WO2014060431A1 - Pyrrolotriazinone derivatives as pi3k inhibitors - Google Patents

Pyrrolotriazinone derivatives as pi3k inhibitors Download PDF

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Publication number: WO2014060431A1
Authority: WO; WIPO (PCT)
Prior art keywords: group; phenyl; methyl; branched; linear
Prior art date: 2012-10-16

Application number

PCT/EP2013/071550

Other languages

English (en)

French (fr)

Inventor

Jordi Gracia Ferrer

Marta Carrascal Riera

Montserrat Erra Sola

Original Assignee

Almirall, S.A.

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2012-10-16

Filing date

2013-10-15

Publication date

2014-04-24

2013-10-15 Application filed by Almirall, S.A. filed Critical Almirall, S.A.

2014-04-24 Publication of WO2014060431A1 publication Critical patent/WO2014060431A1/en

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0 *c1c(*)[n]c(C(O)=O)c1* Chemical compound *c1c(*)[n]c(C(O)=O)c1* 0.000 description 3

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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

Phosphoinositide 3-Kinases are among the enzymes involved in early signalling events to a plethora of different types of stimuli.
PI3Ks phosphorylate the 3-hydroxyl group of the inositol ring of phosphatidylinositol (Ptdlns), Ptdlns-4-phosphate (Ptdlns4P), and Ptdlns-4,5-bisphosphate (Ptdlns(4,5)P2).
Ptdlns phosphatidylinositol
Ptdlns4P Ptdlns-4-phosphate
Ptdlns(4,5)P2 Ptdlns(4,5)P2
PI3K class I PI3K class II
class III PI3K class III
the best characterized is the PI3K class I with the preferential substrate Ptdlns- (4,5)P2. It englobes 4 different isoforms which originally were further subdivided into class IA (p1 10a, p1 10b, p1 10d), binding to a p85 type of regulatory subunit, and class IB (p110g) which is regulated by p101 and p87 subunits.
p1 10a PI3Ka or PI3Ka
p1 10b PI3Kb or ⁇ 3 ⁇
p110g PI3Kg or ⁇ 3 ⁇
p1 10d PI3Kd or PI3K5
PI3Kd and PI3Kg are involved in activation of immune cells by a large variety of different stimuli.
Pharmacological inhibition or genetic deficiency in active p1 10d has been shown to inhibit T cell proliferation and cytokine production in response to different stimuli such as anti-CD3, anti-CD3/CD28, superantigen or antigen in vitro (Ji H, Blood 2007; Okkenhaug K, Science 2002; Garcon F, 2009; Soond DR, Blood 2010; Herman SEM, Blood June 3, 2010; William O, Chemistry & Biology 17, 2010) and to suppress concanavalin A and anti-CD3 induced cytokine production as well as antigen- dependent tissue retention in vivo (Soond DR, Blood 2010; Jarmin SJ, JCI 2008).
B cell function is critically dependent on functional PI3Kd activity as demonstrated by suppressed B cell proliferation and cytokine release in vitro in response to anti-lgM (Bilancio A, Blood 107, 2006), toll like receptor agonists such as LPS and oligodeoxynucleotides (Dil N, Mol Immunol 46, 2009) or impaired ability to stimulate antigen-specific T cells (Al-Alwan M, Jl 2007) in the absence of functional p110d or pharmacological inhibition.
PI3Kg deficient mice display partially suppressed antibody production upon immunization (Garcon F, 2009; Durand CA, Jl 2009). Further studies have demonstrated an important role of PI3Kd in inhibition of T cell apoptosis and in TH17 differentiation (Haylock-Jacobs S, J. Autoimmun 2010).
mast cell degranulation was reduced in cells from mice with inactivated PI3Kd or by pharmacological inhibition of PI3Kd (AN K, Nature 431 :1007-1011 , 2004; Ali K, Journal of Immunology 180:2538-2544, 2008) and basophil activation via the FcE receptor is suppressed by pharmacological inhibition of PI3Kd (Lannutti BJ, Blood Oct. 2010).
PI3Kd inhibition inhibits migration of mouse neutrophils to fMLP in an under-agarose migration assay by inhibiting cell polarization and directional movement (Sadhu C, Jl 170, 2003) and mouse PI3Kd deficient or inhibitor treated neutrophils show slightly (25%) reduced in vitro chemotaxis to LTB4, whereas in vivo accumulation in the lung in response to LPS was reduced by more than 80%, indicating an important role of PI3Kd in endothelial cells for mediating PMN
TNF induced neutrophil infiltration to an air pouch in mice and elastase release is partially inhibited by a PI3Kd selective inhibitor (Sadhu C, Biochem Biophys Res Comm 308, 2003).
PI3Kd selective inhibitor Sadhu C, Biochem Biophys Res Comm 308, 2003.
TNF mediated priming of oxidative burst by human neutrophils depends on PI3Kd activity (Condliffe AM, Blood 106, 2005).
PI3Kg seems to affect primarily chemotaxis of different immune cells induced by various mediators and chemokines (Martin AL, Jl 180, 2008; Thomas MS, J Leukoc Biol 84, 2008; Jarmin SJ, JCI 2008; Matthew T, Immunology 126, 2008), as well as degranulation and oxidative burst of innate immuce cells induced by GPCR mediated stimuli such as fMLP, IL-8 or C5a (Condliffe AM, Blood 106, 2005; Yum HK, Jl 167, 2001 ; Pinho V, Jl 179, 2007
PI3Kd or dual PI3Kd/PI3Kg pharmacological inhibition represents a promising approach for treating a variety of diseases such as respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis), allergic diseases (allergic rhinitis), inflammatory or autoimmune diseases (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, myastenia gravias, acute disseminated encephalomyelitis, idiopathic thromocytopenic purpura, Sjoegren's syndrome, autoimmune hemolytic anemia, type I diabetes, psoriasis, acrodermatitis, angiodermatitis, atopic dermatitis, contact dermatitis, e
COPD chronic
PI3Kd inhibition Puri KD, Blood 2004;103:3448
inflammation in response to LPS or tobacco smoke exposure is suppressed by a dual PI3Kd/g inhibitor
PI3Kd seems to be involved in the reduction of responsiveness to corticosteroid treatment associated with oxidative stress and chronic obstructive pulmonary disease (COPD).
COPD chronic obstructive pulmonary disease
PI3Kd selective inhibitor To Y, AJRCCM 182:897- 904, 2010.
in vitro induction of corticosteroid resistance by oxidative stress is prevented by PI3Kd inhibition (To Y, AJRCCM 2010).
lung macrophages display increased expression of PI3Kd and phosphorylation of its downstream effector Akt and non-selective PI3K or PI3Kd- selective inhibition restored the impaired inhibitory efficacy of dexamethasone in PBMC from COPD patients (To Y, AJRCCM 182:897-904, 2010; Marwick JA, JACI 125:1 146-53, 2010).
PI3Kd inhibition was effective in a model of contact hypersensitivity (Soond DR, Blood Jan 2010).
Soond DR Blood Jan 2010
PI3Kd inhibition was effective in a model of contact hypersensitivity (Soond DR, Blood Jan 2010).
PI3Kd deficiency or pharmacological inhibition of PI3Kd attenuated T cell activation and function and reduced T cell numbers in the CNS suggesting a therapeutic benefit of PI3Kd inhibitor in multiple sclerosis and other Th17-mediated autoimmune diseases (Haylock-Jacobs S, J. Autoimmun 2010).
genetic deficiency or pharmacological inhibition of PI3Kd diminished joint erosion in a mouse model of inflammatory arthritis (Randis TM, Eur J Immunol 38, 2008).
PI3Kd overexpression seems to contribute to excessive vascular contraction and PI3Kd inhibition normalized vascular contractive responses in a mouse model of type I diabetes, suggesting a therapeutic potential of PI3Kd blockade to treat vascular dysfunction in diabetic patients (Pinho JF, Br. J. Pharmacol 161 , 2010).
pharmacolocical inactivation of PI3Kd or dual PI3Kd/g dual inhibition is effective in the treatment of cancers including but not restricted to leukemias, such as chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, acute myeloid leukaemia, myelo-dysplastic syndrome or myelo-proliferative diseases.
leukemias such as chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, acute myeloid leukaemia, myelo-dysplastic syndrome or myelo-proliferative diseases.
the selective PI3Kd inhibitor CAL-101 demonstrated anti-proliferative properties on different tumor cells in vitro and efficacy in cancer patients with a dysregulated PI3Kd activity, such as chronic lymphocytic leukemia (Hermann SE, Blood 1 16:2078-88, 2010; Lannutti BJ, Blood Oct. 2010).
a dysregulated PI3Kd activity such as chronic lymphocytic leukemia (Hermann SE, Blood 1 16:2078-88, 2010; Lannutti BJ, Blood Oct. 2010).
Conditions in which targeting of the PI3K pathway or modulation of the PI3 Kinases, particularly PI3Kd or PI3Kd/g, are contemplated to be therapeutically useful for the treatment or prevention of diseases including: respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis), allergic diseases (allergic rhinitis), inflammatory or autoimmune-mediated diseases (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, myastenia gravias, acute disseminated encephalomyelitis, idiopathic thromocytopenic purpura, Sjoegren's syndrome, autoimmune hemolytic anemia, type I diabetes, psoriasis, acrodermatitis, angiodermatitis,
novel pyrrolotriazinone derivatives for use in the treatment of conditions in which targeting of the PI3K pathway or inhibition of PI3 Kinases can be therapeutically useful.
the compounds described in the present invention are potent PI3K inhibitors, particularly PI3Kd or dual PK3Kd/g inhibitors. This property makes them useful for the treatment or prevention of pathological conditions or diseases such as respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis), allergic diseases (allergic rhinitis), inflammatory or autoimmune diseases (rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, myastenia gravias, acute disseminated encephalomyelitis, idiopathic thromocytopenic purpura, Sjoegren's syndrome, autoimmune hemolytic anemia, type I diabetes, psoriasis, acrodermatitis, angiodermatitis, atopic derma
the compounds described in the present invention are particularly useful for the treatment or prevention of pathological conditions or diseases such as neoplastic diseases (e.g. leukemia, lymphomas, solid tumors); transplant rejection, bone marrow transplant applications (e.g., graft- versus-host disease); autoimmune diseases (e.g.
rheumatoid arthritis multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis and blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa; respiratory inflammation diseases (e.g.
asthma chronic obstructive pulmonary disease
cystic fibrosis cystic fibrosis
idiopathic pulmonary fibrosis sarcoidosis
skin inflammatory diseases e.g., atopic dermatitis, contact dermatitis, eczema or psoriasis
premalignant and malignant skin conditions e.g. basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or actinic keratosis (AK)
BCC basal cell carcinoma
SCC squamous cell carcinoma
AK actinic keratosis
neurological disorders and pain such as pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, inflammatory neuropathic pain, trigeminal neuralgia or central pain
the compounds described in the present invention are particularly useful for the treatment or prevention of pathological conditions or diseases selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic ker
n 0, 1 , 2 or 3;
X represents N or CH;
R a and R b each independently represent a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group;
Ri represents a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C 6 -Ci 4 aryl group, a 5- to 14- membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom selected from O, S and N,
cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a -(CH 2 )i -3 CN group, a -(CH 2 ) 0 -3OR 9 group, a -(CH 2 )o-3N R 9 Rio group, a -C(0)-(CH 2 )i-3-CN group, a -C(O)-(CH 2 ) 0 .3-R 9 group, a -C(0)-(CH 2 )o- 3 -N R 9 R 10 group, a - -
R 9 group a -S(0)(CH 2 )o- 3 R9 group, a -S(O)(CH 2 ) 0 .3N R 9 R 10 group, a -S(O) 2 (CH 2 ) 0 - 3 R 9 group, a -S(O) 2 (CH 2 ) 0 - 3 N R 9 R 10 group or
R 2 and R 3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a C1-C4 alkoxy group, a -NH 2 group, a -N(CH 3 )H group or a -N(CH 3 ) 2 group;
R 4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH 2 ) 0 -3-(C 3 -C4 cycloalkyl) group, a - (CH 2 )o-3-0(Ci-C 4 alkyl) group, a -(CH 2 )o- 3 -S-(CH 2 )o- 3 -(phenyl) group, a -(CH 2 ) 0 - 3 -S- (CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 ) 0 -3-0-(CH 2 )o-3-(phenyl) group, a -(CH 2 ) 0 -O- (CH 2 )o-3-(5-
phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3NR 9 Rio group, a -(CH 2 )o-3-0(CrC 4 alkyl) group, a -(CH 2 )o-3-(C 3 -C 4 cycloalkyl) group, a C2-C4 alkynyl group, a -(CH 2 ) 0- 3-(phenyl) group, a -(CH 2 ) 0- 3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH 2 ) 0-3 - S(O) 2 (CH 2 ) 0 .
phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH 2 )o-4-C(0)-N(R')-(CH 2 )o-4-R" group, a -(CH 2 )o- 4 -C(0)-(CH 2 )o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 ) 0-3 - 0(Ci-C 4 alkyl) group, a linear or branched C1-C4 alkyl group, a
R 6 and R 7 each independently represent a hydrogen atom, a -(CH 2 ) 0-3 CN group, a - C(0)-(CH 2 )i. 3 -CN group, a -C(O)-(CH 2 ) 0 - 3 -R' group, a -C(O)-(CH 2 ) 0 - 3 -NR'R", a -(CH 2 ) 0 .
R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-0(Ci-C 4 alkyi) group or a linear or branched Ci- C 4 alkyi group;
R 8 represents a monocyclic or bicyclic C 6 -Ci 4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N , or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N
a hydrogen atom independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyi group, a -(CH 2 ) 1-3 NR a R b group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyi group, a CrC 4 alkoxy group or a C 3 -C 4 cycloalkyl group;
R 9 and Ri 0 each independently represent a hydrogen atom, a CrC 4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyi group, which alkyi group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C3-C4 cycloalkyl group.
R11 represents a linear or branched C1-C4 alkyi group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -NH 2 group, a -N H(Ci-C 4 alkyi) group, a - N H-S(0) 2 -(CrC 4 alkyi) group
R- 12 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH 2 )i-4 group; wherein R
the invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy.
the invention also provides a pharmaceutical composition
a pharmaceutical composition comprising the compounds of the invention and a pharmaceutically-acceptable diluent or carrier.
the invention is also directed to the compounds of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type
the invention is also directed to use of the compounds of the invention as described herein, in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is as defined above.
PI3Ks Phosphoinositide 3-Kinases
the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is as defined above.
the invention also provides a combination product comprising (i) the compounds of the invention as described herein; and (ii) one or more additional active substances which are known to be useful in the treatment of respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral
C1-C6 alkyl embraces linear or branched radicals having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n- propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 1 -methylbutyl, 2-methylbutyl, isopentyl, 1-ethylpropyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2- ethylbutyl, 1 , 1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl and iso-hexyl radicals.
the alkyl radical may be optionally substituted it is meant to include linear or branched alkyl radical as defined above, which may be unsubstituted or substituted in any position by one or more substituents, for example by 1 , 2 or 3 substituents. When two or more substituents are present, each substituent may be the same or different.
the term C1-C4 haloalkyl group is an alkyl group, for example a C1-C4 or C1-C2 alkyl group, which is bonded to one or more, preferably 1 , 2 or 3 halogen atoms.
said haloakyl group is chosen from -CCI3, -CHF 2 and -CF 3 .
Ci-C 4 hydroxyalkyl embraces linear or branched alkyl radicals having 1 to 4 carbon atoms, any one of which may be substituted by one or more, preferably 1 or 2, more preferably 1 hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.
C1-C4 alkoxy (or alkyloxy) embraces linear or branched oxy- containing radicals each having alkyl portions of 1 to 4 carbon atoms.
C3-C10 cycloalkyl embraces saturated monocyclic or polycyclic carbocyclic radicals having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms.
An optionally substituted C3-C10 cycloalkyl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
substituents may be the same or different.
substituents on a C3-C10 cycloalkyl group are themselves unsubstituted.
Polycyclic cycloalkyl radicals contains two or more fused cycloalkyl groups, preferably two cycloalkyl groups.
polycyclic cycloalkyl radicals are selected from decahydronaphthyl (decalyl), bicyclo[2.2.2]octyl, adamantly, camphyl or bornyl groups.
Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.
C 3 -Cio cycloalkenyl embraces partially unsaturated carbocyclic radicals having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms.
a C 3 -Ci 0 cycloalkenyl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
the substituents may be the same or different.
the substituents on a cycloalkenyl group are themselves unsubstituted.
C 6 -Ci 4 aryl radical embraces typically a C 6 -C-
a said optionally substituted Ce-C-u aryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
a C6-C14 aryl radical When a C6-C14 aryl radical carries 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, the substituents on a C6-C14 aryl group are typically themselves unsubstituted.
the term 5- to 14- membered heteroaryl radical embraces typically a 5- to 14- membered ring system, preferably a 5- to 10- membered ring system, more preferably a 5- to 6- membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N.
a 5- to 14- membered heteroaryl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom.
a said optionally substituted 5- to 14- membered heteroaryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
substituents may be the same or different.
the substituents on a 5- to 14- membered heteroaryl radical are typically themselves unsubstituted.
Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2
the term 5- to 14-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C5-C14 carbocyclic ring system, preferably C 5 - do carbocyclic ring system, more preferably C5-C6 carbocyclic ring system, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S.
a heterocyclyl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom. When a 5 to 14-membered heterocyclyl radical carries 2 or more substituents, the substituents may be the same or different.
a said optionally substituted 5- to 14-membered heterocyclyl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different. Typically, the substituents on a 5 to 14-membered heterocyclyl radical are themselves unsubstituted.
Examples of 5- to 14-membered heterocyclyl radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, imidazolyl, oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, 4,5-dihydro-oxazolyl, 2-benzofuran-1 (3H)-one, 1 ,3-dioxol-2-one, tetrahydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyrany
the bicyclic N-containing heteroaryl group is a C 8 -Ci 0 membered ring system where two rings have been fused and wherein at least in one ring one of the carbon atoms is replaced by N and optionally in which 1 , 2, 3, or 4, preferably 1 , 2, or 3 further carbon atoms of any ring which form the group are replaced by N.
Examples include indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3- b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3- d]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolinyl, indazolyl, purinyl, indolinyl, imidazo[1 ,2-a]pyridinyl, imidazo[1 ,5-a]pyridinyl, pyrazolo[1
atoms, radicals, moieties, chains and cycles present in the general structures of the invention are "optionally substituted".
substituents can be either unsubstituted or substituted in any position by one or more, for example 1 , 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically acceptable atoms, radicals, moieties, chains and cycles.
substituents When two or more substituents are present, each substituent may be the same or different. The substituents are typically themselves unsubstituted.
halogen atom embraces chlorine, fluorine, bromine and iodine atoms.
a halogen atom is typically a fluorine, chlorine or bromine atom, most preferably chlorine or fluorine.
the term halo when used as a prefix has the same meaning.
Compounds containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, in the form of racemic mixtures and in the form of mixtures enriched in one or more stereoisomer.
the compounds of Formula (I) as described and claimed encompass the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC).
HPLC high pressure liquid chromatography
the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
a suitable optically active compound for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
the resulting diastereoisomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994).
Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
Oki (Oki, M; Topics in Stereochemistry 1983, 1 ) defined atropisomers as conformers that interconvert with a half-life of more than 1000 seconds at a given temperature.
the scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual atropisomers (an atropisomer "substantially free" of tis corresponding enantionmer) and stereoisomer-enriched mixtures, i.e. mixtures of atropisomers.
Atropisomers Separation of atropisomers is possibly by chiral resolution methods such as selective crystallization.
an atropo-enantioselective or atroposelective synthesis one atropisomer is formed at the expense of the other.
Atroposelective synthesis may be carried out by use of chiral auxiliaries like a Corey-Bakshi-Shibata (CBS) catalyst (asymmetric catalyst derived from proline) in the total synthesis of knipholone or by approaches based on thermodynamic equilibration when an isomerization reaction favors one atropisomer over the other.
CBS Corey-Bakshi-Shibata
the compounds of Formula (I) may exhibit the phenomena of tautomerism and structural isomerism.
Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of Formula (I).
the compounds of formula (I) may exist in different physical forms, i.e. amorphous and crystalline forms.
the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism.
Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of formula (I), including all polymorphic forms (“polymorphs”) or amorphous forms thereof, are included within the scope of the invention.
Pharmaceutically acceptable salts are included within the scope of the invention.
the term pharmaceutically acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
the term pharmaceutically acceptable salt embraces salts with a pharmaceutically acceptable acid or base.
Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid; and organic acids, for example citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic acid, xinafoic (1 -hydroxy-2-naphthoic acid), napadisilic (1 ,5-naphthalenedisulfonic acid) and the like.
Particularly preferred are salts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric, methan
Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts.
Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the
X- may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate or methanesulphonate.
an N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
the invention also includes isotopically-labeled derivatives of the compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 1 1 C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 1231 and 1251, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulfur, such as 35S.
Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies.
the radioactive isotopes tritium, 3H, and carbon-14, 14C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, 2H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as 1 1 C, 18F, 150 and 13N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
PET Positron Emission Topography
Isotopically-labeled derivatives of the compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
Preferred isotopically-labeled derivatives include deuterated derivatives of the compounds of the invention.
the term deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
Deuterium (D or 2H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
the compounds of the invention may exist in both unsolvated and solvated forms.
solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules.
hydrate is employed when said solvent is water.
solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate.
solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non- solvate form of the compounds.
Prodrugs of the compounds described herein are also within the scope of the invention.
certain derivatives of the compounds of the present invention which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage.
Such derivatives are referred to as 'prodrugs'.
Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
PI3Kd inhibitor generally refers to a compound that inhibits the activity of the PI3Kd isoform more effectively than other isoforms of the PI3K family.
PI3Kd/g inhibitor generally refers to a compound that inhibits the activity of both the PI3Kd isoform and the PI3Kg isoform more effectively than other isoforms of the PI3K family.
the relative efficacies of compounds as inhibitors of an enzyme activity can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results.
the preferred determination is the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or "IC 50 .”
IC 50 determinations can be accomplished using conventional techniques known in the art. In general, an IC 50 can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the inhibitor under study. The experimentally obtained values of enzyme activity then are plotted against the inhibitor concentrations used. The concentration of the inhibitor that shows 50% enzyme activity (as compared to the activity in the absence of any inhibitor) is taken as the IC 50 value.
a PI3Kd inhibitor alternatively can be understood to refer to a compound that exhibits a 50% inhibitory concentration (IC 5 o) with respect to PI3Kd that is at least of less than about 100 ⁇ , preferably of less than about 50 ⁇ , more preferably of less than about 20 ⁇ , even more preferably of less than about 10 ⁇ PI3K HTRF assay (as described in Gray et al. Anal Biochem, 2003; 313: 234-45)
X represents N (a nitrogen atom) or CH.
X represents N.
R a and Rb each independently represent a hydrogen atom, a Ci-C 4 haloalkyl group, a Ci-C 4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group.
R a and R b each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group. More preferably R a and Rb each independently represent a hydrogen atom, a methyl group or an ethyl group.
Ri represents a C3-C10 cycloalkyl group, a C 3 - C10 cycloalkenyl group, a monocyclic or bicyclic C 6 -Ci 4 aryl group, a 5- to 14- membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-
Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group or a morpholinyl group;
cycloalkyl, phenyl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl or morpholinyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a CrC 4 haloalkyl group, a Ci-C 4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a -S(CH 2 ) 0 - 3 R 9 group, a -S(O)(CH 2 ) 0-3 R9 group, a -S(0)(CH 2 )o-3N R 9 Rio group, a -S(0) 2 (CH 2 )o-3R9 group, a -S(0) 2 (CH 2 )o-3N R 9 Rio group or
Ri represents a phenyl group
said phenyl group is directly bonded to the pyrrolotriazinone group.
the linker -(R a -C-Rb) n - is not present.
R 2 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C1-C4 haloalkyl group, a Ci-C 4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a C C 4 alkoxy group, a -NH 2 group, a -N(CH 3 )H group or a -N(CH 3 ) 2 group.
R 2 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a linear or branched C C 4 alkyl group. More preferably R 2 represents a hydrogen atom.
R 3 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a C1-C4 alkoxy group, a -NH 2 group, a -N(CH 3 )H group or a -N(CH 3 ) 2 group.
R 3 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a linear or branched C1-C4 alkyl group. More preferably
R4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a - (CH 2 )o-3-(C3-C 4 cycloalkyl) group, a -(CH 2 )o- 3 -0(Ci-C 4 alkyl) group, a -(CH 2 ) 0 - 3 -S-(CH 2 ) 0 _ 3 -(phenyl) group, a -(CH 2 )o- 3 -S-(CH 2 ) 0 -3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o-3-0-(CH 2 ) 0 -3- (phenyl) group, a -(CH 2 )o-3-0-(CH 2 ) 0 -3
R 4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a - (CH 2 )o-3-(C 3 -C 4 cycloalkyl) group, a -(CH 2 )o-3-S-(CH 2 )o-3-(phenyl) group, a -(CH 2 ) 0 - 3 -S- (CH 2 )o- 3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o-3-0-(CH 2 ) 0 -3-(phenyl) group, or a -(CH 2 ) 0- 3- 0-(CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituenta
R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3NR 9 R 10 group, a -(CH 2 ) 0 - 3 -O(Cr C 4 alkyl) group, a -(CH 2 ) 0 - 3 -(C 3 -C4 cycloalkyl) group, a C 2 -C 4 alkynyl group, a -(CH 2 ) 0 .
R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-0(Ci-C 4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a -(CH 2 ) 0- 3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH 2 )o-3-(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a linear or branched C 1 -C4 alkyl group
R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C 1 -C4 alkyl group, a C 1 -C4 haloalkyl group, a C 1 -C4 hydroxyalkyl group, a C 2 -C4 alkynyl group, a -(CH 2 )o-3-(phenyl) group, a -(CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH 2 )o-3-S(0) 2 (CH 2 )o-3-(phenyl) group, a -(CH 2 )o.3-S(0) 2 (CH 2 )o -3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o
R 6 represents a hydrogen atom, a -(CH 2 )o-3CN group, a -C(0)-(CH 2 )i. 3 -CN group, a -C(0)-(CH 2 )o-3-R' group, a -C(O)-(CH 2 ) 0 - 3 -NR'R", a -(CH 2 )o- 3 NR'R” group, or a linear or branched C 1 -C4 alkyl group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C 1 -C4 haloalkyl group, a C 1 -C4 hydroxyalkyl group, a -(CH 2 ) 0 -3-O(Ci-C 4 alkyl) group or a linear or branched C 1 -C4 alkyl group.
R 6 represents a hydrogen atom, a -C(0)-(CH 2 )o-3-(CrC 4 alkyl) group, a -NH 2 group, a -N(CH 3 )H group, a -N(CH 3 ) 2 group, or a linear or branched C 1 -C4 alkyl group. More preferably R 6 represents a hydrogen atom or a -NH 2 group.
R 7 represents a hydrogen atom, a -(CH 2 ) 0 .3CN group, a -C(0)-(CH 2 )i -3 -CN group, a -C(O)-(CH 2 ) 0 - 3 -R' group, a -C(O)-(CH 2 ) 0 - 3 -NR'R", a -(CH 2 )o- 3 NR'R” group, or a linear or branched C 1 -C4 alkyl group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C 1 -C4 haloalkyl group, a C 1 -C4 hydroxyalkyl group, a -(CH 2 ) 0 - 3 -O(Ci-C 4 alkyl) group or a linear or branched C 1 -C4 alkyl group.
R 7 represents a hydrogen atom, a -C(0)-(CH 2 )o-3-(CrC 4 alkyl) group, a -NH 2 group, a -N(CH 3 )H group, a -N(CH 3 ) 2 group, or a linear or branched C 1 -C4 alkyl group. More preferably R 7 represents a hydrogen atom or a -NH 2 group.
R 8 represents a monocyclic or bicyclic C 6 -Ci 4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a bicyclyl group which is a monocyclic C 6 -C 9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyi or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the aryl, heteroaryl, and the bicyclyl group which is a monocyclic C 6 -C 9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyi or heterocyclyl group are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a
8 represents a phenyl group or a 5- to 10- membered heteroaryl group containing at least one heteroatom selected from O, S and N ; wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched CrC 4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-0(Ci-C 4 alkyl) group, a -(CH 2 )o-3-0(Ci-C 4 haloalkyl) group, a -(CH 2 )o- 3-0-(CH 2 )i-3-0(Ci-C4 alkyl) group, a -(CH 2 ) 0 -3-O-(CH 2 )i
R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a -(CH 2 ) -3 N R a R b group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C 3 -C 4 cycloalkyl group.
R 8 represents a monocyclic or bicyclic C 6 -Ci 4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a bicyclyl group which is a monocyclic C 6 -C 9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N; wherein the aryl, heteroaryl, and the bicyclyl group which is a monocyclic C 6 -C 9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group,
R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched Ci-C 4 alkyl group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C 3 -C 4 cycloalkyl group.
R 8 preferably represents a phenyl group or a 5- to 10- membered heteroaryl group containing at least one heteroatom selected from O, S and N; wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group, a - (CH 2 )o-3-0(Ci-C 4 alkyl) group, a C 3 -C 7 cycloalkyl group, a -(CH 2 ) o-3NR' R" group, a - (CH2)o-3-C(0)-(CH 2 ) o-3-N R'R"group or a -(CH 2 ) o-3NR'-S(0) 2 R" group, wherein R
R 9 represents a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group or a linear or branched C C 4 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C C 4 alkoxy group, a cyano group or a C 3 -C 4 cycloalkyl group.
R 9 represents a hydrogen atom or a linear or branched C1-C4 alkyl group.
Rn represents a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyi group, a C1-C4 alkoxy group, a -NH 2 group, a -NH(d-C 4 alkyl) group or a -NH-S(0) 2 -(Ci-C 4 alkyl) group group.
R 12 represents represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N.
Ri 2 represents a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrrolyl group, a pyrrazolyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a
L represents a direct bound or a linker selected from -0-, -S-, a -N R'- group, a C(0)-N R'- group, a C(0)-0-R"'- group or a - (CH 2 )i-4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched C1-C4 alkyl group.
L represents a direct bound or a linker selected from -0-, -S-, a -NH- group or a -(CH 2 )i-4 group.
R' and/or R" When R' and/or R" are attached to a nitrogen atom, preferably R' and/or R" do not represent a hydroxyl group or alkoxy group. Where any of the above moieties represent -(CH 2 )o-4-C(0)-(CH 2 )o-4- R' or -C(0)-(CH 2 )o- 3-R', it is preferable that R' does not represent a hydrogen atom if the alkylene spacer moiety is absent.
n 0, 1 , or 2;
X represents N or CH;
R a and R b each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group;
Ri represents a C 3 -C 7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a
R 9 and R-io each independently represent a hydrogen atom or a C1-C4 alkyl group;
R 2 and R 3 each independently represent
R 4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a -(CH 2 ) 0 . 3 -(C 3 - C 4 cycloalkyl) group, a -(CH 2 )o-3-S-(CH 2 )o-3-(phenyl) group, a -(CH 2 )o- 3 -S-(CH 2 ) 0 -3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH 2 ) 0 -3-O-(CH 2 ) 0 -3-(phenyl) group, or a -(CH 2 ) 0 -3-O-(CH 2 ) 0 -3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group,
phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C C 4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C 2 -C 4 alkynyl group, a -(CH 2 ) 0 - 3 -(phenyl) group, a -(CH 2 ) 0 - 3 -(5- to 7- membered heteroaryl group containing at least
alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH 2 ) 0 -4-C(0)-N(R')-(CH 2 )o-4-R" group, a -(CH 2 )o- 4 -C(0)-(CH 2 )o ⁇ -R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 ) 0-3 - 0(Ci-C 4 alkyl) group, a linear or branched C1-C4 alkyl group,
R 6 and R 7 each independently represent a hydrogen atom, a -N H 2 group, a -N(CH 3 )H group, a -N(CH 3 )2 group, or a linear or branched C1-C4 alkyl group;
Rs represents a phenyl group or a 5- to 10- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-0(Ci-C 4 alkyl) group, a -(CH 2 )o-3-0(CrC 4 haloalkyl) group, a -(CH 2 )o-3-0-(CH 2 )i-3-0(Ci-C4 alkyl) group, a -(CH 2 ) 0 - 3 -O- (CH 2 ) 1-3 -0(C 1 -C 4 haloalkyl) group, a -(CH 2 ) 0 -3-0-(CH 2 ) o- 3 Ri 2 group,
a hydrogen atom independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a -(CH 2 ) 1-3 NR a R b group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a C 3 -C 4 cycloalkyl group;
R 9 and Ri 0 each independently represent a hydrogen atom or a linear or branched Cr C 4 alkyl group
Ri 2 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
L represents a direct bound or a linker selected from -0-, -S-, a -N R'- group, a C(O)- N R'- group, a C(0)-0-R"'- group or a -(CH 2 )i -4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched d- C 4 alkyl group.
n represents 0, 1 , or 2;
X represents N or CH;
R a and R b each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group
Ri represents a C3-C7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a
R 9 and Ri 0 each independently represent a hydrogen atom or a C1-C4 alkyl group;
R 2 and R 3 each independently represent a hydrogen atom, a halogen atom or a hydroxyl group or a linear or branched C1-C4 alkyl group;
R 4 represents a hydrogen atom, a linear or branched C C 4 alkyl group, a -(CH 2 ) 0 . 3 -(C 3 - C 4 cycloalkyl) group, a -(CH 2 ) 0 -3-S-(CH 2 )o- 3 -(phenyl) group, a -(CH 2 ) 0 - 3 -S-(CH 2 ) 0 - 3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 ) 0 - 3 -O-(CH 2 ) 0 - 3 -(phenyl) group, or a -(CH 2 ) 0 - 3 -O-(CH 2 ) 0 - 3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH
phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a
R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched CrC 4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C 2 -C 4 alkynyl group, a -(CH 2 )o-3-(phenyl) group, a -(CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o-3-S(0)2(CH 2 )o-3-(phenyl) group, a -(CH 2 ) 0 -3-S(0) 2 (CH 2 )o- 3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o-3-S(0)2(
alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C C 4 alkyl group, a C C 4 haloalkyl group, a C C 4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH 2 )o-4-C(0)-N(R')-(CH 2 )o.
R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 ) 0 - 3 - 0(Ci-C 4 alkyl) group, a linear or branched C1-C4 alkyl group, a phenyl group, a - (CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, or a -(CH 2 ) 0 - 3 -(5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N) group; wherein the phenyl, heteroaryl and heterocyclyl groups are
R 6 and R 7 each independently represent a hydrogen atom, a -NH 2 group, a -N(CH 3 )H group, a -N(CH 3 ) 2 group, or a linear or branched C1-C4 alkyl group;
R 8 represents a phenyl group or a 5- to 10- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-0(Ci-C 4 alkyl) group, a -(CH 2 ) 0 - 3 -O(Ci-C 4 haloalkyl) group, a -(CH 2 )o- 3 -0-(CH 2 )i.3-0(Ci-C 4 alkyl) group, a -(CH 2 ) 0 .
a hydrogen atom independently represent a hydrogen atom, a hydroxyl group, a linear or branched Ci-C 4 alkyl group, a -(CH 2 )i -3 NR a Rb group or a phenyl group, which phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a Ci-C 4 hydroxyalkyl group, a Ci-C 4 haloalkyl group, a Ci-C 4 alkoxy group or a C 3 -C 4 cycloalkyl group;
R g and Ri 0 each independently represent a hydrogen atom or a linear or branched Cr C 4 alkyl group
R 12 represents a phenyl group, a 5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N or a 5- to 7- membered heterocyclyl group containing at least one heteroatom selected from O, S and N;
L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH 2 ) 1-4 group; wherein R' represents hydrogen or a linear or branched Ci-C alkyl group, and R'" represents a linear or branched C C 4 alkyl group.
n is 0 or 1 ;
X represents N or CH;
R a and R b each independently represent a hydrogen atom or C 1 -C4 alkyl group;
Ri represents a phenyl group, a tetrahydro-2H-thiopyran group or a tetrahydro-2H- thiopyran 1 ,1 -dioxide group,
phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched Ci-C 3 alkyl group, a C 1 -C3 alkoxy group, a -S(Ci-C 4 alkyl) group, a -
R 2 and R 3 each independently represent a hydrogen atom or a linear or branched C 1 -C4 alkyl group
R 4 represents a hydrogen atom or a linear or branched C1-C4 alkyl group
R 5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C2-C4 alkynyl group, a -(CH 2 )o-3-(phenyl) group, a -(CH 2 )o-3-S(0) 2 -(CH 2 )o-3-(phenyl) group or a -(CH 2 ) 0 -3-S-(CH 2 )o -3 -(phenyl) group;
phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group or a linear or branched C 1 -C4 alkyl group;
alkynyl group is unsubstituted or substituted by one or more substituents selected from a -(CH 2 )o-4-C(0)-N(H)-(CH 2 )o-4-(morpholinyl) group, a
R 6 and R 7 each independently represent a hydrogen atom, a -NH 2 group, or a linear or branched C 1 -C4 alkyl group;
R 8 represents a phenyl group or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C 1 -C4 alkyl group, a C 1 -C4 haloalkyl group, a -(CH 2 ) 0 .
n 0, 1 , 2 or 3;
X represents N or CH;
R a and R b each independently represent a hydrogen atom, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C4 alkyl group;
Ri represents a C 3 -C 7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, or a 5- to 10- membered heterocyclyl group containing containing one, two or three heteroatoms selected from O, S and N;
cycloalkyl, phenyl, heteroaryl or heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a -
R 2 and R 3 independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C3 alkoxy group, a linear or branched C1-C4 alkyl group, a C1-C3 haloalkyi group, a C 3 -C 4 cycloalkyl group or a -NH 2 group;
R 4 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyi group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-(C 3 -C4 cycloalkyl) group, a - (CH 2 )o-3-0(Ci-C 4 alkyl) group, a -(CH 2 )o-3-S-(CH 2 )o- 3 -(phenyl) group, a -(CH 2 ) 0 - 3 -S-
R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3NR 9 Rio group, a -(CH 2 )o-3-0(CrC 4 alkyl) group, a -(CH 2 )o-3-(C 3 -C 4 cycloalkyl) group, a C2-C4 alkynyl group, a -(CH 2 ) 0- 3-(phenyl) group, a -(CH 2 ) 0- 3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from 0, S and N) group, a -(CH 2 ) 0 - 3 - S(O) 2 (CH 2 ) 0 - 3 -Rn group,
phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH 2 )o-4-C(0)-N(R')-(CH 2 )o-4-R" group, a -(CH 2 )o- 4 -C(0)-(CH 2 )o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 ) 0 -3- 0(Ci-C 4 alkyl) group, a linear or branched C1-C4 alkyl group, a
R 8 represents a monocyclic or bicyclic C 6 -Ci 4 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N , or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N ,
aryl , heteroaryl, and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyi group, a C C 4 haloalkyl group, a C1-C4 hydroxyalkyi group, a -(CH 2 )o-3-0(C C 4 alkyi) group, a C 3 -C 7 cycloalkyl group, a -(CH 2 ) o- 3 NR'R" group, a -(CH 2 ) 0 - 3 -C(O)-(CH 2 ) 0 -3-NR'R"group, a -((CH
R 9 and Ri 0 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyi group or a linear or branched C1-C4 alkyi group, which alkyi group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group or a C 3 -C 4 cycloalkyl group;
R11 represents a linear or branched C1-C4 alkyi group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyi group, a C1-C4 alkoxy group, a -NH 2 group, a -N H(CrC 4 alkyi) group or a - NH-S(0) 2 -(Ci-C 4 alkyi) group;
L represents a direct bound or a linker selected from -0-, -S-, a -NR'- group, a C(O)- NR'- group, a C(0)-0-R"'- group or a -(CH 2 )i -4 group; wherein R' represents hydrogen or a linear or branched CrC 4 alkyi group, and R'" represents a linear or branched d- C 4 alkyi group.
R' represents hydrogen or a linear or branched CrC 4 alkyi group
R'" represents a linear or branched d- C 4 alkyi group.
n 0, 1 , or 2;
X represents N or CH;
R a and R b each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group;
Ri represents a C 3 -C 7 cycloalkyl group, a phenyl group, a 5- to 10- membered heteroaryl group containing containing one, two or three heteroatoms selected from O, S and N, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a
R 9 and R b each independently represent a hydrogen atom or a C1-C4 alkyl group;
R 2 and R 3 each independently represent a hydrogen atom, a halogen atom or a hydroxyl group or a linear or branched C1-C4 alkyl group;
R 4 represents a hydrogen atom, a linear or branched C C 4 alkyl group, a -(CH 2 ) 0 .
phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a C1-C4 alkoxy group;
R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C2-C4 alkynyl group, a -(CH 2 )o-3-(phenyl) group, a -(CH 2 )o-3-(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o-3-S(0)2(CH 2 )o-3-(phenyl) group, a -(CH 2 )o- 3 -S(0) 2 (CH 2 )o- 3 -(5- to 7- membered heteroaryl group containing at least one heteroatom selected from O, S and N) group, a -(CH 2 )o-3-S(0)2(
alkynyl group is unsubstituted or substituted by one or more substituents selected from a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a -(CH 2 )o-4-C(0)-N(R')-(CH 2 )o.4-R" group, a -(CH 2 ) 0 -4-C(0)-(CH 2 )o-4-R' group; wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 ) 0-3 - 0(Ci-C 4 alkyl) group, a linear or branched C1-C4 alkyl group,
R 6 and R 7 each independently represent a hydrogen atom, a -NH 2 group, a -N(CH 3 )H group, a -N(CH 3 ) 2 group, or a linear or branched C1-C4 alkyl group;
Rs represents a phenyl group or a 5- to 10- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a -(CH 2 )o-3-0(Ci-C 4 alkyl) group, a C3-C7 cycloalkyl group, a -(CH 2 ) o- 3 NR'R" group, a -(CH 2 )o-3-C(0)-(CH 2 ) o-3-NR'R”group or a - (CH 2 ) o- 3 NR'-S(0) 2 R" group, wherein R' and R" each independently represent a hydrogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group or a
L represents a direct bound or a linker selected from -0-, -S-, a -N R'- group, a C(O)- N R'- group, a C(0)-0-R"'- group or a -(CH 2 ) 1-4 group; wherein R' represents hydrogen or a linear or branched C1-C4 alkyl group, and R'" represents a linear or branched C C 4 alkyl group;
n is O or l ;
X represents N or CH ;
R a and R b each independently represent a hydrogen atom or C1-C4 alkyl group
Ri represents a phenyl group, a tetrahydro-2H-thiopyran group or a tetrahydro-2H- thiopyran 1 , 1 -dioxide group,
phenyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-C3 alkyl group, a -S(d-C 4 alkyl) group, a -S(0)(C C 4 alkyl) group, or a -S(0) 2 (d-C 4 alkyl) group;
R 2 and Rs each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group
R4 represents a hydrogen atom or a linear or branched C1-C4 alkyl group
R 5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C 1 -C4 alkyl group, a C 1 -C4 haloalkyl group, a C 2 -C 4 alkynyl group, a -(CH 2 )o-3-(phenyl) group, a -(CH 2 )o-3-S(0)2-(CH 2 )o-3-(phenyl) group or a -(CH 2 )o-3-S-(CH 2 )o-3-(phenyl) group;
phenyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group or a linear or branched C 1 -C4 alkyl group;
alkynyl group is unsubstituted or substituted by one or more substituents selected from a -(CH 2 ) 0 -4-C(O)-N(H)-(CH 2 ) 0 -4-(morpholinyl) group, a -(CH 2 ) 0- 4-C(0)-N-[(CH 2 )o -3 -0(Ci-C4 alkyl)] 2 group or a -(CH 2 ) 0- 4-C(O)-(CH 2 ) 0- 4-
R 6 and R 7 each independently represent a hydrogen atom, a -NH 2 group, or a linear or branched C C 4 alkyl group;
R 8 represents a phenyl group or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, S and N,
phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C 1 -C4 alkyl group, a C 1 -C4 haloalkyl group, a -(CH 2 ) 0 - 3 -O(Ci-
C 4 alkyl) group a -(CH 2 ) 0 - 3 NH 2 group or a -(CH 2 ) 0 . 3 NR'-S(O) 2 (Ci-C 4 alkyl) group, wherein R' represents a hydrogen atom or a linear or branched C-i-C 4 alkyl group; L represents a direct bound or -S-.
Particular individual compounds of the invention include:
the invention is also directed to the compounds of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type
the invention is also directed to use of the compounds of the invention as described herein, in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is as defined above.
PI3Ks Phosphoinositide 3-Kinases
the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is as defined above, which comprises administering to said subject a therapeutically effective amount of a compound of the invention as described herein.
PI3Ks Phosphoinositide 3-Kinases
the term therapeutically effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
treatment refers to the treatment of a disease or medical condition in a human patient which includes:
the compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
the choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic
amino-protecting group refers to a protecting group suitable for preventing undesired reactions at amino nitrogen.
Representative amino-protecting groups include, but are not limited to, formyl; acyl groups, for example alkanoyi groups such as acetyl; alkoxycarbonyl groups such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), and 1 ,1-di-(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.
hydroxy-protecting group refers to a protecting group suitable for preventing undesired reactions at a hydroxy group.
Representative hydroxy-protecting groups include, but are not limited to, alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, for example alkanoyi groups, such as acetyl; arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.
alkyl groups such as methyl, ethyl, and tert-butyl
acyl groups for example alkanoyi groups, such as acetyl
arylmethyl groups such as benzyl (Bn), p-
compounds of general Formula (I) may be prepared by the synthetic route illustrated in Scheme 1 , from compounds of Formula (III), where the group Zi represents a halogen atom such as chlorine, bromine and iodine or another suitable leaving group such as methanesulfonate or
trifluoromethanesulfonate or other groups such as hydroxyl that can be converted to suitable leaving groups by standard methods described in the literature, such as the Mitsunobu reaction and others.
Compounds of Formula (I) can be obtained directly from compounds of Formula (I I I) or in a two steps synthesis, by treatment of (I II) with compounds of Formula (I I) or compounds of Formula (IV) in the presence of a suitable base such as potassium carbonate, diisopropylethylamine or sodium hydride in an appropriate solvent such as fert-butanol, ⁇ /,/V-dimethylformamide or tetrahydrofurane at temperatures ranging from room temperature to 160 °C, with or without the use of microwaves irradiation.
a suitable base such as potassium carbonate, diisopropylethylamine or sodium hydride
an appropriate solvent such as fert-butanol, ⁇ /,/V-dimethylformamide or tetrahydrofurane at temperatures ranging from room temperature to 160 °C, with or without the use of microwaves irradiation.
⁇ is a halogen atom such as chlorine
it can be converted to another more reactive halogen atom such as iodine by treating the compound with the chlorine atom with sodium iodide in acetone at a temperature from room temperature to reflux.
synthesis compounds of Formula (V) can be converted to compounds of Formula (I) by reacting with the corresponding boronic acid using standard Suzuki coupling conditions.
compounds of general Formula (I) where the group L represents a NH , O or S can be obtained from compounds of Formula (V), by reacting with the corresponding aniline or thiophenol or phenol by using copper or palladium catalysed coupling methods well known in the art.
Boronic acids, anilines, thiophenols or phenols can be commercial or prepared by standard methods and can be used in a protected form to prevent certain functional groups from undergoing undesired reactions. In these cases, standard methods for the removal of these protecting groups can be used at the suitable step of the synthesis. Numerous protecting groups, their introduction and their removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
the compounds of Formula (I II) can also be prepared by treating the compounds of Formula (VI I) with 2-chloro-1 ,1 , 1 -trimethoxyethane in the presence of pyridinium p-toluenesulfonate at a temperature between 50 °C and 150 °C.
Compounds of Formula (VI I) can be transformed in amides of Formula (VI) by treatment with carboxylic acids of Formula (IX) in the presence of an activating agent by methods and conditions well described in the literature, for example using T3P®, EDC.HCI or HATU as an activating agent in a solvent such as ,/V-dimethylformamide, tetrahydrofurane or dichloromethane or mixtures of these solvents at temperatures ranging from room temperature to 80 °C.
an activating agent for example using T3P®, EDC.HCI or HATU as an activating agent in a solvent such as ,/V-dimethylformamide, tetrahydrofurane or dichloromethane or mixtures of these solvents at temperatures ranging from room temperature to 80 °C.
amides of Formula (VI) can be obtained from compounds of Formula (VII) by treatment with acid chlorides of Formula (VIII) at room temperature in a suitable solvent such as acetic acid or 1 ,4-dioxane or alternatively in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane.
a suitable solvent such as acetic acid or 1 ,4-dioxane
a base such as triethylamine in a suitable solvent such as dichloromethane.
compounds of Formula (VI) can yield compounds of Formula (III) by treatment with phosphorous oxychloride at temperatures ranging from room
compounds of Formula (VI) can yield compounds of Formula (III) by treatment of compounds of Formula (VI) with the complex resulting from the treatment of triphenylphosphine with bromine in a solvent such as dichloromethane in the presence of a base such as triethylamine at a temperature from room temperature to reflux, with or without a subsequent treatment with a base such as ammonia, pirrolidine, piperidine or potassium carbonate or a nucleophile such us sodium methanethiolate in a solvent such as methanol, ethyl acetate or N,N- dimethylformamide at a temperature between room temperature and 100 °C.
a base such as triethylamine
Carboxylic acids (XII) can be activated with any activating reagent described in the literature such as thionyl chloride, oxalyl chloride, phosphorous oxychloride, 2-(3H- [1 ,2,3]triazolo[4,5-6]pyridin-3-yl)-1 ,1 ,3,3-tetramethylisouronium
a base such as diisopropylethylamine
a suitable solvent such as dioxane, dichloromethane, /V,/V-dimethylformamide or tetrahydrofurane at temperatures ranging from 0 °C to reflux to give amides of Formula (X).
amides of Formula (X) can be aminated on the nitrogen atom in position 1 by any of the aminating reagents described in the literature, such as O- (mesitylenesulfonyl)hydroxylamine, 0-(p-nitrobenzoyl)-hydroxylamine, 0-(diphenyl- phosphinyl)-hydroxylamine, 0-(2,4-dinitrophenyl)-hydroxylamine, hydroxylamine-O- sulfonic acid using a suitable base such as triethylamine, potassium carbonate, sodium hydride or butyl lithium in an appropriate solvent such as ⁇ /, ⁇ '-dimethylformamide, tetrahydrofurane, 1 ,4-dioxane at temperatures ranging from -78 to 100 °C.
the amination reaction can be carried out in a biphasic system using an aqueous solution of ammonia, sodium hydroxide, ammonium chloride and sodium hypochlorite and a suitable organic solvent such as dialkyl ethers and adding a phase transfer catalyst such as Aliquat 336 ® at temperatures ranging from 0 °C to room temperature.
a phase transfer catalyst such as Aliquat 336 ® at temperatures ranging from 0 °C to room temperature.
Compounds (XII) can either be commercially available compounds or can be prepared by the synthetic scheme illustrated in Schemes 4.
R 5 represents a C 3 -C 7 cycloalkyl group, or a linear or branched Ci-C 4 alkyl group
compounds (Xlla) can be prepared, as illustrated in Scheme 4, from bromopyrrol of Formula (XIV) 2 by Suzuki coupling with the corresponding alkyl or cycloalkylboronic acids in the presence of a palladium catalyst such as tetrakis(triphenylphosphane) palladium(O) and appropriate base such as potassium carbonate and in a suitable solvent such as toluene at a temperature ranging from 60°C to 150°C.
a palladium catalyst such as tetrakis(triphenylphosphane) palladium(O)
appropriate base such as potassium carbonate
Compounds of Formula (Xlla) can be obtained by simultaneous cleavage of the sulphone and ester groups of compounds of Formula (XIII) by means of a base such as lithium hydroxide in a suitable solvent or mixture of solvents such as water or tetrahydrofurane at temperatures ranging from room temperature to 220 °C, with or without the use of microwaves irradiation.
a base such as lithium hydroxide
suitable solvent or mixture of solvents such as water or tetrahydrofurane
the cleavage of the sulphone and ester groups of compounds of Formula (XIII) can be done sequentially by treatment of compounds (XII I) with tetrabutylammonium fluoride in an appropriate solvent such as
compounds (Xa) can be prepared, as illustrated in Scheme 5, from pyrrols of Formula (XVI). Pyrrols of Formula (XVI) can be reacted with 2,2,2-trichloroacetyl chloride in a suitable solvent such as diethyl ether at a temperature ranging from room temperature to reflux affording ketones of Formula (XV). These intermediate compounds of Formula (XV) can be reacted with the corresponding amines of Formula (XI) with or without solvent in the presence of a base such as triethylamine at a temperature ranging from room te
compounds of general Formula (VI) may be prepared by the synthetic route illustrated in Scheme 6.
compounds of Formula (VI) can be prepared from compounds of Formula (XVI I) by known amide formation methods such as those described above.
Compounds of Formula (XVII) can be prepared by the known coupling methods previously described.
Compounds of Formula (XVI II) can be obtained by amination of compounds of Formula (XIX) by the methods already described.
compounds of general Formula (1Mb) can also be synthesized from compounds of Formula (Ilia) as shown in Scheme 7 by the general methods described as it follows.
the bromine atom of compound of Formula (Ilia) has to be converted first into a iodine atom by treatment of (Ilia) with sodium iodide in the presence of a catalysts such as copper (I) iodide and a chelating amine such as frans-1 ,2-bis(methylamino)cyclohexane in an appropriate solvent such as 1 ,4-dioxane at a temperature ranging from 60°C to reflux.
a catalysts such as copper (I) iodide and a chelating amine such as frans-1 ,2-bis(methylamino)cyclohexane
an appropriate solvent such as 1 ,4-dioxane
R 5 is a alkyl or cycloalkyl group
an aromatic or heteroaromatic ring compounds of Formula (III) can be obtained by standard Suzuki or Stille couplings with the corresponding boronic acid or organotin compound in the presence of a palladium catalyst such as tetrakis(triphenylphosphane) palladium(O) or palladium acetate with or without an appropriate base such as potassium carbonate or cesium carbonate and in a suitable solvent such as toluene or dioxane or N,N- dimethylformamide at temperatures ranging from 60°C to 150°C.
a palladium catalyst such as tetrakis(triphenylphosphane) palladium(O) or palladium acetate with or without an appropriate base such as potassium carbonate or cesium carbonate
a suitable solvent such as toluene or dioxane or N,N- dimethylformamide at temperatures ranging from 60°C to 150°C.
compound of Formula (Ilia) can be treated with a lithiating agent such as n-BuLi, in a non protic solvent such as hexanes and at a temperature between -78°C and 0°C and subsequently treated with a suitable fluorine source such as /V-fluoro-/V-(phenylsulfonyl)-benzenesulfonamide at a temperature between -78°C and room temperature.
a lithiating agent such as n-BuLi
a non protic solvent such as hexanes
compounds of Formula (1Mb) where R 5 is hydrogen can alternatively be obtained by hydrogenolysis of compounds of Formula (Ilia) using an appropriate catalyst such as 10% palladium on charcoal in a suitable solvent such as an alkyl alcohol under a hydrogen atmosphere at pressures ranging from atmospheric pressure to 60 psi and at temperatures ranging from room
compounds of Formula (Ilia) can be converted first into a iodine following the general methods previously described.
the iodine intermediate can then react with the corresponding thiophenol in the presence of copper (I) iodide and a base such as potassium carbonate in solvent such as DMF and at temperatures ranging from room temperature to 150°C.
compounds of Formula (lllb) can be obtained by reacting with the corresponding alkyne derivative in the presence of a palladium catalyst such as bis(triphenylphosphine)palladium(ll) chloride and copper (I) iodide in a suitable solvent such as diethylamine at temperatures ranging from room temperature to 100°C.
a palladium catalyst such as bis(triphenylphosphine)palladium(ll) chloride and copper (I) iodide
a suitable solvent such as diethylamine
compounds of general Formula (I) can also be synthesized from compounds of Formula (la) or (lb) as shown in Scheme 8 by the same general methods previously described.
Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received. Concentration or evaporation refers to evaporation under vacuum using a BGchi rotatory evaporator. Reaction products were purified, when necessary, by flash or reverse phase chromatography in a Biotage SP1 ® or Isolera ® automatic purification systems.
Preparative HPLC-MS were performed on a Waters instrument equipped with a 2767 injector/collector, a 2525 binary gradient pump, a 2996 PDA detector, a 515 pump as a make-up pump and a ZQ4000 Mass spectrometer detector.
the HPLC chromatographic separations were obtained using a Waters 2795 system equipped with a Symmetry C18 (2.1 x 50 mm, 3.5 ⁇ ) column for methods A, B and C and a Symmetry C18 (2.1 x 100 mm, 3.5 ⁇ ) for method D.
the mobile phases were (B): formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) and (A): formic acid (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A), the gradients are specified in the following table for each method used.
the flow rate was 0.8 mL/min for method A and 0.4 mL/min for method B, C and D.
the injection volume was 5 microliter.
a Waters 2996 diode array was used as a UV detector.
Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization in a Micromass ZMD or in a Waters ZQ detectors coupled to the HPLC.
the UPLC chromatographic separations were obtained using a Waters Acquity UPLC system coupled to a SQD mass spectrometer detector.
the system was equipped with an ACQUITY UPLC BEH C-18 (2.1x50mm, 1 .7 ⁇ ) column.
the mobile phase was formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A).
a gradient between 0 to 95% of B was used.
the run time was 3 or 5 minutes
the injection volume was 0.5 microliter. Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization.
2,2,2-Trichloroacetyl chloride (5 mL, 45.27 mmol) was dissolved in 30 mL diethyl ether. 3-Methyl-1 H-pyrrole (3.1 g, 38.10 mmol) dissolved in 12 mL diethyl ether was added dropwise over 1 h and the reaction mixture was then heated at 45°C for 2 h. The mixture was diluted in diethyl ether and washed with water and brine. The organics were dried over sodium sulphate, filtered and evaporated. The residue was purified using SP1 Purification System (hexane-dichloromethane, 0% to 30%) to give 1.31 g (15 % yield) of the title compound. Purity 100%.
o-Toluidine (730 ⁇ , 6.84 mmol) and triethylamine (960 ⁇ , 6.89 mmol) were added to 2,2,2-trichloro-1 -(3-methyl-1 H-pyrrol-2-yl)ethanone (1.26 g, 5.56 mmol) in a Schlenk vessel and the reaction mixture was submitted to three vacuum-argon cycles. The mixture was heated at 60°C for two days. The solvent was concentrated and the residue was re-dissolved in ethyl acetate. The organic phase was washed with water, sodium bicarbonate 4% and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure.
PREPARATION 8 2- ((4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1 - yl)methyl)-5-bromo-3-(3-(methylsulfinyl)phenyl)pyrrolo[2,1 -/][1,2,4]triazin-4(3H)- one 2-((4-Amino-3-iodo-1 H-pyrazolo[3,4-c ]pyrimidin-1 -yl)methyl)-5-bromo-3-(3-
Methyl 3-Bromo-1 -(phenylsulfonyl)-1 H-pyrrole-2-carboxylate 2 (25 g, 0.07 mol) was treated with aniline (10 ml_, 0.1 1 mol) and trimethyl aluminium (2 M in toluene, 109 ml_, 0.22 mol) according to the method of Preparation 5a to give 29.80 g (88% yield) of the title compound as a colourless oil.
reaction vessel was sealed and the mixture was heated at 80°C overnight.
the reaction mixture was partitioned with ethyl acetate and it was washed with water and brine.
the organic layer was dried over sodium sulphate, filtered and evaporated to give 780 mg of the title compound used in the following step without further purification.
Methanesulfonyl chloride (49 ⁇ , 0.63 mmol) was added and the mixture was stirred for 1 h in the ice bath. The mixture was diluted in dichloromethane and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain 195 mg of the title compound pure enough to follow the next step.
Triphenylphosphine (2.13 g, 8.12 mmols) was dissolved in 45 mL dichloromehtane. Bromine (420 ⁇ , 8.19 mmol) was added dropwise over 30 min and then triethylamine (4.35 mL, 31.38 mmol) and ethyl 1-(2-methoxyacetamido)-3-methyl-1 H-pyrrole-2- carboxylate dissolved in 2 mL dichloromethane were added. The mixture was stirred at room temperature for 2 h. The solvent was concentrated and the residue was suspended in 1 15 mL toluene.
Tetrahydro-2H-thiopyran-4-amine (3.65 g, 31.14 mmol) was added and the reaction was stirred at 100°C for 48 h. The mixture was diluted with ethyl acetate and washed sequentially twice with 1 N hydrochloric acid and brine, dried over sodium sulphate, filtered and evaporated. The residue was purified using Isolera Purification System by reverse phase to give 1.05 g (53% yield) of the title product as a white solid.
the crude was cooled at room temperature and saturated sodium bicarbonate solution (750 mL), ethyl acetate (400 mL) and sodium tartrate (0.5M in water, 750 mL) were added.
the organics were washed with water and brine, dried over sodium sulphate , filtered and evaporated.
the residue was purified using SP1 Purification System (0% to 30%, hexane-ethyl acetate) to give 10.41 g (75% yield) of the desired compound as a white solid. Purity 99%.
the semi-solid was crystallized with diethyl ether and isopropyl ether to obtain a solid that was filtered and dried in the oven to give 720 mg (58% yield) of the final compound as a mixture of boronic acid and boronate. Yield 100%.
Triethylamine (55 ⁇ , 0.39 mmol) and palladium on carbon (10 %, 14 mg, 0.03 mmol) were added under nitrogen atmosphere.
the reaction was hydrogenated at 30 psi overnight. Under nitrogen conditions was filtered and evaporated.
the crude was re-dissolved in dichoromethane and washed with 1 N hydrochloric acid, water and brine. The residue was dried over sodium sulphate, filtered and evaporated to obtain 70 mg (95% yield) of the title compound. Purity 92%.
the semi-solid was crystallized with diethyl ether and isopropyl ether to obtain a solid that was filtered and dried in the oven to give 270 mg (78% yield) of the final compound as a mixture of boronic acid and boronate. Purity 77%.
Methyl 3-methyl-1 H-pyrrole-2-carboxylate (10 g, 0.07 mol) was dissolved in 200 mL methanol and a solution of sodium hydroxide (2N, 108 ml_, 0.22 mol) was added. The mixture was heated at 60 °C overnight. The solvent was evaporated and the residue was acidified to pH 2-3 with 2N hydrochloric acid. A white precipitate was formed and was filtered and washed with cool water. The solid was dried in the oven to give 6.97 g (77% yield) of the desired compound. Purity 100%.
Hex-5-ynoic acid 200 mg, 1 .78 mmol was dissolved in 10 mL dichoromethane.
N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (394 mg, 2.05 mmol) and 4- (dimethylamino)pyridine (1 1 mg, 0.09 mmol) were added and the mixture was cooled at 0°C.
1 -lsopropylpiperazine (229 mg, 1 .78 mmol) dissolved in 1 mL dichloromethane was added and the reaction mixture was stirred at room temperature overnight. The mixture was washed with 4% sodium bicarbonate solution.
N-(3-bromo-5-hydroxyphenyl)methanesulfonamide (0.87 g, 3.27 mmol, prepared as described at C.Cannizzaro et al. US7417055 B2 20080826) was treated with bis(pinacolato)diboron (1.25 g, 4.90 mmol), potassium acetate (0.96 g, 9.81 mmol) and bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.27 g, 0.33 mmol) according to the method described in Preparation 16. The crude was purified using SP1 Purification System (0%-100%, hexane- ethyl acetate) to give 390 mg (31% yield) to the title compound as a solid.
SP1 Purification System 0%-100%, hexane- ethyl acetate
indium(lll) chloride (2 mg, 0.02 mmol) was dissolved in 1 ml anhydrous tetrahydrofuran under nitrogen atmosphere. Titanium tetrachloride (5 ⁇ , 0.05 mmol) was added and the mixture was stirred at room temperature for 1 h.
2,4,6-Trimethylboroxin (57 ⁇ , 0.41 mmol), sodium carbonate (2M, 246 ⁇ , 0.49 mmol) and tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.50 mmol) were added in a Schlenck vessel under argon conditions. The mixture was heated at 150°C for 30 min. The mixture was allowed to cool and was filtered through a plug of Celite, washing several times with dichloromethane. The combinated filtrates were concentrated under reduced pressure. The residue was directly purified by reverse phase using the Isolera Purification System (0% to 5%, dichloromethane-methanol) to give 9 mg (20% yield) as a solid. Purity 98%.

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