridin-2~yl)-biphenyl-4-yl]-acetyl} -piperidine l-{[2^l-hydroxy-3'-(l/f-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4-oxazol- 2-ylmethyl-piperidine-4-carboxylic acid; l-{[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4-oxazol- 2-ylmethyl~piperidme-4-carboxylic acid methyl ester;

1 - {[2'-hydroxy-3 '-(l/f-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl} - 4-phenylamino-ρiperidine-4-carbonitrile; l-{[2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}- 4-phenylamino-piperidine-4-carboxylic acid amide; l-{2-[2'-hydroxy-3'-(l//-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetyl}- 4-(4-fluorobenzyl)-4-aminomethyl-piperidine; l-{2-[2'-hydroxy-3'-(li7-ρyrrolo[2,3-c]pyridin-2-yl)-biρh.enyl-4-yl]-acetyl}- 4-(4-fluorobenzyl)-4-(2,2,2-trifluoro- 1 -hydroxyethyl)-ρiperidine;

(4-(4-fluoro-benzyl)- 1 - {[2'-hydroxy-3 '-( lH-pyrrolo[2,3 -c]ρyridin-2-yl)-biρhenyl- 4-yl]-acetyl} -piperidin-4-yl)-hydroxy-acetic acid;

4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(lH^"-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]- acetyl} -piperidine-4-carboxylic acid ethyl ester;

(4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(l//^'-pyrrolo[2₅3-c]ρyridin-2-yl)-biρhenyl- 4-yl]-acetyl}-piperidin-4-yl)-acetic acid methyl ester;

(4-(4-fluoro-benzyl)-l-{[2^l-hydroxy-3^I-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biρhenyl- 4-yl]-acetyl}-ρiperidin-4-yl)-hydroxy-acetic acid methyl ester;

(4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl]-acetyl} -ρiperidin-4-ylmethoxy)-acetic acid;

3-(4-(4-fluoro-benzyl)-l-{[2^t-hydroxy-3'-(l/-^'-ρyrrolo[2,3-c]ρyridin-2-yl)-biphenyl- 4-yl]-acetyl} -piperidin-4-yl)-3-hydroxy-propionic acid;

4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperidine-4-carboxylic acid 2-methoxy-ethyl ester;

4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperidine-4-carboxylic acid (2-methoxy-ethyl)-amide; 4-(4-fluoro-benzyl)- 1 - {[2'-hydroxy-3 '-(l#-pyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]- acetyl}-piperidine-4-carboxylic acid (2-hydroxy-l-hydroxymethyl-ethyl)-amide;

(4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl]-acetyl}-piperidin-4-ylmethoxy)-acetic acid ethyl ester;

(4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl- 4-yl]-acetyl}-piperidin-4-yl)-acetic acid 2-methoxy-ethyl ester;

3-(4-(4-fluoro-benzyl)-l-{[2^l-hydroxy-3^l-(l//-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl- 4-yl] -acetyl }-piperidin-4-yl)-3 -hydroxy-propionic acid ethyl ester;

4-[(4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl] -acetyl } -piperidine-4-carbonyl)-amino] -3 -hydroxy-butyric acid;

4-[(4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl]-acetyl}-piperidine-4-carbonyl)-amino]-(S)-2 -hydroxy-butyric acid;

2-dimethylamino-N-(4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-ρiperidin-4-ylmethyl)-acetamide;

4-(4-fluoro-benzyl)- 1 - {[2'-hydroxy-3 '-(lH-ρyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]- acetyl}-piperidine-4-carboxylic acid (2-dimethylamino-ethyl)-amide;

(ιS)-3-amino-N-(4-(4-fluoro-benzyl)-l-{[2^I-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidin-4-ylmethyl)-succinamic acid;

4-[(4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl- 4-yl]-acetyl}-piperidine-4-carbonyl)-amino]-(S)-2 -hydroxy-butyric acid methyl ester;

4-[(4-(4-fluoro-benzyl)-l-{[2^t-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin-2-yl)-biρhenyl- 4-yl]-acetyl}-piperidine-4-carbonyl)-amino]-3-hydiOxy-butyric acid methyl ester;

/V-(4-(4-fluoro-benzyl)- 1 - {[2'-hydroxy-3 '-(li7-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl]-acetyl}-piperidin-4-ylmethyl)-(S)-2-hydroxy-succinamic acid methyl ester; iV-(4-(4-fluoro-benzyl)- 1 - {[2'-hydroxy-3 '-(lH^"-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl- 4-yl]-acetyl}-piperidin-4-ylmethyl)-(R)-2-hydroxy-succinamic acid methyl ester; l-{[2'-hydroxy-3'-(l//-ρyrrolo[2,3-c]ρyridm-2-yl)-biρhenyl-4-yl]-acetyl}- 4-(4-fluorobenzyl)-4-(2-dimethylamino-ethoxymethyl)-piperidine;

N,N-Diethyl-2-(4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(lH-ρyrrolo[2₅3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidin-4-ylmethoxy)-acetamide;

4-(4-fluoro-benzyl)-l-{[2^l-hydiOxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperidine-4-carboxylic acid (2-diethylamino-ethyl)-amide; l-{[2'-hydroxy-3^!-(lH-pyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]-acetyl}- 4-(l-methyl-cyclopropylmethyl)-piperidine-4-carboxylic acid benzyl ester; 4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3^I-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]- acetyl}-piperidine-4-carboxylic acid 2-morpholin-4-yl-ethyl ester;

4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3^!-(l//-pyrrolo[2₅3-c]ρyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperidine-4-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;

4-(4-fluoro-benzyl)- 1 - {[2'-hydroxy-3 '-(lH-pyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]- acetyl} -piperidine-4-carboxylic acid (2-piperidin- 1 -yl-ethyl)-amide;

4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(lH^'-pyrrolo[2,3-c]pyridm-2-yl)-biphenyl-4-yl]- acetyl} -piperidine-4-carboxylic acid (lϋ/-tetrazol-5-yl)-amide; l-{[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetyl}-4-(4- fluorobenzyl)-4-[5-(trimethylsilanyl)-li7-[l,2,3]triazol-4-yl]-piperidine; l-{[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4-(4- fluorobenzyl)-4-(benzoxazol-2-ylaminomethyl)-piperidine;

4-(4-fluoro-benzyl)- 1 - {[2'-hydroxy-3 '-(3//-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4- ylJ-acetyl}-piperidine-4-carbonitrile; l-{[2^l-hydroxy-3'-(3H-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4-arnino-4- benzyl-piperidine;

4-benzyl-l-{[2'-hydroxy-3'-(3H-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}- piperidine-4-carboxylic acid;

4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(3/ir-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4- yl]-acetyl}-piperidine-4-carboxylic acid 2-diethylamino-ethyl ester;

4-(4-fluoro-benzyl)-l-{[2'-hydroxy-3'-(3H^"-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4- yl]-acetyl} -piperidine-4-carboxylic acid 2-morpholin-4-yl-ethyl ester;

1 - {[2'-hydroxy-3 '-(3//-imidazo[4,5-c]pyridin-2-yl)-biprienyl-4-yl]-acetyl} -4-(4- fluorobenzyl)-4-(5-methyl-2i7-[l,2,4]triazol-3-yl)-piperidine;

4-benzyloxy- 1 - {[2'-hydroxy-3 ^l-(3_Jy-imidazo[4,5-c]ρyridin-2-yl)-biρhenyl-4-yl]- acetyl } -pyrrolidine-2-carboxylic acid;

4-benzyloxy- 1 - {[2'-hydroxy-3 ^l-(3H^r-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -pyrrolidine-2-carboxylic acid methyl ester

4-benzyl- 1 - {[2'-hydroxy-3 '-(3//-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl} - piperazine-2-carboxylic acid;

1 -benzyl-4- {[2'-hydroxy-3 '-(3//-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl} - piperazine-2-carboxylic acid; and l-benzyl-4-{[2^l-hydroxy-3'-(3//-imidazo[4,5-c]pyridin-2-yl)-biρhenyl-4-yl]-acetyl}- piperazine-2-carboxylic acid methyl ester. Another selected group of compounds of the invention are provided in Table 2, having Formula I

where R¹, R², and R³ are hydrogen; and R¹⁰⁰ is

(Al) where R^4a, R^4b, R⁸, and R⁹ are hydrogen; L is -X'-Y^Z¹- where X¹ is -CH₂-, Y¹ is -C(O)-, and Z¹ is a bond; and all other groups are as defined below: Table 2.

1 -yl

W 2

and are named as:

4-(2-fluoroρhenylmethyl)-l-{2-[2^t-hydroxy-3'-(lH-pyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperazine;

4-(phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(l//-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -3,6-dihydro-2H-pyridine;

4-(ρhenyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biρhenyl-4-yl]- acetyl } -piperazine;

4-(l -methylbutyl)- 1 - {2-[2'-hydroxy-3'-(lH^"-pyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4- yl]-acetyl} -piperazine;

4-ethyl-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetyl}- piperazine;

4-(pyridin-4-yl)-l-{2-[2'-hydroxy-3^l-(lH^"-pyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-yl]- acetyl } -piperazine;

4-(isopropyl)-l-{2-[2^l-hydroxy-3'-(lH-ρyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl } -piperazine;

4-(phenylmethyl)-l-{2-[2'-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl } -piperazine;

4-[(thien-2-yl)methyl]-l-{2-[2^I-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl] -acetyl } -piperazine;

4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-ρyπOlo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

4-(4-chloro-ρhenylmethyl)-l-{2-[2'-hydroxy-3^t-(lH^r-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

4-(2-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3^l-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

4-[(thien-2-yl)methyl]- 1 - {2-[2'-hydroxy-3 '-(lH-pyrrolo[3 ,2-c]pyridin-2-yl)-biphenyl- 4-yl] -acetyl } -piperazine;

4-phenylmethyl-l-{2-[2'-hydroxy-3^I-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl}-piperazine;

4-(4-chlorophenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(l//-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-[(thien-3-yl)methyl]-l-{2-[2^I-hydroxy-3'-(l//-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl- 4-yl] -acetyl } -piperazine;

4-(3-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH^'-ρyrrolo[3_:,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(3-chloro-phenylmethyl)-l-{2-[2^!-hydroxy-3^l-(lH-ρyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(4-methylpyridin-2-yl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3_J2-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

4-[2-(thien-2-yl)ethyl]-l-{2-[2'-hydroxy-3^l-(lJ/-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl- 4-yl]-acetyl} -piperazine;

4-(4-fluorophenylmethyl)-l-{2-[2'-hydroxy-3^I-(lH-ρyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(2-chloro-4-fluorophenylmethyl)-l-{2-[2'-hydroxy-3^l-(liJ-ρyrrolo[3,2-c]pyridin-2- yl)-biphenyl-4-yl]-acetyl}-piρerazine;

4-(2-chlorophenylmethyl)-l-{2-[2^!-hydroxy-3^l-(lH-ρyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(3 -carboxyphenylmethyl)- 1 - {2- [2'-hydroxy-3 '-( 1 H-pyrrolo [3 ,2-c]pyridin-2-yl)- biρhenyl-4-yl]-acetyl}-piperazine;

4-(2-methylρhenylmethyl)- 1 - {2-[2'-hydroxy-3 ^?-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

4-(phenethyl)-l-{2-[2^l-hydroxy-3^l-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl } -piperazine;

4-(ρyridin-4-ylmethyl)-l-{2-[2'-liydroxy-3'-(l_JH-ρyrrolo[3,2-c]ρyridin-2-yl)-biphenyl- 4-yl] -acetyl} -piperazine;

4-(pyridin-3-ylmethyl)-l-{2-[2'-hydroxy-3'-(l/i-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl- 4-yl] -acetyl } -piperazine;

4-(phenylaminocarbonyl)-l-{2-[2'-hydroxy-3'-(li^:/-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

4-(pyridin-2-yl)- 1 - {2-[2'-hydroxy-3 '-(lH-pyrrolo[3 ,2-c]pyridin-2-yl)-biphenyl-4-yl] - acetyl } -piperazine;

4-(3-methoxycarbonylphenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin- 2-yl)-biphenyl-4-yl] -acetyl } -piperazine;

4-(3-methylρyridin-2-yl)-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]pyiidin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(4-fluorophenylaminocarbonyl)- 1 - {2-[2'-hydroxy-3 '-( l//-pyrrolo[3 ,2-c]pyridin-2- yl)-biphenyl-4-yl]-acetyl}-piperazine;

4-isobutyl-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[3₅2-c]pyridm-2-yl)-biplienyl-4-yl]- acetyl } -piperazine;

4-(ρhenylthiomethylcarbonyl)-l-{2-[2^l-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(ρhenylmethyl)-l-{2-[2'-hydroxy-3^t-(lH-pyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-yl]- acetyl} -homopiperazine;

4-(3,4-dichloro-ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(lH^"-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(4-fluoro-phenyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4- yl]-acetyl}-piperazine;

4-(p3^dm-2-ylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl- 4-yl] -acetyl } -piperazine;

4-(cyclohexylmethyl)-l-{2-[2'-hydroxy-3'-(lH^"-ρyrrolo[3,2-c]ρyridin-2-yl)-biphenyl- 4-yl] -acetyl} -piperazine;

4-(isopentyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperazine;

4-(isopropylaminocarbonyl)- 1 - {2-[2'-hydroxy-3 '-( l.H-pyrrolo[3 ,2-c]pyridin-2-yl)~ biphenyl-4-yl]-acetyl}-piperazine;

4-(l-phenyl-eth-l-yl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridm-2-yl)-biphenyl- 4-yl] -acetyl } -piperazine;

4-(phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(4-chloro- lϋT-pyrrolo[3 ,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-φhenylmethyl)-l-{2-[2'-hydroxy-3^t-(6-chloro-lH-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(2-oxo-l,3-dihydro-benzoimidazol-l-yl)-l-{2-[2^t-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl] -acetyl } -piperidine;

4-(2-methyl-benzoimidazol- 1 -yl)- 1 - {2-[2'-hydroxy-3 '-( lH-pyrrolo[2,3 -c]ρyridin-2- yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-(phenylcarbonyl)-l-{2-[2^l-hydroxy-3^l-(lH^"-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4- yl]-acetyl}-piperidine;

4-(phenoxy)-l-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperidine;

4-( 1 -hydroxy- 1 -phenyl-methyl)- 1 - {2-[2'-hydroxy-3 '-( 1/f-ρyrrolo [3 ,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine;

4-hydroxy-l-{2-[2'-hydroxy-3^I-(lH^"-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl } -piperidine;

4-phenylmethyl-l-{2-[2'-hydroxy-3'-(l/f-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperidine;

4-(3,4-difluorophenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]ρyridin-2-yl)- W

biphenyl-4-yl] -acetyl } -piperidine;

4-(benzoimidazol-l-yl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidine;

4-(thieno[3,2-d]pyrimidin-7-yl)-l-{2-[2'-hydroxy-3'-(l//-pyrrolo[2,3-c]pyridm-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

4-(2-methyl-pyridin-5-yl)-l-{2-[2'-hydroxy-3^I-(lH^"-pyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-[2-(moφholin-4-yl)-ethyl]-l-{2-[2'-hydroxy-3'-(lH:-pyrrolo[2,3-c]pyridm-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(pyridin-4-yl)-l-{2-[2^I-hydroxy-3'-(l_JH-ρyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]- acetyl } -piperazine;

4-(phenylaminocarbonyl)- 1 - {2-[2'-hydroxy-3 '-( lH-pyrrolo[2,3 -c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(pyridin-2-ylaminocarbonylmethyl)-l-{2-[2'-hydroxy-3'-(lJ/^:-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl] -acetyl} -piperazine;

4-( 1 -phenyl-eth- 1 -yl)- 1 - {2-[2'-hydroxy-3 '-( lH-pyrrolo [2,3-c]pyridin-2-yl)-biρhenyl- 4-yl]-acetyl} -piperazine;

4-(ethylaminocarbonyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

3-(4-chloro-ρhenylmethyloxy)-l-{2-[2^l-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl} -pyrrolidine;

4-[N-(ethylcarbonyl)-N-phenyl-amino]-l-{2-[2^I-hydroxy-3^l-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-(cyclopentanecarbonyl)-l-{2-[2'-hydroxy-3'-(liJ-pyrrolo[2,3-c]pyridin-2-yl)- biρhenyl-4-yl] -acetyl } -piperazine;

4-(methoxyethyloxycarbonylmethyl)-l-{2-[2^l-hydroxy-3^l-(l//-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

1 -[3 '-(5-amino- lH-pyrrolo[2,3-c]pyridin-2-yl)-2'-hydroxy-biρhenyl-4-yl]-4-(4- fluorobenzyl)-4-oxy-piperazine;

(^N-Cl-benzyl-pyrrolidin-S-yO^-P'-hydroxy-S'-ClH-pyrrolop^-cJpyridin^-yl)- biphenyl-4-yl] -acetamide;

(,S)iV-(l-benzyl-ρyrrolidin-3-yl)-2-[2^l-hydroxy-3^I-(lH-pyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl] -acetamide; l-{2-[2'-hydroxy-3'-(lH^"-ρyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]-acetyl}-4- (pyridin-2-ylmethyl)-piperazine; l-{2-[2^l-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4-benzyl- 4-oxy-piperazine; l-{2-[2'-hydroxy-3'-(l/f-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetyl}-4-(4- fluorobenzyl)-4-oxy-piperazine; l-{2-[2^l-hydroxy-3^t-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetyl}-4-benzyl- piperidine; l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4- phenethyl-piperazine l-{[2^l-hydroxy-3'-(3H-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4- phenylsulfonyl-piperazine; l-{[2'-hydroxy-3'-(3H^"-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4-(pyridin- 2-ylmethyl)-piperazine; l-{[2'-hydroxy-3'-(3H-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4-benzyl- piperazine; l-{[2'-hydroxy-3'-(3H-imidazo[4₅5-c]ρyridin-2-yl)-biphenyl-4-yl]-acetyl}-4-(4- chlorobenzyl)-piperazine; l-{[2'-hydroxy-3'-(3H^"-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4-(4- fluorobenzyl)-piperazine;

4-carboxy-{[2^l-hydroxy-3'-(lϋr-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}- piperidine;

4-(N,N-dimethylaminocarbonyl)- { [2'-hydroxy-3 '-( lH-pyrrolo [2,3 -c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

4-(cyclopropylaminocarbonyl)-{[2'-hydroxy-3'-(liJ-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperidine;

4-(cyclopropylmethylaminocarbonyl)-{[2^l-hydroxy-3'-(l_JH-pyrrolo[2,3-c]pyridin-2- yl)-biphenyl-4-yl] -acetyl } -piperidine;

4-(cyclopropylmethyloxycarbonyl)-{[2'-hydroxy-3'-(5-amino-lH-pyrrolo[2,3- c]ρyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-(piperidinylcarbonyl)-{[2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl] -acetyl} -piperazine; and l-{[2'-hydroxy-3^!-(li7-pyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetyl}-4- (benzoxazol-2-yl)-piperazine. Another selected group of compounds of the invention are provided in Table 3, having Formula I

where R ι l , τ R>2 , and Ic are hydrogen; D is — = rC-<rR>⁶ - where R is hydrogen; and R , 1¹0^U0 . is

(Al) where R >4a , τ R)4b , R r> 8 , and R are hydrogen; L is -X Λ- ΛYZI-Z τl-; and all other groups are as defined below:

Table 3.

and are named as:

2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-iV-(3-pyrrolidin-l-yl- propyl)-acetamide; iV-(l-phenylmethyl-pyrrolidm-3-yl)-2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetamide; iV^'-[2'-hydroxy-3^l-(lH^"-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-ylmethyl]-4- phenylmethyl-piperazine- 1 -carboxamide;

4-ρhenyl-4-oxo-l-{2-[2^l-hydroxy-3^l-(lH-ρyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -4λ⁵-[ 1 ,4] azaphosphinane;

4-methyl-4-oxo-l-{2-[2'-hydroxy-3'-(l/f-pyπOlo[3,2-c]pyridm-2-yl)-biphenyl-4-yl]- acetyl } -4λ⁵-[ 1 ,4] azaphosphinane;

1 - {2-[2'-hydroxy-3 ^l-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]-dimethylacetyl} - 4-benzyl-piperazine;

4-(cyclopropylmethyl)-4-oxo-l-{2-[2'-hydroxy-3^l-(lΗ-ρyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl }-4λ⁵-[l ,4]azaphosphinane; and

4-(4-fluorobenzyl)-4-oxo-l-{2-[2'-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl} -4λ⁵-[ 1 ,4] azaphosphinane.

Another selected group of compounds of the invention are provided in Table 4, having Formula I

where R¹, R , and R are hydrogen; D is

a „—nd,4 R n lO ^uO^u is

(Al) where R ₁ ⁴4^aa, R r>^w 4b, and R^y are hydrogen; L is -X'-Y'-Z¹-; and all other groups are as defined below:

Table 4.

and are named:

N-[2'-Hydroxy-3'-(lH-pyrrolo[3,2-c]ρyridin-2-yl)-biphenyl-4-ylmethylcarbonyl]-l,3- dihydrospiro(indene-2,4-piperidine);

N-[2^I-Hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-ylmethylcarbonyl]-l,3- dihydrospiro(indene-2,4-piρeridine); 3-ethyl-l-(methoxycarbonyl)-8-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-2-oxa-8-aza-spiro[4.5]decatie;

3(i2)-ethyl-l(Λ)-(methoxycarbonyl)-8-{2-[2^I-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2- yl)-biphenyl-4-yl]-acetyl}-2-oxa-8-aza-sρiro[4.5]decane; and

3 -ethyl- 1 -(carboxy)-8- {2-[2'-hydroxy-3 '-(lH^"-ρyrrolo[2,3 -c]ρyridin-2-yl)-biρhenyl-4- yl]-acetyl}-2-oxa-8-aza-spiro[4.5]decane.

Another selected group of compounds of the invention are provided in Table 5, having Formula I

where R .1 , R n2 , and R are hydrogen; D is =CR - where R is hydrogen; and R is

(Al) where R >4a^a, τ Rj4b , R r>8 , and R are hydrogen; L is -X -; and all other groups are as defined below:

Table 5.

Cmpd.

A Het R⁷

No. XT

N

309 CH₂CH₂ f-N N— I phenylmethyl

N *

310 CH₂CH₂ f-N N-? 4-fluorophenyl

and are named as:

4^l-[2-(4-phenylmethyl-piperazin-l-yl)-ethyl]-3-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-2-ol; and

4'-{2-[4-(4-Fluoro-ρhenyl)-ρiρerazin-l-yl]-ethyl}-3-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-2-ol. Another selected group of compounds of the invention are provided in Table 6, having Formula I

where R¹, R², and R³ are hydrogen; D is =€R⁶- where R⁶ is hydrogen; and R¹⁰⁰ is

(Al) where R ₁4a^a, R r> 4b , R , and R are hydrogen; L is -Y -Z -; and all other groups are as defined below:

Table 6.

Cmpd.

A Y² Z²

No. Het R⁷

311 NHC(O) CH₂ phenylmethyl

and is named as 2-(4-phenylmethyl-piperazin-l-yl)-N-[2'-hydroxy-3'-(l/J-pyrrolo[3,2- c]pyridin-2-yl)-biphenyl-4-yl]-acetamide.

Another selected group of compounds of the invention are provided in Table 7, having Formula I

where R¹, R², and R³ are hydrogen; and R¹⁰⁰ is

(Al) where and R are hydrogen; L is -Y /2 -Z τ-2 -; and all other groups are as defined below: Table 7.

and are named as:

4-(phenylmethyl)-4-hydroxy-l-{2-[5'chloro-2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl} -piperidine; and methyl l-{2-[5'-chloro-2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]- acetyl}-4-(4-fluoro-phenylmethyl)-piperidine-4-carboxylate.

Another selected group of compounds of the invention are provided in Table 8, having Formula I:

where R , 1 , R t>2 , and R^ are hydrogen; and R 100 ^υ is W

(A2) where R^4a and R^4b are hydrogen, R⁵ is X^12a-Y¹²-X^12b-Q¹², and all other groups are as defined below: Table 8.

and are named:

2-[2'-hydroxy-3^l-(lH^"-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-N-(3-phenyl- propyl)-acetamide;

2- {2'-hydroxy-3 '-[5-(5-methyl-[ 1 ,2₅4]oxadiazol-3-yl)- l//-indol-2-yl]-biphenyl-4-yl} - N-(3 -phenyl-propyl)-acetamide;

2-[3'-(4-chloro-l//-pyrrolo[3,2-c]pyridin-2-yl)-2'-hydroxy-biphenyl-4-yl]-iV-(3- phenyl-propyl)-acetamide;

2-[3'-(6-chloro-l_Jf/-pyrrolo[3,2-c]pyridin-2-yl)-2^l-hydroxy-biphenyl-4-yl]-N-(3- phenyl-proρyl)-acetamide;

3-phenylmethyloxy-2-{2-[2'-hydroxy-3'-(li7-iniidazo[4,5-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino} -propionic acid;

3-phenylmethyloxy-2-{2-[2'-hydroxy-3'-(lH-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino}-propionic acid methyl ester;

2-{2-[2'-hydroxy-3'-(lH^'-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-4- phenyl-butyric acid; 2-{2-[2'-hydroxy-3'-(l/J-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetylainino}-5- phenyl-pent-4-enoic acid ethyl ester;

2-{2-[2'-hydroxy-3'-(liϊ-iniidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-5- phenyl-pent-4-enoic acid;

2-{2-[2'-hydroxy-3'-(li?-iniidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-5- phenyl-pentanoic acid ethyl ester;

2-(2-{2-[2^I-hydroxy-3^I-(lH-imidazo[4,5-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetylamino}- ethoxy)-benzoic acid];

2-{2-[2'-hydroxy-3^l-(l/i-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-5- phenyl-pentanoic acid;

2-{2-[3'-(5-amino-l/i-ρyrrolo[2,3-c]ρyridin-2-yl)-2'-hydroxy-biρhenyl-4-yl]- acetylamino}-5-phenyl-pentanoic acid ethyl ester;

2-{2-[3'-(5-amino-l/f-pyrrolo[2,3-c]pyridin-2-yl)-2'-hydroxy-biphenyl-4-yl]- acetylamino}-5-phenyl-pentanoic acid; and

2-{2-[3^!-(3-chloro-lH-pyrrolo[2,3-c]ρyridin-2-yl)-2'-hydroxy-biphenyl-4-yl]- acetylamino}-3-methyl-3-phenylmethanesulfonyl-butyric acid methyl ester.

Another selected group of compounds of the invention are provided in Table 9, having Formula I:

where R¹, R², and R³ are hydrogen; D is =CR⁶- wherein R⁶ is hydrogen; and R¹⁰⁰ is

(A2) where R^4a and R^4b are hydrogen; and R⁵ is -Y^X¹¹-^)¹¹; and all other groups are as defined below: Table 9.

and are named as follows:

5-thiophen-2-yl-pentanoic acid [2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -amide; iV-[2^t-hydroxy-3^l-(l/f-ρyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-yl]-3-ρhenyl- propionamide;

2-hydroxy-N-[2'-hydroxy-3'-(lH^r-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-3-phenyl- propionamide; iy-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-4-phenoxy- butyramide;

1 -phenylmethyl-3 - [2'-hydroxy-3 '-(1 H-pyrrolo [3 ,2-c]pyridin-2-yl)-biphenyl-4-yl] - urea; iV-[2^I-hydroxy-3'-(lH^'-pyrrolo[3,2-c]pyridm-2-yl)-biphenyl-4-yl]-3-phenoxy- propionamide; iV-[2^l-hydroxy-3'-(li7-ρyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-yl]-3-phenyl- acrylamide; l-[2'-hydroxy-3'-(lH-pyrrolo[3₅2-c]pyridin-2-yl)-biphenyl-4-yl]-3-phenethyl-urea; quinoline-3-carboxylic acid [2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl- 4-yl] -amide;

[2^l-hydroxy-3'-(lH^'-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-carbamic acid benzyl ester; biphenyl-4-carboxylic acid [2'-hydroxy-3^l-(lΗ-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl- 4-yl] -amide;

3-phenylmethyloxy-2-{[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- carbonyl]-amino}-propionic acid methyl ester; and

2'-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-carboxylic acid (2 -hydroxy- 3 -phenoxy-propyl)-amide.

Another selected group of compounds of the invention are provided in Table 10, having Formula I:

where R , 1 , R r>2 , and R are hydrogen; D is =CR - wherein R is hydrogen; the A ring is a fused pyrido ring; and R¹⁰⁰ is

(A2) where R^4a and R^4b are hydrogen, R⁵ is X^12a-Y¹²-X^12b-Q¹², and all other groups are as defined below: Table 10.

are named as follows:

3-phenylmethyloxy-2-{2-[2^l-hydroxy-3'-(l/f-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino}-propionic acid;

3-phenylmethyloxy-2-{2-[2^l-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino}-propionic acid methyl ester;

(R)-2-{2-[2'-hydroxy-3^I-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]-acetylamino}- 4-phenyl-butyric acid methyl ester;

(6)-2-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}- 4-ρhenyl-butyric acid methyl ester; 2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-4- phenyl-butyric acid;

2-{2-[2^l-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]-acetylamino}-5- phenyl-pent-4-enoic acid ethyl ester;

N-hydroxy-2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-iV^'-(3- phenyl-propyl)-acetamide;

2-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biρlienyl-4-yl]-acetylamino}-3- (indan-2-ylamino)-propionic acid methyl ester;

3-(benzoxazol-2-ylamino)-2-{2-[2'-hydroxy-3'-(l/J-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetylamino} -propionic acid methyl ester;

2-(2-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}- acetylamino)-3-phenyl-propionic acid methyl ester; and

2-{2-[2^l-hydroxy-3'-(lH-pyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetylamino}-3- (lH-indol-3-yl)-propionic acid methyl ester.

Another selected group of compounds of the invention are provided in Table 11, having Formula I:

where R¹, R², and R³ are hydrogen; D is =CR⁶- wherein R⁶ is hydrogen; the A ring is a fused pyrido ring; and R¹⁰⁰ is

(A2) where R^4a and R^4b are hydrogen, R⁵ is X^12a-Y¹²-X^12b-Q¹² ₅ and all other groups are as defined below: Table 11.

and are named:

2- {2- [2'-hydroxy-3 '-( lH-pyrrolo [3 ,2-c]pyridin-2-yl)-biphenyl-4-yl] -acetylamino } -A- phenyl-butyric acid methyl ester;

(5)-2-{2-[2^I-hydroxy-3'-(lH-ρyrrolo[3₅2-c]ρyridin-2-yl)-biphenyl-4-yl]-acetylamino}- 4-phenyl-butyric acid methyl ester; 3-phenylmethyloxy-2-{2-[2'-hydroxy-3^l-(lH^'-ρyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino} -propionic acid methyl ester;

3-phenylmethyloxy-2-{2-[2'-hydroxy-3^l-(lH-ρyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino}-propionic acid;

2-{2-[2'-hydroxy-3'-(l/f-ρyrrolo[3,2-c]pyridin-2-yl)-biρhenyl-4-yl]-acetylamino}-4- phenyl-butyric acid methyl ester;

2-[2^I-hydroxy-3'-(l//-ρyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-N-(3-ρhenyl-allyl)- acetamide;

3-{2-[2^l-hydroxy-3^l-(l//-ρyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetylamino}-5- phenyl-pentanoic acid methyl ester;

2-{2-[2'-hydroxy-3^l-(l/J-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-4- phenyl-butyric acid; iV-[2-(4-fluoro-phenoxy)-ethyl]-2-[2'-hydroxy-3'-(lH^"-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetamide;

2-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biρhenyl-4-yl]-acetylamino}-4- phenyl-butyric acid;

N-[2-(benzooxazol-2-ylamino)-ethyl]-2-[2'-hydroxy-3^I-(lΗ-pyrrolo[3,2-c]pyridin-2- yl)-biphenyl-4-yl] -acetamide; l-[2'-hydroxy-3'-(l_JH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-ylmethyl]-3-phenethyl- urea;

2-{2-[2^l-hydroxy-3'-(lH-pyrrolo[3₅2-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetylamino}-3- naphthalen-2-yl-propionic acid;

2-{2-[2^l-hydroxy-3^I-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-3- naphthalen-2-yl-propionic acid methyl ester;

2-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-4- phenyl-butyric acid;

N-[2-(l,3-dihydro-isomdol-2-yl)-ethyl]-2-[2'-hydroxy-3'-(l//-pyrrolo[3,2-c]ρyridin-2- yl)-biphenyl-4-yl]-acetamide;

2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-yl]-iV-(2-ρhenoxy-ethyl)- acetamide;

2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)-biphenyl-4-yl]-iV-(2-phenyl- cyclopropyl)-acetamide;

2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)-biphenyl-4-yl]-7V-(2-phenyl- cyclopropylmethyl)-acetamide; 2-{2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetylamino}-4- phenyl-butyric acid;

2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]pyridm-2-yl)-biphenyl-4-yl]-iV-(l-metliyl-3- phenyl-propyl)-acetamide;

2-(2-{2-[2'-hydroxy-3'-(li-^r-pyrrolo[3,2-c]ρyridin-2-yl)-biphenyl-4-yl]-acetylamino}- ethoxy)-benzoic acid methyl ester;

4-ρhenyl-but-3-enoic acid [2'-hydroxy-3'~(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4- ylmethyl] -amide;

2-(2-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-acetylammo}- ethoxy)-benzoic acid; iV-(3,4-dichloro-ρhenylmethyl)-2-[2'-hydroxy-3'-(lH^r-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetamide; iV^"-[2-(3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-2-[2'-liydroxy-3^I-(lH-pyrrolo[3,2- c]pyridin-2-yl)-biphenyl-4-yl]-acetamide;

N-[3-(lH-benzoimidazol-2-yl)-propyl]-2-[2'-hydroxy-3^l-(lH-pyrrolo[3,2-c]pyridin-2- yl)-biphenyl-4-yl]-acetamide;

N-(2-dimethylamino-ethyl)-2-(2-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetylamino}-ethoxy)-benzamide;

N-[2^l-hydroxy-3'-(l/f-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-ylmetliyl]-4-phenyl- butyramide;

N- [2'-hydroxy-3 '-( liJ-pyrrolo [3 ,2-c]pyridin-2-yl)-biphenyl-4-ylmethyl] -4-phenoxy- butyramide;

2- {2-[2'-hydroxy-3 '-( 1/f-pyrrolo [3 ,2-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino } -3 - phenyl-propionic acid methyl ester;

2-(2-{2-[2^l-hydroxy-3^l-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetylamino}- ethoxy)-JV-(2-piperidin- 1 -yl-ethyl)-benzamide;

2-[2'-hydroxy-3^l-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-N-[2-(lH-indol-3- yl)-ethyl]-acetamide;

N-(2-phenylmethyloxy-cyclopentyl)-2-[2'-hydroxy-3'-(l/i-pyrrolo[3,2-c]pyridin-2- yl)-biphenyl-4-yl] -acetamide;

2-[2'-hydroxy-3^l-(lH-pyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-yl]-N-[2-(4-methyl- [l,2,3]thiadiazol-5-ylsulfanyl)-ethyl]-acetamide;

2-(2- {2-[2'-hydroxy-3 ^!-(lH-ρyrrolo[3₅2-c]ρyridin-2-yl)-biρhenyl-4-yl] -acetylamino } - ethoxy)-benzamide; 2-{2-[2'-hydroxy-3'-(lH^'-pyrrolo[3,2-c]ρyridin-2-yl)-biphenyl-4-yl]-acetylamino}-3- naphthalen-2-yl-propionic acid methyl ester;

2-[2^t-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)-biphenyl-4-yl]-N-(3-iinidazol-l-yl- propyl)-acetamide;

N-[2-(3,4-dichloro-ρhenyl)-ethyl]-2-[2'-hydroxy-3'-(li/-pyrrolo[3,2-c]ρyridm-2-yl)- biρhenyl-4-yl] -acetamide;

2-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-3- naphthalen-2-yl-propionic acid;

2-[2'-hydroxy-3^t-(liJ-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-N-(2-pyridin-4-yl- ethyl)-acetamide;

2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-iV-(2-thiophen-2-yl- ethyl)-acetamide;

2-(4-aminomethyl-phenyl)-oxazole-4-carboxylic acid [2'-hydroxy-3'-(li7-pyrrolo[3,2- c]pyridin-2-yl)-biphenyl-4-ylmethyl]-amide;

3 -amino-iV-[2'-hydroxy-3 '-(lH-pyrrolo[3 ,2-c]pyridin-2-yl)-biphenyl-4-ylmethyl] -3 - phenyl-propionamide;

N-[2-(3-bromo-phenyl)-ethyl]-2-[2'-hydroxy-3'-(lH^"-ρyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetamide;

2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-N-(2-pyridin-2-yl- ethyl)-acetamide;

2-[2'-hydroxy-3'-(17iT-pyrrolo[3,2-c]pyridm-2-yl)-biphenyl-4-yl]-iV-thiophen-2- ylmethyl-acetamide;

N-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethyl]-2-[2^!-hydroxy-3^t-(l/f-pyrrolo[3,2- c]pyridin-2-yl)-biphenyl-4-yl]-acetamide;

N-[2'-hydroxy-3^t-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-ylmethyl]-3-(lH-indol- 3-yl)-propionamide; and

2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-iV-(3-phenyl-propyl)- acetamide.

Another selected group of compounds of the invention are provided in Table 12, having Formula I:

where R¹ and R² are hydrogen; D is =CR⁶- wherein R⁶ is hydrogen; the A ring is a fused pyrido ring; and R¹⁰⁰ is

(A2) where R^4a and R^4b are hydrogen, R⁵ is X^12a-Y¹²-X^12b-Q¹², and all other groups are as defined below: Table 12.

and is named 7V-[3-(4-fluoro-phenyl)-proρyl]-2-[2'-hydroxy-5'-[(2-mercaρto-ethylcarbamoyl)- methyl]-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-acetamide.

Another selected group of compounds of the invention are provided in Table 13, having Formula I:

(A2) where R^4a and R^4b are hydrogen, R⁵ is X^12a-Y¹²-X^12b-Q¹², and all other groups are as defined below: Table 13.

and are named:

2-{2-[2^I-hydroxy-3'-(lH-ρyrrolo[2₅3-c]ρyridin-2-yl)-biρhenyl -4-yl] -acetylamino } -4- phenyl-butyric acid;

2-{2-[2'-hydroxy-3^!-(li7-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl -4-yl] -acetylamino } -3 - phenylmethanesulfonyl-propionic acid methyl ester; 2-{2-[2'-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-4- phenyl-but-3-enoic acid;

2-{2-[2'-hydroxy-3'-(lH^'-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}- l,2,3,4~tetrahydro-naphthalene-2-carboxylic acid methyl ester;

{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}- indan-1-yl-acetic acid methyl ester;

N-[3-(4-chloro-phenyl)-l-cyano-propyl]-2-[2'-hydroxy-3'-(lJ/-pyrrolo[2,3-c]pyridin- 2-yl)-biρhenyl-4-yl] -acetamide;

3-phenylmethyloxy-2-{2-[2'-hydroxy-3'-(l/i^"-pyrrolo[2₃3-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino-N-methyl-propionamide;

3-{2-[2^l-hydroxy-3^l-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-5- phenyl-pentanoic acid methyl ester;

2-{2-[2^t-hydroxy-3^l-(liJ-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-3- naphthalen-2-yl-propionic acid methyl ester;

2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]-N-(3-phenyl-allyl)- acetamide;

3-{2-[2'-hydroxy-3'-(liϊ-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-5- phenyl-pentanoic acid;

N-[3-(4-chloro-phenyl)-l-(l/J-tetrazol-5-yl)-propyl]-2-[2¹-hydroxy-3'-(lH^"- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetamide;

2-{2-[2^l-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-3- naphthalen-2-yl-propionic acid;

2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]-acetylamino}-4- (4-methoxy-ρhenyl)-butyric acid methyl ester;

2-{2-[2'-hydroxy-3'-(liy-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-4- (4-methoxy-phenyl)-butyric acid;

N-[2-(4-fluoro-phenoxy)-ethyl]-2-[2^I-hydroxy-3^I-(lH^r-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetamide;

N-[2-(benzoxazol-2-ylamino)-ethyl]-2-[2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]ρyridin-2- yl)-biphenyl-4-yl] -acetamide;

N-(2-hydroxy-3-phenoxy-propyl)-2-[2'-hydroxy-3'-(li-^r-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetamide;

2-{2-[2^l-hydroxy-3'-(l//-ρyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]-acetylamino}-4- phenoxy-butyric acid ethyl ester; 2-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]-acetylamino}-5- phenoxy-pentanoic acid ethyl ester;

2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]-acetylamino}-4- phenyl-N-[l,3,4]thiadiazol-2-yl-butyramide;

2-{2-[2'-hydroxy-3'-(lH^'-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-4- phenoxy-butyric acid;

2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-5- phenoxy-pentanoic acid;

2-{2-[2^l-hydroxy-3^l-(l/f-ρyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-4- phenyl-N-thiazol-2-yl-butyramide;

2-{2-[2^l-hydroxy-3'-(lJf-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylammo}-4- phenyl-butyric acid methyl ester;

4-(4-chloro-phenyl)-2-{2-[2'-hydroxy-3^I-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino}-butyric acid methyl ester;

4-(4-fluoro-phenoxy)-2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl]-acetylamino}-butyric acid ethyl ester;

4-(4-chloro-phenyl)-2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino}-butyric acid;

4-(4-fluoro-phenoxy)-2-{2-[2^l-hydroxy-3'-(l/i-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl]-acetylamino} -butyric acid;

2-{2-[2'-hydroxy-3'-(lH^'-pyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]-acetylamino}-5- phenyl-pentanoic acid ethyl ester;

2-{2-[2^l-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-5- phenyl-pentanoic acid;

3 -cyclopropylmethylsulfanyl-2- {2- [2'-hydroxy-3 '-( l//-pyrrolo[2,3 -c]pyridin-2-yl)- biphenyl-4-yl]-acetylamino} -propionic acid methyl ester;

3-cyclopropylmethanesulfonyl-2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetylamino} -propionic acid methyl ester;

2-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-2-methyl- propionylamino } -5-phenyl-pentanoic acid;

3-cyclopropylmethylsulfanyl-2-{2-[2^I-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetylamino } -propionic acid;

3-Cyclopropylmethanesulfonyl-2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl] -acetylamino } -propionic acid; 3-cyclopropylmethoxy-2-{2-[2'-hydroxy-3'-(lH^'-pyrrolo[2,3-c]ρyridin-2-yl)-biphenyl- 4-yl]-acetylamino} -propionic acid methyl ester;

3-cyclopropylmethoxy-2-{2-[2'-hydroxy-3'-(lH^'-pyrrolo[2,3-c]ρyridin-2-yl)-biphenyl- 4-yl]-acetylamino} -propionic acid;

2-[2^l-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]-iV-[4-phenyl-l- (2,2,2-trifluoro- 1 -hydroxy~ethyl)-butyl]-acetamide;

3-(cyclopropylmethyl-amino)-2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetylamino} -propionic acid methyl ester;

N-(2-hydroxy-4-ρhenyl-butyl)-2-[2'-hydroxy-3'-(l/i-ρyrrolo[2,3-c]ρyridm-2-yl)- biphenyl-4-yl]-acetamide;

3-(cyclopropylmethyl-amino)-2-{2-[2'-hydroxy-3'-(liϊ-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetylamino } -propionic acid;

N-cycloρropyl-2-{2-[2^l-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetylamino-succinamic acid;

4-phenylmethyloxy-2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4- yl]-acetylamino-butyric acid methyl ester;

3-[N-(cyclopropylmethyl)-7V-methyl-ammo]-2-{2-[2'-hydroxy-3'-(l/J-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino} -propionic acid methyl ester;

4-phenylmethyloxy-2-{2-[2'-hydroxy-3'-(l/J-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl] -acetylamino} -butyric acid;

3-cyclobutylmethoxy-2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl]-acetylamino-propionic acid methyl ester;

3-phenylmethyloxy-2-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino-butyric acid methyl ester;

3-cyclobutylmethoxy-2-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl]-acetylamino} -propionic acid;

3-ρhenylmethyloxy-2-{2-[2^l-hydroxy-3'-(li7-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4- yl] -acetylamino} -butyric acid;

3-benzylsulfanyl-2-{2-[2^l-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]- acetylamino} -3 -methyl-butyric acid methyl ester;

3-[N-(cycloρroρylmethyl)-N-methyl-amino]-2-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-propionic acid;

2-({2-[2^t-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]-acetylamino}- methyl)-4-phenyl-butyric acid ethyl ester; 2-({2-[2'-hydroxy-3'-(l/f-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetylamino}- methyl)-4-phenyl-butyric acid;

2-{2-[2'-hydroxy-3'-(l/f-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-3- methyl-3-phenylmethanesulfonyl-butyric acid methyl ester;

4-cyclopropylmethoxy-2-{2-[2'-hydroxy-3^l-(l/i-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl]-acetylamino}-butyric acid methyl ester;

4-cyclopropylmethoxy-2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl]-acetylamino} -butyric acid;

N-(2-hydroxymethyl-4-ρhenyl-butyl)-2-[2'-hydroxy-3 '-( lH-pyrrolo [2,3 -c]ρyridin-2- yl)-biphenyl-4-yl] -acetamide;

3-benzylsulfanyl-2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetylamino } -3 -methyl-butyric acid;

3-phenylmethyloxy-2-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino}-N,N-dimethyl-propionamide; iV-(2-hydroxymethyl-3-phenoxy-propyl)-2-[2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-iV-isopropyl-acetamide;

[2'-hydroxy-3'-(l/i-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid 4-phenyl- butyl ester;

2-{2-[2'-hydroxy-3'-(l_JH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-3- methyl-3 -phenylmethanesulfonyl-butyric acid;

3-phenylmethyloxy-2-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino}-iV-(2-methoxy-ethyl)-propionamide;

3-phenylmethyloxy-2-{2-[2'-hydroxy-3'-(l/f-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl]-acetylamino}-iV-methoxy-propionamide;

2-[2'-hydroxy-3'-(lH^r-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-N-(4-phenyl-butyl)- acetamide;

2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-N-(3-phenyl-propyl)- acetamide; iV-(2-hydroxy-3 -ρhenoxy-propyl)-2-[2'-hydroxy-3 '-( lH-pyrrolo [2,3 -c]ρyridin-2-yl)- biphenyl-4-yl]-Ν-methyl-acetamide;

2-[2^t-hydroxy-3'-(lH^"-pyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]-N-(2-ρhenoxy-ethyl)- acetamide;

(2-phenylmethyloxy-l-{[2^l-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- ylmethyl]-carbamoyl}-ethyl)-carbamic acid tert-butyl ester; 2-amino-3-phenylmethyloxy-N-[2'-hydroxy-3^l-(liJ-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-ylmethyl]-propionamide;

2-{2-[2^l-hydroxy-3'-(l/f-ρyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetylamino}-5- phenyl-pentanoic acid dimethylamide;

N-[2-(4-fluoro-phenylmethyloxy)-ethyl]-2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin- 2-yl)-biρhenyl-4-yl]-acetamide;

N-(2-phenylmethyloxy-l-hydroxymethyl-ethyl)-2-[2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetamide;

5-phenyl-pentanoic acid [2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- ylmethyl] -amide; iV-(2-phenylmethyloxy-ethyl)-2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biρhenyl-4-yl] -acetamide;

2-({2-[2^l-hydroxy-3'-(lH^'-pyrrolo[2,3-c]pyridin-2-yl)-biplienyl-4-yl]-acetyl}-methyl- amino)-N,N-dimethyl-4-phenyl-butyramide;

3-phenylmethyloxy-2-({2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridm-2-yl)-biphenyl-4- yl]-acetyl}-methyl-amino)-iV,iV-dimethyl-propionamide; iV-(2-phenylmethyloxy-l-dimethylaminomethyl-ethyl)-2-[2'-hydroxy-3'-(lH- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetamide;

N-(l-hydroxymethyl-3-phenyl-propyl)-2-[2'-hydroxy-3^l-(l/f-pyrrolo[2,3-c]pyridin-2- yl)-biphenyl-4-yl] -acetamide;

3-(4-fluoro-phenylmethyloxy)-2-{2-[2'-hydroxy-3'-(l//-pyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl]-acetylamino} -propionic acid methyl ester;

3-(4-fluoro-phenylmethyloxy)-2-{2-[2^l-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetylamino}-propionic acid;

3-(4-fluoro-phenylmethyloxy)-2-{2-[2'-hydroxy-3'-(lH^'-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetylamino}-iV,iV-dimethyl-propionamide; and

N-[2-(4-fluoro-ρhenylmethyloxy)-l-hydroxymethyl-ethyl]-2-[2'-hydroxy-3'-(lH^'- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetamide.

Another selected group of compounds of the invention are provided in Table 14, having Formula I:

(A2) where R^4a and R^4b are hydrogen, R⁵ is X^12a-Y¹²-X^12b-Q¹², and all other groups are as defined below: Table 14.

and are named:

/γ_[2-(4-Fluoro-phenylmethyloxy)-ethyl]-2-[2'-hydroxy-3'-(5-amino-lH^"-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetamide; and

N-(3-phenylpropyl)-2-[2'-hydroxy-3^l-(5-amino-lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetamide.

Another selected group of compounds of the invention are provided in Table 15, having Formula I:

(A3), where X⁴, Y⁴, and Z⁴ are as defined below: Table 15.

and are named: methyl 4-(cyclopropylmethyl)-{4-[2-hydroxy-3-(lH^'-pyrrolo[2,3-c]pyridm-2-yl)- phenyl]-piperidin-l-ylacetyl}-piperidine-4-carboxylate;

4-(cyclopropylmethyl)-{4-[2-hydroxy-3-(lH-ρyrrolo[2,3-cJρyridin-2-yl)-phenyl]- piperidin-l-ylacetyl}-piperidine-4-carboxylic acid;

4-(phenetliyl)-{4-[2-hydroxy-3-(lϋ/-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-piperidin-l- ylacetyl } -piperazine;

4-(phenylmethyl)-{4-[2-hydroxy-3-(lH-pyrrolo[2,3-c]pyridin-2-yl)-plienyl]- piperidin-l-ylacetyl}-piperazine;

{4-[2-hydroxy-3-(lH-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-piperidin-l-ylacetyl}- piperidine;

4-cyano-{4-[2-hydroxy-3-(li7-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-piperidin-l- ylacetyl} -piperidine;

4-(4-fluorophenylmethyl)-4-cyano-{4-[2-hydroxy-3-(lH-pyrrolo[2,3-c]pyridin-2-yl)- phenyl]-piperidin-l-ylacetyl}-piperidine; 4-(cyclopropylmethyl)-4-cyano-{4-[2-hydroxy-3-(lH-ρyrrolo[2,3-c]pyridin-2-yl)- phenyl] -piperidin- 1 -ylacetyl } -piperidine;

4-(phenylcarbonyl)-{4-[2-hydroxy-3-(lH-pyrrolo[2,3-c]ρyridin-2-yl)-phenyl]- piperidin- 1 -ylacetyl} -piperazine;

4-(phenylmethyl)-4-hydroxy-{4-[2-hydroxy-3-(lH-pyrrolo[2,3-c]pyridin-2-yl)- phenyl] -piperidin- 1 -ylacetyl } -piperidine; methyl 4-(4-fluorophenylmethyl)-{4-[2-hydroxy-3-(lH-pyrrolo[2,3-c]pyridin-2-yl)- phenyl] -piperidin- 1 -ylacetyl} -piperidine-4-carboxylate;

4-(4-fluorophenylmethyl)-{4-[2-hydroxy-3-(lH-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]- piperidin- 1 -ylacetyl} -piperidme-4-carboxylic acid;

4-(4-fluorophenylmethyl)-4-oxo-{4-[2-hydroxy-3-(l//-pyrrolo[2,3-c]pyridin-2-yl)- phenyl] -piperidin- 1 -ylacetyl } -4λ⁵- [ 1 ,4] azaphosphinane; and

4-(4-fluorophenylmethyl)-4-hydroxy-{4-[2-hydroxy-3-(lH-pyrrolo[2,3-c]pyridin-2- yl)-phenyl] -piperidin- 1 -ylacetyl } -piperidine.

Another selected group of compounds of the invention are provided in Table 16, having Formula I

where R¹, R², and R³ are hydrogen; D is -CvR⁶- w ^όh^Re²re R⁶ is hydrogen; and R¹⁰⁰ is

(A3), where Z⁴ is -NR^5OaR^5Ob and R^5Oa, R^50b, X⁴, and Y⁴, are as defined below:

Table 16.

and are named: iV-[4-phenyl-l-(ethoxycarbonyl)-butyl]-2-{4-[2-hydroxy-3-(lH^'-pyrrolo[2,3-c]pyridin-2-yl)- phenyl] -piperidin- 1 -yl } -acetamide; iV-(2-hydroxy-4-phenyl-butyl)-2-{4-[2-hydroxy-3-(lH-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]- piperidin- 1 -yl} -acetamide;

N-(4-phenyl-butyl)-2-{4-[2-hydroxy-3-(li/-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-piperidin-l- yl} -acetamide;

7V-[4-phenyl-2-(ethoxycarbonyl)-butyl]-2-{4-[2-hydroxy-3-(lH-pyrrolo[2,3-c]ρyridin-2-yl)- phenyl]-piperidin-l-yl}-acetamide; and iV-(3-phenyl-propyl)-2-{4-[2-hydroxy-3-(li/-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-piperidin-l- yl} -acetamide.

Another selected group of compounds of the invention are provided in Table 17, having Formula I

(Al) where R ₁4™a, R r> 4^TOb, and R⁹ are hydrogen; L is -X⁵-Y^5a-Z⁵-Y^5b-; and all other groups are as defined below:

Table 17.

and is named N-(l-benzyloxymethyl-2-oxo-2-pyrrolidin-l-yl-ethyl)-2-[2'-hydroxy-3'-(lH- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetamide.

GENERAL SYNTHESIS

Compounds of this invention can be made by the synthetic procedures described below.

The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), or Bachem (Torrance, Calif.), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4^th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). In particular, 2-chloro-oxazole-4-carboxylic acid ethyl ester can be prepared according to methods described in KJ. Hodgetts, M.T. Kershaw, Org. Lett., 2002, 4, 2905-7. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.

The starting materials and the intermediates of the reaction maybe isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about -78 ⁰C to about 150⁰C, more preferably from about 0⁰C. to about 125⁰C. and most preferably at about room (or ambient) temperature, e.g., about 20⁰C. Unless otherwise stated (as in the case of an hydrogenation), all reactions are performed under an atmosphere of nitrogen.

Compounds of Formula I that may be prepared through the syntheses described herein may exist as a single isomer or a mixture of isomers.

Compounds of Formula I, where each A, D, R¹, R², R³, R^4a and R^4b are as defined in the Summary of the Invention, can be prepared by reacting a compound of Formula II:

II where R is a substituent that contains a reactive functional group, e.g., -COOH or -NH₂, with an intermediate that contains a complementary reactive group, e.g., -NHR or -COOH, respectively, to form the group L where R¹⁰⁰ is a group of formula (Al), or to form the groups Y¹¹, Y¹², Y¹³, or Y¹⁴ when R¹⁰⁰ is a group of formula (A2), or to form -Y^Z⁴ when R¹⁰⁰ is a group of formula (A3). Preferably R²⁰ is a reactive functional group containing a protecting group that can be removed by methods known in the art. The reactive group is preferably amino, alkylamino, dialkylamino, hydroxy, carboxy, and thio. The reactive group can be made to react under conditions known to those skilled in the art with a complementary reactive group.

For example, compounds of Formula I in which D is =CH-; R¹ is hydrogen; A, R³, R^4a, and R^4b are as defined in the Summary of the Invention; R¹⁰⁰ is a group of formula (Al), and L is -X¹-Y¹-Z¹-(where Y¹ is -C(O)NR¹³- and Z¹ is as defined in the Summary of the Invention; or Y¹ is -C(O)- and Z¹ is a bond), or L is -Y²-Z²- (where Y² is -C(O)NR¹⁵- and Z² is as defined in the Summary of the Invention) can be prepared by reacting a deprotected carboxylic acid of Formula II(a) with a primary or secondary amine or amine salt, e.g., an amine of the formula NHR²¹R²² as in the following reaction scheme:

II(a) I(a)

where X' in the above scheme is a bond or -X¹-; R²¹ is R¹³ or R¹⁵, as applicable; and R²² is -Z -R or -Z -R , as applicable, and R is a moiety of Formula (a):

(a); or R²¹ and R²² together with the nitrogen atom to which they are attached form a moiety of Formula (a) and R⁷, R⁸ and R⁹ are as defined in the Summary of the Invention.

The reaction can be carried out with an acid halide of the carboxylic acid in the presence of a suitable base, such as triethylamine, N,N-diethylaniline, diisopropylethylamine and the like, in a suitable reaction solvent, such as THF, DMF and the like. The acid halide can be prepared by methods known to those of skill in the art. For example the acid chloride can be can be prepared by reacting the acid with a halogenating agent, such as oxalyl chloride, thionyl chloride, phosphorous oxychloride, and the like.

The reaction can be carried out with the acid in the presence of a coupling agent such as benzotriazole-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP®), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop®), Obenzotriazol-1-yl- N,N,NyV'-tetrmnethyl-uronium hexafluorophosphate (HBTU),

^-(V-azabenzotriazol-l-y^-ΛζΛζN'^V'-tetramethyluronium hexafluorophosphate (HATU), or 1,3-dicyclohexylcarbodiimide (DCC) or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) optionally in the presence of 1-hydroxybenzotriazole (HOBT). As appropriate, a base such as N,N-diisopropylethylamine, triethylamine, or N- methylmorpholine can be used. The reaction is carried out in suitable organic solvents, such as DMF and the like. Suitable amines and amine salts are either commercially available or they can be prepared from commercially available starting materials by methods known in the art.

Similarly, for example, compounds of Formula I in which D is =CH-, R¹ is hydrogen, R¹⁰⁰ is a group of formula (A2), and Y¹¹, Y¹², Y¹³, or Y¹⁴ is -C(O)NR^26a- can be prepared using conventional amide forming reactants and conditions as in the following reaction scheme:

where X" in the above scheme is a bond, X^12a, or X¹³; R²¹ is R^26a; and R²² is -X¹ ^Q¹¹, - _χ12b__Q12_; __Z13_{5 or} __zl_{4j respectivel}y₅ ^d _{each Aj R}3_{5 R}4a_{s R}4_bj -^ _χ13_{? R}2₆a_{; χ}12_bj QU _z_3 _? and Z¹⁴ are as defined in the Summary of the Invention.

Similarly, for example, compounds of Formula I in which D is =CH-, R¹ is hydrogen, R¹⁰⁰ is a group of formula (A3), Y⁴ is -C(O)-, and A, R³, and X⁴ are as defined in the Summary of the Invention can be prepared using conventional amide forming reactants and conditions as in the following reaction scheme:

When Z⁴ is -NR^50aR^50b, R²¹ is R^50a and R²² is R^50b. When Z⁴ is heterocycloalkyl, R²¹ and R²² together with the nitrogen atom to which they are attached form heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, carboxy, aryl, aralkyl, cyano, arylcarbonyl, alkoxy, and hydroxy.

A compound of Formula I in which D is =CH-; R¹ is hydrogen; A, R³, R^4a, and R^4b are as defined in the Summary of the Invention; R¹⁰⁰ is a group of formula (Al), and L is -X¹-Y¹-Z¹-(where Y¹ is -NR¹³C(O)- and Z¹ is as defined in the Summary of the Invention), or L is -Y³- where -Y³- is -NR¹⁷C(O)-, or L is -Y²-Z²- (where Y² is -C(O)NR¹⁵- and Z² is as defined in the Summary of the Invention) can be prepared using conventional amide forming reactants and conditions by reacting a deprotected amine of Formula II(e) with a carboxylic acid or carboxylic acid salt, e.g., an intermediate of the formula R⁵⁵C(O)OH, as in the following reaction scheme:

II(c) I(c) where A, D, R³, R^4a, and R^4b are as defined in the Summary of the Invention and R" in the above scheme is -Z -R , -Z -R , or -R , as applicable, and R is a moiety of Formula (a):

(a); where R , R and R are as defined in the Summary of the Invention. The reaction can also be carried out with a sulfonylating agent instead of the carboxylic acid, preferably a sulfonyl halide, in the presence of a suitable base, such as triethylamine, AζiV-diethylaniline, diisopropylethylamine and the like, in a suitable reaction solvent, such as methylene chloride and the like.

Similarly, for example, compounds of Formula I in which D is =CH-, R¹ is hydrogen, R¹⁰⁰ is a group of formula (A2), and Y¹¹, Y¹², Y¹³, or Y¹⁴ is -NR²⁶³C(O)- can be prepared using conventional amide forming reactants and conditions as in the following reaction scheme:

IKd) I(d) where X" in the above scheme is a bond, X^12a, or X¹³; R" is -X¹ '-Q¹¹, -X^12b-Q¹², -Z¹³, or -Z¹⁴, respectively, and each A₅ R³, R^4a, R^4b, X^12a, X¹³, R^26a, X^12b, Q¹², Z¹³, and Z¹⁴ are as defined in the Summary of the Invention. The reaction can also be carried out with a sulfonylating agent instead of the carboxylic acid, preferably a sulfonyl halide, in the presence of a suitable base, such as triethylamine, AζTV-diethylaniline, diisopropylethylamine and the like, in a suitable reaction solvent, such as methylene chloride and the like.

Intermediates of Formula II, wherein R¹ is hydrogen and D is =CH- can be prepared by the following reaction scheme:

4 5 II(e) wherein PG¹ and PG² are a nitrogen-protecting and oxygen-protecting group, respectively, and A, R³, R^4a, and R^4b are as defined in the Summary of the Invention and R²⁰ is, for example,

-X¹³- C(O)OPG³,

-X⁴-C(O)OPG³, -NHPG¹, or -C(O)OPG³ where PG¹ is as described above, PG³ is an acid-protecting group, and all other groups are as defined in the Summary of the Invention.

Intermediates of of Formula II can be prepared by reacting a compound of Formula 4 with a compound of Formula 5 and then deprotecting. The reaction can be carried out in the presence of acetonitrile, dichloro-bis(triphenylphosphine)palladium (II), copper iodide, and a base, such as triethylamine, at 50 to 100 °C and requires 1 to 8 hours to complete.

The protecting groups represented by PG², PG¹ and PG³ can be removed in the presence of acid or base, preferably 4 M aqueous hydrochloric acid for the deprotection of PG² where PG² is methoxyethoxymethyl. 4 M Aqueous hydrochloric acid also is preferred for the removal of PG³ which is typically an ester or a tert-butoxycarbonyl group. Preferably, when PG¹ is methanesulfonyl, aqueous sodium hydroxide or tetrabutylammonium fluoride is used to remove the group.

Compounds of Formula 5 can be prepared from the correspondintg aldehyde of Formula 6 by treating the aldehyde with l-diazo-2-oxopropyl)phosphonate and potassium carbonate or cesium carbonate as described in Ohira, S. Synth. Commun. 1989, 19, 561.

Intermediates of Formula II, wherein R¹ is hydrogen and D is =N- can be prepared by the following reaction scheme:

II(f) wherein A, R³, R^4a, and R^4b are as defined in the Summary of the Invention and R >2^z0^υ is, for example, -X^NHPG¹, -X¹C(O)OPG³, -X¹²^NHPG¹, -X^12a-C(O)OPG³, -X^-NHPG¹, -X¹³-C(O)OPG³, -X^NHPG¹, -X⁴-C(O)OPG³, -NHPG¹, or -C(O)OPG³ where PG¹ is as described above, PG³ is an acid-protecting group, and all other groups are as defined in the Summary of the Invention. The aldehyde of Formula 7 is reacted with a diamino of Formula 6 in the presence of 7\ζiV-dimethylformamide and sodium metabisulfite at about 130 ⁰C for approximately 24 to 48 hours.

The aldehyde of Formula 7 can be prepared by the following reaction scheme:

8 7 wherein A, R³, R^4a, and R^4b are as defined in the Summary of the Invention and R²⁰ is, for example, -X^NHPG¹, -X¹C(O)OPG³, -X¹^-NHPG¹, -X^12a-C(O)OPG³, -X¹^NHPG¹, -X¹³-C(O)OPG³,

The reaction illustrated in the above scheme is carried out with a boronate ester or acid of Formula 6, potassium carbonate, tetrakis(triphenylphosphine)ρalladium (O), and solvent DME and water at 50 to 100 °C and takes 3 to 5 hours to complete. The aldehyde of Formula 7 where PG is a protecting group such as alkyl or alkyloxyalkyl can be prepared from the compound where PG is hydrogen by methods known in the art. For example, the compound where PG is hydrogen can be reacted in the presence of MEM-Cl, cesium chloride and DMF at 0 to 20 °C and requires approximately 1 to 4 hours to complete. Aldehydes of Formula 7 where PG is hydrogen can be obtained commercially or preferably can be prepared from corresponding 2-halophenols in the presence of THF, paraformaldehyde, triethylamine, and magnesium chloride at ambient temperature and requires 8 to 10 hours to complete.

Boronates of Formula 9 can be obtained from commercially available aryl halides by treating with 1,4-dioxane, potassium acetate, έw(pinacolato)diboron, and a catalyst, preferably [l,r-bis-(diphenylphosphmo)ferrocene]dichloropalladium(II)*CH₂Cl₂ complex.

Intermediates of Formula IΙI(a) where A, X⁴, and R³ are as defined in the Summary of the Inventioncan be prepared by the following reaction scheme: N-protection (HCHOJn

base

20 πi(a)

The methoxy group in an intermediate of formula 9, which is commercially available or can be prepared by one of ordinary skill in the art, is converted to the hydroxy of an intermediate of formula 10 using a strong acid such as aqueous HBr at reflux temperature. The nitrogen is then protected. For example PG¹ is a CBz which is installed under basic conditions using solvent(s) such as acetonitrile and water. The aldehyde of formula 12 is prepared by reacting 11 with paraformaldehyde in the presence OfMgCl₂ and a base such as triethylamine. The reaciton is carried out in a solvent such as THF. The reaction is then quenched with phosphoric acid.

The hydroxy group is then protected. This can be accomplished by reacting in the presence of MEM-Cl, a base such as cesium chloride and a solvent such as DMF at 0 to 20 ⁰C. The reaction is allowed to proceed for approximately 1 to 4 hours yielding the O-protecetd product 13. The alkyne 15 is prepared by reacting 14 in the presence of Ohira- Bestmann's reagent (14) and abase such as cesium carbonate in a solvent such as ethanol under an inert atmosphere at approximately 0 ⁰C. The reaction is then quenched with a mixture of 5% NaHCO₃ and ethyl acetate.

An intermediate of formula 17 can be prepared by reacting an intermediate of formula 15 with an intermediate of formula 16 where PG⁴ is a nitrogen-protecting group (orthogonal to PG¹) and LG' is a leaving group, such as halo; and where LG' and NHPG⁴ are attached on adjacent carbon atoms. The reaction is carried out under an inert atmosphere in the presence of copper halide, such as copper iodide, and a catalyst such as PdCl₂(PPh₃)₂ and a base such as triethylamine, in a solvent such as acetonitrile and heated to approximately 75 ⁰C.

The piperidine protecting group is then removed. Where PG¹ is CBz the intermediate is treated with a strong acid such as HBr (a solution in acetic acid) in a solvent such as methylene chloride to yield the intermediate 18. In a solvent such as acetonitrile, 18 is then treated with a base such as N,N-diisopropylethylamine, and with LG-X⁴-C(O)OPG³ (20) where LG is a leaving group, such as halo, and PG³ is a carboxy-protecting group. The reaction is then neutralized with an acid such as IN HCl . Preferably, PG³ and PG⁴ can both be removed under the same conditions, e.g. PG⁴ is methansulfonyl and PG³ is methyl or ethyl, and are removed under basic conditions. The deprotection under basic conditions can be carried out using a base such as sodium hydroxide in a solvent such as THF and heating to approximately 65 ⁰C to yield an intermediate of formula IΙI(a).

IIntermediates of Formula III(b) where A, X⁴, and R³ are as defined in the Summary of the Invention can be prepared by the following reaction scheme:

iπ(b)

The intermediate of formula 12, prepared as described above, is reacted with an intermediate of formula 21 to yield 22. The reaction is carried out in the presence of N, N- dimethylformamide and sodium metabisulfite at about 130 ⁰C for approximately 24 to 48 hours. PG¹ is removed using conditions, known to one of ordinary skill in the art, depending on the type of protecting group used. 23 is then reacted with 20 using conditions described above and 24 is subsequently deprotected to yield an intermediate of formula III(b).

UTILITY

The compounds of this invention are tryptase inhibitors. As such the compounds of Formula I are useful for treating diseases, particularly immunomediated inflammatory diseases in which tryptase activity contributes to the pathology and/or symptomatology of the disease. For example, immunomediated inflammatory diseases in which tryptase activity contributes to its pathology and/or symptomatology include asthma, allergic rhinitis, rheumatoid spodylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczematous dermatitis, anaphylaxis, hyper proliferative skin disease, peptic ulcers, inflammatory bowel disease, ocular and vernal conjunctivitis, inflammatory skin conditions, chronic obstructive pulmonary disease, and the like.

Suitable in vitro assays for measuring tryptase activity and the inhibition thereof by compounds are known (e.g., see Sturzebecher et al, Biol. Chem. Hoppe-Seyler, 1992, 373, 1025-1030). Typically, the assay will measure tryptase induced hydrolysis of peptide base substrate. For further details of an in vitro assay for measuring tryptase activity see Biological Examples, Example 1 infra.

Assays for measurement of efficacy in treatment of skin diseases, ulcers, and Syncytial Virus Infection are described in Biological Examples, Example 3, 5, and 6, infra.

Suitable in vivo models of inflammation are known to those of ordinary skill in the art. For example, in vivo models for asthma are described by Larsen (1991) Experimental Models of Reversible Airway Obstruction, hi: West et al, eds. The Lung: Scientific Foundations Raven Press, New York). Further, in vivo models of inflammatory skin conditions (Walsh et al. Br. J. Pharmacol, 1995, 114, 1343-1350; and Armstrong et al. Prostaglandins, 1995, 49, 205-224), arthritic conditions (Peacock et al. Cell Immunol, 1995, 160, 178-184; and Houri et al Curr. Opin. Rheumatol, 1995, 7, 201-205) and gastrointestinal diseases (Anthony et al Int. J. Exp. Pathol, 1995, 76, 215-224.; and Carter et al Dig. Dis. Set, 1995, 40, 192-197) are known. For further details of in vivo assays see Biological Examples 2 and 4, infra.

ADMINISTRATION AND PHARMACEUTICAL COMPOSITIONS

In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.

Therapeutically effective amounts of compounds of Formula I may range from approximately 0.1-50 mg per kilogram body weight of the recipient per day; preferably about 0.5-20 nig/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 35 mg to 1.4 g per day. If a known β-2 adrenoreceptor agonist(s), corticosteroid(s), leukotriene antagonist(s), and/or phosphodiesterase 4 inhibitor(s) is also administered, each is administered in an amount which is effective to achieve its intended purpose. The amounts of such known β-2 adrenoreceptor agonist(s), corticosteroid(s), leukotriene antagonist(s), and/or phosphodiesterase 4 inhibitor(s) effective for asthma are well known to those of skill in the art.

Therapeutic agents that may be useful for administration in combination with compounds of Formula I in treating asthma include β-2 adrenoreceptor agonists (e.g., salmeterol, albuterol, terbutaline, formoterol, fenoterol, prenaline and the like), methylxanthines (e.g., caffeine, theophylline, aminophylline, theobromine and the like), cromoglycates (e.g., cromolyn, nedocromil, and the like), corticosteroids (e.g., budesonide, fluticasone, beclomethasome, triamcinolone, flurisolide, dexamethasone and the like), leukotriene D4 antagonists (e.g., montelukast and the like), and phosphodiesterase 4 inhibitors (e.g., roflumilast and the like). In general, one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given inflammatory disease.

Therapeutic agents that may be useful for administration in combination with compounds of Formula I in treating COPD include corticosteroid(s), xanthines (e.g., theophylline), anticholinergic compounds (e.g., ipratropium, tiotropium), biologies, small molecule immunomodulators, and beta receptor agonists/bronchdilators (e.g., albuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol scetate, salmeterol xinafoate, and terbutaline).

In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral or parenteral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Oral compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

The compositions are comprised of in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula I. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18* 6^, 1990). The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula I based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of Formula I are described below.

The compounds of this invention can be administered in combination with known asthma, COPD, and/or allergic rhinitis agents. Such known asthma, COPD, and/or allergic rhinitis agents include β-2 adrenoreceptor agonists, corticosteroids, leukotriene antagonists, and phosphodiesterase 4 inhibitors. Preferred β-2 adrenoreceptor agonists include salmeterol. Preferred corticosteroids include budesonide and fluticasone. Preferred leukotriene antagonists include montelukast. Preferred phosphodiesterase 4 inhibitors include roflumilast.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.

EXAMPLES

The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Synthetic Examples

Reference 1

Synthesis of 3-Bromo-2-(methoxyethoxymethoxy)-benzaldehyde

Step l

2-Bromoρhenol (97 g, 0.56 mol), THF (1.0 L), and paraformaldehyde, prilled (84.0 g, 2.80 mol) were charged to a 5 L 3-neck round-bottom flask. Triethylamine (TEA) (400 mL) was added, followed by MgCl₂ (200 g, 2.10 mmol) added portionwise over a 90 minutes, while stirring with an overhead stirrer. The reaction was white, cloudy, and viscous, and turned bright yellow on addition of the MgCl₂. The reaction was allowed to stir overnight under a nitrogen atmosphere. The reaction was neutralized causiously with phosphoric acid (300 mL) and brine (500 mL) diluted with ethyl acetate (500 mL). The organic layer was separated and washed with water (500 mL X 3) and brine (500 mL), and dried over Na₂SO₄. The solvents were evaporated and the residue was dissolved in ethyl acetate. The solution was filtered through 6 x 4 inch a silica gel plug with ethyl acetate (1.5 L) as eluant. The solution was concentrated to give crude 3-bromo-2-hydroxy-benzaldehyde. (107g, 96%). ¹H NMR (400 MHz, DMSO) δ ppm 11.28 (s, IH), 10.06 (s, IH), 7.89 (dd, IH, J= 1.6, 7.8 Hz), 7.78 (dd, IH, J= 1.6, 7.4 Hz), 7.02 (t, IH, J= 7.8 Hz). Step 2

A 3 L round bottom flask was charged with 3-bromo-2-hydroxy-benzaldehyde (80.00 g, 398.0 mmol) and DMF (300 mL). Cs₂CO₃ (155.6 g, 475.7 mmol) was added and the solution was stirred for 15 minutes. Methoxyethoxymethylchloride (54.53 mL, 477 mmol) was added dropwise via an addition funnel. The reaction solution became a bright yellow, viscous mixture. The reaction mixture turned to a white/light beige, viscous solution as the reaction progressed. When the reaction was complete, the solid was filtered from the reaction solution. Hexane (750 mL) and ether (750 mL) were added to the filtrate. The organic layer was washed with water (3 X 700 mL) and brine (2 X 500 mL), dried over Na₂SO₄, and concentrated to give 3-bromo-2-(methoxyethoxymethoxy)-benzaldehyde (crude yield of 105g) which was used in Reference 23 without further purification. ¹H NMR (400 MHz, DMSO) δ 10.22 (d, IH, J= 0.8 Hz), 7.97 (dd, IH, J= 2, 7.8 Hz), 7.75 (dd, IH, J= 1.6, 7.8 Hz)₅ 7.27 (dt, IH, J= 0.7, 7.8 Hz), 5.26 (s, 2H), 3.87 (m, 2H), 3.46 (m, 2H), 3.22 (s, 3H).

Reference 2 Ethyl [4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-acetate

Ethyl (4-bromophenyl)-acetate (100 g, 411 mmol) Z?ώ-(pinacolato)diboron (125.4 g,

493.7 mmol) and potassium acetate (125.4 g, 493.7 mmol) were charged to a 2 L round bottom flask. 1,4-Dioxane (1 L) was added and the mixture was stirred under a nitrogen atmosphere for 15 minutes. [1,1 '-Z?w-(Diphenylphosphino)-ferrocene]dichloropalladium(II) CH₂Cl₂ complex (1:1) (3.36 g, 4.11 mmol) was added and the reaction was heated in an 100 ⁰C oil bath for 2 hours. The reaction was determined complete by analytical HPLC. The solution was concentrated under reduced pressure to remove the dioxane and the residue was dissolved in ethyl acetate. The solution was filtered through a 6 x 4 inch silica gel plug with ethyl acetate (1.5 L) as eluant to give ethyl [4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenylj-acetate (117 g, 98%). ¹H NMR (400 MHz, DMSO) δ ppm 7.63 (d, 2H₅ J= 8 Hz), 7.27 (d, 2H, J= 8 Hz), 4.07 (q, 2H, J= 7 Hz), 3.68 (s, 2H), 1.28 (s, 12H), 1.16 (t, 3H, J= 7 Hz).

Reference 3

Step l

4-Aminopyridine (40.5 g, 0.4303 mol) was placed in a 1 L 3-neck flask and then

Na₂CO₃ (22.78 g, 0.2150 mmol) and water (100 mL) was added. The mixture was heated to reflux and stirred for 5 minutes. Iodine (81.84 g, 0.3224 mol) and potassium iodide (71.36 g, 0.4301 mol) were dissolved in water (500 mL) and placed in an addition funnel. The iodide/potassium iodide/water mixture was added to the reaction dropwise while the mixture continued to be heated and stirred. An additional 0.25 equiv of the iodide/potassium iodide/water mixture was prepared and added to the reaction mixture. The mixture was heated and stirred for 8 hours and then allowed to cool to room temperature. Ethyl acetate was added and the mixture was washed with water, Na₂S₂O₃, and brine. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated. The residue was dissolved in dichloromethane and filtered using a silica plug (30% EtOAc / 70% hexane system, followed by 100% EtOAc system). The filtrate was dried under reduced pressure to give 4-amino-3- iodopyridine (27.0 g, 29%) as a beige solid. Step 2

4-Amino-3-iodopyridine (20.00 g, 90.87 mmol) was placed in a 500 mL round- bottom flask. Dichloromethane (150 mL) and triethylamine (12.67 mL, 90.87 mmol) were added with stirring under nitrogen. The mixture was cooled to 5 °C and stirred under nitrogen while methanesulfonyl chloride (7.01 mL, 90.9 mmol) was added dropwise. The mixture formed a white precipitate as the reaction progressed and after 5 hours additional triethylamine (15.2 mL, 109 mmol) and methanesulfonyl chloride (8.41 mL, 109 mmol) were added and the reaction was allowed to proceed for an additional 2 hours. The white precipitate was filtered from the reaction solution and dissolved in THF (400 mL) and water (200 mL). The solution was heated to reflux for 30 minutes and then the THF was then removed under reduced pressure. Solids precipitated out of the aqueous residue and were collected to giveN-(3-iodo-pyridin-4-yl)-methanesulfonamide (21 g).

Reference 4

Synthesis of 4-iodo-3 -(methylsulfonylamino)-pyridine

iV-(4-Iodo-pyridin-3-yl)-2,2-dimethyl-propionamide (20.00 g, 65.76 mmol) was charged to a 2 L round-bottom flask and 24% sulfuric acid in water (640 mL) was added carefully. The mixture was heated to 100 °C for 4 hours. The reaction was determined complete by analyitical HPLC. The mixture was allowed to cool to room temperature and then carefully adjusted to pH 7-8 with 4Ν NaOH (approximately 700 mL). Saturated sodium bicarbonate was added to the mixture and the product extracted into dichloromethane (3 X 500 mL). The organic layers were combined and concentrated to give 3-amino-4-iodo- pyridine (13.3 g, 92%). Step 2

3-Amino-4-iodo-pyridine (15.0 g, 68.2 mmol) was charged to a 1 L round-bottom flask and then dichloromethane (200 mL) and triethylamine (21.1 mL, 152 mmol) were added. The mixture was cooled to 5 ⁰C in an ice bath and methanesulfonyl chloride (11.61 mL, 17.18 g) was added via an addition funnel. The reaction was determined greater than 95% after 30 minutes by analytical HPLC. The mixture was quenched with saturated NH₄Cl (300 mL) and extracted with ethyl acetate (1 L). The organic layer was filtered through a silica gel plug with ethyl acetate as eluant and concentrated to give crude 4-iodo-3-(fos- methylsulfonylammo)-pyridine (25.0 g, 97%) which was used in the next step without purification. ¹H NMR (400 MHz, DMSO) δ 8.25 (d, IH, J= 5.5 Hz), 8.07 (d, IH, J= 0.8 Hz), 7.68 (dd, IH, J= 0.8, 5.5 Hz). Step 3

N-(4-Iodo-pyridin-3-yl)-N-methylsulfonyl-methanesulfonamide (25.64 g, 68.16 mmol), THF (300 mL), water (100 mL) and 4 N NaOH (75 mL) were sequentially added to a 2 L round-bottom flask and the mixture was warmed in a 75 ⁰C oil bath overnight. The reaction was determined complete by analytical HPLC. The THF was removed under reduced pressure and the aqueous layer was adjusted to a pH of 7 using 4 M hydrochloric acid (approximately 75 mL) caustiously added. A solid precipitated out of the mixture, which was was collected by filtration to give 4-iodo-3-(methylsulfonylamino)-pyridine (16.5 g, 81%) as an off-white solid. ¹H NMR (400 MHz, DMSO) δ ppm 9.64 (s, IH), 8.46 (s, IH)₅ 8.07 (d, IH, J= 5.1 Hz), 7.99 (d, IH, J= 5.1 Hz), 3.12 (s, 3H).

Reference 5 Synthesis of 4-iodo-3-(methylsulfonylamino)-pyridine

H O Step l

3-(tert-Butylcarbonylamino)-4-iodo-pyridine (20.00 g, 65.76 mmol) was charged to a 2 L round-bottom flask, and sulfuric acid, 24% in water (640 mL) was carefully added. The reaction was heated to 100 ⁰C. After 4 hours, the reaction was shown to be complete as determined by HPLC. After cooling to room temperature, the solution was carefully neutralized with 4 M NaOH until a pH of 7-8 was achieved. Saturated bicarbonate was added to the reaction mixture, and the product extracted into dichloromethane (3 X 500 mL). The organic layers were combined and concentrated to give 13.3 g of 3-amino-4-iodo-pyridine. Step 2

3-Amino-4-iodo-pyridine (15.0 g, 68.2 mmol) was charged to a 1 L round-bottom flask, and dichloromethane (200 mL) and triethylamine (21.1 mL, 152 mmol) were added. The mixture was cooled to 5 ⁰C in an ice bath, and methanesulfonyl chloride (11.61 mL, 17.18 g) was added via an addition funnel to give a cloudy, viscous, pumpkin-colored solution, which changed to a cream-colored viscous mixture. After 30 minutes the reaction was shown to be >95% complete by analytical HPLC. The reaction was quenched with saturated NH₄Cl (300 mL) and extracted with EtOAc (1 L). The organic fraction was passed through a silica gel plug and concentrated to give 25.0 g of crude 4-iodo-3-(bis- methylsulfonylamino)-ρyridine. ¹H NMR (400 MHz₅ DMSO) δ 8.25 (d, IH₅ J = 5.5 Hz)₅ 8.07 (d, IH, J= 0.8 Hz)₅ 7.68 (dd, IH₅ J= 0.8, 5.5 Hz). Step 3

To a 2 L round-bottom flask was added 4-iodo-3-(tø-memylsulfonylamino)-pyridine (25.64 g, 68.16 mmol), followed by addition of THF (300 mL), water (100 mL) and 4 M NaOH (75 mL). The reaction solution was stirred at room temperature overnight, at which time HPLC showed the reaction to be complete. THF was removed under reduced pressure, and the aqueous layer was neutralized to a pH of 7. The product precipitated out of the reaction mixture and was collected by filtration, giving 4-iodo-3-(methylsulfonylamino)- pyridine with a purity > 98 % by HPLC. ¹H NMR (400 MHz, DMSO) δ 9.64 (s, IH), 8.46 (s, IH), 8.07 (d, IH, J= 5.1 Hz), 7.99 (d, IH, J= 5.1 Hz), 3.12 (s, 3H).

Reference 6

Methyl l-tert-butoxycarbonyl-4-phenylmethyl-piperidine-4-carboxylate

Step l l-tert-Butoxycarbonyl-4-phenylmethyl-piperidine-4-carboxylic acid (310 mg, 0.97 mmol) was dissolved in methanol (10 mL) and benzene (10 mL). TMS-diazomethane (2 M solution in hexanes, 1.2 mL, 2.4 mmol) was added to the solution via a syringe under a nitrogen atmosphere and the mixtuere was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure and ethyl ether (30 mL) was added. The mixture was washed with saturated ammonium chloride and brine, dried over Na₂SO₄ and concentrated to give methyl l-tert-butoxycarbonyl-4-phenylmethyl-piperidine-4-carboxylate, 350 mg (quant.)

Reference 7 tert-Butyi 4-phenylmethyl-4-cyano-ρiperidine-l -carboxylate

fc/t-Butyl 4-cyano-piperidine-l -carboxylate (630 mg, 3 mmol) was dissolved in THF (20 mL). The solution was cooled in an ice bath and then potassium bis(trimethylsilyl) amide (0.50 M solution in toluene (12 mL, 6.0 mmol) was added. The mixture was stirred under nitrogen in the ice bath for 45 minutes and then benzyl bromide (0.40 mL, 3.3 mmol) in THF (1 mL) was added slowly dropwise via a syringe at 0⁰C. The reaction was monitored by both analytical HPLC and LCMS and upon the completion of the reaction (approximately 2.5 hours) ether (200 mL), water (50 mL) and saturated ammonium chloride aqueous solution (50 mL) were added. The mixture was stirred vigorously for 15 minutes at room temperature. The organic layer was separated, washed with saturated ammonium chloride aqueous solution, water, and brine, dried over MgSO₄, and concentrated to give tert-bxxtyl A- phenylmethyl-4-cyano-piperidine-l-carboxylate as a pale yellow-colored solid (quantitative yield). LCMS: (M+23)⁺ 323.

One of ordinary skill in the art would know procedures to remove the Boc-protecting group.

Reference 8 tert-Butyl 4-phenylmethyl-4-(5-oxo-4,5-dihydro-[l,2,4]oxadiazol-3-yl)-piperidine-

1-carboxylate

Step l tert-Butyl 4-phenylmethyl-4-cyano-piperidine-l-carboxylate (100 mg, 0.33 mmol) was dissolved in ethanol (4 mL) and a small amount of powder 4A molecular sieve and hydroxylamine (50% wt. % solution in water, 1.0 mL, 30 mmol) were added sequentially. The mixture was stirred at 55 ⁰C. The reaction was monitored by both analytical HPLC and LCMS and upon completion of the reaction (approximately 72 hours) the insoluble molecular sieve was filtered off. The product was separated by preparative HPLC and lyophilized to give tert-bntyl 4-phenylmethyl-4-(iV-hydroxycarbamimidoyl)-piperidine-l-carboxylate (75 mg, 70%) as a white solid. MS(ES) m/z 334.3 (MH⁺); MS cald: 333.4 (M). Step 2

A mixture of tert-butyl 4~phenylmethyl-4-(N-hydroxycarbamimidoyl)-piperidine- 1-carboxylate hydrochloride (70 mg, 0.21 mmol) and triethylamine (0.3 mL, 2 mmol) was dissolved in acetonitrile (1 mL) and dioxane (1.5 mL). N,N-Carbonyldiimidazole (243 mg, 1.50 mmol) was added to the solution and the mixture was stirred at room temperature. The progress of the reaction was followed by analytical HPLC and LCMS and upon completion (approximately 72 hours), the solvent was removed in vacuo and ethyl acetate (50 mL) was added. The organic layer was washed with HCl solution (1 Ν), water and brine, dried over MgSO₄ and then concentrated to give tert-bntyl 4-phenylmethyl-4-(5-oxo-4,5-dihydro- [l,2,4]oxadiazol-3-yl)-piρeridine-l-carboxylate (58 mg, 76%) as a pale yellow solid. MS(ES) m/z 382 (M+Na); MS cald: 359.4 (M).

Reference 9 tert-BvΛyl 3 -(4-chloro-phenylmethyloxy)-pyrrolidine- 1 -carboxylate

Step l

Pyrrolidin-3-ol (1.09 g, 12.5 mmol) was dissolved in dichloromethane (20 mL), cooled to 0⁰C in an ice bath. Triethylamine (1.93 mL, 13.8 mmol), di-fert-butyl dicarbonate (3.06 g, 13.8 mmol) and dimethylaminopyridine (153 mg, 1.25 mmol) were added. The reaction mixture was allowed to warm up to room temperature while stirring. Progress of the reaction was monitored by TLC (silica gel, hexane: EtOAc (1:1, v/v) stained by nihydrin and upon completion (approximately 3.5 hours) 1 M NaOH aqueous solution (10 mL) was added. The mixture was stirred vigorously for 5-10 minutes and the organic layer was separated, washed with saturated sodium bicarbonate (twice), saturated ammonium chloride and brine, dried over MgSO₄, concentrated. Product was purified from the residue by flash column chromatography (50% hexanes / ethyl acetate) to give fert-3-hydroxy-pyrrolidine- 1 -carboxylate (2.3 g, 98%) as a white solid. Step 2

Sodium hydride (60% dispersed in mineral oil, 92 mg, 5.8 mmol) in THF (1 mL) was cooled to 0 ⁰C in an ice bath under nitrogen, tert-3 -Hydroxy-pyrrolidine- 1 -carboxylate (212 mg, 1.13 mmol) in THF (4 mL) was added slowly via a syringe. The mixture was stirred for 30 minutes at 0 ⁰C and 4-chlorobenzylbromide (257 mg, 1.25 mmol) in THF was added dropwise. The mixture was kept in ice bath for another 30 minutes then stirred at room temperature overnight. Ether (5OmL) was added to the reaction mixture and then water (10 mL) was added to quench the reaction. The mixture was stirred for 15-20 minutes and then the organic layer was separated, washed with water and brine, dried over MgSO₄ and concentrated. Product was purified from the residue by flash column chromatography (80% hexanes / ethyl acetate) to give tert-butyl 3-(4-chloro-phenylmethyloxy)-pyrrolidine- 1-carboxylate (250 g, 71.0%) as a colorless oil. MS(ES) m/z 334.1 (M+Na); MS cald: 311.8 (M).

Reference 10 tert-Butyl 4-phenylmethyl-4-(4,5-dihydro-thiazol-2-ylcarbamoyl)-piperidine- 1 -carboxylate

l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol), 1-hydroxybenzotriazole hydrate (16 mg, 0.12 mmol), 2-amino-2-thiazoline (12 mg, 0.12 mmol) and di-isopropylethylamine (45 μL, 0.25 mmol) were added to a solution of \-tert- butoxycarbonyl-4-phenylmethyl-piperidine-4-dicarboxylic acid (31 mg, 0.097 mmol) in 1 mL DMF. The reaction was allowed to proceed for 20 hours at room temperature and then the mixture was acidified. Product was purified by preparative reversed phase HPLC to give N-tert-butoxycarbonyl-4-(4,5-dihydro-thiazol-2-ylaminocarbonyl)-4-(phenylmethyl)- piperidine (16 mg, 37 %). MS(ES) m/z 404.2(MH⁺); MS cald: 403.19 (M).

Reference 11

1 -tert-Butyl 4-methyl 4-thiophen-3-ylmethyl-piperidine- 1 ,4-dicarboxylate

Step 1

A solution of phosphorus tribromide (2.24 g, 8.23 mmol) in 10 mL DCM was added dropwise to a solution of 3-thiophenemethanol (0.66 g, 5.8 mmol) in DCM (30 mL) at 0⁰C. The mixture was stirred at room temperature for 3 hours and then poured onto ice. The layers were separated and the organic phase was washed with saturated NaHCO₃ solution, dried over sodium sulfate and concentrated to give 3-bromomethylthiophene (1.1 g) as a clear liquid, which was used in the next step without further purification. Step 2

A solution of lithium diisopropylamide in heptane/THF/ethylbenzene (2.0 M, 1.1 mL, 2.0 mmol) was added dropwise to a solution of 1-tert-butyl 4-methyl piperidine-1,4- dicarboxylate (320 mg, 1.31 mmol) in THF (15 mL) at -78 ⁰C. The mixture was maintained at -78 ⁰C for 15 minutes and then stirred at -20 and -30 °C for 1 hour. A solution of 3- bromomethylthiophene (242 mg, 1.37 mmol) in THF (2 mL) was added dropwise to the chilled mixture and the mixture was maintained at this temperature for 1 hour. The mixture was then allowed to slowly warm to 0 ⁰C and then the reaction was quenched with saturated aqueous NH₄Cl (10 mL). The aqueous phase was separated and extracted with ethyl acetate (20 mL). The combined organic layer was washed with brine (10 mL), dried over Na₂SO4, filtered and concentrated under reduced pressure to give a crude yellow oil. The crude oil was flash chromato graphed [n-hex/EtOAc (9:1 v/v)] to give l-tert-butyl 4-methyl 4-thiophen- 3-ylmethyl-piperidine-l,4-dicarboxylate (100 mg, 23%) as a light yellow oil. MS(ES) m/z 362.4 (MNa⁺); MS cald: 339.15 (M).

Reference 12

1 -tert-Butyl 4-methyl 4-(4-fluoro-phenylmethyl)-piperidine-l ,4-dicarboxylate

Step l

A solution of trimethylsilyl diazomethane in hexanes (2.00 M, 52.9 mL, 106 mmol) was added dropwise to a suspension of l-fert-butoxycarbonyl-piperidine-4-carboxylic acid (12.14 g, 52.95 mmol) in acetonitrile (100 mL) and methanol (10 mL) at 0 °C. The mixture let stand for 30 minutes and then was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and product was purified from the residue by column chromatography [n-hex/EtOAc (4.5:1 v/v)] to give l-tert-butyl 4-methyl piperidine-1,4- dicarboxylate as an oil (11.5 g, 90%). ¹H NMR (400 MHz, d₆-DMSO) δ 4.02 (dt, 2H, J= 3.5, 13.7 Hz), 3.69 (s, 3H), 2.82 (ddd, 2H₅ J= 3, 11.5, 14.5 Hz), 2.45 (tt, 1H, J= 3.9, 11.5 Hz), 1.90-1.84 (m, 2H), 1.67-1.57 (m, 2H), 1.45 (s, 9H). MS(ES) m/z 265.8 (MNa⁺); MS cald: 243.1 (M). Step 2

A solution of lithium diisopropylamide in heptane/THF/ethylbenzene (2.0 M, 35.5 mL, 71.1 mmol) was added dropwise through an addition funnel over 30 minutes to a solution of 1-fert-butyl 4-methyl piperidine-l,4-dicarboxylate (11.53 g, 47.39 mmol) in THF (200 mL) at -78 ⁰C. The mixture was let stand for 15 minutes and then was stirred at 20-30 °C for 50 minutes. The mixture was cooled to -20 °C and then 4-fluorobenzyl bromide (6.50 mL, 52.13 mmol) was added. The mixture was allowed to slowly warm to 0 °C over 2.5 hours and the reaction was quenched with saturated aqueous NH₄Cl (100 mL). The aqueous phase was separated and extracted with ethyl acetate (100 mL). The combined organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a crude orange oil (18.77 g). Product was purified from the crude oil by flash chromatography [n-hex/EtOAc (8:1 v/v)] to give l-tert-butyl 4-methyl 4-(4-fluoro- phenylmethyl)-piperidine-l,4-dicarboxylate (13.5 g, 81%) as a light yellow oil. ¹H NMR (400 MHz, d₆-DMSO) δ 7.11-7.06 (m, 4H), 3.77 (brd, 2H, J= 13.3 Hz), 3.59 (s, 3H), 2.74 (brs, 2H), 1.88 (brd, 2H, J= 13.3 Hz), 1.43-1.36 (m, 2H), 1.38 (s, 9H). MS(ES) m/z 374.1 (MNa⁺); MS cald: 351.2 (M).

Reference 13 l-tert-Butoxycarbonyl-4-(4-fluoro-phenylmethyl)-piperidine-4-carboxylic acid

Step l

A solution of lithium hydroxide monohydrate (11.2 g, 267 mmol) in water (50 mL) was added to a solution of l-tert-butyl 4-methyl 4-(4-fluoro-phenylmethyl)-piperidine-l,4- dicarboxylate (9.37 g, 26.7 mmol), prepared using procedures similar to those in Reference 12, in THF/MeOH (200 mL, 1 :1 v/v). The mixture then was heated to 65 °C for 1 day. The mixture was allowed to cool to room temperature and a solution of sodium hydroxide (I M, 100 mL) and ether (300 mL) was added. The aqueous phase was separated and acidified with cone, hydrochloric acid (~35 mL) to pH 1. The aqueous phase was extracted with ethyl acetate (200 mL, 100 mL) and the organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The ethereal layer was acidified with cone, hydrochloric acid and the aqueous phase separated. The ethereal layer then was dried over Na₂SO₄, filtered to give l-tert-butoxycarbonyl-4-(4-fluoro-phenylmethyl)-piperidine-4- carboxylic acid as a white powder (8.16 g). ¹H NMR (400 MHz, d₆-DMSO) δ 1.29-1.39 (m, 2H), 1.37 (s, 9H), 1.84 (brd, 2H₅ J= 13.2 Hz)₅ 2.78 (brs, 4H), 3.77 (brd, 2H, J= 13.2 Hz)₅ 7.06-7.16 (m, 4H)₅ 12.58 (brs, IH). MS(ES) m/z 336.4 (M-I)-; MS cald: 337.2 (M).

Reference 14 tert-Butyl 4-phenylmethyloxycarbonylmethyl-4-(4-fluoro-phenylmetriyl)-piperidine- 1 - carboxylate

Step l

A solution of oxalyl chloride in DCM (2.00 M, 889 μL, 1.78 mmol) and followed by a drop of DMF was added to a suspension of l-tert-butoxycarbonyl-4-(4-fluoro-phenylmethyl)- piperidine-4-carboxylic acid (150 mg, 0.445 mmol), which can be prepared as in Reference 13, in DCM (4 mL). The reaction was allowed to proceed for 2.5 hours and then the mixture was concentrated under reduced pressure to give tert-butyl 4-chlorocarbonyl-4-(4-fluoro- phenylmethyl)-piperidine-l -carboxylate as an oil. To the crude reaction mixture in THF/ACN (4 mL, 1:1 v/v) was added a solution of trimethylsilyl diazomethane in hexanes (2.00 M, 445 μL, 0.890 mmol). The mixture was stirred for 2.5 hours at room temperature followed by evaporation of solvent under reduced pressure to give tert-butyl 4-(2-diazo- acetyl)-4-(4-fluoro-phenylmethyl)-piperidine-l -carboxylate (145 mg) which was used in the next step without further purification. MS(ES) m/z 384 (MNa⁺); MS cald: 361.2 (M). Step 2

2,4,6-Collidine (0.3 mL, 2 mmol) and benzyl alcohol (0.3 mL, 3 mmol) was added to crude tert-butyl 4-(2-diazo-acetyl)-4-(4-fluoro-phenylmethyl)-piperidine-l -carboxylate (144.6 mg, 0.4 mmol) in in a sealed tube and the mixture was heated at 180 ⁰C for 10 minutes. The mixture was allowed to cool to room temperature and then was diluted with acetonitrile/water. Product was purified by reversed phase HPLC purification to give tert- butyl 4-phenylmethyloxycarbonylmethyl-4-(4-fluoro-phenylmethyl)-piperidine- 1 -carboxylate (34.8 mg, 18% for 2 steps) as a brown oil. ¹H NMR (400 MHz, d₆-DMSO) δ 7.41-7.35 (m, 5H)₅ 7.19-7.04 (m, 4H), 5.13 (s, 2H), 3.54-3.49 (m, 2H), 3.19 (brs, 2H), 2.71 (s, 2H), 2.29 (s, 2H), 1.42-1.29 (m, 4H), 1.37 (s, 9H). MS(ES) m/z 464.4 (MNa⁺); MS cald: 441.2 (M).

Reference 15 tert-Butyl 4-(4-fluoro-ρhenylmethyl)-4-(5-methyl-2H-[ 1 ,2,4]triazol-3-yl)-ρiρeridine- 1 - carboxylate

Step l

<9-(7- Azabenzotriazol- 1 -yϊ)-N,N,N ^J,N'-tetramethyluronium hexafluorophosphate (676 mg, 1.78 mmol) and N,iV-diisopropylethylamine (1.55 mL, 8.89 mmol) was added to a solution of l-tert-butoxycarbonyl-4-(4-fluoro-phenylmethyl)-piperidine-4-dicarboxylic acid (500 mg, 1.48 mmol), which can be prepared as described in Example 12, and NH₄Cl (119 mg, 2.22 mmol) in DMF (8 mL) at room temperature and the reaction was allowed to proceed for 13.5 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with an aqueous solution of hydrochloric acid (IN, 2 x 50 mL), saturated aqueous solution of NaHCO₃ (2 x 50 mL), and brine (50 mL). The organic layer then was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give tert-butyϊ 4~carbamoyl-4-(4-fluoro- phenylmethyl)-piperidine-l -carboxylate (514.5 mg, quantitative) as a white solid. ¹H NMR (400 MHz, d₆-DMSO) δ 1.23-1.30 (m, 2H), 1.37 (s, 9H), 1.88 (brd, 2H, J= 13.3 Hz), 2.75 (s, 2H), 2.82 (brs, 2H), 3.69 (brd, 2H, J= 13.3 Hz), 7.04-7.16 (m, 5H), 7.28 (s, IH). MS(ES) m/z 337.2 (MH⁺); MS cald: 336.2 (M). Step 2

A solution of tert-butyl 4-carbamoyl-4-(4-fluoro-phenylmethyl)-piperidine-l- carboxylate (200 mg, 0.595 mmol) was heated in ΛζiV-dimethylacetamide dimethyl acetal at 100 °C for 2 hours. The mixture was allowed to cool, diluted with ethyl acetate (50 mL) and washed with water (2 x 50 mL) and then brine (15 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a brown oil. A premixed solution of hydrazine (47 μL, 1.5 mmol) and glacial acetic acid (5 mL) was added to the crude oil. The mixture was then heated at 90 °C for 2 hours. The mixture was allowed to cool and poured into water (50 mL). The mixture was extracted with ethyl acetate (50 mL) and the organic layer was separated and washed successively with water (50 mL), saturated aqueous solution OfNaHCO₃ (50 mL) and brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give tert-Butyl 4-(4-fluoro-phenylmethyl)-4-(5- methyl-2H-[l,2,4]triazol-3-yl)-piperidine-l-carboxylate (232.4 mg, quantitative) as an orange semi-solid. ¹H NMR (400 MHz, d₆-DMSO) δ 1.36 (s, 9H), 1.46-1.64 (m, 2H), 2.06 (brd, 2H, J= 12.5 Hz), 2.21 (s, IH), 2.34 (s, 2H), 2.60-2.85 (brs, 2H), 2.81 (bra, 2H), 3.74 (bra, 2H), 6.66-6.98 (m, 4H), 13.09 (s, 0.34H), 13.20 (s, 0.66H). MS(ES) m/z 375.1 (MH⁺); MS cald: 374.2 (M).

Reference 16

4-Acetylamino-4-(4-fluoro-phenylmethyl)-piperidine- 1 -carboxylic acid

Step l

Triethylamine (0.23 mL, 1.6 mmol) and diphenylphosphoryl azide (0.320 mL, 1.48 mmol) was added to a solution of tert-butoxycarbonyl-4-(4-fluoro-phenylmethyl)-piperidine- 4-carboxylic acid (0.500 g, 1.48 mmol), which can be prepared as in Reference 13, in toluene (10 mL) under nitrogen. The solution was heated to 90 ⁰C for five hours and then benzyl alcohol (0.770 mL, 7.40 mmol) was added. The reaction was allowed to proceed at 90 °C for 3 hours and then the mixture was diluted with ethyl acetate (75 mL). The mixture was washed successively with saturated aqueous solution OfNaHCO₃ (50 mL), water (50 mL), and brine (15 mL). Organic extracts were dried over MgSO₄, filtered and concentrated under reduced pressure. Product was purified from the residue by flash chromatography [n- hexanes/EtOAc (4:1 Wv)] to give tert-butyl 4~phenylmethylamino-4-(4-fluoro- phenylmethyl)-piperidine-l-carboxylate (530 mg, 81%) as a colorless oil. MS(ES) m/z 465.4 (MNa⁺);MS cald: 442.2 (M). Step 2

A mixture of tert-butyl 4-phenylmethylamino-4-(4-fluoro-phenylmethyl)-piperidine- 1-carboxylate (0.30 g, 0.68 mmol) and 10% Pd/C (0.03 g) in ethanol (20 mL) was stirred under H₂ at atmospheric pressure for three hours. The mixture was filtered through Celite into a flask containing a solution of hydrochloride in 1,4-dioxane (4 M, 0.34 mL). Concentration of the mixture under reduced pressure yielded tert-butyl 4-amino-4-(4-fluoro-phenylmethyl)- piperidine- 1-carboxylate hydrochloride (208 mg, 89%) as a grainy oil. MS(ES) m/z 342.9 (M-I)^"; MS cald: 344.2 (M). Step 3

Acetic anhydride (40 μL, 0.44 mmol) and triethylamine (66 μL, 0.48 mmol) was added to a solution of tert-buiyϊ 4-amino-4-(4-fluoro-phenylmethyl)-piperidine- 1 -carboxylate hydrochloride (0.15 g, 0.44 mmol) in dichloromethane (5 mL). The reaction was allowed to proceed for 1 hour and the mixture was diluted with ethyl acetate (50 mL). The mixture was washed successively with water (50 mL), aqueous hydrochloric acid (0.1 M, 50 mL), and saturated aqueous solution OfNaHCO₃ (25 mL). The organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure to give 4-acetylamino-4-(4-fluoro- phenylmethyl)-piperidme-l-carboxylic acid (152 mg, quantitative) as a tan oil.

Reference 17 tert-Butyl 4-(4-fluoro-phenylmethyl)-4-hydroxy-piperidine- 1 -carboxylate

Step l

4-Fluorobenzyl magnesium bromide (0.24 M THF solution, 18 mL, 4.5 mmol) was added slowly to a solution of JV-fert-butoxycarbonyl-4-piperidone (600 mg, 3.00 mmol) in THF (20 mL) at 0 ⁰C. The mixture was stirred for 2 hours at room temperature and quenched with 1 mL of saturated NH₄Cl. The mixture was diluted with ether (20 mL) and washed with saturated NH₄Cl solution and saturated sodium chloride. The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/n-hexanes) to give tert-bntyl 4-(4-fluoro-phenylmethyl)-4-hydroxy-piperidine-l- carboxylate (350 mg, 38%). MS(ES) m/z 332.3 (M+Na); MS cald: 309.4 (M), ¹H NMR (400 MHz, CDCl₃): δ 7.17 (m, 2H)₅ 7.00 (m, 2H), 3.85 (m, 2H), 3.08 (m, 2H), 2.74 (s, 2H), 1.58 (m, 2H), 1.50 (s, 9H), 1.46 (m, 2H). Reference 18

Methyl 4-phenylmethyl-piperidine-4-carboxylate hydrochloride

Methyl 1 -tert-butoxycarbonyW-phenylmethyl-piperidine^-carboxylate was dissolved in ethanol (5 mL) and EtOAc (5 mL), and a solution of HCl in dioxane (4N, 1 niL, 4 eq) was added, and the solution warmed at 50 ⁰C until complete by HPLC. 4- (methoxycarbonyl)-4-(phenylmethyl)-piperidine hydrochloride (crop 1, 210 mg, 77%) crystallized as white needles, and was collected by filtration and washed with ether and pentane. MS(ES) m/z 243.0 (MH⁺); MS calc: 233.31 (M).

Proceeding as in Reference 18, but substituting iV-tert-butoxycarbonyl-4-cyano-4- (phenylmethyl)-piperidine, gave 4-cyano-4-phenylmethyl-piperidine hydrochloride.

Proceeding as in Reference 18, but substituting N-tert-butoxycarbonyl-4- (phenylmethyl)-4-(5-oxo-4,5-dihydro-[l ,2,4]oxadiazol-3-yl)-piperidine gave 4- (phenylmethyl)-4-(5-oxo-4,5-dihydro-[l,2,4]oxadiazol-3-yl)-piperidine hydrochloride.

Proceeding as in Reference 18, but substituting iV-tert-butoxycarbonyl-3 -(4- chlorophenylmethyloxy)-pyrrolidine, gave 3 -(4-chlorophenylmethyloxy)-pyrrolidine hydrochloride.

Proceeding as in Reference 18, but substituting N-tert-butoxycarbonyl-4-(4,5-dihydro- thiazol-2-ylaminocarbonyl)-4-(phenylmethyl)-piperidine gave 4-(4,5-dihydro-thiazol-2- ylaminocarbonyl)-4-(phenylmethyl)-piperidine hydrochloride. MS(ES) m/z 304.3(MH⁺); MS cald: 303.19 (M).

Proceeding as in Reference 18, but substituting 4-thiophen-3-ylmethyl-piperidine-l,4- dicarboxylic acid 1-tert-butyl ester 4-methyl ester, gave 4-methoxycarbonyl-4-(thien-3- ylmethyl)-piperidine hydrochloride. MS(ES) m/z 240.9 (M-H⁺); MS cald: 239.1 (M).

Proceeding as in Reference 18, but substituting 4~(4-fluoro-phenylrnethyl)-piperidine- 1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester gave 4-(4-fluoro-phenylmethyl)- piperidine-4-carboxylic acid methyl ester hydrochloride. MS(ES) m/z 251.8 (MH⁺); MS calc: 251.3 (M).

Proceeding as in Reference 18, but substituting l-fert-butoxycarbonyl-4-(4-fmoro- phenylmethyl)-piperidine-4-carboxylic acid, gave 4-(4-fluoro-phenylmethyl)-piperidine-4- carboxylic acid.

Proceeding as in Reference 18, but substituting 4-phenylmethyloxycarbonylmethyl-4- (4-fluoro-phenylmethyl)-piperidine-l -carboxylic acid tert-butyl ester gave [4-(4-fluoro- phenylmethyl)-piperidin-4-yl]-acetic acid phenylmethyl ester hydrochloride. MS(ES) m/z 341.7 (MH⁺); MS cald: 341.2 (M).

Proceeding as in Reference 18, but substituting 4-(4-fluoro-phenylmethyl)-4-(5- methyl-2H-[l,2,4]triazol-3-yl)-piperidine-l-carboxylic acid tert-butyl ester gave 4-(4-fluoro- phenylmethyl)-4-(5-methyl-2H-[l,2,4]triazol-3-yl)-ρiρeridine hydrochloride. ¹H NMR (400 MHz, de-DMSO) δ 1.83-1.91 (m, 2H), 2.29 (d, 2H, J= 14 Hz), 2.47 (s, 3H), 2.72 (brq, 2H, J = 11 Hz), 2.93 (s, 2H), 3.22 (brd, 2H₅ J= 13 Hz), 6.80-7.04 (m, 4H), 8.56-8.70 (m, IH), 8.90- 9.00 (brs, IH). MS(ES) m/z 275.3 (MH⁺); MS cald: 274.2 (M).

Proceeding as in Reference 18, but substituting 4-acetylamino-4-(4-fluoro- phenylmethyl)-piperidine-l -carboxylic acid tert-butyl ester, gave N-[4-(4-fluoro- phenylmethyl)-piρeridin-4-yl]-acetamide hydrochloride. MS(ES) m/z 251.1 (MH⁺), 248.8 (M-I)^"; MS cald: 250.2 (M).

Reference 19

Methyl 4-phenylmethyl-piperidine-4-carboxylate hydrochloride

1-tert-Butyl 4-methyl 4-phenylmethyl-piperidine-l,4-dicarboxylate was dissolved in methanol, saturated with HCl gas, and the reaction was allowed to proceed overnight at room temperature. The solvent was evaporated and the residue was treated with ether to form a white crystalline solid. The crystals were collected by filtration, washed with ether, and dried to give methyl 4-phenylmethyl-piperidine-4-carboxylate (0.31 mg). MS(ES) m/z 234.1(MH⁺); MS cald: 233.14 (M). Reference 20

4-Phenylmemyl~4-(lH-tetrazol-5-yl)-piperidine hydrochloride

A mixture of tert-butyl 4-phenylmethyl-4-cyano-piperidine-l-carboxylate (120 mg, 0.399 mmol), sodium azide (260 mg, 4.00 mmol) and zinc bromide (104 mg, 0.462 mmol) in a mixed solvent of isopropanol (1.5 mL) and water (1.5 mL) was heated to 150 ⁰C in a microwave reactor for 16 hours. The product was separated by preparative HPLC and further lyophilized to give 4-phenylmethyl-4-(lH-tetrazol-5-yl)-piperidine hydrochloride (60 mg, 54%) as a fluffy white solid. LCMS: (M+l)⁺ 244.

Reference 21

4-(4-Fluoro-phenylmethyl)-piperidin-4-ol

Step l

4-Fluorophenylmethyl Grignard reagent was added to a solution of tert-butyl 4-oxo- piperidine-1-carboxylate (199 mg, 1 mmol) in THF (2 mL) at 0⁰C. The mixture was stirred for 1 hour at room temperature, quenched by 1 mL OfNH₄Cl and then diluted with ether (20 mL). The mixture was washed with sat. NH₄Cl solution and brine and concentrated under reduced pressure. Product was purified from the residue by column chromatography (20% EtOAc/n-hexanes) to give 4-(4-fluoro-phenylmethyl)-piperidin-4-ol magnesium bromide (135 mg). LCMS (M+Na)⁺ 332.3, ¹H NMR (400 MHz, CDCl₃): δ 7.17 (m, 2H), 7.00 (m, 2H), 3.85 (m, 2H), 3.08 (m, 2H), 2.74 (s, 2H), 1.58 (m, 2H), 1.50 (s, 9H), 1.46 (m, 2H). Step 2

4 N Hydrochloric acid in dioxane (0.2 mL) was added to a solution of the 4-(4-fluoro- phenylrnethyl)-piperidin-4-ol magnesium bromide (50 mg, 0.16 mmol) in dichloromethane (1 mL) and ACN (1 mL). The mixture was stirred for 1 hour at room temperature and concentrated under reduced pressure to give 4-(4-fluoro-phenylmethyl)-piperidin-4-ol. Reference 22 4-(4-Fluorophenylmethyl)-[l,4]azaphosphinane 4-oxide hydrochloride

Step l

4-fluorobenzyl bromide (25 mL, 0.20 mol) was added to a stirred solution of trimethyl phosphite (35.9 mL, 0.30 mol) at ambient temperature, under a nitrogen atmosphere. The resulting solution was heated at 110 ⁰C for six hours, and then at 90 ⁰C overnight. The reaction mixture was allowed to cool to ambient temperature and then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) and then with saturated brine (2 x 350 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated by rotatry evaporation. The resulting crude product was purified by flash silica chromatrography using 0-35% acetonitrile in ethyl acetate as eluant to yield (4- fluoro-benzyl)-phosphonic acid dimethyl ester (29.44 g, 135 mmol, 66% yield) as a colorless oil. ¹H NMR (400 MHz, DMSO) δ 7.33-7.28 (m, 2H); 7.17-7.12 (d of d, 2H); 3.61-3.58 (d, 6H); 3.31-3.24 (d, 2H); ESMS (m/z): (M+l)⁺ found, 219. Step 2

Bromotrimethylsilane (6.0 mL, 45.4 mmol) was added dropwise to (4-fluoro-benzyl)- phosphonic acid dimethyl ester (4.57g, 20.95 mmol) and stirred in a reaction flask chilled to 0 ⁰C. The resulting solution was allowed to warm to ambient temperature and stirred for an additional hour, then concentrated by rotary evaporation to remove volatiles yielding crude (4-fluoro-benzyl) phosphonic acid bis(trimethylsilyl) ester which was used without further purification. Step 3

To the (4-fluoro-benzyl) phosphonic acid bis(trimethylsilyl) ester was added 25 mL of dry methylene chloride, 12 drops of dry DMF, then dropwise 6 mL of oxalyl chloride (68.3 mmol). The resulting solution was stirred overnight at ambient temperature as gas was generated. The reaction was concentrated by rotary evaporation to yield 5.2 g of a yellow waxy solid that was purified by distillation at reduced pressure to yield 1.71 g (37%) of 4- fluorobenzyl phosphonic dichloride as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.31 (m, 2H); 7.11-7.05 (m, 2H); 3.93-3.87 (d, 2H). Step 4 4-Fluorobenzyl phosphonic dichloride (1.71 g, 7.82 mmol) was dissolved in 10 mL of dry THF, under a nitrogen atmosphere, and chilled to -70⁰C. To this stirred solution was added dropwise vinyl magnesium bromide in THF (18.3 mL, IM). The resulting solution was stirred for 30 minutes at -70 ⁰C. An aqueous solution of ammonium chloride (100 mL, 2M) was chilled to 0 ⁰C and stirred rapidly while the cold reaction mixture was added. The product was extracted into dichloromethane and washed with saturated aqueous sodium bicarbonate, and then with water. The organic phase was dried with sodium sulfate, filtered, and concentrated by rotary evaporation to yield 1.375 g of (4-fluorophenylmethyl) divinyl phosphine oxide (6.55 mmol, 84%) as a white solid. ¹H NMR (400 MHz, CDCl₃) 7.20-7.14 (m, 2H); 7.01-6.95 (m 2H); 6.29-6.08 (m, 6H); 3.20-3.15 (d, 2H); ESMS (m/z): (M+l)⁺ found, 211. Step 5

Divmyl-(4-Fluorophenylmethyl)-phosphine oxide (0.719g, 3.42 mmol) and benzylamine (0.45 mL, 4.11 mmol) were dissolved in a mixture of THF (15 mL) and deionized water (15 mL). The reaction mixture was heated at 82 ⁰C for 22 hours. The reaction was not complete and so an additional 0.04 mL of benzylamine was added and the reaction mixture was heated for an additional six hours at 90 ⁰C. The reaction mixture was concentrated by rotary evaporation and the product was extracted into dichloromethane and washed with saturated brine. The organic phase was dried with sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was taken up in 1 : 1 ethyl acetate: dichloromethane and passed through a plug of silica. The product was then eluted from the silica with a solution of 10% methanol in ethyl acetate. The solvents were removed by rotary evaporation to yield 0.84g of l-benzyl-4-(4-fluorophenylmethyl)- [l,4]azaphosphinane 4-oxide (2.65 mmol, 77%). ¹H NMR (400 MHz, CDCl₃) 7.34-7.25 (m, 5H); 7.25-7.20 (m, 2H); 7.04-6.98. (m, 2H); 3.6 (s, 2H); 3.17-3.12 (d, 2H); 3.00-2.85 (m, 2H); 2.81-2.66 (m, 2H); 1.98-1.75 (m, 4H). Step 6

The material from Step 5 was dissolved in ethanol (100 mL). Aqueous HCl (5.2 mL, lM) and of water (20 mL) were added. The solution was degassed with a stream of nitrogen and then palladium on carbon (10%, 0.5 g) was added. The mixture was hydrogenated on a Parr shaker overnight at 60 psi. The mixture was filtered through Celite and all solvents were removed under reduced pressure. The product was recrystallized from methanol/diethyl ether to yield 0.659g (2.50 mmol, 93%) of 4-(4-fluorophenylmethyl-[l,4]azaphosphinane 4-oxide hydrochloride as a white crystalline solid. ¹H NMR (400 MHz, DMSO) δ 7.38-7.32 (m, 2H); 7.23-7.18 (m, 2H) 3.46-3.36 (m, 6H); 2.10-1.96 (m, 4H); ESMS (m/z): (M+l)⁺ found, 228; (M+23)⁺ found, 250.

The free base of 4-(4-fluorophenylmethyl-[l,4]azaphosphinane 4-oxide hydrochloride was prepared. The free base can be obtained by treating with MP-carbonate resin in an appropriate solvent followed by filtration to remove the resin and then concentrating to remove the solvent.

Reference 23

Ethyl [3'-ethynyl-2'-(2-methoxyethoxymethoxy)-biphenyl-4-yl]-acetate

Step l

3-Bromo-2-(2-methoxyethoxymethoxy)-benzaldehyde (40.0 g, 154 mmol), which was prepared using procedures similar to those described in Reference 1, was dissolved in ethylene glycol dimethyl ether (DME) (10OmL) in a 1 L round-bottom flask. Ethyl [4- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-acetate (40 g, 138 mmol), which can be prepared as described in Reference 2, was dissolved in DME (200 mL) and the solution was added to the flask. A suspension OfK₂CO₃ (38.26 g, 277 mmol in water (75 mL) was added to the flask and the mixture was degassed under nitrogen for 30 minutes. Tetrakis(triphenylphosphine)palladium (0) (400 mg, 0.346 mmol) was added and the mixture was heated in an 85 ⁰C oil bath and stirred for 4 hours under nitrogen. The reaction was determined complete by analytical HPLC. The DME was removed under reduced pressure and the residue was dissolved in ethyl acetate (1 L). The solution was washed with 5% citric acid (2 X 200 mL) and brine (2 X 200 mL), dried over Na₂SO₄, and concentrated. Product was purified from the crude mixture by silica flash chromatography [n-Hexane/EtOAc (4:1 Wv)] to give ethyl 2-[3'-formyl-2'-(2-methoxyethoxymethoxy)-biphenyl-4-yl]-acetate (34.5 g, 67 %). MS(ES) m/z 373.1 (MH⁺); MS calc: 372.41 (M). ¹H NMR (400 MHz₅ DMSO) δ ppm d 1.20 (t, 3H, J= 7 Hz), 3.12 (s, 3H), 3.20 (m, 2H), 3.41 (m, 2H), 3.73 (s, 2H), 4.10 (q, 2H, J= 7 Hz), 4.79 (s, 2H), 7.37-7.43 (m, 3H)₅ 7.51 (brd, 2H, J= 8.2 Hz), 7.70 (dd, IH, J= 2, 7.4 Hz)₅ 7.78 (dd, IH₅ J= 2, 7.8 Hz)₅ 10.34 (s, IH). Step 2 Ethyl [3'-formyl-2'-(2-methoxyethoxymethoxy)-biρlienyl-4-yl]-acetate (19.0 g, 51.0 mmol) and ethanol (200 mL) was added to a 2 L round bottom flask and then CS₂CO₃ (41.6 g, 128 mmol) suspended in ethanol (100 mL) was added to the mixture. The mixture was degassed with nitrogen for 15 minutes while stirring at room temperature and then cooled to 5 °C in an ice bath. l-Diazo-2-oxopropyl)phosphonate (12.8 g, 66.3 mmol) was dissolved in ethanol (50 mL) and the solution added dropwise to the mixture via an addition runnel and then the ice bath was removed. The mixture was stirred for 45 minutes of stirring at room temperature and the diethylether (1 L) was added. The mixture was filtered to remove solids and the organic layer was separated and washed with 5% citric acid (3 X 150 mL), brine (1 X 200 mL), dried over Na₂SO₄, and concentrated. Product was purified from the residue by silica flash chromatography [n-Hexane/EtOAc (4:1 v/v)] to give ethyl [3'-ethynyl-2'-(2- methoxy-ethoxymethoxy)-biphenyl-4-yl]-acetate (15.6 g, 83 %). MS(ES) m/z 391.3 (MNa⁺); MS calc: 368.42 (M). ¹H NMR (400 MHz, DMSO) δ ppm 1.19 (t, 3H, J= 7 Hz), 1.99 (s, IH), 3.10 (m, 2H), 3.10 (s, 3H), 3.23 (m, 2H), 3.70 (s, 2H), 4.09 (q, 2H, J= 7 Hz), 4.93 (s, 2H), 7.22 (t, IH, J= 7.8 Hz), 7.34 (brd, 2H, J= 8.2 Hz), 7.39 (dd, IH, J= 2, 7.4 Hz), 7.44 (brd, 2H, J= 8.2 Hz), 7.50 (dd, IH, J= 2, 7.4 Hz).

Reference 24

Proceeding as in Reference 23, but substituting 3-bromo-2~(2- methoxyethoxymethoxy)-benzaldehyde andN-fe7*t-butoxycarbonyl-4-aminomethyl- phenylboronic acid, gave tert-bntyl [3'-ethynyl-2'-(2-methoxy-ethoxymethoxy)-biphenyl-4- ylmethyl]-carbamate. MS(ES) m/z 434.2(M+Na); MS cald: 411.2(M).

Reference 25

[2'-Hydroxy-3 '-( Ii7-pyrrolo[3 ,2-c]pyridin-2-yl)-biphenyl-4-yl] -acetic acid

Step l iV-(3-Iodo-pyridin-4-yl)-methanesulfonamide (1.61 g, 5.40 mmol), which was prepared using procedures as described in Reference 3, was dissolved in acetonitrile (10 mL) and triethylamine (3.9 mL, 28 mmol). The solution was evacuated and purged with nitrogen. Ethyl [3'-ethynyl-2'-(2-methoxyethoxymethoxy)-biphenyl-4-yl]-acetate (1.9 g, 5.3 mmol), which was prepared using procedures similar to those described in Reference 23, was dissolved in acetonitrile (10 mL) and added to the reaction mixture, followed by dichloro-b/s- (triphenylphosphine) palladium (87 mg, 0.12 mmol) and copper iodide (50.4 mg, 0.265 mmol). The reaction mixture was purged with a mixture of nitrogen / hydrogen after each addition. The reaction was then heated to 70 ⁰C for 2 hours. The solution was concentrated, then partitioned between ethyl acetate (100 mL) and 5% citric acid (100 mL). After washing with brine (100 mL), the organic layer was concentrated to a brownish syrup to give [2'-(2- methoxyethoxymethoxy)-3'-(l-methylsulfonyl-lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4- yl]-acetic acid ethyl ester. MS(ES) m/z 538.5 (MH⁺); MS calc: 538.61 (M). Step 2

[2^l-(2-Methoxyethoxymethoxy)-3'-(l-methylsulfonyl-lH^r-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl] -acetic acid ethyl ester (from the above step) was dissolved in THF (5 mL). Tetrabutylammonium fluoride (TBAF) in THF solution (1 M, 5.3 mL, 5.3 mmol) was added, and the reaction allowed to stir at room temperature. After 2 hours the reaction was concentrated, then flash chromatographed on silica gel [EtOAc/MeOH (9:1 v/v)] to give [2'- (2-methoxyethoxymethoxy)-3'-(liJ-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid ethyl ester as a brownish oil. MS(ES) m/z 461.2 (MH⁺); m/z 459.2 (MH^"); MS calc: 460.52 (M). Step 3

[2^l-(2-Methoxyethoxymethoxy)-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetic acid ethyl ester (from the previous step) was dissolved in acetonitrile (5 mL) and TΗF (5 mL), and mercaptoethylaminomethyl polystyrene scavenger resin (2.0 mmol/g loading, 9 mmol) was added, followed by aqueous HCl (4 N, 6 mL, 24 mmol). The mixture was heated to 50 ⁰C for 24 hours, cooled, and filtered to remove resin. The resin was washed with TΗF, ACN, and water. The product was then purified by reverse-phase preparative ΗPLC to give [2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (727 mg, 39% yield over three steps). MS(ES) m/z 344.8 (MH⁺); m/z 342.5 (MH^"); MS calc: 344.36 (M). ¹H NMR (400 MHz, DMSO) δ 12.36 (brs, IH), 9.24 (s, IH), 8.38 (dd, IH, J= 0.8, 6.6 Hz), 7.95 (d, IH, J= 6.6 Hz), 7.80 (dd, IH, J= 1.6, 7.8 Hz), 7.53 (brd, 2H, J= 8.2 Hz), 7.46 (d, IH, J= 0.8 Hz), 7.38 (brd, 2H, J= 8.2 Hz), 7.34 (dd, IH, J= 1.6, 7.4 Hz), 7.16 (t, IH, J= 7.4 Hz), 3.64 (s, 2H). Reference 26 tert-Butyl [2'-(2-methoxyethoxymethoxy)-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4- ylmethyl]-carbamate

Proceeding as in Reference 25, but substituting tert-butyl [3'-ethynyl-2'-(2-methoxy- ethoxymethoxy)-biphenyl-4-ylmethyl]-carbamate, gave tert-butyl [2'-(2- methoxyethoxymethoxy)-3 '-( lH-pyrrolo [3 ,2-c]pyridin-2-yi)-biphenyl-4-ylmethyl] - carbamate. MS(ES) m/z 504.0 (MH⁺); MS cald: 503.24(M).

Reference 27

[2'-Hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid

Step l iV-(3-Iodo-pyridin-4-yl)-methanesulfonamide (3.00 g, 10.1 mmol), which can be prepared as described in Reference 3, was suspended in acetonitrile (10 ml) and then ethyl [3'-ethynyl-2'-(2-methoxy-ethoxymethoxy)-biphenyl-4-yl]-acetate (3.68 g, 10.9 mmol), as a suspension in acetonitile (10 ml), was added to the sulfonamide suspension. The mixture was stirred at room temperature and then triethylamine (7 mL, 49.8 mmol) was added. The mixture was purged with nitrogen for 15 minutes and dichloro- bis(triphenylphosphine)palladium (III), (212 mg, 0.0302 mmol) was added. Copper iodide (57 mg, 0.18 mmol) was added and the mixture was placed under a hydrogen/nitrogen atmosphere and heated at 75 ⁰C for 2 hours. The reaction was determined complete by analytical HPLC. The mixture was concentrated and eluted through a 3 x 3 inch silica flash plug with ethyl acetate as aluant (100 mL) and concentrated to give ethyl [2'-(2-methoxy- ethoxymethoxy)-3'-(l-methanesulfonyl-lH-pyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]- acetate, which was used in the Step 2 without further purification. Step 2 Ethyl [[2'-(2-methoxy-ethoxymethoxy)-3'-(l-methanesulfonyl-lH-ρyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetate (21.0 g, 40.1 mmol) was suspended in acetonitrile (600 niL) and L-cysteine (9.7 g, 0.080 mmol) and aqueous 4 N HCl (200 mL, 0.8 mol) were added to the suspension. The mixture was heated to 70 ⁰C and stirred for 3 hours. The reaction was detemined complete by analytical HPLC. The acetonitrile was evaporated and the subsequent aqueous residue was adjusted to pH 5 with aqueous 4 N NaOH (approximately 200 mL). A solid precipitated out of solution and was collected and dried to give [2'-hydroxy-3'-(l- methanesulfonyl-lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]-acetic acid (16.9 g, 99 %. ¹H NMR (400 MHz, DMSO) δ ppm 9.19 (s, IH), 8.43 (d, IH, J= 5.5 Hz), 7.69 (d, IH, J= 5.5 Hz), 7.49 (brd, 2H, J= 8.2 Hz), 7.35-7.32 (m, 3H), 7.30 (dd, IH, J= 2, 7.4 Hz), 7.01 (t, IH, J = 7.4 Hz), 6.85 (s, IH), 3.61 (s, 2H), 3.51 (s, 3H). Step 3

A l L round-bottom flask was charged with [2'-hydroxy-3'-(l-methanesulfonyl-li7- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (13.4 g, 31.7 mmol) and then THF (30 ml) was added forming a suspension. The suspension was stirred at room temperature for 10 minutes and NaOH (6.34 g, 159 mmol) in water (150 mL) was added forming a clear, yellow solution. The mixture was warmed in an oil bath at 70 °C for 3 hour. The reaction was determined complete by HPLC analysis. The THF was removed under reduced pressure and aqueous residue adjusted to pH 3-4 by addition of aqueous 6N hydrochloric acid (approximately 25 mL). Solids precipitated out of solution and were collected by filtration to give [2'-Hydroxy-3'-(lH^r-ρyrrolo[2,3-c3pyridin-2-yl)-biρhenyl-4-yl]-acetic acid (10.9 g, 99 %). MS(ES) m/z 345.0 (MH⁺); MS calc: 344.43 (M). ¹H NMR (400 MHz₅ DMSO) δ ppm 12.8 (br s, IH), 8.89 (s, IH), 8.05 (d, IH, J= 6 Hz), 7.91 (d, IH, J= 4 Hz), 7.86 (d, IH, J= 6.4 Hz), 7.59 (d, 2H, J= 6 Hz), 7.38 (d, 2H, J= 8.4 Hz), 7.35 (d, IH, J= 4 Hz), 7.28 (s, IH), 7.10 (t, IH, J= 8.0 Hz), 3.65 (s, 2H).

Reference 28

[2'-Hydroxy-3'-(lH-imidazolo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid

Step l

Pyridine-3,4-diamine (140 mg, 1.28 mmol), methyl 2-(3'-formyl-2'-hydroxy-biphenyl- 4-yl)-acetate (182 mg, 0.673 mmol) and sodium metabisulfite (418 mg, 2.20 mmol) were combined and dissolved in DMF (4 mL) and heated at 130 °C until addition and cyclization were complete as determined by HPLC, LCMS, and TLC [EtOAc/MeOH (9:1 v/v) and CH₂Cl₂/MeOH (9:1 v/v)], 36 hours. The solution was partitioned between EtOAc (50 mL) and saturated sodium bicarbonate (50 ml), the organic layer washed again with brine (50 mL), and concentrated. The residue was purified by silica column chromatography [EtOAc/MeOH (9:1 v/v)] to give methyl 2-[2^l-hydroxy-3'-(lH-imidazolo[4,5-c]ρyridin-2-yl)- biphenyl-4-yl]-acetate. MS(ES) m/z 360.1 (MH⁺); m/z 358.1 (MH^"); MS calc: 359.38 (M). Step 2

Methyl [2'-hydroxy-3'-(li7-imidazolo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetate was dissolved in methanol (3 mL) and acetonitrile (3 mL) and aq. 4 M KOH (0.30 mL, 1.2 mmol) was added. The solution was warmed to 50 °C for 2 hours and then adjusted to pH 3 with aq. 4 N HCl. A precipitated was collected, washed with water and dried to give [2'-hydroxy-3'- (lH-imidazolo[4,5-c]pyridin-2-yl)-biρhenyl-4-yl]-acetic acid (195 mg, 84%). MS(ES) m/z 346.0 (MH⁺); m/z 343.6 (MH^"); MS calc: 345.35 (M).

Reference 29

[2'-Hydroxy-3'-(lH-imidazolo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid

Step l

Pyridine-3,4-diamine (430 mg, 3.94 mmol), Ethyl [3'-formyl-2'-(2- methoxyethoxymethoxy)-biphenyl-4-yl]-acetate (1.1 g, 3.0 mmol), which was prepared using procedures similar to those in Reference 23, Steps 1, and sodium metabisulfite (1.54 g, 8.10 mmol) were combined and dissolved in DMF (4 mL). The mixture was heated at 130 °C until reactions were complete as determined by HPLC, LCMS, and TLC [EtOAc/MeOH (9:1 v/v)] and [CH₂Cl₂/Me0H (9:1 v/v)] at 36 hours. The solution was partitioned between EtOAc (50 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separtated and washed with brine (50 mL) and concentrated. Product was purified form the residue by silica column chromatography [EtOAc/MeOH (9:1 v/v)] to give ethyl [3'-(lH-imidazolo[4,5- c]pyridin-2-yl)-2'-(2-methoxyethoxymethoxy)-biphenyl-4-yl]-acetate (800 mg, 1.73 mmol, 57 %). MS(ES) m/z 462.3 (MH⁺); m/z 460.0 (MH^"); MS calc: 461.51 (M). Step 2

Ethyl [3'-(lH-imidazolo[4,5-c]pyridin-2-yl)-2'-(2-methoxyetlioxyinetlioxy)-biphenyl- 4-yl]-acetate (800 mg, 1.73 mmol) was dissolved in acetonitrile (10 niL) and aq. 4 N hydrochloric acid (4 mL) and the solution was heated at 60 ⁰C for 8 hours. The mixture was allowed to cool to room temperature. A precipitate was collected, washed with acetone and acetonitrile, and dried to give [3'-(lH-imidazolo[4,5-c]pyridin-2-yl)-2'-hydroxy-biphenyl-4- yl]-acetic acid (600 mg, quantitative). MS(ES) m/z 345.8 (MH⁺); m/z 343.8 (MH^"); MS calc: 345.35 (M).

Reference 30

[5^l-Chloro-2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid

Step l

4 N hydrogen chloride in dioxane (5 mL) was added to a solution of [2'-hydroxy-3'- (l-methanesulfonyl-l//-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (248 mg, 0.587 mmol), prepared as in Reference 27, in MeOH (15 mL). The mixture was stirred for 1 hour at 60⁰C and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and the solution waas washed with sat. NaHCO₃ solution and then brine, dried over MgSO₄ and concentrated under reduced pressure to give crude methyl 2-[2'-hydroxy-3'-(l- methanesulfonyl-lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetate. Step 2 iV-Chlorosuccinimide (102 mg, 0.764 mmol) was added to a solution of methyl [2'- hydroxy-3'-(l-methanesulfonyl-l//-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetate in THF (6 mL). The mixture was stirred for 2 hours at 50 ⁰C and then diluted with ethyl acetate (30 mL). The mixture was washed with sat. NaHCO₃ solution and then brine, dried over MgSO₄ and concentrated under reduced pressure. Product was purified from the crude residue by column chromatography (10% EtOAc/n-hexanes) to give methyl 2-[5'chloro-2'- hydroxy-3'-(l-methanesulfonyl-lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetate (96 mg, 35%) as a pale yellow viscous oil. LCMS (M+l)⁺ 471.1; ¹H NMR (400 MHz, CDCl₃): δ 9.16 (s, IH), 8.30 (d, IH), 7.52 (d, 2H), 7.48 (d, IH), 7.41 (d, 2H), 7.38 (d, IH), 7.31 (d, IH), 7.30 (s, IH), 6.72 (s, IH), 3.74 (s, 3H), 3.70 (s, 2H), 3.23 (s, 3H). Step 3

0.21 M aq. Sodium hydroide (3 mL) was added to a solution of methyl [5'chloro-2⁵- hydroxy-3'-(l-methanesulfonyl-lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetate (100 mg, 0.21 mmol) in THF (5 mL). The mixture was stirred for 6 hours at 65 ⁰C and then the THF was removed under reduced pressure. The aqueous solution was adjusted to pH 6 to give a precipitate. The precipitate was collected by filtration, washed with water several times and dried under vacuum to give [5'-chloro-2'-hydroxy-3'-(li7-pyrrolo[2,3-c]pyridin-2- yl)-biphenylyl-4-yl]-acetic acid (80 mg, quantitative) as a pale yellow solid. LCMS (M+l)⁺ 378.7; ¹H NMR (400 MHz, DMSOd₃): δ 8.75 (s, IH), 7.89 (d, IH), 7.82 (d, IH), 7.63 (d, IH), 7.60 (d, 2H), 7.31 (d, 2H), 7.25 (d, IH), 7.16 (s, IH), 3.61 (s, 2H).

Reference 31

[3'-(3-Chloro-lH-pyrrolo[2,3-c]pyridin-2-yl)-2'-hydroxy-biphenyl-4-yl]-acetic acid

Step l

N-Chlorosuccinimide (70 mg, 0.52 mmol) was added to a solution of ethyl [2'-(2- methoxyethoxymethoxy)-3'-(l//-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetate (200 mg, 0.43 mmol) in THF (8 mL). The mixture was stirred for 5 hours at ambient temperature and then diluted with ether (30 mL) and ethyl acetate (30 mL). The mixture was washed with sat. NaHCO₃, and brine, dried over MgSO₄ and concentrated under reduced pressure. Product was purified from the crude residue by column chromatography (80% EtOAc/n-hexanes) to give ethyl [2^l-(2-methoxyethoxymethoxy)-3'-(3-chloro-lH^"-pyrrolo[2,3-c]pyridin-2-yl)- biρhenyl-4-yl]-acetate (135 mg, 63%) as a pale yellow viscous oil. LCMS (M+l)⁺ 495.3, ¹H NMR (400 MHz₅CDCl₃) δ 8.88 (s, IH), 8.36 (s, IH), 7.92 (m, IH), 7.62 (d, IH), 7.56 (d, 2H), 7.48 (m, IH), 7.40 (m, 3H), 4.70 (s, 2H), 4.23 (q, 2H), 3.71 (s, 2H), 3.34 (m, 4H), 3.29

(s, 3H), 1.31 (t, 3H).

Step 2

Cysteine (75 mg, 0.62 mmol) and 4 N hydrogen chloride in dioxane (1 mL) was added to a solution of ethyl [2'-(2-methoxyethoxymethoxy)-3'-(3-chloro-lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetate (128 mg, 0.259 mmol) in acetonitrile (5 mL). The mixture was stirred for 2 hours at 60 ⁰C and then concentrated under reduced pressure and adjusted to apH of 6 to give 2-[2'-hydroxy-3'-(3-chloro-l/i-pyrrolo[2,3-c]pyridin-2-yl)- biρhenyl-4-yl]-acetic acid as a pale yellow solid (80 mg). LCMS (M+l)⁺ 379.1, ¹H NMR (400 MHz, DMSOd₃) δ 8.80 (s, IH), 8.02(s, IH), 7.59 (d, 2H), 7.56 (d, IH), 7.35 (d, IH)₅ 7.33 (m, 3H), 7.03 (dd, IH), 3.63 (s, 2H).

Reference 32 {4-[2-Hydroxy-3-(l/i-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-piρeridin-l-yl}-acetic acid

Step l

A suspension of commercially available 4-(2-methoxyphenyl)-piperidine (5.0 g, 26.1 mmol) in 48% HBr, aq. (20 mL) was heated at reflux for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 4-(2- hydroxyphenyl)-piperidine which was used in the next step without further purification. Step 2

To a solution of 4-(2-hydroxyphenyl)-piperidine in acetonitrile (65 mL) and water (65 mL) at ambient temperature was added NaOH (20 mL, IM solution, 20.0 mmol) and benzyl chloroformate (2.25 mL, 16.0 mmol). After stirring for 10 min, the reaction was extracted into methylene chloride and washed with acidified aq. NH₄Cl (pH 2). The aqueous layer was separated and extracted with methylene chloride (3x100 mL). The organic layers were combined, washed with brine (50 mL), dried over Na₂SO₄, and concentrated. The residue was purified by flash column chromatography (hexanes/ethyl acetate, 3:1) to give 4-(2- hydroxy-phenyl)-piperidine-l-carboxylic acid benzyl ester (2.9 g, 42% over Steps 1 and 2): ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.44-7.35 (m, 5H), 7.16-7.09 (m, 2H), 6.93 (dt, J= 7.6, 1.2 Hz, IH), 6.80 (dd, J= 8.4, 1.2 Hz, IH), 5.86 (s, IH), 5.21 (s, 2H), 4.37 (s, 2H), 3.12 (tt, J = 12.4, 3.6 Hz₅ IH), 2.96 (m, 2H), 1.90 (d, J= 12.8, 2H), 1.73-1.67 (in, 2H)₅ MS (calc): 311.2; MS: 312.5 (M+H)⁺, 310.8 (M-H)^". Step 3

To a solution of 4-(2-hydroxy-phenyl)-piperidine-l-carboxylic acid benzyl ester (2.2 g, 7.07 mmol) in THF (12 mL) was added triethylamine (5.2 mL), paraformaldehyde (prilled, 1.07 g, 35.4 mmol) and MgCl₂ (2.55 g, 26.5 mmol). The resulting mixture was heated at 60 °C for 24 h, and was cooled to room temperature. The reaction was quenched with slow addition of phosphoric acid, and the product extracted into ethyl acetate (3x100 mL). The organic layers were combined, washed with water (50 mL), brine (50 mL), dried over Na₂SO₄, and concentrated. The residue was purified by flash column chromatography (hexanes/ethyl acetate, 2:1) to give 4-(3-formyl-2-hydroxy-phenyl)-piperidine-l-carboxylic acid benzyl ester (1.7 g, 71 %) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ (ppm) 11.46 (s, IH), 9.92 (s, IH), 7.48-7.30 (m, 7H), 7.28 (t, J= 7.6 Hz₅ IH), 5.20 (s, 2H), 4.38 (s, 2H), 3.22 (tt, J- 12.0, 3.6 Hz, IH), 2.98 (bs, 2H), 1.90 (d, J= 12.4 Hz, 2H), 1.25 (m, 2H). Step 4

To a solution of 4-(3-formyl-2-hydroxy-phenyl)-piperidine-l-carboxylic acid benzyl ester (1.70 g, 5.17 mmol) in DMF (5.0 mL) at 0 ⁰C was added Cs₂CO₃ (2.02 g, 6.20 mmol) and methoxyethoxymethylchloride (0.71 mL, 6.20 mmol). After stirring at room temperature for 1 h, the mixture was added to water and ethyl acetate. The aqueous layer was separated and was extracted with ethyl acetate (3x75 mL). The organic layers were combined, washed with brine (40 mL), dried and concentrated to give 4-[3-formyl-2-(2-methoxy- ethoxymethoxy)-phenyl]-piperidine-l-carboxylic acid benzyl ester which was used in the next step without further purification. Step 5

To a solution of 4-[3-formyl-2-(2-methoxy-ethoxymethoxy)-phenyl]-piperidine-l- carboxylic acid benzyl ester in ethanol (25 mL) was added Cs₂CO₃ (4.21 g, 12.91 mmol). The resulting suspension was purged with argon for 10 min. To this mixture at 0 ⁰C was added a solution of dimethyl- l-diazo-2-oxopropylphosphonate [Ohira, S. Synth. Commun. 1989, 19, 561-54] (1.49 g, 7.76 mmol) in EtOH (3 mL), and the reaction was warmed to ambient temperature. After 40 min of stirring at ambient temperature, the reaction was quenched with a mixture of 5% NaHCO₃ and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (3x75 mL), the organic layer was combined, washed with brine (40 mL), dried and concentrated. The residue was purified by flash column chromatography (hexanes/ethyl acetate, 2:1) to give 4-[3-ethynyl-2-(2-methoxy- ethoxymethoxy)-phenyl]-piperidine-l-carboxylic acid benzyl ester (1.40 g, 64% over Steps 3 and 4) as a colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.43-7.35 (m₅ 6H), 7.21 (dd, J= 7.6, 1.6 Hz, IH), 7.08 (t, J= 7.6 Hz, IH), 5.37 (s, 2H), 5.19 (s, 2H), 4.36 (bs, 2H), 3.99-3.96 (m, 2H), 3.63-3.61 (m, 2H), 3.42 (s, 3H), 3.33-3.26 (m, IH), 2.97 (bs, 2H), 2.08 (s, IH)₅ 1.86-1.83 (m, 2H), 1.62 (m, 2H). MS (calc): 423.2; MS: 424.2 (M+H)⁺. Step 6

To a suspension of 4-[3-ethynyl-2-(2-methoxy-ethoxymethoxy)-ρhenyl]-piperidine-l- carboxylic acid benzyl ester (1.40 g, 3.31 mmol) and N-(4-iodo-pyridin-3-yl)- methanesulfonamide (1.0 g, 3.34 mmol), prepared using procedures as described in Reference 4, in acetonitrile (8 mL) was added triethylamine (2.31 rnL, 16.55 mmol). The solution was purged with argon for 10 min. PdCl₂(PPh₃)₂ (0.07 g, 0.1 mmol) and CuI (0.019 g, 0.1 mmol) were added . After purging with argon for an additional 10 min, the reaction was heated at 75 °C for 2 h. The solution was concentrated, and the residue was purified by flash column chromatography (methylene chloride/MeOH, 40:1) to give 4-[3-(l-methanesulfonyl-lH- pyrrolo[2,3-c]pyridin-2-yl)-2-(2-methoxy-ethoxymethoxy)-phenyl]-piperidine-l-carboxylic acid benzyl ester (1.75 g, 89%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.44- 7.23 (m, HH), 6.72 (s, IH), 5.20 (s, 2H), 4.93 (bs, IH), 4.81 (bs, IH), 4.39 (bs, 2H), 3.62 (m, IH), 3.44 (m, IH), 3.32-3.21 (m, 10 H), 2.93 (bs, 2H), 1.80-1.60 (m, 3H). MS (calc): 593.2; MS: 594.2 (M+H)⁺, 592.2 (M-H)^". Step 7

To a solution of 4-[3-(l-methanesulfonyl-lH-pyrrolo[2,3-c]pyridin-2-yl)-2-(2- methoxy-ethoxymethoxy)-phenyl]-piperidine-l-carboxylic acid benzyl ester (1.60 g, 2.70 mmol) in methylene chloride (8.5 mL) at ambient temperature was added HBr (30% in acetic acid, 2.1 mL). After stirring for 10 min, ether was added. The resulting precipitate was isolated by filtration and dried to give 2-(l-methanesulfonyl-lH-pyrrolo[2,3-c]pyridin-2-yl)- 6-piperidin-4-yl-phenol as the HBr salt (1.45 g, 97%) which was used without further purification. Step 8

To a suspension of 2-(l-methanesulfonyl-lH-ρyrrolo[2,3-c]pyridin-2-yl)-6-piperidin- 4-yl-phenol as the HBr salt (1.35 g, 2.50 mmol) in acetonitrile (12.5 mL) at ambient temperature was added 7V,iV-diisopropylethylamine (0.178 mL, 10.0 mmol) and ethyl bromoacetate (0.28 mL, 2.5 mmol). The solution gradually turned to clear. After stirring for 10 min, the mixture was concentrated, and the residue was dissolved in IN HCl (50 mL), extracted with ether (2x20 mL). The aqueous layer was then lyophilized to give {4-[2- hydroxy-3-(l-methanesulfonyl-lH-ρyrrolo[2,3-c]pyridin-2-yl)-phenyl]-piperidin-l-yl}-acetic acid ethyl ester. MS (calc): 457.2; MS: 458.0 (M+H)⁺, 456.1 (M-H)⁺. Step 9

To a solution of {4-[2-hydroxy-3-(l-methanesulfonyl-l/f-pyrrolo[2,3-c]pyridin-2-yl)- phenyl]-piperidin-l-yl}-acetic acid ethyl ester in THF (2.2 mL) and H₂O (11.0 mL) was added solid NaOH (1.2 g, 30 mmol). The mixture was heated at 65 ⁰C for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by preparative hplc to give {4-[2-hydroxy-3-(lH-pyrrolo[2,3-c]pyridin-2-yl)~ phenyl]-piperidin-l-yl}-acetic acid (0.6 g, 60 % over Steps 7-9). ¹H NMR (400 MHz, DMSO) δ (ppm) 8.96 (s, IH), 8.15 (d, J= 6.8 Hz, IH), 7.97 (d, J= 6.4 Hz, IH), 7.74 (dd, J= 8.0, 1.6 Hz, IH), 7.31 (s, IH), 7.25 (d, J= 7.2 Hz, IH), 7.05 (t, J= 7.2 Hz, IH), 4.09 (s, 2H), 3.57-3.16 (m, 8 H), 2.01-1.89 (m, 4H). MS (calc): 351.2; MS: 352.5 (M+H)⁺, 350.3 (M-H)^".

Reference 33

3 -Amino- 1,1,1 -trifluoro-6-phenyl-hexan-2-ol

Step l

To a solution of 2-tert-butoxycarbonylamino-5-phenyl-pentanoic acid (330 mg, 1.12 mmol) in DCM (4 mL) was added at room temperature l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (260 mg, 1.35 mmol), 1-hydroxybenzotriazol hydrate (182 mg, 1.35 mmol), iV-methoxy-N-methylamine hydrochloride (163 mg, 1.68 mmol) and N,N- diisopropylethylamine (608 μL, 3.36 mmol). After stirring for 1 hour, the mixture was diluted with ethyl acetate, washed with 1 Ν HCl, sat. NaHCO₃, and brine. The organic layers were collected and dried over Na₂SO₄. Ethyl acetate was removed under vacuo, and the residue was purified by column chromatography (hexanes / ethyl acetate, 3:1) to provide [1- (methoxy-methylcarbamoyl)-4-phenylbutyl] carbamic acid tert-butyl ester (210 mg, 56%). MS (ES) m/z: 359.1(M+23)⁺; MS cald: 336.20 (M). Step 2

To a solution of [l-(methoxy-methylcarbamoyl)-4-phenylbutyl] carbamic acid tert- butyl ester (200 mg, 0.613 mmol) in ether (6 mL) at -40 ⁰C was added LiAlH₄ in ether (1 M, 1.23 mL, 1.23 mmol). The mixture was gradually warmed to 0 °C and stirred for additional 10 minuntes at 0 ⁰C. The reaction was diluted with ethyl acetate, washed with acidified sat. NH₄Cl solution, sat NaHCO₃, and brine. The organic layer were collected, dried over Na₂SO₄, and concentrated to yield crude (l-formyl-4-phenyl-butyl)-carbamic acid tert-butyl ester, which was used directly in the next step. Step 3

To a solution of (l-formyl-4-phenyl-butyl)-carbamic acid tert-butyl ester, from Step 2, in THF (4 mL) at 0 °C was added trimethyltrifluromethylsilane (144 μL, 0.92 mmol) and tetrabutylammonium fluoride in THF (1 M, catalytic amount). After stirring for 10 minutes at 0 ⁰C, the reaction mixture was diluted with ethyl acetate, washed with sat. NaHCO₃, and brine. The organic layers were collected, dried over Na₂SO₄, and concentrated to yield 3-tert- butoxycarbonylamino- 1,1,1 -trifluoro-ό-phenyl-hexan-2-ol. Step 4

The product from Step 3 was dissolved in DCM (2 mL) and was treated with HCl in dioxane (4 M, 2 mL). After stirring overnight, the mixture was concentrated to give crude 3- amino- 1,1,1 -trifluoro-6-phenyl-hexan-2-ol.

Example 1

4-Hydroxy-4-phenylmethyl- 1 - {2- [5 ' chloro-2'-hydroxy-3 '-(lH-ρyrrolo[2,3 -c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine

4-Phenylmethyl-piperidin-4-ol (30 mg, 0.16 mmol), EDCI (38 mg, 0.19 mmol), HOBt (24 mg, 0.16 mmol) and DIPEA (0.07 mL, 0.40 mmol) were added to a solution of [5'- chloro-2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (59 mg, 0.16 mmol) in DMF (1 mL) in an ice bath. The mixture was stirred for 24 hours and diluted with ethyl acetate (50 mL). The mixture was washed with sat. NaHCO₃, and brine, dried over MgSO₄ and concentrated under reduced pressure. Product was purified from the crude residue by preparative HPLC and lyophilized to give 4-hydroxy-4-phenylmethyl-l-{2- [5'chloro-2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine (40 mg, 45% yield) as pale yellow solid. LCMS (M+l)⁺ 552.3.

Examples 2-24

Proceeding as in Example 1, but substituting [2^l-hydroxy-3'-(lΗ-pyrrolo[3,2- c]pyridin-2-yl)-biphenyl-4-yl] -acetic acid and 4~phenylmethyl-piperidin-4-ol, gave 4- hydroxy-4-phenylmethyl- 1 - {2-[2'-hydroxy-3 '-(lH-ρyrrolo[2,3-c]pyridin~2-yl)-biphenyl-4-yl]- acetyl}-ρiρeridine. MS(ES) CaId. 517.62. MS(ES) Obsd. m/z 518.4. MS(ES) Obsd. m/z 518.4.

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(lH-pyrrolo[3,2- c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid and 1-benzyl-piperazine, gave 4-phenylmethyl-l- {2-[2'-hydroxy-3'-(li-^r-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperazine. MS(ES) CaId. 502.61. MS(ES) Obsd. m/z 503.1 (MH⁺); m/z 501.3 (MH^').

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(lH-pyrrolo[3,2- c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid and methyl 4-phenylmethyl-piperidine-4- carboxylate, gave 4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl }-piperidine-4-carboxylic acid methyl ester. MS(ES) CaId. 559.65. MS(ES) Obsd. m/z 559.8 (MH⁺); m/z 558.4 (MH^").

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(l-methanesulfonyl-lH- pyrrolo [2,3 -c]pyridm-2-yl)-biphenyl-4-yl] -acetic acid and 4-cyano-4-phenylmethyl- piperidine, and then deprotecting gaveN-[2'-hydroxy-3'-(l/f-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-ylmethylcarbonyl]-4-(cyano)-4-(phenylmethyl)-piperidine.

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(l-methanesulfonyl-lϋ/- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid and 4-(phenylmethyl)-4-(lH-tetrazol- 5-yl)-piperidine hydrochloride, gave 4-phenylmethyl-4-(lH-tetrazol-5-yl)-l-{2-[2'-hydroxy- 3^l-(lH^"-pyrrolo[2,3-c]pyridm-2-yl)-biphenyl-4-yl]-acetyl}-piperidine.

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(l-methanesulfonyl-lH- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid and 4-(phenylmethyl)-4-(5-oxo-4,5- dihydro-[l,2,4]oxadiazol-3-yl)-piperidine, and then deprotecting gave 3-(4-Phenylmethyl-l- {2-[2'-hydroxy-3'-(lΗ-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidin-4-yl)-4Η- [l,2,4]oxadiazol-5-one.

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(l-methanesulfonyl-lH- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid and 3-(4~chlorophenylmethyloxy)- pyrrolidine gave 3-(4-chloro-phenylmethyloxy)-l- {2-[2'-hydroxy-3'-(lϋ-^r-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-pyrrolidine.

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(3-chloro-lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (19 mg, 0.050 mmol) and 4-(phenylmethyl)-4-(lH- tetrazol-5-yl)-piperidine (12 mg, 0.049 mmol) gave 4-phenylmethyl-4-(liϊ-tetrazol-5-yl)-l- {2-[2'-hydroxy-3^l-(3-chloro-lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine (13 mg, 43% yield). LCMS (M+l)⁺ 604.3.

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (55 mg, 0.16 mmol) and 4-(4-fluoro- phenylmethyl)-piperidm-4~ol in DMF (2 mL) gave 4-(4-fluorophenylmethyl)-4-hydroxy-l- {2-[2'-hydroxy-3'-(lH^r-pyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-yl]-acetyl}-ρiρeridine (31 mg, 36% yield). LCMS (M+l)⁺ 536.1, ¹H NMR (400 MHz, DMSOd₃): δ 13.25 (br, IH)₅ 9.65 (br, IH), 9.03 (s, IH), 8.30 (d, IH)₅ 8.08 (d, IH)₅ 7.90 (d, IH)₅ 7.50 (d, 2H)₅ 7.42 (s, IH)₅ 7.39 (d, IH), 7.31 (d, 2H), 7.22 (m, 3H), 7.05 (dd, 2H)₅ 4.12 (m, IH), 3.73 (m, 3H), 2.85 (m, IH), 2.67 (s, 2H), 1.45 (m, 4H).

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (190 mg, 0.551 mmol) and methyl 4-phenylmethyl- piperidine-4-carboxylate hydrochloride (150 mg, 0.55 mmol) gave methyl 4-phenylmethyl-l- {2-[2'-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4- carboxylate (130 mg, 46%). ¹H NMR (400 MHz, d_δ-DMSO) δ 9.04 (s, IH,), 8.26 (d, IH, J =6.8 Hz), 8.08 (d, IH, J= 6.0 Hz), 7.90 (dd, IH₅ J= 1.6, 7.8 Hz), 7.52 (brd, 2H, J= 8.0 Hz), 7.42 (s, IH), 7.41 (dd, IH, J= 1.6, 6.4 Hz), 7.35 (brd, 2H, J= 8.2 Hz), 7.31-7.19 (him, 4H), 7.04 (d, 2H, J= 8.4 Hz), 4.22 (brd, IH₅ J= 13 Hz)₅ 3.95 (brd, IH, J= 13 Hz), 3.78 (dd, 2H, J = 15 Hz)₅ 3.60 (s, 3H)₅ 3.06 (t, IH, J= 12 Hz), 2.84 (d, 2H, 7=3.2), 2.69 (bit, IH, J= 12 Hz), 1.96 (brt, 2H₅ J= 13 Hz), 1.44 (brq, 2H, J= 11 Hz); MS(ES) m/z 560.0(MH⁺); MS cald: 559.25 (M).

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (15 mg, 0.044 mmol) and iV-(4,5-dihydro-thiazol- 2-yl)-4-phenylmethyl-piperidine-4-carboxamide hydrochloride (12 mg, 0.035 mmol) gave iV- (4,5-dihydro-thiazol-2-yl)-4-phenylmethyl-l-{2-[2^t-hydroxy-3^I-(lH-pyrrolo[2,3-c]pyridin-2- yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide (10 mg, 40% yield). MS(ES) m/z 630.4(MH⁺); MS cald: 629.25 (M).

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (50 mg, 0.13 mmol) and methyl 4-thiophen-3- ylmethyl-piperidine-4-carboxylate hydrochloride (38 mg, 0.14 mmol) gave methyl l-{2-[2'- hydroxy-3'-(lΗ-pyπOlo[2₅3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4-thiophen-3-ylmethyl- piperidine-4-carboxylate (60 mg, 82%). MS(ES) m/z 566.2(MH⁺); MS cald: 665.20 (M).

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (25 mg, 0.073 mmol) and l-piperidin-4-yl-l,3- dihydro-benzoimidazol-2-one (16 mg, 0.072 mmol) gave l-(l-{2-[2'-hydroxy-3'-(lΗ- pyrrolo[2₅3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidin-4-yl)-l₅3-dihydro- benzoimidazol-2-one (21 mg, 65%). MS(ES) m/z 544.2(MH⁺); MS cald: 543.23 (M).

Proceeding as in Example I₅ but substituting [2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (30 mg₅ 0.087 mmol) and 4-piperazinothieno[3,2- d]ρyrimidine (25 mg, 0.093 mmol) gave 4-(thieno[3,2-d]ρyrimidm-7-yl)-l-{2-[2'-liydroxy-3'- (lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]-acetyl}-piρerazine (30 mg, 64%). MS(ES) m/z 547.5MH⁺); MS cald: 546.18 (M).

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(lH~ρyrrolo[2,3- c]pyridin-2-yl)-biplienyl-4-yl]-acetic acid (23.4 mg, 0.0680 mmol) and 4- (phenylmethyloxycarbonylmethyl)-4-(4-fluorophenylmethyl)-pipeπdme hydrochloride (47.7 mg, 0.0747 mmol), and then deprotecting gave (4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy- 3'-(lΗ-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidin-4-yl)-acetic acid (22 mg, 67%). ¹H NMR (400 MHz, d₆-DMSO) δ 9.02 (s, IH), 8.24 (d, IH, J= 6.5 Hz), 8.06 (d, IH, J = 6.5 Hz), 7.89 (dd, IH, J= 1.5, 7.5 Hz), 7.41 (s, IH), 7.52 (d, 2H, J= 8 Hz), 7.39 (dd, IH, J = 1.5, 7.9 Hz), 7.33 (d, 2H, J- 8Hz), 7.25-7.21 (m, 2H), 7.18 (t, IH, J= 7.9 Hz), 7.11 (brt, 2H, J= 9Hz), 3.84-3.70 (m, 2H), 3.76 (s, 2H), 3.46-3.25 (m, 2H), 2.77 (s, 2H), 2.19 (s, 2H), 1.50-1.30 (m, 4H). MS(ES) m/z 578.2 (MH⁺); MS cald: 577.2 (M).

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(liJ-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl] -acetic acid (86 mg, 0.25 mmol) and 4-(5-methyl-2H- [l,2,4]triazol-3-yl)-4-(4-fluorophenylmethyl)-piperidine hydrochloride (101 mg, 0.325 mmol) gave 4-(4-fluoro-phenylmethyl)-4-(5-methyl-2H-[l,2,4]triazol-3-yl)-l-{2-[2'-hydroxy-3'-(lH- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine (62.0 mg, 41%). ¹H NMR (400 MHz, d₆-DMSO) δ 13.04 (s, IH), 9.64 (s, IH), 9.03 (s, IH), 8.26 (d, IH, J= 6.3 Hz), 8.07 (d, IH, J= 6.3 Hz), 7.90 (dd, IH, J= 1.6, 7.8 Hz), 7.50 (brd, 2H, J= 8.2 Hz), 7.42 (s, IH), 7.39 (dd, IH, J= 1.6, 7.4 Hz), 7.31 (brd, 2H, J= 8.2 Hz), 7.19 (t, IH, J= 7.4 Hz), 6.98 (t, 2H, J= 9 Hz), 6.74 (dd, 2H, J= 5.5, 8.6 Hz), 4.22 (brd, IH, J= 13 Hz), 3.92 (brd, IH, J= 13 Hz), 3.82 (d, IH, J= 15 Hz), 3.72 (d, IH, J= 15 Hz), 3.00 (t, IH, J= 12 Hz), 2.89 (s, 2H), 2.62 (brt, IH, J= 12 Hz), 2.42 (s, 3H), 2.15 (brd, 2H, J= 13 Hz), 1.59 (brq, 2H, J= 11 Hz). MS(ES) m/z 601.4 (MH⁺); MS cald: 600.3 (M).

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(lH^"-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (119 mg, 0.346 mmol) and N-[4-(4-fluoro- phenylmethyl)-piperidin-4-yl]-acetamide hydrochloride salt (122 mmol, 0.424 mmol) gave N-(4-(4-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3^l-(lH-pyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl- 4-yl]-acetyl}-piρeridin-4-yl)-acetamide (24 mg, 10%). ¹H NMR (400 MHz, d₆-DMSO) δ 9.02 (s, IH), 8.24 (d, IH, J= 6.3 Hz), 8.06 (d, IH, J= 6.3 Hz), 7.90 (dd, IH, J= 1.7, 8 Hz), 7.52 (brd, 2H, J= 8.2 Hz), 7.42 (s, IH), 7.39 (dd, IH, J= 1.8, 7.7 Hz), 7.25 (s, IH), 7.18 (t, IH, J= 7.7 Hz), 7.14-7.06 (m, 4H), 4.17 (brd, IH, J= 14.3 Hz), 3.82 (brd, 2H, J= 15.5 Hz), 3.72 (d, IH, J= 15.5 Hz), 3.11 (hit, IH, J= 12 Hz), 2.98 (d, IH, J= 13 Hz), 2.93 (d, IH, J= 13 Hz), 2.73 (brt, IH, J= 12 Hz), 2.06-1.97 (m, 2H), 1.84 (s, 3H), 1.40-1.30 (m, 2H). MS(ES) m/z 577.3 (MH^"1); MS cald: 576.3 (M).

Proceeding as in Example 1, but substituting [2'~hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl] -acetic acid (50 mg, 0.145 mmol) and 4-(4-fluoro- phenylmethyl)-piperidine-4-carboxylate hydrochloride (50 mg, 0.173 mmol, 1.2 eq) gave methyl 4-(4-fluoro-ρhenylmethyl)-l-{2-[2^l-hydroxy-3'-(lΗ-ρyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperidine-4-carboxylate (69.8 mg, 83 % yield). MS(ES) m/z 578.0 (MH⁺); m/z 576.3 (MH^"); MS calc: 577.64 (M).

Proceeding as in Example 1, but substituting [3'-(lH-imidazolo[4,5-c]pyridm-2-yl)-2'- hydroxy-biphenyl-4-yl] -acetic acid and methyl 4-(4-fluoro-phenylmethyl)-piperidine-4- carboxylate hydrochloride, gave methyl 4-(4-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(lH- imidazo[4,5-c]pyridin-2-yl)-biρhenyl-4-yl]-acetyl}-piperidine-4-carboxylate. MS(ES) m/z 579.1 (MH⁺); m/z 577.4 (MH^"); MS calc: 578.63 (M).

Proceeding as in Example 1, but substituting [2'-hydroxy-3'-(l/ir-pyrrolo[3,2- c]pyridin-2-yl)-biphenyl-4-yl] -acetic acid and methyl 4-phenylmethyl-piperidine-4- carboxylate hydrochloride, gave 4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylic acid. MS(ES) m/z 546.5 (MH⁺); m/z 544.0 (MH^"); MS calc: 545.63 (M).

Proceeding as in Example 1, but substituting [2'-hdroxy-3'-(l//-pyrrolo[3,2-c]pyridin- 2-yl)-biphenyl-4-yl] -acetic acid and 1-phenyl-piperazine, gave 4-phenyl-l-{2-[2'-hydroxy-3'- (lH^"-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperazine.

Proceeding as in Example 1, but substituting 4^?-aminomethyl-3-(l//-pyrrolo[3,2- e]pyridin-2-yl)-biphenyl-2-ol hydrochloride and (4-phenylmethyl-piperazin-l-yl)-acetic acid, gave 2-(4-phenylmethyl-piperazin-l-yl)-iV-[2'-hydroxy-3^l-(li7-pyrrolo[3,2-c]pyridin-2-yl)- biρhenyl-4~ylmethyl]-acetamide. MS(ES) m/z 532.4 (MH⁺); MS cald: 531.26(M).

Proceeding as in Example 1, but substituting 4'-amino-3-(lH-pyrrolo[3,2-c]pyridin-2- yl)-biphenyl-2-ol hydrochloride and (4-phenylmethyl-piperazin-l-yl)-acetic acid, gave 2-(4- phenylmethyl-piperazin-l-yl)-iV-[2^l-hydroxy-3^l-(l//-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4- yl]-acetamide. MS(ES) m/z 518.5 (MH⁺); MS cald: 517.25(M).

Examples 25-183

Proceeding as in Example 1 the following compounds of Formula I were made:

4-(3,4-difluoro-phenylmethyl)-l-{2-[2^I-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylic acid; 4-(3-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylic acid;

N-(4-ρhenylmethyl-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4- yl]-acetyl}-piperidine-4-carbonyl)-methanesulfonamide;

-¥-hydroxy-4-(4-fluoro-phenylmetliyl)- 1 - {2- [2'-hydroxy-3 '-(1 H-pyrrolo [2,3 -cjpyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide; methyl 4-ρhenylmethyl-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate;

4-(4-fluoro-phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(1 H-pyrrolo [2,3 -c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide; methyl 4-(3 ,4-difluoro-phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-( 1 H-ρyrrolo[2,3 -c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate; methyl 4-(3 -fluoro-phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-( 1 H-pyrrolo [2,3-c]pyridin-2- yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate;

[(4-(4-fluoro-phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-( lH-pyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carbonyl)-amino]-acetic acid;

4-(4-fluoro-phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-( 1 H-pyrrolo [2,3 -c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}- iV-methyl-piperidine-4-carboxamide;

4-(2-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylic acid; methyl [(4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2- yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carbonyl)-amino]-acetate;

7V^'-(4-phenylmethyl-l-{2-[2^I-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl]-acetyl}-piperidin-4-yl}-acetate;

N-(2,2,2-trifluoro-ethyl)-4-phenylmethyl-l-{2-[2^I-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide;

4-(3 ,4-difluoro-phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(1 H-ρyrrolo[3 ,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylic acid; iV-phenylmethyloxy-4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl] -acetyl} -piperidine-4-carboxamide;

4-ρhenylmethyl-4-hydroxy- 1 - {2-[2'-hydroxy-3 '-( lH-pyrrolo [2,3 -c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-ρiρeridine;

4-(4-fluoro-ρhenylmethyl)-l-{2-[2^t-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-ρiperidine-4-carboxylic acid; me%14-(2-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy--3'-(lH-ρyrrolo[2,3-c]ρyridin-2- yl)-biphenyl-4-yl] -acetyl } -piperidine-4-carboxylate; methyl 4i?-(4-fluoro-phenylmethyloxy)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-ρyrrolidine-2iS^r-carboxylate; methyl 4-(4-fluoro-phenylmethyl)-l-{2-[2^!-hydroxy-3^l-(lH-pyrrolo[3,2-c]pyridin-2- yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate; methyl 4-(3,4-difluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate;

N-(I H-tetrazol-5-yl)r4-phenylmethyl- 1 - {2-[2'-hydroxy-3 '-(1 H-pyrrolo [2,3 -c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide;

7V₅N-dimethyl-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidine-4-carboxamide; methyl 4-(2-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2- yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate;

N-thiazol-2-yl-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide;

4-fluoro-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridm-2-yl)- biphenyl-4-yl]-acetyl}-piperidine; methyl 4-allyl-l-{2-[2'-hydroxy-3'-(lH^"-ρyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperidine-4-carboxylate;

4-allyl-l-{2-[2'-hydroxy-3^I-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}- piperidine-4-carboxylic acid;

4-(2-fluoro-ρhenylmethyl)- 1 - {2-[2'-hydroxy-3 '-( lH-pyrrolo [3 ,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylic acid; methyl 4-phenylmethyloxy- 1 - {2-[2'-hydroxy-3 '-( lH-pyrrolo [3 ,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-pyrrolidine-2-carboxylate;

4-fluoro-4-phenylmethyl- 1 - {2-[2'-hydroxy-3 '-( lH-pyrrolo [3 ,2-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperidine;

N-dimethyl-4-Phenylmethyl-l-{2-[2'-hydiOxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide;

4-phenylmethyloxy-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3₅2-c]pyridin-2-yl)-biphenyl-4- yl]-acetyl}-pyrrolidine-2-carboxylic acid;

4-amino-4-phenylmethyl-l-{2-[2'-hydroxy-3^l-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine; 4-hydroxy-4-phenyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4- yl]-acetyl}-piperidine;

3-hydroxy-4-(3-trifluoromethyl-phenyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-(4-chloroρhenyl)-4-hydroxy-l-{2-[2'-hydroxy-3'-(17f-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine;

4-hydroxy-4-(3-trifluoromethyl-ρhenyl)-l-{2-[2'-hydroxy-3'-(lJf-ρyrrolo[3,2- c]pyridin-2-yl)~biphenyl~4-yl] -acetyl} -piperidine; methyl l-{2-[2^t-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4- methyl-piperidine-4-carboxylate; phenylmethyl (4-phenylmethyl-l-{2-[2'-hydroxy-3^l-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidin-4-yl)-carbamate;

2-(hydroxymethyl)-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2- yl)-biphenyl-4-yl] -acetyl } -piperazine; methyl l-phenylmethyl-4-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine-2-carboxylate; methyl 4-ρhenylmethyl- 1 - {2-[2'-hydroxy-3 '-(1 H-ρyrrolo[3 ,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine-2-carboxylate; l-phenylmethyl-4-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl}-piperazine-2-carboxylic acid;

4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-yl]- acetyl} -piperazine-2-carboxylic acid;

4R-(4-fluoro-phenylmethyloxy)-l-{2-[2'-hydroxy-3^I-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -pyrrolidine-2)S-carboxylic acid;

7V-(lH-[l,2,4]triazol-3-yl)-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide; methyl 4i?-(4-fluoro-phenylmethyloxy)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-pyrrolidine-2i<!-carboxylate; methyl l-phenylmethyl-4-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine-2-carboxylate;

4-hydroxy-4-phenyl-l-{2-[2'-hydroxy-3^l-(l//-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl]-acetyl}-piperidine;

4-hydroxy-4-(4-chlorophenyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine; 4-phenylmethyl-4-(morpholin-4-ylcarbonyl)-l-{2-[2'-hydroxy-3'-(lH^"-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl] -acetyl} -piperidine;

N-methoxy-4-(4-fluoro-ρhenylmetliyl)-l-{2-[2^I-liydroxy-3^t-(lH-ρyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl] -acetyl} -piperidine-4-carboxamide; l-ρhenylmethyl-4-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperazine-2-carboxylic acid;

4i?-(4-fluoro-phenylmetliyloxy)- 1 - {2-[2'-hydroxy-3 '-( 1 H-pyrrolo[2,3 -c]pyridin-2-yl)- biphenyl~4-yl]-acetyl}-pyrrolidine-2i?-carboxylic acid;

N-methoxy-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine-2-carboxamide;

4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl } -piperazine-2-carboxylic acid;

4-hydroxy-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridm-2-yl)- biphenyl-4-yl] -acetyl } -piperidine

N-cyclopropylmethyl-4-phenylmethyl-l-{2-[2'-hydroxy-3'-(l/f-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxyamide; iV-(2,2,2-trifluoro-ethyl)-4-(4-fluoro-phenylnietliyl)-l-{2-[2'-hydroxy-3'-(lH- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide; phenylmethyl (4-(4-fluoro-ρhenylmethyl)-l - {2-[2^t-hydroxy-3'-(lH^r-ρyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidin-4-yl)-acetate;

N-(4-(4-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(lH^r-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidin-4-yl)-methanesulfonamide;

4-phenylmethyl-4-hydroxy-l-{2-[2'-riydroxy-3'-(lH-imidazo[4,5-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidine;

(4-(4-fluoro-prienylmethyl)-l-{2-[2^l-hydroxy-3^l-(lH-ρyrrolo[2,3-c3ρyridm-2-yl)- biphenyl-4-yl]-acetyl}-piperidin-4-yl)-urea;

4-(4-fluoro-phenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(1 H-imidazo[4,5-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl} -piperidine-4-carboxylic acid;

4-(4,5-dihydro-thiazol-2-yl)-4-(4-fluoro-phenylmethyl)-l-{2-[2^!-riydroxy-3'-(lH^"- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-(4-fluoro-phenylmethyl)-4-(lH-[l,2,3]triazol-4-yl)-l-{2-[2^I-hydroxy-3^l-(li7- pyrrolo[2,3 -c]pyridin-2-yl)-biphenyl-4-yl] -acetyl} -piperidine;

N-cyclopropylmethyl-4-(4-fluoro-phenylmetriyl)-l-{2-[2^t-liydroxy-3'-(li^:-^r- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxamide; ρhenylmethyl (4-ρhenylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidin-4-yl)-carbamate; methyl 4-cyclopropylmethyl-l-{2-[2'-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate;

4-cyclopropylmethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- yl]-acetyl}-piperidine-4-carboxylic acid;

4-(4-fluoro-phenylmethyl)-4-h.ydroxy-l-{2-[2'-hydroxy-3'-(lH-imidazo[4,5- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piρeridine;

2-diethylamino-ethyl 4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lΗ-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate;

ΛζiV- dimethyl-4-phenylmethyl- 1 - {2-[2'-hydroxy-3 '-(1 H-pyrrolo[3 ,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidine-4-carboxamide;

4-(4-fluoro-phenylmethyl)-4-hydroxymetb.yl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-(4-fluoro-phenylmethyl)-4-hydroxymethyl-l-{2-[2'-b.ydroxy-3^l-(lH^"-imidazo[4,5- c]pyridin-2-yl)-biphenyl-4-yl] -acetyl } -piperidine;

4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3^l-(lΗ-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carbonitrile;

4-cyclopropylmethyl-4-hydroxymethyl-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4~yl]-acetyl}-piperidine; methyl 4-benzyl-l-{2-[2'-hydroxy-3'-(lH-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl } -piperidine-4-carboxylate; methyl l-{2-[3'-(5,7-dihydro-4H-purin-8-yl)-2'-hydroxy-biphenyl-4-yl]-acetyl}-4-(4- fluoro-benzyl)-piperidine-4-carboxylate;

4-hydroxy-4-(3-trifluoromethyl-phenyl)-l-{2-[2'-hydroxy-3'-(lH^'-imidazo[4,5- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine; methyl 4-cyclopentylmethyl-l - {2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate; methyl l-{2-[2^!-hydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]-acetyl}-4- isobutyl-piperidine-4-carboxylate;

4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piρeridin-4-ylmethyl cyclopropanecarboxylate; methyl 4-(3,3-difluoro-allyl)-l-{2-[2^l-hydroxy-3^l-(lH-pyrrolo[2₅3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine-4-carboxylate; N-(4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3^l-(lH-pyrrolo[2₅3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidin-4-ylmethyl)-methanesulfonamide;

N-(4-(4-fluoro-phenylmethyl)-l-{2-[2'-liydroxy-3'-(lH-ρyrrolo[2,3-c]pyridm-2-yl)- biphenyl-4-yl]-acetyl}-piperidin-4-ylmethyl)-cyclopropanecarboxamide; methyl l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4- (2,2,2-trifluoro-ethyl)-piperidine-4-carboxylate;

4-(2-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

4-phenylmethyl-l-{2-[2'-hydroxy-3^l-(l/f-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -3 ,6-dihydro-2H-pyridine;

4-phenyl-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]pyridm-2-yl)-biplienyl-4-yl]-acetyl}- piperazine;

4-(l-methyl-butyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biρhenyl-4- yl]-acetyl} -piperazine;

4-ethyl-l-{2-[2'-h.ydroxy-3'-(lH-pyrrolo[3,2-c]pyridm-2-yl)-biphenyl-4-yl]-acetyl}- piperazine;

4-(ρyridin-4-yl)-l-{2-[2^!-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperazine;

4-isopropyl-l-{2-[2'-hydroxy-3'-(lϋr-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperazine;

4-ρhenylmethyl-l-{2-[2'-hydroxy-3^l-(lH-ρyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl } -piperazine;

4-(thiophen-2-ylmethyl)-l-{2-[2'-hydroxy-3^t-(lH^'-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperazine;

4-(4-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperazine;

4-(4-chloro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(2-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperazine;

4-(thioρhen-2-ylmethyl)-l-{2-[2^I-hydroxy-3'-(lH-pyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(4-cnloro-ρhenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-ρiρerazine; 4-(thiophen-3-ylmethyl)-l-{2-[2'-hydroxy-3^I-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(3-fluoro-ρhenylmethyl)-l-{2-[2'-hydroxy-3^l-(l_JH-pyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(3 -chloro-phenylmethyl)- 1 - {2- [2'-hydroxy-3 '-( lH-pyrrolo [3 ,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(4-methyl-pyridin-2-yl)-l-{2-[2'-hydroxy-3'-(l/f-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-[2-(thiophen-2-yl)-ethyl)]-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridm-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

4-(2-cMoro-4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(liJ-pyrrolo[3,2-c]pyridin-2- yl)-biphenyl-4-yl]-acetyl}-piperazine;

4-(2-chloro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH^'-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperazine;

4-(3-carboxyphenylmethyl)-l-{2-[2^I-hydroxy-3'-(lijr-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-oxo-4-phenyl-l-{2-[2'-hydroxy-3^l-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -4λ⁵- [ 1 ,4] azaphosphinane;

4-(2-methyl-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH^r-ρyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

4-phenethyl- 1 - {2-[2'-hydroxy-3 '-( lH-ρyrrolo[3 ,2-c]ρyridin-2-yl)-biphenyl-4-yl] - acetyl} -piperazine;

4-(pyridin-4-ylmethyl)-l-{2-[2'-hydroxy-3'-(li/-pyrrolo[3,2-c]pyridm-2-yl)-biphenyl- 4-yl] -acetyl } -piperazine;

4-(ρyridm-3-ylmethyl)-l-{2-[2^l-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl- 4-yl] -acetyl } -piperazine;

N-phenyl-4- {2-[2'-hydroxy-3 '-( 1/i-pyrrolo [3 ,2-c]pyridin-2-yl)-biphenyl-4-yl] -acetyl} ■ piperazine- 1 -carboxamide;

4-φyridin-2-yl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]ρyridin-2-yl)-biρlienyl-4-yl]- acetyl} -piperazine; methyl 3 -(4- {2-[2^!-hydroxy-3 '-( lH-pyrrolo [3 ,2-c]ρyridin-2-yl)-biρhenyl-4-yl]- acetyl} -piperazin- 1 -ylmethyl)-benzoate; 4-(3-methyl-ρyridin-2-yl)-l-{2-[2^I-liydroxy-3¹-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

N-(4-fluoro-phenyl)-4-{2-[2'-hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4- yl]-acetyl}-piperazine-l-carboxamide;

4-isobutyl-l-{2-[2^l-hydroxy-3'-(lH-ρyrrolo[3,2-c]pyridin-2-yl)-biρhenyl-4-yl]- acetyl} -piperazine;

4-φhenylthiomethylcarbonyl)-l-{2-[2'-hydroxy-3'-(lH^'-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperazine;

4-phenylmethyl-l-{2-[2'-hydroxy-3^I-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -homopiperazine;

4-(3,4-dichloro-phenylmethyl)-l-{2-[2^l-hydroxy-3'-(liJ-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(4-fluoro-ρhenyl)-l-{2-[2'-hydroxy-3'-(lH^'-pyrrolo[3,2-c]pyridin-2-yl)-biρrienyl-4- yl]-acetyl}-piperazine;

4-(pyridin-2-ylrnethyl)-l-{2-[2^t-b.ydroxy-3^I-(liy-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl- 4-yl] -acetyl } -piperazine;

4-(cyclohexylmethyl)-l-{2-[2^l-hydroxy-3'-(lH^'-pyrrolo[3,2-c]ρyridin-2-yl)-biprienyl- 4-yl]-acetyl} -piperazine;

4-(3-methyl-butyl)-l-{2-[2'-hydroxy-3'-(lH^'-pyrrolo[3,2-c]pyridin-2-yl)-biρhenyl-4- yl]-acetyl} -piperazine;

4-(N-isopropylaminocarbonylamino)-l-{2-[2'-hydroxy-3'-(lH^r-pyrrolo[3,2-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperazine;

4-( 1 -phenyl-eth- 1 -yl)- 1 - {2-[2'-hydroxy-3 '-( lH-pyrrolo [3 ,2-c]pyridin-2-yl)-biphenyl- 4-yl] -acetyl } -piperazine;

4-(phenylmethyl)-l-{2-[2'-hydroxy-3'-(4-chloro-lH^"-pyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperazine;

4-methyl-4-oxo-l-{2-[2^t-hydroxy-3'-(lH^r-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl } -4λ⁵- [ 1 ,4] azaphosphinane;

4-(ρhenylmethyl)- 1 - {2-[2'-hydroxy-3 '-(6-chloro- lH^"-pyrrolo[3 ,2-c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

4-(2-methyl-benzoimidazol-l-yl)-l-{2-[2^l-hydroxy-3'-(6-chloro-lH^"-ρyrrolo[2,3- c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine;

4-(ρhenylmethylcarbonyl)-l-{2-[2'-hydroxy-3'-(l/f-ρyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl} -piperidine; 4-ρhenoxy-l-{2-[2'-hydroxy-3'-(liϊ-pyrrolo[3,2-c]ρyridin-2-yl)-biρlienyl-4-yl]- acetyl } -piperidine;

4-(l-hydroxy-l-ρhenyl-methyl)-l-{2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperidine;

4-hydroxy-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[3₅2-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl} -piperidine;

4-phenylmethyl-l-{2-[2'-hydroxy-3'-(l//-pyrrolo[3,2-c]pyridin-2-yl)-biρhenyl-4-yl]- acetyl } -piperidine;

4-(3,4-difluoro-phenylmethyl)-l-{2-[2^l-hydroxy-3'-(lH^:-pyrrolo[3,2-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidine;

4-(benzoimidazol-l-yl)-l-{2-[2^l-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidine;

4-(6-methyl-pyridin-3-yl)-l-{2-[2^I-hydroxy-3'-(lH-ρyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperidine;

4-[2-(morpholin-4-yl)-ethyl]-l-{2-[2'-hydroxy-3'-(liϊ-ρyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-yl]-acetyl}-piperazine;

4-(ρyridin-4-yl)-l-{2-[2'-hydroxy-3'-(lH^"-ρyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]- acetyl } -piperazine;

4-{2-[2'-hydroxy-3'-(lH-pyrrolo[2₅3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}- piperazine-1-carboxylic acid phenylamide;

2-(4-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}- piperazin- 1 -yl)-N-pyridin-2-yl-acetamide;

4-(l-phenyl-eth-l-yl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl- 4-yl]-acetyl} -piperazine;

4-{2-[2'-hydroxy-3'-(l/f-ρyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4-yl]-acetyl}- piperazine-1-carboxylic acid ethylamide;

7V-(l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}- piperidin-4-yl)-iV-ρhenyl-propionaniide;

4-(cyclopentylcarbonyl)- 1 - {2-[2'-hydroxy-3 '-( l/f-ρyrrolo[2,3 -c]ρyridin-2-yl)- biphenyl-4-yl] -acetyl } -piperazine;

2-methoxy-ethyl (l-{2-[2^I-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl}-piperidin-4-yl)-acetate;

2-[2'-hydroxy-3'-(l//-ρyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-yl]-N-(3-ρyrrolidin-l-yl- proρyl)-acetamide; N-(l-phenylmethyl-ρyrrolidin-3-yl)-2-[2'-hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)- biphenyl-4-yl]-acetamide;

N-[2^l-Hydroxy-3'-(lH-ρyrrolo[3,2-c]ρyridin-2-yl)-biρhenyl-4-ylmethylcarbonyl]-l,3- dihydrospiro(indene-2,4-piperidine); iV-[2'-Ηydroxy-3'-(lH-ρyrrolo[2,3-c]ρyridin-2-yl)-biρhenyl-4-ylmethylcarbonyl]-l,3- dihydrospiro(indene-2,4-piperidine); and methyl l-{2-[5^l-chloro-2'-hydroxy-3^l-(lH-pyrτolo[2,3-c]pyridin-2-yl)-biplienyl-4-yl]- acetyl}-4-(4-fluoro-phenylmethyl)-piperidine-4-carboxylate.

Example 184

4-Phenylmethyl- 1 - {2-[2'-hydroxy-3 '-( lH-pyrrolo[2,3 -c]pyridin-2-yl)-biphenyl-4-yl] -acetyl} - piperidine-4-carboxylic acid

2 M Potassium hydroxide (1 mL) was added to a solution of methyl 4-phenylmethyl- l-{2-[2^l-hydroxy-3'-(lΗ-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4- carboxylate (40 mg, 0.071 mmol) in methanol-acetonitrile mixture (v/v, 1:1) (3 mL). The mixture was heated at 60 ⁰C for 20 hours and then acidified with cone, hydrochloric acid. Product was purified by preparative reversed phase HPLC to give 4-phenylmethyl-l-{2-[2'- hydroxy-3 '-( 1 H-pyrrolo [2,3 -c]pyridin-2-yl)-biphenyl-4-yl] -acetyl} -piperidine-4-carboxylic acid (25 mg, 65%). MS(ES) m/z 546.1(MH⁺); MS cald: 545.23 (M).

Examples 185-187

Proceeding as in Example 184, but substituting methyl l-{2-[2'-hydroxy-3'-(lH- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-4-thiophen-3-ylmethyl-piperidine-4- carboxylate, gave l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]- acetyl}-4-thiophen-3-ylmethyl-piperidine-4-carboxylic acid. MS(ES) m/z 552.0 (MH⁺); MS cald: 551.19 (M).

Proceeding as in Example 184, but substituting methyl 4-(4-fluoro-phenylmethyl)-l- {2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]ρyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidme-4- carboxylate, gave 4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl} -piperidine-4-carboxylic acid. MS(ES) m/z 563.7 (MH⁺); m/z 561.5 (MH^"); MS calc: 563.6 (M).

Proceeding as in Example 184, but substituting methyl 4-(4-fluoro-ρhenylmethyl)-l- {2-[2'-hydroxy-3'-(lH-imidazo[4,5-c]pyridin-2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4- carboxylate, gave 4-(4-fluoro-phenylmethyl)-l-{2-[2'-hydroxy-3'-(lH-imidazo[4,5-c]pyridin- 2-yl)-biphenyl-4-yl]-acetyl}-piperidine-4-carboxylic acid. MS(ES) m/z 565.3 (MH⁺); m/z 562.9 (MH^"); MS calc: 564.61 (M).

Example 188

4-phenylmethyl-l-{2-[2^l-hydroxy-3'-(17i^'-ρyrrolo[3,2-c]pyridin-2-yl)-biρhenyl-4-yl]-ethyl}- piperazine

4-Phenylmethyl-l-{2-[2'-b.ydroxy-3'-(lH^"-pyrrolo[3,2-c]pyridin-2-yl)-biplienyl-4-yl]- acetyl} -piperazine (20 mg, 0.04 mmol) was dissolved in THF (2 ml) and the solution was heated under nitrogen to 70 °C. Borane-dimethylsulfide (10 M in THF, 0.05 ml, 0.5 mmol) was added and the mixture was heated for 2 hours. 4 N aq. Hydrochloric acid (2 ml) was added carefully under nitrogen and the mixture heated at 60 ⁰C for 2 hours. The mixture was concentrated and product was purified from the residue by preparative TLC (1 x 2000 micron silica gel plate, [CH₂Cl₂/Me0H (9:1 v/v)]. The product was taken up in 0.1 M hydrochloric acid and dried by lyophilization to give 4-phenylmethyl-l-{2-[2'-hydroxy-3'-(li7-pyrrolo[3,2- c]pyridin-2-yl)-biphenyl-4-yl] -ethyl} -piperazine hydrochloride (6.6 mg). MS(ES) m/z 489.2 (MH⁺); m/z 487.1 (MH^'); MS calc: 488.62 (M).

Example 189

Synthesis of iV-[2'-Hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- ylmethylcarbonyl] -JV- [2-(phenylmethyloxy)- 1 -(methoxycarbonyl)-ethyl] -amine

Step l

To a solution of commercially available 2-amino-3-benzyloxy-N-butoxycarbonyl- propionic acid (340 mg, 1.15 mmol) in methanol (10 mL) and benzene (10 mL) at 20 °C was added dropwise a solution of trimethylsilyl diazomethane in hexanes (2.0 M, 1.3 mL, 2.6 mmol), the reaction was allowed to stir at room temperature for 1 h then the solvent was removed under reduced pressure to give 2-amino~3-benzyloxy-iV-tert-butoxycarbonyl~ propionic acid methyl ester as a clear oil (355 mg). MS(ES) m/z 332.2 (MNa⁺); MS cald: 309.16 (M). Step 2

2-amino-3-benzyloxy-iV-tert-butoxycarbonyl-propionic acid methyl ester from above was dissolved in EtOAc (1 mL), 4 N HCl in dioxane (1 mL, 4 mmol) was added. After 2 h at room temperature the solvent was removed and the residue was treated with ether and dried to give 2-amino-3-benzyloxy-propionic acid methyl ester hydrochloride (260 mg, 92%). MS(ES) m/z 209.9 (MH⁺); MS cald: 209.11 (M). Step 3

[2'-Hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (80 mg, 0.23 mmol), which was prepared using procedures as described in Reference 8, and 2-amino- 3-benzyloxy-propionic acid methyl ester hydrochloride (103 mg, 0.419 mmol) from Step 2, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 80 mg, 0.42 mmol), and 1-hydroxybenzotriazole hydrate (ΗOBt, 57 mg, 0.42 mmol) was added DMF (2 mL) and di-isopropylethylamine (140 μL, 0.8 mmol) at room temperature. After 20 hours, the reaction mixture was purified by ΗPLC to yield N-[2'-Ηydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)- biphenyl-4-ylmethylcarbonyl]-iV-[2-(phenylmethyloxy)-l-(methoxycarbonyl)-ethyl]-amine (62 mg, 64%). MS (ES) m/z 535.7 (MH⁺); MS cald: 535.21 (M).

Examples 190-192

Example 2

Proceeding as above in Example 189, Step 3, but replacing 2-amino-3-benzyloxy- propionic acid methyl ester hydrochloride with 2-amino-3-(cyclopropylmethyl-amino)- propionic acid methyl ester, N-[2^l-hydroxy-3^l-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- ylmethylcarbonyl]-iV-{2-[iV-(cycloρropylmethyl)-amino]-l-(methoxycarbonyl)-ethyl}-amine was prepared. Example 3

Proceeding as above in Example 189, Step 3, but replacing 2-amino-3-benzyloxy- propionic acid methyl ester hydrochloride with 2-amino-3-[(cyclopropymiethyl)-oxy]- propionic acid methyl ester, N-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- ylmethylcarbonyl]-N-{2-[(cyclopropylmethyl)-oxy]-l-(methoxycarbonyl)-ethyl}-amine was prepared. ESMS (m/z): found, 500.0 (M+l)⁺; cald, 499.56 (M). Example 4 Proceeding as above in Example 189, Step 3, but replacing 2-amino-3-benzyloxy- propionic acid methyl ester hydrochloride with 3-amino-l,l,l-trifluoro-6-phenyl-hexan-2-ol, which was prepared as described in Reference 12, the product N-[2'-hydroxy-3'-(lH- pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-yl-methylcarbonyl]-iV-(5-phenyl-l-hydroxy-l- trifluoromethyl-pent-2-yl)-amine was prepared. ESMS (m/z): found, 573.9 (M+l)⁺; calcd., 573.2 (M).

Example 193

Synthesis of iV-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-ylmethylcarbonyl]- iV-{2-[(cyclopropylmethyl)-sulfonyl]-l-(methoxycarbonyl)-ethyl}-amine

Step l

Proceeding as in Example 189, Step 3, but replacing 2-amino-3-benzyloxy-propionic acid methyl ester hydrochloride with 2-mino-3-cyclopropylmethylsulfanyl-propionic acid methyl ester, N-[2'-hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4- ylmethylcarbonyl]-iV-{2-[(cycloproρylmethyl)-sulfanyl]-l-(methoxycarbonyl)-ethyl}-amine was prepared. ESMS (m/z): found, 516.3 (M+l)⁺; cald, 515.6 (M).

The product from Step 1 (65 mg, 0.126 mmol) was dissolved in MeOH (3 mL) and oxone (239 mg, 0.39 mmol) in H₂O (3 mL) was added. The suspension was stirred for 1 hour at room temperature. The crude reaction mixture was purified by preparative HPLC afforded the product (20 mg, 29%). ESMS (m/z): found, 548.4 (M+l)⁺; cald., 547.6 (M).

Example 194

Synthesis of N-[2'-Hydroxy-3'-(lH^"-ρyrrolo[2,3-c]pyridin-2-yl)-biρhenyl-4- ylmethylcarbonyl]-N-[2-(phenylmethyloxy)-l-carboxyethyl]-amine

Step l

A mixture of N-[2^l-Hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-ylmethyl- carbonyl]-iV-[2-(phenylmethyloxy)-l-(inethoxycarbonyl)-ethyl]-aniine (32 nig, 0.060 mmol), lithium hydroxide monohydrate (7.0 mg, 0.17 mmol), acetonitrile (3 mL) and water (1 mL) was heated at 60 ⁰C for 1 h. The reaction was acidified with 4 N HCl and purified by HPLC to give N-[2'-Hydroxy-3'-(lH-pyrrolo[2,3-c]pyridin-2-yl)-biphenyl-4-ylmethylcarbonyl]-iV- [l-carboxy-2-(phenylmethyloxy)-ethyl]-amine (24 mg, 77 %) as a white solid; MS (ES) m/z 521.9 (MH⁺); MS cald: 521.2 (M).

Example 195

Synthesis ofN-[2^I-Hydroxy-3'-(lH-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4- ylmethylcarbonyl] -N- [ 1 -(methoxycarbonyl)-3 -phenylpropyl] -amine

Step l

D,L-2-Amino-4-phenyl-butyric acid (248 mg, 1.38 mmol) was suspended in MeOH (5 mL), cone. H₂SO₄ (0.1 mL) was added, and the mixture heated to reflux. After 48 hours the reaction was cooled to room temperature, and basified with 4 M NaOH. The product was extracted with EtOAc (50 mL), and the organic layer washed with brine. 4 Ν HCl in dioxane solution (0.5 mL) was added, followed by ethyl ether (20 mL) and hexane (20 mL). D,L-2- Amino-4-phenyl-butyric acid methyl ester precipitated as white needles and was collected by filtration and dried to give 130 mg (crop 1). MS(ES) m/z 193.5 (MH⁺); MS calc: 193.25 (M) Step 2

[2'-Hydroxy-3'-(lH^"-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-yl]-acetic acid (40 mg, 0.116 mmol), prepared using the procedures described in Reference 7, was dissolved in DMF (2 mL). EDC-ΗC1 (26 mg, 0.132 mmol), ΗOBt (18.0 mg, 0.132 mmol), and AζiV-diisopropylethylamine (0.266 ml, 1.52 mmol) were added, followed by D_sL-2-Amino-4- phenylbutyric acid methyl ester HCl (26.1 mg, 0.114 mmol). The reaction was allowed to stir overnight at room temperature. Methylene chloride (98 mL) was added, and the organic layer extracted three times with water (5 mL portions) and brine (5 mL), then dried over sodium hydrogen sulfate. The organic layer was concentrated and the residue purified by silica gel chromatograhy, using methylene chloride-methanol (19:1) as eluent. N-[2'- Hydroxy-3'-(li-^r-pyrrolo[3,2-c]pyridin-2-yl)-biphenyl-4-ylmethylcarbonyl]-N-[l- (methoxycarbonyl)-3-phenylpropyl]-amine was obtained (33.5 mg, 56%). MS(ES) (m/z)

519.9 (M+l)⁺; (m/z) 517.8 (M-I)^"; MS calc: 519.59 (M).

Example 196

4-(4-fluorophenylmethyl)-4-cyano-{4-[2-hydroxy-3-(liϊ-pyrrolo[2₅3-c]pyridin-2-yl)-ρhenyl]- piperidin- 1 -ylacetyl} -piperidine

To a solution of {4-[2-hydroxy-3-(lH-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-piperidin- l-yl}-acetic acid (0.035 g, 0.08 mmol), prepared using procedures similar to those in Reference 32, in DMF (0.8 mL) was added at ambient temperature tert-butyl 4-fluoro- phenylmethyl-4-cyano-piperidine, prepared using procedures similar to those described in Reference 7 (except by replacing benzyl bromide with 4-fluorobenzyl bromide), (0.024 g, 0.096 mmol), PyBOP (0.041 g, 0.096 mmol) and DIPEA (0.071 mL, 0.40 mmol). After stirring for 30 min, the reaction was diluted with ethyl acetate, washed with sat. NaHCO₃, brine, dried and concentrated. The residue was then purified by preparative HPLC to give 14 (7 mg, 12%): ). ¹H NMR (400 MHz, DMSO) δ (ppm) 8.95 (s, IH)₅ 8.16 (s, IH), 8.0 (s, IH), 7.72 (d, J= 6.8 Hz, IH), 7.28 (m, 5H), 7.15 (m, 6H), 4.37 (m, 2H), 3.80 (m, IH), 3.53 (m, 2H), 3.22 (m, IH ), 3.10 (m, 2H), 2.87 (s, 2H), 2.61 (m, 2H), 2.60 (m, IH), 2.43 (m, IH), 2.26 (m, IH), 2.0 (m, IH), 1.85 (m, 2H), 1.65 (m, IH). MS (calc): 551.3; MS: 552.8 (M+H)⁺, 550.6 (M-H)^".

Proceeding as above in Example 196, Table 15 and Table 16 compounds were prepared using the following procedure.

Biological Examples Example 1

Inhibitory Activity Against Human Tryptase

The following protocol represents an assay for determination of inhibition of tryptase under physiological conditions (pH 7.4). Human skin Beta-1 tryptase can be purchased from Promega. Tosyl-Gly-Pro-Lys-para-nitroanilide (tos-GPK-pNa) can be purchased from Centerchem, Inc. Inhibitor profiles were generated by incubating each enzyme in the presence of inhibitor (various concentrations) or 10% DMSO (vehicle control) for 30 minutes in 96 well clear polystyrene plates at room temperature prior to the addition of substrate. Specifically, 400 μM tos-GPK-pNa was added to 1 nM enzyme in 50 mM Tris (7.4), 150 mM NaCl, 0.02% Tween-20, 1 mM EDTA, 50 μg/mL heparin. Enzyme activity can be measured by monitoring the hydrolysis of the synthetic substrate tos-GPK-pNa at 405 nM over 5 minutes using a UV/MAX kinetic plate reader (Molecular Devices). The apparent inhibition constants (Ki, app) can be calculated from the progress curves using the software package BatchKi (BioKin, Ltd.). BatchKi uses nonlinear least-squares regression to fit experimental data to the Morrison equation for tight binding inhibitors.

Example 2

Identification of Compounds with Anti-inflammatory Efficacy The efficacy of the compounds of the present invention for the treatment of imrnunomediated inflammatory disorders can be evaluated by either in vitro or in vivo procedures. Thus, the anti-inflammatory efficacy of the compounds of the present invention can be demonstrated by assays well known in the art, for example, the Reversed Passive Arthus Reaction technique (see US Patent 5,126,352).

Example 3

Identification of Compounds with Efficacy in Treatment of Skin Diseases Assays for determining the therapuetic value of compounds in the treatment of various skin conditions, such as hyperproliferative skin disease, are well known in the art, for example, the Arachidonic Acid Mouse ear Test.

Example 4

Primate Acute Asthma Model

A primate acute asthma model may be employed for the in vivo evaluation of the compounds of the invention as antiasthmatics.

Example 5

Identification of Compounds with Anti-ulcer Efficacy

The compounds of the present invention can be evaluated for their antiulcer activitiy according to the procedures described in Chiu, Archives Internationales de Pharmacodynamie et de Therapie, 1984, 270, 128-140. Example 6

Identification of Compounds with Activity Against Syncytial Virus Infection The efficacy of the compounds of the present invention in blocking cell fusion caused by a syncytial virus infection can be evaluated by the methods generally set forth in Tidwell, J. Med. Chem., 1983, 26, 294-298.

Pharmaceutical Composition Examples

The following are representative pharmaceutical formulations containing a compound of Formula I.

Tablet Formulation The following ingredients are mixed intimately and pressed into single scored tablets.

Ingredient Quantity per tablet, mg compound of this invention 400

Cornstarch 50 croscarmellose sodium 25

Lactose 120 magnesium stearate 5

Capsule Formulation The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.

Ingredient Quantity per tablet, mg compound of this invention 200 lactose, spray-dried 148 magnesium stearate 2

Suspension Formulation The following ingredients are mixed to form a suspension for oral administration.

Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 g sodium chloride 2.O g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g

Veegum K (Vanderbilt Co.) 1.0 g

Flavoring 0.035 mL

Injectable Formulation The following ingredients are mixed to form an injectable formulation.

Ingredient Amount compound of this invention 1.2 g sodium acetate buffer solution 0.4 M 2.0 mL

HCl (1 N) or NaOH (1 M) q.s. to suitable pH water (distilled, sterile) q.s.to 20 mL

All of the above ingredients, except water, are combined and heated to 60-70.degree. C. with stirring. A sufficient quantity of water at όO.degree. C. is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. to 100 g.

Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol.RTM. H- 15 (triglycerides of saturated vegetable fatty acid; Riches- Nelson, Inc., New York), and has the following composition:

Ingredient Quantity per tablet, mg compound of this invention 500

Witepsol^®H-15 balance

The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

Claims

WE CLAIM:

1. A Compound of Formula I:

I where

R² is hydrogen, alkyl, alkylsulfonyl, alkylphosphonyl, or alkoxyalkyloxyalkyl;

R³ is hydrogen, alkyl, hydroxy, halo, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl, alkylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, R^10aR^10bNC(O)NR^10c- (where R^1Oa, R^10b, and R^1Oc are independently hydrogen, alkyl, or substituted alkyl), R^{l la}R^llbNC(O)O- (where R^lla and R^llb are independently hydrogen, alkyl, or substituted alkyl), or R^12aOC(O)NR^12b- (where R^12a and R^12b are independently hydrogen, alkyl, or substituted alkyl); and R¹⁰⁰ is a group of formula (Al):

(Al) where

R^4a and R^4b are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, halo, alkoxy, acyl, acyloxy, acylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, -NR^19cC(O)NR^19aR^1% (where R^19a, R^19b, and R^19c are independently hydrogen, alkyl, or substituted alkyl), -OC(O)NR^24aR^24b (where R^24a and R^24b are independently hydrogen, alkyl, or substituted alkyl), or -NR^25bC(O)OR^25a (where R^25a and R^25b are independently hydrogen, alkyl, or substituted alkyl); and where alkyl, alkenyl, and alkynyl, either alone or as part of another group are independently optionally substituted with one, two, three, four, or five halo; and

L is -X¹^-Z¹- where X¹ is alkylene, alkenylene, or cycloalkylene and where X¹ is optionally substituted by one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, alkylamino, and dialkylamino; Y¹ is -O-, -NR¹³-, -C(O)-, -C(O)O-, -C(O)NR¹³-, -NR¹³C(O)-, -C(O)NR¹³C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹³-, -NR¹³SO₂-, -OC(O)-, -OC(O)NR¹³-, -NR¹³C(O)O-, or -NR¹³C(O)NR¹⁴- (where R¹³ and R¹⁴ are independently hydrogen, alkyl, or substituted alkyl); and Z¹ is a bond, alkylene, alkenylene, or cycloalkylene;

L is -X⁵-Y^5a-Z⁵-Y^5b- where X⁵ is alkylene, alkenylene, or cycloalkylene and where X⁵ is optionally substituted by one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, alkylamino, and dialkylamino; Y^5a is -0-, -NR¹³-, -C(O)-, -C(O)O-, -C(O)NR¹³-, -NR¹³C(O)-, -C(O)NR¹³C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹³-, -NR¹³SO₂-, -OC(O)-, -OC(O)NR¹³-, -NR¹³C(O)O-, or -NR¹³C(O)NR¹⁴- (where R¹³ and R¹⁴ are independently hydrogen, alkyl, or substituted alkyl); Z⁵ is a bond, alkylene, alkenylene, or cycloalkylene where the alkylene or alkenylene are optionally substituted with aralkyloxyalkyl; and Y^5b is -C(O)-; Het is heterocycloalkyl; and

R⁷, R⁸, and R⁹ are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, acylamino, acyloxy, acylaminoalkyloxycarbonyl, alkylthio, alkylsulfonyl, alkoxy, alkoxycarbonyl, alkoxyalkylamino, alkoxyalkylaminocarbonyl, alkoxyalkyloxy, alkoxyalkyloxycarbonyl, amino, alkylamino, dialkylamino, aminoalkyloxy, carboxy, carboxyalkylaminocarbonyl where the "alkyl" is optionally substituted with one or two hydroxy, cyano, cyanoalkylaminocarbonyl, aryl, aryloxy, arylsulfonyl, arylthioalkylcarbonyl, aralkyl where the alkyl is optionally substituted with one or two hydroxy, aralkyloxy, aralkyloxycarbonyl, aralkyloxyaminocarbonyl, aralkyloxycarbonylamino, aralkenyl, cycloalkyl, cycloalkyloxy, cycloalkylaminocarbonyl, cycloalkylalkyl where the "alkyl" is optionally substituted with one or two hydroxy, cycloalkylalkylaminocarbonyl, cycloalkylalkyloxycarbonyl, heteroaryl, heteroarylaminocarbonyl, heteroaralkyl, heteroaralkenyl, heteroaralkyloxy, halo, hydroxy, hydroxyalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, N-hydroxyaminocarbonyl, iV-alkoxyaminocarbonyl, hydroxyalkylaminocarbonyl, dialkylaminoalkyloxycarbonyl, dialkylaminoalkylaminocarbonyl, arylamino, arylaminocarbonyl, alkylsulfonylamino, alkylsulfonylaminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylaminocarbonyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkylalkyloxycarbonyl, optionally substituted heterocycloalkylalkylaminocarbonyl, aminocarbonylamino, N-aryl-iV-(alkylcarbonyl)-amino, N-(alkylsulfonyl)-iV-alkyl-amino₅ alkoxycarbonylalkylaminocarbonyl where the "alkyl" is optionally substituted with one or two hydroxy, or trialkylsilyl; or any two of R⁷, R⁸, and R⁹ attached to the same carbon atom together with the carbon to which they are attached form indanylene or optionally substituted heterocycloalkylene; and where the alkyl, alkenyl, and alkynyl in R⁷, R⁸, and R⁹, either alone or part of another group, independently are optionally substituted with one, two, three, four, or five halo; or

R¹⁰⁰ is a group of formula (A2):

(A2) where

R^4a and R^4b are as defined above;

R⁵ is -Y^X¹¹^¹¹ where Y¹¹ is -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR^26a-, -NR²⁶³C(O)-, -OC(O)-, -OC(O)NR^26a-, -NR²⁶³C(O)O-, -C(O)NR^26aC(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are independently hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, or acyl, where X¹¹ is a bond, alkyl ene, or alkenylene, (where X¹¹ is optionally substituted with hydroxy, alkoxycarbonyl, carboxy), and where Q¹¹ is heteroaryl, aryl, aryloxy, or cycloalkyl;

R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is alkylene or alkenylene; Y¹² is -NR^26a-, -0-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR^26a-, -NR^26aC(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are as defined above; X^12b is a bond, alkylene, or alkenylene where X^12b is optionally substituted with one, two, or three groups selected from hydroxy, cyano, halo, heteroaryl, alkylcarbonyl, alkoxycarbonyl, carboxy, -NR R (where R and R are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, heteroaryl, or heteroarylaminocarbonyl), -C(O)NR^28aR^28b (where R^2Sa and R^28b are independently hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, hydroxy, or heteroaryl), and -NR^29aC(O)OR^29b (where R^29a is hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, or hydroxy, and R is alkyl); and Q¹² is aryl, aryloxy, aralkyloxy, heteroaryl, aralkylaminocarbonyl (where the alkyl is optionally substituted with alkoxycarbonyl or carboxy), cycloalkyl, cycloalkylaminocarbonyl, cycloalkylalkyloxy, -NR^30aR^30b (where R^3Oa is hydrogen or alkyl and R^30b is aryl, heteroaryl, or cycloalkylalkyl) or -S(O)_n-R³¹ (where n is 0, 1, or 2 and R³¹ is heteroaryl, cycloalkylalkyl or aralkyl); where the alkyl within any group in Q is optionally substituted with alkoxyalkyl);

R⁵ is -X¹³-Y¹³-Z¹³ where X¹³ is alkylene or alkenylene, where Y¹³ is -NR^26a-, -0-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR²⁶³-, -NR^26aC(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are as defined above, and where Z¹³ is hydrogen, alkyl, or alkenyl (where Z¹³ is optionally substituted with one, two, or three halo, hydroxy, amino, alkoxy, alkoxycarbonyl, carboxy, or alkylcarbonylamino); or

R⁵ is -Y¹⁴-Z¹⁴ where Y¹⁴ is -S(O)-, -NR²⁶³C(O)-, -C(O)NR^26a-, -NR^26aC(O)NR^26b-, -C(O)NR²⁶³C(O)-, -NR²⁶³C(O)O-, -OC(O)NR²⁶³, or -OC(O)-, where R^26a and R^26b are as defiend above, and where Z¹⁴ is alkyl or alkenyl (where Z¹⁴ is optionally substituted with one, two, or three halo, hydroxy, amino, alkoxy, alkoxycarbonyl, carboxy, or alkylcarbonylamino); or

R¹⁰⁰ is a group of formula (A3):

(A3) where

Y⁴ is -C(O)-, -NR³²C(O)-, -S(O)₂-, or a bond;

Z⁴ is heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, carboxy, aryl, aralkyl, cyano, arylcarbonyl, alkoxy, and hydroxy; or Z⁴ is -NR^5OaR^5Ob where R^50a is hydrogen, alkyl, alkoxy, or hydroxy and R^5Ob is -(alkylene)-aryl where the alkylene is optionally substituted with one or two groups selected from halo, alkoxycarbonyl, hydroxy, and carboxy; or a pharmaceutically acceptable salt therof.

2. A Compound of Formula I:

I where

R² is hydrogen, alkyl, alkylsulfonyl, alkylphosphonyl, or alkoxy alkyloxy alkyl;

R³ is hydrogen, alkyl, hydroxy, halo, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl, alkylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaniinosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, R^10aR^10bNC(O)NR^10c- (where R^1Oa, R^10b, and R^1Oc are independently hydrogen, alkyl, or substituted alkyl), R^llaR^llbNC(O)O- (where R^lla and R^llb are independently hydrogen, alkyl, or substituted alkyl), or R^12aOC(O)NR^12b- (where R^12a and R^12b are independently hydrogen, alkyl, or substituted alkyl); and

R¹⁰⁰ is a group of formula (Al):

where

R^4a and R^4b are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, halo, alkoxy, acyl, acyloxy, acylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, -NR^19cC(O)NR^19aR^19b (where R^19a, R^19b, and R^19c are independently hydrogen, alkyl, or substituted alkyl), -OC(O)NR^24aR^24b (where R^24a and R^24b are independently hydrogen, alkyl, or substituted alkyl), or -NR^25bC(O)OR^25a (where R^25a and R^25b are independently hydrogen, alkyl, or substituted alkyl); and where alkyl, alkenyl, and alkynyl, either alone or as part of another group are independently optionally substituted with one, two, three, four, or five halo; and

L is -X¹ -Y¹ -Z¹- where X¹ is alkylene, alkenylene, or cycloalkylene and where X¹ is optionally substituted by one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, alkylamino, and dialkylamino; Y¹ is -O-, -NR¹³-, -C(O)-, -C(O)O-, -C(O)NR¹³-, -NR¹³C(O)-, -C(O)NR¹³C(O)-, -S-, -S(O)-, -SO₂-, -SO₂NR¹³-, -NR¹³SO₂-, -OC(O)-, -OC(O)NR¹³-, -NR¹³C(O)O-, or -NR¹³C(O)NR¹⁴- (where R¹³ and R¹⁴ are independently hydrogen, alkyl, or substituted alkyl); and Z¹ is a bond, alkylene, alkenylene, or cycloalkylene;

Het is heterocycloalkyl; and

R⁷, R⁸, and R⁹ are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, acylamino, acyloxy, acylaminoalkyloxycarbonyl, alkylthio, alkylsulfonyl, alkoxy, alkoxycarbonyl, alkoxyalkylamino, alkoxyalkylaminocarbonyl, alkoxyalkyloxy, alkoxyalkyloxycarbonyl, amino, alkylamino, dialkylamino, aminoalkyloxy, carboxy, carboxyalkylaminocarbonyl where the "alkyl" is optionally substituted with one or two hydroxy, cyano, cyanoalkylaminocarbonyl, aryl, aryloxy, arylsulfonyl, arylthioalkylcarbonyl, aralkyl where the alkyl is optionally substituted with one or two hydroxy, aralkyloxy, aralkyloxycarbonyl, aralkyloxyaminocarbonyl, aralkyloxycarbonylamino, aralkenyl, cycloalkyl, cycloalkyloxy, cycloalkylaminocarbonyl, cycloalkylalkyl where the "alkyl" is optionally substituted with one or two hydroxy, cycloalkylalkylaminocarbonyl, cycloalkylalkyloxycarbonyl, heteroaryl, heteroarylaminocarbonyl, heteroaralkyl, heteroaralkenyl, heteroaralkyloxy, halo, hydroxy, hydroxyalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, N-hydroxyaminocarbonyl, N-alkoxyaminocarbonyl, hydroxyalkylaminocarbonyl, dialkylaminoalkyloxycarbonyl, dialkylaminoalkylaminocarbonyl, arylamino, arylaminocarbonyl, alkylsulfonylamino, alkylsulfonylaminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylaminocarbonyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkylalkyloxycarbonyl, optionally substituted heterocycloalkylalkylaminocarbonyl, aniinocarbonylamino, N-aryl-N-(alkylcarbonyl)-amino, N-(alkylsulfonyl)-N-alkyl-amino, alkoxycarbonylalkylaininocarbonyl where the "alkyl" is optionally substituted with one or two hydroxy, or trialkylsilyl; or any two of R⁷, R⁸, and R⁹ attached to the same carbon atom together with the carbon to which they are attached form indanylene or optionally substituted heterocycloalkylene; and where the alkyl, alkenyl, and alkynyl in R⁷, R⁸, and R⁹, either alone or part of another group, independently are optionally substituted with one, two, three, four, or five halo; or a pharmaceutically acceptable salt thereof.

3. A Compound of Formula I:

I where

D is =N- or ^CR⁶- where R⁶ is hydrogen, alkyl, halo, alkylcarbonyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, haloaloxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl;

R² is hydrogen, alkyl, alkylsulfonyl, alkylphosphonyl, or alkoxyalkyloxyalkyl;

R³ is hydrogen, alkyl, hydroxy, halo, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, R^10aR^10bNC(O)NR^10c- (where R^1Oa, R^1Ob, and R¹⁰° are independently hydrogen, alkyl, or substituted alkyl), R^llaR^llbNC(O)O- (where R^lla and R^llb are independently hydrogen, alkyl, or substituted alkyl), or R^12aOC(O)NR^12b- (where R^12a and R^12b are independently hydrogen, alkyl, or substituted alkyl); and R¹⁰⁰ is a group of formula (A2):

(A2) where

R^4a and R^4b are as defined above;

R⁵ is -Y¹¹-X¹¹-Q¹¹ where Y¹¹ is -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR²⁶³-, -NR^26aC(O)-₅ -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are independently hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, or acyl, where X¹¹ is a bond, alkyl ene, or alkenylene, (where X¹¹ is optionally substituted with hydroxy, alkoxycarbonyl, carboxy), and where Q¹¹ is heteroaryl, aryl, aryloxy, or cycloalkyl;

R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is alkylene or alkenylene; Y¹² is -NR^26a-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR²⁶³-, -NR²⁶³C(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are as defined above; X^12b is a bond, alkylene, or alkenylene where X^12b is optionally substituted with one, two, or three groups selected from hydroxy, cyano, halo, heteroaryl, alkylcarbonyl, alkoxycarbonyl, carboxy, -NR^27aR^27b (where R^27a and R^27b are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, heteroaryl, or heteroarylarninocarbonyl), -C(O)NR^28aR^28b (where R^28a and R^28b are independently hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, hydroxy, or heteroaryl), and -NR^29aC(O)OR^29b (where R^29a is hydrogen, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, or hydroxy, and R^29b is alkyl); and Q is aryl, aryloxy, aralkyloxy, heteroaryl, aralkylaminocarbonyl (where the alkyl is optionally substituted with alkoxycarbonyl or carboxy), cycloalkyl, cycloalkylaminocarbonyl, cycloalkylalkyloxy, -NR^30aR^30b (where R^30a is hydrogen or alkyl and R^30b is aryl, heteroaryl, or cycloalkylalkyl) or -S(O)_n-R³¹ (where n is O, 1, or 2 and R³¹ is heteroaryl, cycloalkylalkyl or aralkyl); where the alkyl within any group in Q is optionally substituted with alkoxyalkyl);

R⁵ is -X¹³-Y¹³-Z¹³ where X¹³ is alkylene or alkenylene, where Y¹³ is -NR^26a-, -0-, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -NR²⁶³SO₂-, -SO₂NR²⁶³-, -C(O)NR²⁶³-, -NR²⁶³C(O)-, -OC(O)-, -OC(O)NR²⁶³-, -NR²⁶³C(O)O-, -C(O)NR²⁶³C(O)-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are as defined above, and where Z¹³ is hydrogen, alkyl, or alkenyl (where Z¹³ is optionally substituted with one, two, or three halo, hydroxy, amino, alkoxy, alkoxycarbonyl, carboxy, or alkylcarbonylamino); or

R⁵ is -Y¹⁴-Z¹⁴ where Y¹⁴ is -S(O)-, -NR^26aC(O)-, -C(O)NR^26a-, -NR^26aC(O)NR^26b-, -C(O)NR^26aC(O)-, -NR²⁶³C(O)O-, -OC(O)NR^26a, or -OC(O)-, where R^26a and R^26b are as defiend above, and where Z¹⁴ is alkyl or alkenyl (where Z¹⁴ is optionally substituted with one, two, or three halo, hydroxy, amino, alkoxy, alkoxycarbonyl, carboxy, or alkylcarbonylamino) ; or a pharmaceutically acceptable salt thereof.

4. A Compound of Formula I:

I where

R² is hydrogen, alkyl, alkylsulfonyl, alkylphosphonyl, or alkoxyalkyloxyalkyl;

R³ is hydrogen, alkyl, hydroxy, halo, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl, alkylthio, alkylsulfϊnyl, alkylsulfonyl, alkylsulfonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, carboxy, alkylcarbonyloxy, amino, alkylamino, dialkylamino, mercaptoalkylaminocarbonylalkyl, R^10aR^10bNC(O)NR^10c- (where R^1Oa, R^1Ob, and R^1Oc are independently hydrogen, alkyl, or substituted alkyl), R^llaR^llbNC(O)O- (where R^lla and R^{l lb} are independently hydrogen, alkyl, or substituted alkyl), or R¹²³OC(O)NR^12b- (where R^12a and R^12b are independently hydrogen, alkyl, or substituted alkyl); and R¹⁰⁰ is a group of formula (A3):

(A3) where

Y⁴ is -C(O)-, -NR³²C(O)-, -S(O)₂-, or a bond;

Z⁴ is heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, carboxy, aryl, aralkyl, cyano, arylcarbonyl, alkoxy, and hydroxy; or Z⁴ is -NR^50aR^50b where R^5Oa is hydrogen, alkyl, alkoxy, or hydroxy and R^50b is -(alkylene)-aryl where the alkylene is optionally substituted with one or two groups selected from halo, alkoxycarbonyl, hydroxy, and carboxy; or a pharmaceutically acceptable salt therof.

5. The compound of Claim 1 where

D is =N- or =CR⁶- where R⁶ is hydrogen, halo, or carboxyalkyl;

R¹ is hydrogen;

R is hydrogen;

R³ is hydrogen, halo, or mercaptoalkylaminocarbonylalkyl; and

R¹⁰⁰ is a group of formula (Al):

(Al) where

R^4a and R^4b are hydrogen;

L is -X¹ -Y^Z¹- where X¹ is alkylene; Y¹ is -C(O)-, -C(O)NH-, or -NHC(O)- and Z¹ is a bond, alkylene, or alkenylene;

L is -X - where X is alkylene;

L is -Y²-Z²- where Y² is -C(O)NH- or -NHC(O)-; and Z² is alkylene; or

L is ~X⁵-Y^5a-Z⁵-Y^5b- where X⁵ is alkylene; Y^5a is -C(O)NH- or -NHC(O)-; Z⁵ is alkylene where the alkylene is optionally substituted with aralkyloxyalkyl; and Y^5b is -C(O)-; Het is piperidinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, or 4-oxo-4λ⁵- [l,4]azaphosphinanyl; and

R⁷ and R⁸ are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, acyl, acylamino, acylaminoalkyloxycarbonyl, alkoxycarbonyl, alkoxyalkylaminocarbonyl, alkoxyalkyloxycarbonyl, amino, carboxy, carboxyalkylaminocarbonyl (where the "alkyl" is optionally substituted with one or two hydroxy), cyano, cyanoalkylaminocarbonyl, aryl, aryloxy, arylsulfonyl, arylthioalkylcarbonyl, aralkyl (where the alkyl is optionally substituted with one or two hydroxy), aralkyloxy, aralkyloxyaminocarbonyl, aralkyloxycarbonylamino, cycloalkylaminocarbonyl, cycloalkylalkyl (where the "alkyl" is optionally substituted with one or two hydroxy), cycloalkylalkylaminocarbonyl, cycloalkylalkyloxycarbonyl, heteroaryl, heteroarylaminocarbonyl, heteroaralkyl, halo, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, iV-hydroxyaminocarbonyl, N-alkoxyaminocarbonyl, hydroxyalkylaminocarbonyl, dialkylaminoalkyloxycarbonyl, dialkylaminoalkylaminocarbonyl, arylamino, arylaminocarbonyl, alkylsulfonylamino, alkylsulfonylaminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylaminocarbonyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxycarbonyl, optionally substituted heterocycloalkylalkylaminocarbonyl, aminocarbonylamino, iV-aryl-iV-(alkylcarbonyl)-amino, or alkoxycarbonylalkylaminocarbonyl (where the "alkyl" is optionally substituted with one or two hydroxy); or any two of R⁷, R⁸, and R⁹ attached to the same carbon atom together with the carbon to which they are attached form indanylene or optionally substituted heterocycloalkylene; and where the alkyl, alkenyl, and alkynyl in R⁷, R⁸, and R⁹, either alone or part of another group, independently are optionally substituted with one, two, three, four, or five halo; and

R⁹ is hydrogen;or

R¹⁰⁰ is a group of formula (A2):

(A2) where

R^4a and R^4b are hydrogen; R⁵ is -Y¹¹OC"^¹¹ where Y¹¹ is -C(O)NR^26a-, -NR²⁶³C(O)-, -NR²⁶³C(O)O-, or -NR^26aC(O)NR^26b-, where R^26a and R^26b are independently hydrogen or hydroxy, where X¹¹ is a bond, alkylene, or alkenylene, (where X¹¹ is optionally substituted with hydroxy), and where Q¹¹ is heteroaryl, aryl, aryloxy, or cycloalkyl; or

R⁵ is -X^12a-Y¹²-X^12b-Q¹² where X^12a is alkylene; Y¹² is -C(O)NH-, -NHC(O)-, or -NHC(O)NH-; X^12b is a bond, alkylene, or alkenylene where X^12b is optionally substituted with one, two, or three groups selected from hydroxy, cyano, halo, heteroaryl, alkoxycarbonyl, carboxy, -NR^27aR^27b (where R^27a and R^27b are independently hydrogen or alkyl), -C(O)NR^28aR^28b (where R^28a and R^28b are independently hydrogen, alkyl, alkoxy, or heteroaryl), and -NR^29aC(O)OR^29b (where R^29a is hydrogen and R^29b is alkyl); and Q¹² is aryl, aryloxy, aralkyloxy, heteroaryl, aralkylaminocarbonyl (where the alkyl is optionally substituted with alkoxycarbonyl or carboxy), cycloalkyl, cycloalkylaminocarbonyl, cycloalkylalkyloxy, -NR^30aR^30b (where R^3Oa is hydrogen or alkyl and R^30b is aryl, heteroaryl, or cycloalkylalkyl) or -S(O)_n-R³¹ (where n is O or 2 and R³¹ is heteroaryl, cycloalkylalkyl or aralkyl); where the alkyl within any group in Q¹² is optionally substituted with alkoxyalkyl); or

R¹⁰⁰ is a group of formula (A3):

(A3) where

X⁴ is alkylene;

Y⁴ is -C(O)-;

Z⁴ is heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkylalkyl, alkoxycarbonyl, carboxy, aralkyl, cyano, acyl, and hydroxy; or Z⁴ is ~NR^5OaR^5Ob where R^5Oa is hydrogen and R^5Ob is -(alkylene)-aryl where the alkylene is optionally substituted with one or two groups selected from alkoxycarbonyl, hydroxy, and carboxy.

6. The Compound of Claim 1 where A is optionally substituted pyridino; D is =CH-; and and R¹, R², R³, R^4a and R^4b are hydrogen.

7. The Compound of Claim 6 where A is

*

8. The Compound of Claim 2 where A is N. ~^ sy ** and j n Rl¹, r Ri 2², and R³ are hydrogen.

9. The Compound of Claim 2 where L is -CH₂C(O)-.

10. The Compound of Claim 2 where Het is piperidinyl, the N-oxide of piperazinyl, or 4-oxo-4λ⁵-[l,4]azaphosphinanyl (where the phosphorous atom is substituted with alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl).

11. The Compound of Claim 10 where Het is piperidinyl and L is attached at the

1 -position and R⁷ and R⁸ are attached at the 4-position; Het is piperazinyl and L is attached at the 1 -position and R⁷ is attached at the 4-position; or Het is 4-oxo-4λ⁵-[l,4]azaphosphinanyl where the phosphorous atom is substituted with alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl.

12. The Compound of Claim 11 where Het is piperidinyl where L is attached at the 1 -position and R⁷ and R⁸ are attached at the 4-position.

13. The Compound of Claim 2 where R⁷ and R⁸ are independently hydrogen, optionally substituted alkyl (preferably alkyl substituted with one or two alkoxyalkyloxycarbonyl, dialkylaminoalkyloxy, hydroxy or carboxy), optionally substituted alkenyl (preferably alkenyl), alkoxycarbonyl, carboxy, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, hydroxy, alkylsulfonylaminocarbonyl, alkoxycarbonylalkylaminocarbonyl, optionally substituted heterocycloalkyl, cycloalkylalkyl, amino, acyl (preferably optionally substituted heterocycloalkylcarbonyl), alkoxyalkyloxycarbonyl, dialkylaminoalkyloxycarbonyl, optionally substituted heterocycloalkylalkyloxycarbonyl, dialkylaminoalkylaminocarbonyl, or cyano; and R⁹ is hydrogen.

14. The Compound of Claim 13 where R⁷ is hydrogen, cyano, carboxy, or alkoxycarbonyl and R⁸ is aralkyl, heteroaralkyl, or cycloalkylalkyl; and R⁹ is hydrogen.

15. The Compound of Claim 13 where R⁷ is carboxy, R⁸ is aralkyl, and R⁹ is hydrogen; R⁷ is alkoxycarbonyl, R⁸ is aralkyl, and R⁹ is hydrogen; R⁷ is carboxy, R⁸ is heteroaralkyl, and R⁹ is hydrogen; R⁷ is alkoxycarbonyl, R⁸ is cycloalkylalkyl, and R⁹ is hydrogen; R⁷ is carboxy, R⁸ is cycloalkylalkyl, and R⁹ is hydrogen; R⁷ is cyano, R⁸ is cycloalkylalkyl, and R 9 is hydrogen; or R⁷ and R⁹ are hydrogen and R⁸ is aralkyl.

16. The Compound of Claim 15 where R⁷ is carboxy, R⁸ is aralkyl, and R⁹ is hydrogen; R is carboxy, R is cycloalkylalkyl, and R is hydrogen; R is cyano, R is cycloalkylalkyl, and R⁹ is hydrogen; or R⁷ and R⁹ are hydrogen and R⁸ is aralkyl.

17. The Compound of Claim 3 where A is optionally substituted pyridino; D is =CH-; and R¹, R², R³, R^4a and R^4b are hydrogen.

18. The Compound of Claim 17 where A is

19. The Compound of Claim 3 where R⁵ is -Y¹¹^-Q¹¹ or -X^12a-Y¹²-X^12b-Q¹².

20. The Compound of Claim 19 where R⁵ is -X^12a-Y¹²-X^12b-Q¹² and Q¹² is aryl, aryloxy, aralkyloxy, or -S(O)₂-R³¹ where R³¹ is aryl.

21. The Compound of Claim 20 where Q¹² is phenyl, phenyloxy, phenylmethyloxy, 4- methoxyphenyl, indanyl, phenylmethylsulfonyl, or 4-chlorophenyl.

22. The Compound of Claim 4 where A is optionally substituted pyridino; D is =CH-; and R , R , and R are hydrogen.

23. The Compound of Claim 22 where A is N^,

24. The Compound of Claim 4 where X⁴ is -CH₂- and Y⁴ is -C(O)-.

25. The Compound of Claim 24 where Z⁴ is heterocycloalkyl optionally substituted with one, two, three, or four groups selected from cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, carboxy, aryl, aralkyl, cyano, arylcarbonyl, alkoxy, and hydroxy.

26. The compound named N-(4-iodo-pyridin-3 -yl)-methanesulfonamide.

27. A method of treating a disease, disorder, or syndrome responsive to the inhibition of tryptase in an animal suffering said disease, disorder, or syndrome, comprising administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I.

28. The method of Claim 27 wherein said animal is human.

29. The method of Claim 27 wherein the syndrome is asthma.

30. A method of treating an immunomediated respiratory disease independently selected from the group consisting of asthma, COPD, and allergic rhinitis, in an animal which method comprises administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient in combination with one or more compound(s) independently selected from the group consisting of a β-2 adrenoreceptor agonist, corticosteroid, leukotriene antagonist, phosphodiesterase 4 inhibitor, and antihistamine.

31. The method of Claim 30 wherein the β-2 adrenoreceptor agonist is salmeterol or levalbuterol, the corticosteroid is budesonide or fluticasone, the leukotriene D4 antagonist is montelukast, and the phosphodiesterase 4 inhibitor is roflumilast.

32. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient.