WO2015128698A1 - Dérivés d'amine hétérocycliques substitués comme inhibiteurs de multikinase pour le traitement du cancer - Google Patents
Dérivés d'amine hétérocycliques substitués comme inhibiteurs de multikinase pour le traitement du cancer Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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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
Definitions
- the present invention relates to heterocyclic compounds of formula (I), processes for their preparation, pharmaceutical compositions containing them, their use as multikinase inhibitors and methods of using these compounds in the treatment or prevention of diseases or disorders associated with abnormal protein kinase activity such as proliferative diseases.
- Cancer can be defined as an abnormal growth of tissues characterized by a loss of cellular differentiation. Cancer is caused due to deregulation of the signalling pathways involved in cell survival, cell proliferation and cell death. Current treatments for cancer include surgery, radiation therapy, chemotherapy, bone marrow transplantation, stem cell transplantation, hormonal therapy, immunotherapy, antiangiogenic therapy, targeted therapy and gene therapy.
- Protein kinases are a family of enzymes that play crucial roles in all major cellular processes, such as signal transduction, cell differentiation, cell proliferation and cell cycle progression (Biol. Cell., 2005, 97, 113-118).
- the best-characterized protein kinases phosphorylate proteins on the hydroxyl moiety of serine, threonine and/or tyrosine residues.
- the phosphorylation of proteins represents a major post-translational signaling mechanism and regulatory pathway that controls a diverse set of cellular processes (Cell Mol. Life Sci. 2009, 66, 63-77).
- PTKs Protein Tyrosine Kinases
- EGF epidermal growth factor
- IGF insulin-like growth factor
- VEGF vascular endothelial growth factor
- the RTK dimerizes and activates the intracellular protein kinase domain, resulting in the further activation of signal transduction pathways (Cell Mol. Life Sci. 2009, 66, 63-77).
- the Platelet- derived growth factor (PDGF) subfamily of tyrosine kinase receptors includes PDGF-alpha and PDGF-beta receptors.
- the Fetal liver kinase (FLK) subfamily comprises of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the fms- like tyrosine kinase-1 (Flt-1).
- KDR kinase insert domain receptor
- FLK-1 fetal liver kinase-1
- FLK-4 fetal liver kinase-4
- Flt-1 tyrosine kinase-1
- the insulin-like growth factor I receptor (IGF-IR) pathway plays a major role in cancer growth, tumour cell survival and resistance to therapy (Current Drug Targets 2009, 10(10), 1- 13).
- the insulin-like growth factor (IGF) system is composed of the circulating ligands, insulinlike growth factor-I (IGF-I), IGF-II, and insulin; multiple receptors; and binding proteins.
- the type I IGF receptor (IGF-IR) is a RTK closely related to the insulin receptor (IR). In normal physiology, ligand activation of IGF-IR plays a role in fetal growth and linear growth of the skeleton and other organs, whereas insulin acts via IR to regulate glucose homeostasis (Mol. Cancer Ther. 2007, 6, 1-12).
- IGF-IR is composed of two covalently linked polypeptide chains, each with an extracellular a-subunit and a transmembrane ⁇ -subunit, which possesses tyrosine kinase activity. IGFs are implicated in several different cancers including breast cancer, prostate cancer, colon cancer, liver cancer, pancreatic cancer, melanoma, multiple myeloma, mesothelioma and glioblastoma (Embo J. 1986, 5(10), 2503-2512; Mol. Cancer Ther. 2007, 6, 1- 12).
- the human epidermal growth factor receptor (HER) family members belongs to the ErbB (gene symbol derived from the name of a viral oncogene, Erythroblastic Leukemia Viral Oncogene) family of RTKs and include epidermal growth factor receptor (EGFR; erbB l), i IhR. /;, ⁇ » (erbB2), HERS (erbBS), and HER4 (erbB4) that are structurally related, and all except HERS contain intracellular tyrosine kinase domain.
- EGFR and ER2/neu are over expressed or abnormally activated in several epithelial malignancies (CA Cancer J Clin. 2009, 59, 111-137; Clin. Cancer Res. 2006, 12(18), 5268-5272; The Journal of Biological Chemistry 1990, 265(14), 7709-7712).
- the non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including but not limited to, intracellular Signalling Kinases selected from Src, PI3K, Frk, Tec, Csk, Abl, Syk/Zap70, Fak, Jak, Ack and lymphocyte-specific protein tyrosine kinase (Lck) (Frontiers in Bioscience, 2003, 8, s595-635). Dysregulated Src and Lck activities have been implicated in the development and progression of several human cancers, including breast, colorectal, lung, ovarian, and haematologicai malignancies (CA Cancer J Clin. 2009, 59, 111- 137).
- intracellular Signalling Kinases selected from Src, PI3K, Frk, Tec, Csk, Abl, Syk/Zap70, Fak, Jak, Ack and lymphocyte-specific protein tyrosine kinase (Lck)
- the family of serine-threonine kinases includes, but is not limited to, AGC, Ca 7calmodulin-dependent protein kinase (CaMK) and Casein kinase 1 (CK1).
- AGC Ca 7calmodulin-dependent protein kinase
- CK1 Casein kinase 1
- Aurora kinases identified in mammalian ceils and being implicated as mitotic regulators have generated significant interest in cancer therapy due to their elevated expression in human cancers (Clin. Cancer Res. 2006, 12(23 ), 6869-6875).
- OSI906 or Linsitinib (OSI Pharmaceuticals/Astellas), a small molecule protein kinase inhibitor that targets IGF-1R and IR with proteasome inhibitor, a proteasome inhibitor, is in phase III clinical trials and phase II clinical trials for adrenocotical carcinoma and lung cancers respectively.
- Lapatinib (GlaxoSmithKline), a small-molecule protein kinase inhibitor, that targets both EGFR and HER2 kinase receptors has been approved by the United States Federal Drug Administration (USFDA) for the treatment of breast cancer and is in phase III clinical trials for gastric cancer and head and neck squamous cell carcinoma.
- USFDA United States Federal Drug Administration
- Dasatinib (Bristol-Myers Squibb), a small molecule protein kinase inhibitor of Src family, has been approved by USFDA for chronic myelogenous leukemia and is in phase II clinical trials for NSCLC.
- Sorafenib is a multikinase inhibitor targeting Raf serine/threonine kinases as well as different receptor tyrosine kinases including tyrosine-protein kinase Kit (c-Kit), Fms-like tyrosine kinase 3 (FLT-3), Vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) (Journal of Thoracic Oncology 2011, 6(11 ), SI 758-S1784).
- c-Kit tyrosine-protein kinase Kit
- FLT-3 Fms-like tyrosine kinase 3
- VAGFR Vascular endothelial growth factor receptor
- PDGFR platelet-derived growth factor receptor
- PCT application publication number WO2008150799 A 1 discloses imidazopyridine compounds which are inhibitors of one or more kinases of IGF-1R family tyrosine kinase (particularly, IGF-1R and IR) and ErbB family kinases and are indicated to be useful for the treatment of breast cancer, sarcomas, lung cancer, prostate cancer, colorectal cancer, renal cancer, pancreatic cancer, haematological cancers, neuroblastomas, primary central nervous system (CNS) tumours, secondary CNS tumours, head and neck cancer, thyroid cancer, ovarian cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, buccal cancer, cancer of the mouth, gastrointestinal stromal tumour and skin cancer including melanoma.
- IGF-1R family tyrosine kinase particularly, IGF-1R and IR
- ErbB family kinases and are indicated to be useful for the treatment of breast cancer,
- PCT application publication number WO2010138576A1 discloses pyrimidine compounds which are inhibitors of kinases such as IGF-1R and are reported to be useful for the treatment of bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer and thyroid cancer in mammals.
- the present invention provides compounds of formula (I) as described herein or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof; and at least one pharmaceutically acceptable carrier or excipient.
- the present invention provides the compounds of formula (I) or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof, which are multikinase inhibitors.
- the present invention provides a method for the treatment of a disease or disorder associated with abnormal protein kinase activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.
- the present invention provides use of the compound of formula I or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof; for the treatment of a diseases or a disorder associated with abnormal activity of protein kinases.
- the present invention provides use of the compounds of formula (I) or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in ail ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof; in the manufacture of a medicament, for the treatment a diseases or a disorder associated with abnormal activity of protein kinases.
- a diseases or a disorder associated with abnormal activity of protein kinases is a proliferative disorder.
- One or more further aspects of the present invention are discussed in detail herein below. The other objectives and advantages of the present invention will be apparent to those skilled in the art from the following description. Detailed Description of the Invention
- the present invention relates to a compound of formula (I):
- X is N or S
- Y is N or C
- Z is -CH 2 - or S(0) remember
- Ri and R 2 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (Ci-C 6 )alkoxy, (C3-Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, (C 3 - Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C 6 -Cio)aryl(Ci-C 6 )alkyl-C(0), heteroaryl(Ci-C 6 )alkyl-C(0), -C(0)R 5 , -C(0)NR 6 R 7 , -C(S)NR 6 R 7 and -S(0) p R 8 ; provided that at least one of Ri and R 2 is other than hydrogen;
- R 3 and R 4 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (Ci-C 6 )alkoxy, (C 3 -C 12 )cycloalkyl, (Ci-C 6 )alkyl-C(0), (C 6 -Ci 0 )aryl, heterocyclyl, heteroaryl, -C(0)R 5 , -C(0)NR 6 R 7 , -C(S)NR 6 R 7 and -S(0) P R 8 ; provided that one of R 3 and R 4 is other than hydrogen; or R 3 and R 4 together with the N atom to which they are attached can form a saturated or a partially unsaturated heterocyclic ring optionally containing 1 , 2 or 3 additional heteroatoms selected from O, N or S;
- R5 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl;
- R 6 and R are independently selected from the group consisting of hydrogen, (Ci-
- Rg is selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, (C 6 -Cio)aryl, (C 3 - Ci 2 )cycloalkyl, heterocyclyl and heteroaryl;
- p is an integer selected from 0, 1 or 2;
- n is an integer selected from 0, 1 or 2;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci- C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, -0(C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -NH(Ci-C 6 )alkyl, -N[(Ci-C 6 )alkyl] 2 , -C(0)(Ci-C 6 )alkyl, - C(0)0(Ci-C 6 )alkyl, -C(0)NH 2 and -C(0)NH(Ci-C 6 )alkyl;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci- C 6 )alkyl, halo(Ci-C 6 )alkoxy, amino, cyano and nitro;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci- C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R 5 , -C(0)0(Ci-C 6 )alkyl, -C(0)NH 2 , -C(0)NH(Ci-C 6 )alkyl and -S(0) p R 8 ; wherein R5, Rg and p are as defined above;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci- C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Ci 0 )aryl-O-(Ci-C 6 )alkyl, amino, cyano, nitro, -C(0)R 5 and -NHC(0)(Ci-C 6 )alkyl; wherein R5 is as defined above;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci- C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R5 and -S(0) p R8; wherein R5, Rg and p are as defined above;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine; or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N -oxide thereof.
- substitution means that one or more hydrogen atoms of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.
- (Ci-C 6 )alkyl or "alkyl”, as used herein, alone or as part of a substituent group refers to an aliphatic group, including straight or branched chain alkyl group.
- a straight-chain or branched chain alkyl has six or fewer carbon atoms in its backbone, for instance, Ci-C 6 for straight chain and C3-C6 for branched chain.
- Suitable alkyl groups containing from one to six carbon atoms are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, 1-methylbutyl, secondary butyl, tertiary butyl, tertiary pentyl, neopentyl, 3-methylbutyl, 3,3-dimethylbutyl, 2-methylpentyl or 3-methylpentyl.
- the alkyl groups may be unsubstituted or substituted with one or more groups, preferably one to three groups independently selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, - 0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 3 -C 12 )cycloalkyl, (C 6 -Ci 0 )aryl, -O(C 6 -C 10 )aiyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -NH(Ci-C 6 )alkyl, -N[(Ci-C 6 )alkyl]2, -C(0)(Ci- C 6 )alkyl, -C(0)0(
- (C 2 -C8)alkenyl or “alkenyl”, as used herein, alone or as part of a substituent group, refers to an unsaturated straight or branched chain hydrocarbon radical containing at least one carbon-carbon double bond (two adjacent sp carbon atoms).
- (C 2 -C8)alkenyl refers to an alkenyl group having two to eight carbon atoms.
- the geometry of the double bond may be
- the geometry of the double bond may be
- E), or sixteen (Z), cis or trans examples of alkenyl include, but are not limited to, vinyl, allyl and 2-propenyl.
- the alkenyl groups may be unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci- C 6 )alkyl, amino, nitro and cyano.
- alkynyl refers to an unsaturated, branched or straight chain having from two to eight carbon atoms and at least one carbon-carbon triple bond (two adjacent 'sp' carbon atoms).
- alkynyl include, but are not limited to, ethynyl, 1-propynyl, 3-propynyl and 4- butynyl.
- alkynyl groups may be unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, amino, nitro and cyano.
- halo(Ci- C 6 )alkyl refers to radicals wherein one or more of the hydrogen atoms of the (Ci- C 6 )alkyl group are substituted with one or more halogens.
- a monohalo(Ci-C 6 )alkyl radical for example, may have a chlorine, bromine, iodine or fluorine atom.
- Dihalo and polyhalo(Ci- C 6 )alkyl radicals may have two or more of the same or different halogen atoms.
- halo(Ci-C 6 )alkyl examples include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl and difluoropropyl.
- (Ci- C 6 )alkoxy refers to (Ci-C 6 )alkyl having an oxygen radical attached thereto.
- (Ci- C 6 )alkoxy or "-0(Ci-C 6 )alkyl" wherever used in this specification have the same meaning.
- Representative (Ci-C 6 )alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy and tert-butoxy.
- the (Ci-C 6 )alkoxy or -0(Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci- C 6 )alkyl, hydroxy, halogen, amino and cyano.
- halo(Ci- C 6 )alkoxy refers to radicals wherein one or more hydrogen atoms of the (Ci- C 6 )alkoxy group are substituted with one or more halogens.
- Representative examples of halo(Ci- C 6 )alkoxy groups include, but are not limited to, difluoromethoxy (-OCHF 2 ), trifluoromethoxy (- OCF 3 ) or trifluorethoxy (-OCH 2 CF 3 ).
- (C 3 -Ci 2 )-cycloalkyl or “cycloalkyl” whether used alone or as part of a substituent group, refers to a saturated or partially unsaturated cyclic hydrocarbon radical including 1, 2 or 3 rings and including a total of 3 to 12 carbon atoms forming the rings.
- the term cycloalkyl includes bridged, fused and spiro ring systems.
- (C 3 -Ci 2 )- cycloalkyl refers to a cycloalkyl group having 3 to 8 (both inclusive) carbon atoms.
- cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, l,2,3,3a-tetrahydropentalene, adamantyl, norbornyl, tetrahydronaphthalene bicyclo[2.1.0]pentane, bicyclo[4.2.0]octane, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]hept-2-ene, spiro[3.3]heptane, and the like.
- (C 3 - Ci 2 )cycloalkyl may be unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci- C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 3 -C 12)cycloalkyl, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro.
- (C 3 - Ci 2 )cycloalkyl(Ci-C 6 )alkyl or "cycloalkylalkyl” refers to a cycloalkyl group bonded directly through an alkyl group, wherein the terms “cycloalkyl” and “alkyl” are as defined herein above.
- the cycloalkylalkyl group may be unsubstituted or when substituted the "cycloalkyl” and/or the "alkyl” group may be substituted with one or more groups defined above.
- (C 3 - Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0) refers to a cycloalkylalkyl group which is attached via a carbonyl group on the alkyl portion of the cycloalkylalkyl.
- (C 6 -Cio)aryl refers to a monocyclic or bicyclic hydrocarbon ring system having up to ten ring carbon atoms, wherein at least one carbocyclic ring is having ⁇ electron system.
- Examples of (C 6 -C 10 ) aryl ring systems include, but are not limited to, phenyl or naphthyl.
- aryl group may be unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, halogen, halo(Ci- C 6 )alkyl, hydroxy, 0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 3 -Ci 2 )cycloalkyl, (C 6 -Ci 0 )aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R 5 , -OC(0)R 5 , -C(0)OH, -C(0)0(Ci- C 6 )alkyl, -C(0)NH 2 or -C(0)NH(Ci-C 6 )alkyl and -S(0) p R 8 ; wherein R 5 , R 8 and
- Aryl groups can be substituted in any desired position.
- the substituent in monosubstituted phenyl, the substituent may be located in the 2-position, the 3-position, the 4-position or the 5- position. If the phenyl carries two substituents, they can be located in 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position or 3, 5-position.
- monosubstituted phenyl groups include, but are not limited to 2-fluorophenyl, 2-ethoxyphenyl, 2-ethylphenyl, 4- morpholinophenyl, (4-ethylpiperazin-lyl)phenyl or 4-(2-dimethylaminoethyl)phenyl.
- disubstituted phenyl groups include, but not limited to, 2, 6-difluorophenyl or 3, 5- difluorophenyl.
- 0(C 6 -Cio)aryl or "aryloxy” refers to an (C 6 -Cio)aryl group having an oxygen radical attached thereto.
- aryloxy or -0(C 6 -Cio)aryl wherever used in this specification denote the same meaning.
- Representative aryloxy groups include, but are not limited to, phenoxy or naphthoxy.
- -0(C 6 - Cio)aryl is unsubstituted or substituted with one or more groups as defined herein above for the term "aryl".
- (C 6 -Cio)aryl(Ci- C 6 )alkyl or "arylalkyl” refers to (Ci-C 6 )alkyl group substituted with an (C 6 -Cio)aryl group, and said arylalkyl group is attached via the alkyl group, wherein the terms "(Ci-C 6 )alkyl” and "(C 6 - Cio)" are as defined herein above.
- the arylalkyl group may be unsubstituted or when substituted the "(Ci-C 6 )alkyl" and/or the "(C 6 -Cio)aryl” group may be substituted with one or more groups as defined herein above for the terms "(Ci-C 6 )alkyl” and "(C 6 -Cio)aryr'.
- Representative examples of arylalkyl groups include, but are not limited to, benzyl or 2-phenyl-ethyl.
- (C 6 -Cio)aryl(C 6 - Cio)aryl or "arylaryl” refers to (C 6 -Cio)aryl group substituted with an (C 6 -Cio)aryl group, and said arylaryl group is attached via the aryl group, wherein the term “(C 6 -Cio)aryl” is as defined herein above.
- the "(C 6 -Cio)aryl(C 6 -Cio)aryl” group may be unsubstituted or when substituted either one or both of the aryl groups are substituted with one or more groups as defined herein above for the term "aryl".
- arylaryl groups include, but not limited to, biphenyl or binaphthyl.
- heterocyclyl refers to 3- to 9-membered saturated or partially unsaturated monocyclic, bicyclic or a polycyclic ring system, preferably monocyclic or bicyclic ring system containing one or more hetero atoms, particularly one to three hetero atoms independently selected from the group consisting of: a nitrogen (N), a sulphur (S) and an oxygen (O) atom.
- N nitrogen
- S sulphur
- O oxygen
- saturated and partially unsaturated non-aromatic heterocyclic groups include, but are not limited to, oxetane, azetidine, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dihydropyran, tetrahydropyran, thio-dihydropyran, thiotetrahydropyran, piperidine, piperazine, morpholine, dihydrothiene, dihydropyridine, tetrahydropyridine, isoxazolidine or pyrazolidine.
- Polycyclic or bicyclic heterocyclic ring systems can comprise either fused rings in which two or more carbons are common to two adjoining rings, or bridged rings in which rings are joined through non-adjacent atoms.
- the fused heterocyclyl ring systems can comprise a 5 or a 6-membered heterocyclic ring fused with monocyclic aryl ring or a saturated or a partially unsaturated heterocyclic ring.
- fused heterocyclic rings include, but are not limited to, 1 ,3-benzodioxole, 1,3-benzothiazole or 2,3-dihydrobenzofuran.
- the bridged heterocyclyl ring systems may for instance, comprise a monocyclic or a bicyclic heterocyclic ring containing one or more alkylene bridges comprising 2 to 4 carbon atoms, wherein each bridge links two non-adjacent carbon atoms of the ring system.
- Examples of bridged heterocyclic rings include but not limited to oxobicyclo[2.2.1]heptane, azabicyclo[2.2.1]heptane, 8-oxa-3- azabicyclo[3.2.1]octane or 6-oxa-3-azabicyclo[3.1.1]heptane.
- the 'heterocyclyl' can be part of a bicyclic spiro ring.
- spiro heterocyclyl groups include, but are not limited to, 2-oxa- 6-aza-spiro[3.3]hexane, 2-oxa-6-aza-spiro[3.3]heptane, 2-oxa-6-aza-spiro[3.3]octane, 2-oxa-5- aza-spiro[3.4]heptane or 2-oxa-5-aza-spiro[3.4]octane.
- heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci- C 6 )alkyl, hydroxy, 0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Cio)aryl-0-(Ci-C 6 )alkyl, amino, cyano, nitro, -C(0)R 5 , -C(0)OH, -C(0)NH 2 , and -NHC(0)(Ci-C 6 )alkyl; wherein R 5 is as defined above.
- heteroaryl Heterocyclyl monocyclic or bicyclic ring systems having an aromatic ring containing hetero atom/s are herein referred to as "heteroaryl".
- heteroaryl refers to 3- to 10-membered aromatic monocyclic or bicyclic ring system containing one or more hetero atoms, preferably one to four identical or different hetero atoms selected from the group consisting of: nitrogen (N), sulphur (S) and oxygen (O) atom.
- heteroaryl include, but are not limited to, thiene, furan, pyridine, oxazole, thiazole, pyrazine, pyrimidine, pyrrole, pyrazole, isooxazole, triazole, tetrazole, pyridazine, isothiazole, benzo thiazole, benzooxazole, benzimidazole, quinoline or isoquinoline.
- Heteroaryl group may be unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C8)alkenyl, (C 2 -C8) alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 ) alkyl, halo(Ci-C 6 )alkoxy, (C 3 - Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R5, -OC(0)R5, - C(0)OH, -C(0)0(Ci-C 6 )alkyl, -C(0)NH 2 , -C(0)NH(Ci-C 6 )alkyl, NHC(0)(Ci-C 6 )alkyl and - S(0) p R8 ; wherein R5, R
- Cio)aryl or “heterocyclylaryl” refers to a heterocyclyl group bonded through an aryl group, wherein the terms “heterocyclyl” and “aryl” are as defined herein above. Unless stated otherwise, heterocyclylaryl group may be unsubstituted or when substituted the heterocyclyl and/or the aryl may be substituted with one or more substituents as defined herein above for the terms “heterocyclyl” and "aryl”.
- Representative examples of heterocyclylaryl include, but are not limited to 4-(piperidin-l-yl)phenyl, 4-(4-ethylpiperazin-l-yl)phenyl or 4-morpholinophenyl.
- heterocyclyl- heteroaryl refers to a heterocyclyl group bonded through a heteroaryl group, wherein the terms “heterocyclyl” and “heteroaryl” are as defined herein above. Unless stated otherwise, heterocyclyl-heteroaryl may be unsubstituted or when substituted the heterocyclyl and/or the heteroaryl may be substituted with one or more groups as defined herein above for the terms “heterocyclyl” and “heteroaryl” respectively
- Example of heterocyclylheteroaryl include, but is not limited to 4-(4-methylpiperazin-l-yl)pyridyl.
- heteroatom as used herein, includes nitrogen (N), oxygen (O) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom or a (Ci-C 6 ) alkyl or any other appropriate group to satisfy the valency.
- halogen or "halo" as used herein, unless otherwise indicated refer to bromine, chlorine, fluorine or iodine atom.
- amino refers to the group “NH 2 " which may be optionally substituted by one or more substituents.
- substituents include, but are not limited to, (Ci- C 4 )alkyl or (C 6 -Ci 0 )aryl.
- isotopic forms or “isotopically labelled forms” is a general term used for isotopic forms of the compounds of formula (I), wherein one or more atoms of the compounds of formula (I) are replaced by their respective isotopes. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present invention.
- isotopes examples include, but are not limited to, isotopes of hydrogen such as 2 H (deuterium or D) and 3 H (tritium or T), carbon such as U C, 13 C and 14 C, nitrogen such as 13 N and 15 N, oxygen such as 15 0, 17 0 and 18 0, chlorine such as 36 C1, fluorine such as 18 F and sulphur such as 35 S.
- isotopes of hydrogen such as 2 H (deuterium or D) and 3 H (tritium or T)
- carbon such as U C, 13 C and 14 C
- nitrogen such as 13 N and 15 N
- oxygen such as 15 0, 17 0 and 18
- chlorine such as 36 C1
- fluorine such as 18 F
- sulphur such as 35 S.
- Substitution with heavier isotopes, for example, replacing one or more key carbon-hydrogen bonds with carbon-deuterium bond may show certain therapeutic advantages, resulting from longer metabolism cycles, (e.g., increased in vivo half life or reduced dosage requirements), improved
- isotopic forms of the compounds of formula (I) may include, without limitation, deuterated compounds of formula (I).
- deuterated as used herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), with a deuterium atom.
- the compounds of formula (I) may include in the definitions of one or more of the various variables R 1; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and Rg, wherever applicable, deuterium, deuterated-alkyl, deuterated-alkoxy, deutrated-aryloxy, deuterated- cycloalkyl, deuterated-heterocyclyl, deuterated-aryl or deuterated-heteroaryl.
- deuterated-alkyl refers to an (Ci-C 6 )alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium. That is, in a deuterated alkyl group, at least one carbon atom is bound to a deuterium. In a deuterated alkyl group, it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium.
- deuterated and the terms deuterated-heterocyclyl, deuterated-heteroaryl, deuterated-cycloalkyl, deuterated-aryl and “deuterated-alkoxy” each refer to the corresponding chemical moiety wherein at least one carbon is bound to a deuterium.
- stereoisomer is a general term used for all isomers of individual compounds (in the present invention, a compound of formula I) that differ only in the orientation of their atoms in space.
- stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
- tautomer refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.
- pharmaceutically acceptable salts includes salts of the active compounds which are prepared with acids or bases, depending on the particular substituents found on the compounds described herein.
- N-oxide refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle. N-oxide can be formed in the presence of an oxidizing agent such as m-chloro-perbenzoic acid or hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N- 0 bond.
- solvate or “solvate” describes a complex wherein the compound of formula (I) of the present invention, is coordinated with a proportional amount of a solvent molecule.
- prodrug refers to compounds that are drug precursors, which following administration, release the therapeutically active compound (in the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof) in vivo via a chemical or metabolic process, for example, a prodrug on being brought to the physiological pH or through an enzyme action is converted to the therapeutically active compound.
- polymorph or “polymorphic form” refers to crystals of the same compound that differs only in the arrangement and/or conformation of the molecule in the crystal lattice.
- the terms "compound of formula (I)”, “compounds of formula (I)”, and “compounds of the present invention” include all the isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable polymorphs, N-oxides and S-oxides thereof.
- reference to the compounds of the present invention and/or the compounds of formula (I) may include reference to the compounds represented herein by the compounds of formula (la) and/or the compounds of formula (lb).
- the compound(s) of the present invention can also be referred to herein as "the active compound” or "the active ingredient”.
- therapeutically effective amount means an amount of a compound of formula I or a pharmaceutically acceptable salt thereof; or a composition comprising the compound of formula I or a salt thereof, effective in producing the desired therapeutic response in a particular patient suffering from a disease or disorder associated with abnormal protein kinase activity.
- therapeutically effective amount includes the amount of the compound, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject.
- the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment.
- the therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the end user, the severity of the disease or disorder being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized and other factors.
- the term "pharmaceutically acceptable carrier” refers to a material that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type which is compatible with a subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent (in the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof), to the target site without terminating the activity of the agent.
- subject refers to an animal, preferably a mammal, and most preferably a human.
- mammal refers to warm-blooded vertebrate animals of the class 'mammalia', including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
- mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
- treatment is intended to mean to alleviate, slow the progression, attenuation or cure of existing disease or condition (e.g. disease or disorder associated with abnormal protein kinase activity). Treatment also includes treating, preventing development of, or alleviating to some extent, one or more of the symptoms of the diseases or condition.
- multi-kinase inhibitor refers to a compound that exhibits a therapeutic effect by inhibiting more than one protein kinases.
- multi-kinase inhibitor is a compound which does not specifically inhibit only one kinase as a molecular target, but primarily inhibits multiple protein kinases, at least two kinases.
- PK protein kinase
- PK-related disorder refers to a condition characterized by abnormal (i.e., diminished or, more commonly, excessive) PK catalytic activity, where the particular PK can be RTK (receptor tyrosine kinases) or STK (serine/threonine kinases).
- Abnormal PK catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs; (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth; or (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth.
- Excessive-activity of a PK refers to either amplification of the gene encoding a particular PK or its ligand, or production of a level of PK activity, which can correlate with a cell proliferation, differentiation and/or growth disorder such as cancer, inflammatory disorders, CNS disorders and autoimmune disorders.
- the present invention relates to a compound of formula I, wherein, X is N, Y is N, Z is S(0) n , wherein the integer n is as defined; and represents a single bond between the ring atoms 1 and 2 and a double bond between the ring atoms 2 and 3; or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.
- the present invention relates to a compound of formula I;
- the present invention relates to a compound of formula (I);
- Ri and R 2 are independently selected from the group consisting of hydrogen, (C 3 - Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C 6 -Ci 0 )aryl(Ci-C 6 )alkyl-C(O), heteroaryl(Ci-C 6 )alkyl-C(0), - C(0)R 5 , -C(0)NR 6 R7 and -S(0) P R8; provided that one of Ri and R 2 is other than hydrogen; or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N -oxide thereof.
- the present invention relates to a compound of formula (I);
- R 3 and R 4 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl; provided that one of R 3 and R 4 is other than hydrogen; or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.
- the present invention relates to a compound of formula (I), wherein, X, Y and Z are as defined in the first aspect of the invention;
- Ri and R 2 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, (C 3 -Ci 2 )cycloalkyl(Ci- C 6 )alkyl-C(0), (C 6 -Ci 0 )aryl(Ci-C 6 )alkyl-C(O), heteroaryl(Ci-C 6 )alkyl-C(0), -C(0)R 5 , - C(0)NR 6 R 7 , -C(S)NR 6 R 7 and -S(0) p R 8 ; provided that one of Ri and R 2 is other than hydrogen;
- R 3 and R 4 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 3 -C 12 )cycloalkyl, (C 6 -C 10 )aryl, heterocyclyl, heteroaryl, -C(0)R 5 , -C(0)NR 6 R 7 , - C(S)NR 6 R 7 and -S(0) P R8; provided that one of R 3 and R 4 is other than hydrogen;
- R 5 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl or heteroaryl;
- R 6 and R 7 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl; provided that at least one of R 6 and R 7 is hydrogen;
- R 8 is (Ci-C 6 )alkyl or (C 6 -C 10 )aryl
- p is an integer selected from 0, 1 or 2;
- n is an integer selected from 0, 1 or 2;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci- C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, -0(C 6 -Cio)aryl, heteroaryl, amino, cyano, nitro, - NH(Ci-C 6 )alkyl and -N[(Ci-C 6 )alkyl] 2 ;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, amino, cyano and nitro;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups independently selected from (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, amino, cyano, nitro and -NHC(0)(C 1 - C 6 )alkyl;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, heterocyclyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine; or a isotopic form, or a siereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.
- Ri and R 2 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, (C 3 -Ci 2 )cycloalkyl(Ci- C 6 )alkyl-C(0), (C 6 -Ci 0 )aryl(Ci-C 6 )alkyl-C(O), heteroaryl(Ci-C 6 )alkyl-C(0), -C(0)R 5 , - C(0)NR 6 R 7 , -C(S)NR 6 R 7 and -S(0) p R 8 ; provided that one of Ri and R 2 is other than hydrogen;
- R 3 and R 4 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Ci 0 )aryl, heterocyclyl, heteroaryl, -C(0)R 5 , -C(0)NR 6 R 7 , - C(S)NR 6 R 7 and -S(0) P R8; provided that one of R3 and R 4 is other than hydrogen;
- R5 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl;
- R 6 and R 7 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl; provided that at least one of R 6 and R 7 is hydrogen;
- R 8 is (Ci-C 6 )alkyl or (C 6 -C 10 )aiyl;
- p is an integer selected from 0, 1 or 2;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, (C 3 - Ci 2 )cycloalkyl, (C 6 -Cio)aryl, -0(C 6 -Cio)aryl, heteroaryl, amino, cyano, nitro, -NH(Ci-C 6 )alkyl and -N[(Ci-C 6 )alkyl] 2 ;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C8)alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, amino, cyano and nitro;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, amino, cyano, nitro and -NHC(0)(Ci-C 6 )alkyl;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, heterocyclyl, amino,
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine; or a isotopic form, or a stereoisomeric form or a tautomeric form or mixtures thereof in all ratios, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a prodrug or a polymorph or an N-oxide thereof.
- the compound of formula (I) encompasses the compound of formula (la); wherein,
- Ri and R 2 are independently selected from the group consisting of hydrogen, (C3-
- Ci 2 cycloalkyl(Ci-C 6 )alkyl-C(0)-, (C 6 -Ci 0 )aryl(Ci-C 6 )alkyl-C(O), heteroaryl, heteroaryl(Ci- C 6 )alkyl-C(0)-, -C(0)R 5 , -C(0)NR 6 R 7 and -S(0) p R 8 ; provided that one of Ri and R 2 is other than hydrogen;
- R 3 and R 4 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl; provided that one of R 3 and R 4 is other than hydrogen;
- R5 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl;
- R 6 and R 7 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 6 -Cio)aryl and (C 3 -Ci 2 )cycloalkyl; provided that at least one of R 6 and R 7 is hydrogen;
- R 8 is (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl
- p is an integer selected from 0, 1 or 2;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen, hydroxy, -0(Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 - Cio)aryl, -O(C 6 -C 10 )aryl, heteroaryl, amino, -NH(Ci-C 6 )alkyl and -N[(Ci-C 6 )alkyl] 2 ;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy, -0(Ci- C 6 )alkyl and amino;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, hydroxy, amino and -NHC(0)(Ci-C 6 )alkyl;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, heterocyclyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compound of formula (I) encompasses the compound of formula (la); wherein,
- Ri and R2 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Ci 0 )aryl, heteroaryl, (C 3 -Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C 6 - Cio)aryl(Ci-C 6 )alkyl-C(0), heteroaryl(Ci-C 6 )alkyl-C(0), -C(0)R 5 , -C(0)NR 6 R 7 , -C(S)NR 6 R 7 and -S(0) P R8; provided that one of Ri and R2 is other than hydrogen;
- R 3 and R 4 together with the N atom to which they are attached, can form a saturated or a partially unsaturated 3- to 9-membered heterocyclic ring optionally containing 1, 2 or 3 additional heteroatoms independently selected from the group consisting of O, N and S;
- R5 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci2)cycloalkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl;
- R 6 and R 7 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 6 -Cio)aryl and (C 3 -Ci2)cycloalkyl; provided that at least one of R 6 and R 7 is hydrogen;
- R 8 is (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl
- p is an integer selected from 0, 1 or 2;
- n is an integer selected from 0, 1 or 2;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, (C 3 - Ci 2 )cycloalkyl, (C 6 -Cio)aryl, -0(C 6 -Cio)aryl, heteroaryl, amino, cyano, nitro, -NH(Ci-C 6 )alkyl and -N[(C 1 -C 6 )alkyl] 2 ;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, amino, cyano and nitro;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;
- heterocyclyl is 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, (C6-Cio)aryl-0-(Ci-C 6 )alkyl, hydroxy, amino, cyano, nitro and - NHC(0)(Ci-C 6 )alkyl;
- heteroaryl is 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, (C 3 -C9)heterocyclyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compounds of formula (I) encompasses the compound of formula (la); wherein,
- Ri and R 2 are independently selected from the group consisting of hydrogen, (C 3 - Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C 6 -Ci 0 )aryl(Ci-C 6 )alkyl-C(O), heteroaryl, heteroaryl(Ci- C 6 )alkyl-C(0), -C(0)R 5 , -C(0)NR 6 R 7 and -S(0) p R 8 ; provided that one of Ri and R 2 is other than hydrogen;
- R 3 and R 4 are independently selected from the group consisting of hydrogen, (Ci-
- R5 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl;
- R 6 is hydrogen and R 7 is (C 3 -Ci 2 )cycloalkyl
- R 8 is (Ci-C 6 )alkyl or (C 6 -Ci 0 )aryl; p is an integer selected from 0, 1 or 2;
- n is an integer selected from 0, 1 or 2;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen, hydroxy, -0(Ci-C 6 )alkyl, (C3-Ci 2 )cycloalkyl, (C 6 - Cio)aryl, -O(C 6 -Ci 0 )aryl, (C 3 -Ci 2 )heteroaryl, amino, -NH(d-C 6 )alkyl and -N[(Ci-C 6 )alkyl] 2 ;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy, -0(Ci- C 6 )alkyl and amino;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy, amino and -NHC(0)(Ci-C 6 )alkyl;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, heterocyclyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compound of formula (I) encompasses the compound of formula (la); wherein,
- Ri and R 2 are independently selected from the group consisting of hydrogen, (C 3 - Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C 6 -Ci 0 )aryl(Ci-C 6 )alkyl-C(O), heteroaryl(Ci-C 6 )alkyl-C(0)-, -C(0)R 5 , -C(0)NR 6 R 7 and -S(0) p R 8 ; provided that at least one of Ri or R 2 is not hydrogen;
- R 3 and R 4 together with the N atom to which they are attached can form a saturated or a partially unsaturated 3- to 9-membered heterocyclic ring optionally containing one or two additional heteroatoms independently selected from the group consisting of O, N and S;
- R5 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl;
- R 6 is hydrogen and R 7 is (C 3 -Ci 2 )cycloalkyl;
- R 8 is (Ci-C 6 )alkyl or (C 6 -C 10 )aiyl;
- p is an integer selected from 0, 1 or 2;
- n is an integer selected from 0, 1 or 2;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen, hydroxy, -0(Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 - Cio)aryl, -O(C 6 -C 10 )aryl, heteroaryl, amino, -NH(C 1 -C 6 )alkyl and -N[(C 1 -C 6 )alkyl] 2 ;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C8)alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy, -0(Ci- C 6 )alkyl and amino;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, (C 6 -Ci 0 )aryl-O-(Ci-C 6 )alkyl, hydroxy, amino and -NHC(0)(Ci-C 6 )alkyl;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, heterocyclyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compound of formula (I) encompasses the compound of formula (la); wherein,
- R] is hydrogen
- R 2 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, (C 3 -Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C 6 -Ci 0 )aryl(Ci-C 6 )alkyl-C(O), heteroaryl(Ci-C 6 )alkyl-C(0), -C(0)R 5 , -C(0)NR 6 R 7 , -C(S)NR 6 R 7 and -S(0) p R 8 ; wherein R 5 , R 6 , R 7 , R8, n and p are as defined above;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen, hydroxy, -0(Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 - Cio)aryl, heteroaryl and amino;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy, -0(Ci- C 6 )alkyl and amino;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, amino, cyano and nitro;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy and amino;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compound of formula (I) encompasses the compound of formula (la); wherein,
- R 2 is selected from the group consisting of heteroaryl, (C 3 -Ci 2 )cycloalkyl(Ci-C 6 )alkyl-
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen, hydroxy, -0(Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 - Cio)aryl, heteroaryl and amino;
- (C3-Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy, -0(Ci- C 6 )alkyl and amino;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, amino, cyano and nitro;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy and amino;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compounds of formula (I) encompasses the compound of formula (la); wherein,
- R 2 is selected from the group consisting of (C 3 -Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C 6 - Cio)aryl(Ci-C 6 )alkyl-C(0) and heteroaryl(Ci-C 6 )alkyl-C(0);
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen, hydroxy, -0(Ci-C 6 )alkyl and amino;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, amino, cyano and nitro;
- heteroaryl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compound of formula (I) encompasses the compound of formula (la); wherein,
- R 2 is (C 6 -Cio)aryl(Ci-C 6 )alkyl-C(0);
- (Ci-C 6 )alkyl is substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen, hydroxy, amino, cyano and nitro;
- (C 6 -Cio)aryl is substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen and -0(d-C 6 ) alkyl;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compound of formula (I) encompasses the compound of formula (la); wherein,
- R] is hydrogen
- R 2 is -C(0)R 5 ;
- R 5 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen, hydroxy, -0(Ci-C 6 )alkyl and amino;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy, -0(Ci- C 6 )alkyl and amino;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, amino, cyano and nitro;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy and amino;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci- C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compound of formula (I) encompasses the compound of formula (la);
- Ri is hydrogen; and R 2 is -C(0)NR 6 R 7 or -S(0) p R 8 ;
- R 6 is hydrogen
- R 7 is (C 3 -Ci 2 )cycloalkyl
- R 8 is (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl
- p is an integer selected from 0, 1 or 2;
- n is an integer selected from 0, 1 or 2;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, halogen, hydroxy, -0(Ci-C 6 )alkyl and amino;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -Cs)alkenyl, (C 2 -C8)alkynyl, halogen, hydroxy, -0(Ci- C 6 )alkyl and amino;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compound of formula (I) encompasses the compound of formula (la);
- R 3 is hydrogen
- R 4 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, -C(0)R 5 , -C(0)NR 6 R 7 , -C(S)NR 6 R 7 , and -S(0) P R 8 ; wherein R 5 , R 6 , R 7 , Rs, n and p are as defined above;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, -0(C 6 -Cio)aryl, halogen, halo(Ci-C 6 )alkyl, hydroxy, amino, NH(Ci-C 6 )alkyl and -N[(Ci-C 6 )alkyl] 2 ;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl and amino;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from (Ci- C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Cio)aryl, heterocycl
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C 6 )alkyl, (C 2 -C8)alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci- C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, amino and -NHC(0)(Ci-C 6 )alkyl;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci- C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, (C3-C9)heterocyclyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compound of formula (I) encompasses the compound of formula (la);
- R 3 is hydrogen
- R 4 is selected from the group consisting of (C 6 -Cio)aryl, heteroaryl and heterocyclyl; wherein,
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl and amino;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, amino and -NHC(0)(Ci-C 6 )alkyl;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, heterocyclyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compound of formula (I) encompasses the compound of formula (la);
- R 3 and R 4 together with the N atom to which they are attached can form a saturated or a partially unsaturated 3- to 9-membered heterocyclic ring containing 1 or 2 additional heteroatoms independently selected from O, N or S;
- heterocyclyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, -0(Ci- C 6 )alkyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, (C6-Cio)aryl-0-(Ci-C 6 )alkyl and amino; and
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- Ri and R 2 are independently selected from the group consisting of hydrogen, (Ci-
- R 3 and R 4 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Ci 0 )aryl, heterocyclyl, heteroaryl, -C(0)R 5 , -C(0)NR 6 R 7 , - C(S)NR 6 R 7 and -S(0) P R8; provided that one of R 3 and R 4 is other than hydrogen;
- R5 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl;
- R 6 and R are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl; provided that at least one of R 6 and R is hydrogen;
- R 8 is (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl
- p is an integer selected from 0, 1 or 2;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C8)alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, -0(C 6 -Cio)aryl, heteroaryl, amino, cyano, nitro, -NH(Ci-C 6 )alkyl and -N[(Ci-C 6 )alkyl] 2 ;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, amino, cyano and nitro;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, amino, cyano, nitro and -NHC(0)(Ci-C 6 )alkyl;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, heterocyclyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compounds of formula (I) encompasses the compound of formula
- Ri and R 2 are independently selected from the group consisting of hydrogen, (C3- Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C 6 -Ci 0 )aryl(Ci-C 6 )alkyl-C(O), heteroaryl, heteroaryl(Ci- C 6 )alkyl-C(0), -C(0)R 5 , -C(0)NR 6 R 7 and -S(0) p R 8 ; provided that one of Ri and R 2 is other than hydrogen; R 3 and R 4 are independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl; provided that one of R 3 and R 4 is other than hydrogen;
- R5 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Cio)aryl, heterocyclyl and heteroaryl;
- R 6 is hydrogen and R is (C 3 -Ci 2 )cycloalkyl
- R 8 is (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl
- p is an integer selected from 0, 1 or 2;
- n is an integer selected from 0, 1 or 2;
- (Ci-C 6 )alkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C8)alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy, -0(Ci- C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Ci 0 )aryl, -O(C 6 -Ci 0 )aryl, heteroaryl, amino, -NH(Ci-C 6 )alkyl and -N[(Ci-C 6 )alkyl] 2 ;
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy, -0(Ci- C 6 )alkyl and amino;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, hydroxy, amino and -NHC(0)(Ci-C 6 )alkyl;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, heterocyclyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- the compounds of formula (I) encompasses the compound of formula (lb); wherein,
- Ri is hydrogen
- R 2 is selected from the group consisting of (C 3 -Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C 6 - Cio)aryl(Ci-C 6 )alkyl-C(0) and heteroaryl(Ci-C 6 )alkyl-C(0);
- R 3 is hydrogen
- R 4 is selected from the group consisting of (C 6 -Cio)aryl, heteroaryl and heterocyclyl; wherein,
- (C 3 -Ci 2 )cycloalkyl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl and amino;
- (C 6 -Cio)aryl is unsubstituted or substituted with one or more groups selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci-C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Cio)aryl, heterocyclyl, heteroaryl, amino, cyano and nitro;
- heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci- C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, amino and -NHC(0)(Ci-C 6 )alkyl;
- heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups selected from (Ci-C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(Ci- C 6 )alkyl, hydroxy, -0(Ci-C 6 )alkyl, heterocyclyl, amino, cyano and nitro;
- halogen is selected from the group consisting of chlorine, bromine, iodine and fluorine.
- Representative compounds of formula I in accordance with the present invention include:
- the compound of formula (I) can be prepared by various methods including using one or more methods well known to the person skilled in the art. Representative processes for the preparation of the compounds of formula (I) are described herein below and illustrated in the following schemes 1 and 2, but are not limited thereto. It will be appreciated by the person skilled in the art that within certain of the processes described herein, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent such as bases, solvents, coupling agents to be used in the reaction steps.
- the starting compounds including the reactants and reagents as well as intermediates used in the following process are either commercially available or can be prepared according to standard procedures known in the art, for instance those reported in the literature references.
- This process step involves reacting 2-bromo-l-(3-nitrophenyl)ethanone (compound A) in a solvent such as N, N-dimethyl formamide (DMF), N-methyl pyrrolidone (NMP) or ethanol (EtOH) with 4,5-dihydrothiazol-2-amine (compound B) in the presence of an inorganic base such as sodium carbonate (Na 2 C0 3 ), potassium carbonate (K 2 C0 3 ), cesium carbonate (Cs 2 C0 3 ) or sodium bicarbonate (NaHC0 3 ) at a temperature ranging from 70 °C to 120 °C for lh to 2h, according to the method described in J. Med. Chem., 2006, 49(26), 7897-7901, to obtain compound (C).
- a solvent such as N, N-dimethyl formamide (DMF), N-methyl pyrrolidone (NMP) or ethanol (EtOH)
- an inorganic base such
- the compound (C) is acetylated using an acetylating reagent such as acetic anhydride or acetyl chloride in the presence of an acid, such as sulphuric acid (H 2 SO 4 ) or a lewis acid such as aluminium trichloride (AICI 3 ) or boron trifluoride (BF 3 ) at 100 °C to 150 °C for lh to 5h, according to the method described in Organic Letters, 2005, 7, 4753, to obtain compound (D).
- an acetylating reagent such as acetic anhydride or acetyl chloride in the presence of an acid, such as sulphuric acid (H 2 SO 4 ) or a lewis acid such as aluminium trichloride (AICI 3 ) or boron trifluoride (BF 3 ) at 100 °C to 150 °C for lh to 5h, according to the method described in Organic Letters, 2005, 7, 4753
- the compound (D) is reacted with N,N-dimethylformamide dimethyl acetal (DMF. DMA) in the presence of a solvent such as N-methyl pyrrolidine (NMP), N,N-dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) at 70°C to 90°C for 0.5h to 4h, according to the method described in Bioorganic and Medicinal Chemistry Letters, 2010, 20(8), 2452-2455, to obtain compound (E).
- NMP N-methyl pyrrolidine
- DMF N,N-dimethyl formamide
- DMSO dimethyl sulfoxide
- the compound (E) is reacted with guanidine hydrochloride in the presence of an inorganic base such as Na 2 C0 3 , K 2 C0 3 or Cs 2 C0 3 and a solvent such as DMF, NMP or ethanol (EtOH) at 80 °C to 140 °C, for 16h to 18h, according to the method described in Bioorganic and Medicinal Chemistry Letters, 2010, 20(8), 2452-2455, to obtain compound (F).
- an inorganic base such as Na 2 C0 3 , K 2 C0 3 or Cs 2 C0 3
- a solvent such as DMF, NMP or ethanol (EtOH)
- a solution of the compound (F) in acetic acid is subjected to diazotization in the presence of sodium nitrite (NaN0 2 ) at 60 °C to 80 °C followed by the addition of an inorganic base such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or lithium hydroxide (LiOH) and stirring for lh, according to the method described in Bioorganic and Medicinal Chemistry Letters, 2010, 20(8), 2452-2455, to obtain compound (G).
- sodium nitrite NaN0 2
- an inorganic base such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or lithium hydroxide (LiOH)
- the compound (G) is treated with a halogenating agent, for instance, a chlorinating agent such as phosphorous oxychloride (POCI 3 ), thionyl chloride (SOCl 2 ) or phosphorous pentachloride (PCI 5 ) at 60 °C to 120 °C for 0.5h to 6h, according to the method described in Bioorganic and Medicinal Chemistry Letters, 2010, 20(8), 2452-2455, to obtain compound (H).
- a halogenating agent for instance, a chlorinating agent such as phosphorous oxychloride (POCI 3 ), thionyl chloride (SOCl 2 ) or phosphorous pentachloride (PCI 5 )
- the compound (J) is subjected to catalytic reduction using a reducing agent such as stannous chloride or ammonium chloride and a catalyst such as iron or palladium respectively, in the presence of a solvent such as methanol (MeOH), EtOH or ethyl acetate at room temperature to 90 °C for 0.5h to 4h, according to the method described in J. Org. Chem., 1999, 64(6), 2110-2113, to obtain compound (K) (wherein R 3 and R 4 are as defined above for the compound of formula (la)).
- a reducing agent such as stannous chloride or ammonium chloride and a catalyst such as iron or palladium respectively
- a solvent such as methanol (MeOH), EtOH or ethyl acetate
- the compound (K) is reacted with an acid chloride of formula RiCl or R 2 C1 to obtain compound of formula (la), wherein Ri and R 2 are independently selected from the group consisting of hydrogen, (C 3 -Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C 6 -Cio)aryl(Ci-C 6 )alkyl- C(O), heteroaryl (Ci-C 6 )alkyl-C(0) and C(0)R 5 (wherein R5 is as defined above for the compound of formula (la)), provided that one of Ri and R 2 is other than hydrogen; and R 3 and R 4 are as defined above for the compound of formula (la).
- Ri and R 2 are independently selected from the group consisting of hydrogen, (C 3 -Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C 6 -Cio)aryl(Ci-C 6 )alkyl- C(O), heteroaryl
- compound (K) is reacted with an isocyanate or isothiocyanate of formula
- R 6 R 7 NCO or R 6 R 7 NCS] to obtain compound of formula (la), wherein Ri and R 2 are independently selected from the group consisting of hydrogen, -C(0)NR 6 R 7 or -C(S)NR 6 R 7 , wherein, R 6 and R 7 are as defined above and provided that one of Ri and R 2 is other than hydrogen; and R 3 and R 4 are as defined above for the compound of formula (la).
- compound (K) is reacted with a sulphonyl chloride of formula RgS(0) p Cl to obtain compounds of formula (la), wherein Ri and R 2 are independently selected from the group consisting of hydrogen and S(0) p R8, wherein Rg and p are as defined above and provided that one of Ri and R 2 is other than hydrogen; and R 3 and R 4 are as defined above.
- This process step is carried out in accordance with the procedure described in Tetrahedron Letters, 201 1, 52(31), 3963-3968.
- the compound 2D is acetylated using an acetylating reagent such as acetic anhydride or acetyl chloride in the presence of an acid such as sulphuric acid (H 2 SO 4 ) or a lewis acid such as aluminium trichloride (AICI 3 ) or boron trifluoride ⁇ BF 3 ) at 100 °C to 150 °C for lh to 5h, to obtain compound 2E.
- an acetylating reagent such as acetic anhydride or acetyl chloride in the presence of an acid such as sulphuric acid (H 2 SO 4 ) or a lewis acid such as aluminium trichloride (AICI 3 ) or boron trifluoride ⁇ BF 3 ) at 100 °C to 150 °C for lh to 5h, to obtain compound 2E.
- an acetylating reagent such as acetic anhydride or acetyl
- the compound 2E is reacted with ⁇ , ⁇ -dimethyl formamide dimethyl acetal (DMF. DMA) in the presence of a solvent such as N-methyl pyrrolidine (NMP), N,N-dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) at 70°C to 90°C for 0.5h to 4h, to obtain compound 2F.
- a solvent such as N-methyl pyrrolidine (NMP), N,N-dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO)
- the compound 2F is reacted with guanidine hydrochloride in the presence of an inorganic base such as Na 2 C0 3 , K 2 CO 3 or CS 2 CO 3 and a solvent such as DMF, NMP or ethanol (EtOH) at 80 °C to 140 °C, for 16h to 18h, to obtain compound 2G.
- an inorganic base such as Na 2 C0 3 , K 2 CO 3 or CS 2 CO 3
- a solvent such as DMF, NMP or ethanol (EtOH)
- a solution of the compound 2G in acetic acid is subjected to diazotization in the presence of sodium nitrite (NaN0 2 ) at 60 °C to 80 °C followed by the addition of an inorganic base such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or lithium hydroxide (LiOH) and stirring for lh, to obtain compound 2H.
- NaN0 2 sodium nitrite
- KOH potassium hydroxide
- LiOH lithium hydroxide
- the compound 2H is treated with a halogenating agent, for instance, a chlorinating agent such as phosphorous oxychloride (POCI 3 ), thionyl chloride (SOCl 2 ) or phosphorous pentachloride (PCI 5 ) at 60 °C to 120 °C for 0.5h to 6h, to obtain compound 21.
- a chlorinating agent such as phosphorous oxychloride (POCI 3 ), thionyl chloride (SOCl 2 ) or phosphorous pentachloride (PCI 5 )
- the compound 21 is reacted with an organic amine of formula R 3 R 4 NH (wherein R 3 and R 4 are as defined above for the compound of formula (lb)), in the presence of a solvent such as isopropyl alcohol (IPA) and inorganic acid such as hydrogen chloride (HC1), at 110-130 °C for 17-19 h, to obtain compound 2J (wherein R 3 and R 4 are as defined above for the compound of formula (lb)).
- IPA isopropyl alcohol
- HC1 hydrogen chloride
- the compound 2J is subjected to catalytic reduction using reducing agents such as stannous chloride or ammonium chloride and catalyst such as iron or palladium respectively, in the presence of an appropriate solvent such as methanol (MeOH), EtOH or ethyl acetate at room temperature to 90 °C for 0.5h to 4h, to obtain compound 2K (wherein R 3 and R4 are as defined above for the compound of formula (lb)).
- reducing agents such as stannous chloride or ammonium chloride and catalyst such as iron or palladium respectively
- the compound 2K is reacted with an acid chloride of formula RiCl or R 2 C1 to obtain the compound of formula (lb), wherein Ri and R 2 are independently selected from the group consisting of hydrogen, (C 3 -Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C6-Cio)aryl(Ci-C 6 )alkyl- C(O), heteroaryl (Ci-C 6 )alkyl-C(0) and -C(0)R 5 (wherein R5 is as defined above for the compound of formula (lb)), provided that one of Ri and R 2 is other than hydrogen; and R 3 and R4 are as defined above for the compound of formula (lb).
- Ri and R 2 are independently selected from the group consisting of hydrogen, (C 3 -Ci 2 )cycloalkyl(Ci-C 6 )alkyl-C(0), (C6-Cio)aryl(Ci-C 6 )alkyl- C(O),
- the compound 21 is reacted with an isocyanate or isothiocyanate having formula R 6 R 7 NCO or R 6 R 7 NCS to obtain compounds of formula (lb), wherein Ri and R 2 are independently selected from the group consisting of hydrogen, -C(0)NR 6 R 7 or -C(S)NR 6 R 7 , wherein, R 6 and R 7 are as defined above for the compound of formula (lb) and provided that one of Ri and R 2 is other than hydrogen; and R 3 and R 4 are as defined above for the compound of formula (lb).
- the compound 21 is reacted with a sulphonyl chloride [R 8 S(0) P C1] to obtain the compounds of formula (lb), wherein Ri and R 2 are independently selected from the group consisting of hydrogen and S(0) P R8, wherein R$ and p are as defined above and provided that one of Ri and R 2 is other than hydrogen; and R 3 and R 4 are as defined above for the compound of formula (lb).
- Ri and R 2 are independently selected from the group consisting of hydrogen and S(0) P R8, wherein R$ and p are as defined above and provided that one of Ri and R 2 is other than hydrogen; and R 3 and R 4 are as defined above for the compound of formula (lb).
- the schematic process of the present invention described herein, may further include an optional oxidation step.
- an optional oxidation step may optionally be subjected to an oxidation step in the presence of an oxidizing agent, selected from, but not limited to, meta- chloroperbenzoic acid or oxone®, to obtain N-oxide or S-oxide of compounds of formula (la) respectively, wherein R 1; R 2 , R 3 and R 4 are as defined above and n is 1 or 2.
- the compounds of formula (I) of the present invention including the compounds of formula (la) and/or (lb) contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms, as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds.
- chiral refers to molecules which have the property of non-superimposability of the mirror image cohort, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers and enantiomers, as well as mixtures thereof such as racemic mixtures, geometric isomers form part of the present invention.
- the compounds of formula (I) of the present invention including the compounds of formula (la) and/or (lb), contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixtures.
- the enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer- specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form.
- specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
- Designation of a specific absolute configuration at a chiral carbon of the compounds of the invention is understood to mean that the designated enantiomeric form of the compounds is in enantiomeric excess (ee) or in other words is substantially free from the other enantiomer.
- the "R" forms of the compounds are substantially free from the "S” forms of the compounds and are, thus, in enantiomeric excess of the "S” forms.
- “S” forms of the compounds are substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the "R” forms.
- Enantiomeric excess is the presence of a particular enantiomer at greater than 50% relative to the other enantiomer. In a particular embodiment when a specific absolute configuration is designated, the enantiomeric excess of depicted compounds is at least about 90%.
- a compound of formula (I) of the present invention has two or more chiral carbons it can have more than two optical isomers and can exist in diastereoisomeric forms.
- the compound when there are two chiral carbons, the compound can have up to 4 optical isomers and 2 pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)).
- the pairs of enantiomers e.g., (S,S)/(R,R)
- the stereoisomers that are not mirror-images e.g., (S,S) and (R,S)
- the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above.
- the present invention includes each diastereoisomer of such compounds and mixtures thereof.
- the compounds of formula (I) including the compounds of formula (la) and/or (lb), exists as tautomers, and it is intended to encompass all the tautomeric forms of the compounds within the scope of the present invention.
- the isotopically labeled forms of compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described above and in the subsequent section on examples by using an appropriate isotopically labelled reagent instead of non-labelled reagent.
- the present invention also includes within its scope pharmaceutically acceptable salts or solvates thereof of the compounds of formula I.
- pharmaceutically acceptable salts refers to organic and inorganic salts of a compound of formula I of the present invention, depending on the particular group (acidic or basic group) present in the said compounds.
- base addition salts can be obtained by contacting the compounds of formula I with a sufficient amount of an appropriate base, either neat or in a suitable inert solvent.
- pharmaceutically acceptable base addition salts of the compounds of the present invention include their alkali metal salts such as sodium, potassium, calcium, magnesium, ammonium or organic base addition salt.
- pharmaceutically acceptable organic base addition salts include those derived from organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like or other organic bases known to the person skilled in the art.
- acid addition salts can be obtained by contacting the compounds of formula I with a sufficient amount of an appropriate acid, either neat or in a suitable inert solvent.
- an appropriate acid either neat or in a suitable inert solvent.
- pharmaceutically acceptable acid addition salts particularly those derived from inorganic acids include hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, mono-hydrogensulfuric or hydriodic acids or other inorganic acids known to the person skilled in the art.
- examples of pharmaceutically acceptable acid addition salts include the salts derived from organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, j?-tolylsulfonic, citric, tartaric, methanesulfonic, glucuronic or galacturonic acids or other organic acids known to the person skilled in the art.
- Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
- the compounds of formula I may be regenerated from their corresponding salts by contacting the salt with an appropriate base or acid depending on the type of salt and isolating the parent compound in the conventional manner.
- the compound may differ from the various salt forms in certain physical properties.
- An example of physical properties that may differ is solubility in polar solvents.
- Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
- polymorphs of compounds of formula I can be prepared by crystallization of the compounds under different conditions.
- the different conditions are, for example, using different solvents or their mixtures for crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
- Polymorphs can also be obtained by heating or melting the compound followed by gradual or fast cooling.
- the presence of polymorphs can be determined by IR (Infra-Red) spectroscopy, solid probe NMR (Nuclear Magnetic Resonance) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
- the present invention is intended to include all tautomeric forms of the compounds.
- prodrugs of the compound of formula I including that of the compounds of formula (la) and/or (lb),.
- prodrugs are those compounds that are converted intracellularly, more preferably, where the cellular converting location is the site of therapeutic action.
- preferred prodrugs are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid.
- pharmaceutically acceptable esters include lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di- substituted lower alkyl esters such as the pivaloyloxymethyl ester and the like conventionally used in the art (An introduction to Medicinal Chemistry, Graham. L.
- the present invention relates to pharmaceutical composition(s) containing a therapeutically effective amount of at least one compound of formula I including the compounds of formula (la) and/or (lb), or its pharmaceutically acceptable salt or solvate thereof and a conventional pharmaceutically acceptable carrier.
- the present invention also relates to a process for the production of a pharmaceutical composition, which includes bringing at least one compound of formula I, into a suitable administration form using a pharmaceutically acceptable and physiologically tolerable excipient and, if appropriate, further suitable active compounds, additives or auxiliaries can be added.
- composition(s) of the present invention can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.
- composition(s) according to the invention is/are prepared in a manner known and/or familiar to a person skilled in the art.
- Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compound(s) of formula I, including the compounds of formula (la) and/or (lb), and/or its (their) pharmaceutically acceptable salt(s).
- Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc.
- Suitable carriers for the production of solutions for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents which have been mentioned.
- the pharmaceutical composition(s) normally contain about 1 % to 99 %, for example, about 5 % to 70 %, or from about 10 % to about 30 % by weight of the compound of formula I or its pharmaceutically acceptable salt.
- the amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower that the specified range.
- the dosage range which is suitable in a specific case depends on the type of disease or disorder to be treated and on the state of the respective condition or disorder.
- the selected dosage level can be readily determined by a skilled medical practitioner in the light of the relevant circumstances, including the disease or disorder to be treated, the chosen route of administration including other factors such as age, weight and physical health and response of the individual patient (subject), pharmacokinetics, severity of the disease and other like factors known in the medical art.
- Actual dosage levels of the active ingredients i.e. the compounds of formula I in the pharmaceutical composition of this present invention can be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient (subject in need of the treatment), composition, and mode of administration without being toxic to the patient.
- the dose of the compounds of formula I or pharmaceutically acceptable salts thereof, which is to be administered can cover a wide range.
- the dose to be administered daily is to be selected to suit the desired effect.
- a suitable dosage is about 0.01 mg/kg/day to about 200 mg/kg/day of the compound of formula I or its pharmaceutically acceptable salt, for example, about 0.1 mg/kg/day to 100 mg/kg/day of a compound of formula I or its pharmaceutically acceptable salt. If required, higher or lower daily doses can also be administered.
- the pharmaceutical compositions can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants.
- Pharmaceutical compositions can also contain two or more compounds of formula I or their pharmaceutically acceptable salts.
- the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.
- the compounds of formula I or pharmaceutically acceptable salts thereof are multi-kinase inhibitors.
- the compounds of formula I or pharmaceutically acceptable salts thereof are inhibitors of the protein kinases selected from the group consisting of Insulin-like Growth Factor- 1 Receptor (IGF-1R), Insulin Receptors (IR), Vascular Endothelial Growth Factor Receptor (VEGF) and Platelet-Derived Growth Factor Receptors (PDGFR).
- IGF-1R Insulin-like Growth Factor- 1 Receptor
- IR Insulin Receptors
- VEGF Vascular Endothelial Growth Factor Receptor
- PDGFR Platelet-Derived Growth Factor Receptors
- the present invention relates to a method for the treatment of a disease or a disorder associated with abnormal protein kinase activity, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.
- the present invention relates to use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease or a disorder associated with abnormal protein kinase activity.
- the present invention provides use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or a disorder associated with abnormal protein kinase activity.
- the disease or disorder associated with abnormal protein kinase activity is selected from the group consisting of an inflammatory disease, an allergic disorder, a pulmonary disease, diabetes, diabetes related disorder, acromegaly, angiogenesis, a proliferative disease, a CNS (central nervous system) disorder, a cardiovascular disease and an autoimmune disease.
- an inflammatory disease examples include, but are not limited to, acute or chronic pain, arthritis, rheumatoid arthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, spondyloarthropathy, pulmonary disorder such as asthma, chronic obstructive pulmonary disease (COPD) or lung inflammation, inflammatory bowel disease, Crohn's disease, multiple sclerosis, ulcerative colitis, irritable bowel syndrome, idiopathic thrombocytopenic purpura (ITP) and pelvic inflammatory disease.
- COPD chronic obstructive pulmonary disease
- COPD chronic obstructive pulmonary disease
- ITP idiopathic thrombocytopenic purpura
- an allergic disorder examples include, but are not limited to, allergic rhinitis, allergic bronchitis, allergic sinusitis, dermatitis, atopic dermatitis, urticaria and asthma.
- pulmonary disease examples include, but are not limited to, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), lung inflammation, bronchitis obliteraus and primary pulmonary hypertension.
- ARDS adult respiratory distress syndrome
- COPD chronic obstructive pulmonary disease
- lung inflammation bronchitis obliteraus
- primary pulmonary hypertension examples include, but are not limited to, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), lung inflammation, bronchitis obliteraus and primary pulmonary hypertension.
- ARDS adult respiratory distress syndrome
- COPD chronic obstructive pulmonary disease
- proliferative disease examples include, but are not limited to, cancer, tumors, mastocytosis, associated myeloproliferative syndrome, urticaria pigmentosa, an epidermal hyperproliferation, psoriasis and prostate hyperplasia.
- cardiovascular disease examples include, but are not limited to, artherosclerosis, myocardial infarction, congestive heart failure and cardiac reperfusion injury.
- Examples of a central nervous system disorder include, but are not limited to, brain injury, cerebrovascular disease, corticobasal degeneration, dementia, Parkinson's disease, Alzheimer's disease, vascular dementia, dementia with Lewy bodies and frontotemporal dementia.
- autoimmune disease examples include, but are not limited to, lupus, systemic lupus erythematosus (SLE), Sjogren's syndrome, urticarial, scleroderma, psoriasis and renal disease.
- diabetes related diseases include, but are not limited to, diabetic retinopathy, retinal ischemia, and retinal neovascularization.
- the disease or disorder associated with abnormal protein kinase activity is cancer.
- the present invention relates to a method for the treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.
- the present invention relates to use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of cancer.
- the present invention provides use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.
- cancer is selected from leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplasia syndrome (MDS), myeloproliferative neoplasms (MPN), diffuse large B-cell lymphoma and follicular lymphoma, astrocytoma, basal or squamous cell carcinoma, brain cancer, gliobastoma, bladder cancer, breast cancer, colorectal cancer, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, sarcoma
- ALL acute lympho
- cancer is selected from brain cancer, breast cancer, prostate cancer, epithelial cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, sarcoma, pancreatic cancer, renal cell carcinoma or endometrial carcinoma.
- the compounds of the present invention can be administered alone or in combination with other therapies suitable for the disease or disorder being treated. Where separate dosage formulations are used, the compound and the other therapeutic agent can be administered at essentially the same time (concurrently) or at separately staggered times (sequentially).
- the pharmaceutical combination is understood to include all these regimens. Administration in these various ways are suitable for the present invention as long as the beneficial therapeutic effect of the compound of formula I or a pharmaceutically acceptable salt thereof and the other therapeutic agent are realized by the patient at substantially the same time. Such beneficial effect is achieved when the target blood level concentrations of each active drug are maintained at substantially the same time.
- the present invention encompasses use of the compound of formula I or a pharmaceutically acceptable salt thereof in combination with one further therapeutically active agent for the treatment of diseases or disorders associated with abnormal activity of protein kinases.
- the compounds of the present invention are useful in combination with known anti-cancer agents.
- Combinations of the compounds of the present invention with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.
- a person of ordinary skill in the art would be able to discern which combinations of therapeutic agents would be useful based on the particular characteristics of the therapeutic agents and the cancer involved.
- anti-cancer agents that can be used in combination with the compounds of formula I include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signalling, agents that interfere with receptor tyrosine kinases and cancer vaccines.
- the compounds of the present invention can be co-administered with radiation therapy.
- N-(4-cyclohexylphenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl) pyrimidin-2-amine was obtained by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)- 2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-cyclohexylaniline (commercially available) according to procedure followed in step lg of Example 1.
- the title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)-N-(4- (piperidin-l-yl)phenyl)pyrimidin-2-amine with 2-phenylacetyl chloride according to procedure followed in Step li in Example 1.
- N-(4-(4-methylpiperidin-l-yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l- b]thiazol-5-yl)pyrimidin-2-amine was prepared by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-(4- methylpiperidin- 1 -yl) aniline according to procedure followed in Step lg of Example 1.
- N-(3-(2-methylpiperidin-l-yl)propyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l- b]thiazol-5-yl)pyrimidin-2-amine was prepared by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2, 1 -b]thiazole with 3-(2-methylpiperidin- 1 -yl)propan- 1 -amine (commercially available) according to the procedure followed in Step lg of Example 1.
- Step lh of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with benzoyl chloride according to procedure followed in step li of Example 1. Yield: 58.2%;
- Step lh of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with 2-fluorobenzoyl chloride according to procedure followed in step li of Example 1. Yield: 64.3%;
- Example 1 The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with cyclopentanecarbonyl chloride according to procedure followed in step li of Example 1.
- Step lh of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with piperidine-1- carbonyl chloride according to procedure followed in step li of Example 1. Yield: 40.9%;
- N-(4-morpholinophenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine was obtained by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)- 2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-morpholinoaniline according to procedure followed in Step lg of Example 1.
- N-(4-morpholinophenyl)-4-(6-(3-nitrophenyl)- 2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.
- Example 1 The title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- morpholino)phenyl)pyrimidin-2-amine (prepared according to procedure given in Example 21) with cyclohexylcarbonyl chloride according to procedure followed in Step li of Example 1.
- N-(l-(4-((4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2- yl)amino)phenyl)piperidin-4-yl)acetamide was obtained by the reduction of N-(l-(4-(4-(6-(3- nitrophenyl)-2,3-dihydroimidazo[2, 1 -b]thiazol-5-yl)pyrimidin-2-ylamino)phenyl) piperidin-4- yl)acetamide according to procedure followed in Step lh of Example 1.
- N-(l-(4-(4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)pyrimidin-2-yl amino)phenyl)piperidin-4-yl)acetamide was obtained by reaction of 5-(2-chloropyrimidin-4-yl)- 6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazole (compound of step If, Example 1) with N- (l-(4-aminophenyl) piperidin-4-yl)acetamide according to procedure followed in Step lg of Example 1.
- the title compound was prepared in an analogous manner as the compound 1 of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with cyclohexyl isocyanate using THF as solvent and at RT for 16h to 18h. Yield: 51.3%;
- Step lh of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with nicotinyl chloride according to procedure followed in step li of Example 1. Yield: 46.8%;
- Step lh of Example 1 involving reaction of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4- ethylpiperazin-l-yl)phenyl)pyrimidin-2-amine (Step lh of Example 1) with (1R, 4S)- bicyclo[2.2.1]heptane-2-carbonyl chloride according to procedure followed in step li of Example 1. Yield: 45.2%;
- N-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo [2,l-b]thiazol-5-yl)pyrimidin-2-amine was obtained by 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (compound of Step If, Example 1) with 6-(4- methylpiperazin-l-yl)pyridin-3-amine according to procedure followed in Step lg of Example 1.
- N-(l-(4-((4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2- yl)amino)phenyl)piperidin-4-yl)acetamide was obtained by the reduction of N-(l-(4-(4-(6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-ylamino)phenyl)piperidin-4- yl)acetamide according to procedure followed in Step lh of Example 1.
- N-(l-(4-(4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol-5-yl)pyrimidin-2- ylamino)phenyl)piperidin-4-yl)acetamide was obtained by reaction of 5-(2-chloropyrimidin-4- yl)-6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (compound of Step If, Example 1) with N-(l-(4-aminophenyl)piperidin-4-yl)acetamide according to procedure followed in Step lg of Example 1.
- N-(4-(2-(dimethylamino)ethyl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l- b]thiazol-5-yl)pyrimidin-2-amine was obtained by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (compound of Step If, Example 1) with 4-(2- (dimethylamino)ethyl)aniline according to procedure followed in Step lg of Example 1.
- N-(4-(4-methylpiperazin-l-yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l- b]thiazol-5-yl)pyrimidin-2-amine was obtained by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (compound of Step If, Example 1) with 4-(4- methylpiperazin-l-yl)aniline according to procedure followed in Step lg of Example 1.
- N-(4-(2,6-dimethylmorpholino)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l- b]thiazol-5-yl)pyrimidin-2-amine was prepared by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3- nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-(2,6- dimethylmorpholino)aniline (prepared as per the procedure given in compound 35A).
- N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-4-(6-(3-aminophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine was prepared by reduction of N-(4-(8-oxa- 3-azabicyclo[3.2J]octan-3-yl)phenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine according to the procedure followed in Step lh in Example 1.
- N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-4-(6-(3-nitrophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine was prepared by reaction of 5-(2- chloropyrimidin-4-yl)-6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)aniline (prepared as per the procedure given in compound 36A) according to procedure followed in Step lg of Example 1.
- the title compound was prepared by the reduction of 3-(4-nitrophenyl)-8-oxa-3- azabicyclo[3.2.1]octane. 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)aniline obtained in this reaction step was used in the subsequent reaction step without purification.
- the title compound was prepared in an analogous manner as the compound 35B involving the reaction of l-fluoro-4-nitrobenzene with 8-oxa-3-azabicyclo[3.2.1]octane to obtain 3-(4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane. This compound was used in the subsequent reaction step without purification.
- N-(4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-yl)quinolin- 7-amine was prepared by reduction of N-(4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2, l-b]thiazol- 5-yl)pyrimidin-2-yl)quinolin-6-amine amine according to the procedure followed in Step lh in Example 1.
- N-(4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-yl)quinolin- 7-amine was prepared by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)-2,3- dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with quinolin-6-amine (Commercially available) as per the procedure given in step li of Example 1.
- N-(4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-(6-(3-nitrophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)pyrimidin-2-amine was prepared by reaction of 5-(2- chloropyrimidin-4-yl)-6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-((2S,6R)-2,6-dimethylmorpholino)aniline as per the procedure given in step li of Example 1.
- N-(4-bromophenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5- yl)pyrimidin-2-amine was prepared by reaction of 5-(2-chloropyrimidin-4-yl)-6-(3-nitrophenyl)- 2,3-dihydroimidazo[2,l-b]thiazole (Step If of Example 1) with 4-bromoaniline N-(4- bromophenyl)-4-(6-(3-nitrophenyl)-2,3-dihydroimidazo[2,l-b]thiazol-5-yl)pyrirmdin-2-amine obtained in this reaction step was used in the subsequent reaction step without purification.
- the title compound was prepared by reacting 4-(6-(3-aminophenyl)-2,3- dihydroimidazo[2,l-b]thiazol-5-yl)-N-(4-(4-methylpiperidin-l-yl)phenyl)pyrimidin-2-amine (105 mg, 0.211 mmol) with 2-chlorobenzimidazole (35.3 mg, 0.232 mmol) in presence of IPA.HC1 (3 mL) in microwave condition (300 W) at 150°C for lh. After the completion of reaction, the reaction mixture was basified by saturated bicarbonate solution (15 mL) and the product was extracted in ethyl acetate (15 mL X 2).
- Step 43 a
- Cyclopentanone (119 mM) was dissolved in cyclohexane and anhydrous sodium sulphate (416 mM) was added in one portion under a nitrogen atmosphere. The mixture was cooled to 0
- N-(4-morpholinophenyl)-4-(2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3- yl)pyrimidin-2-amine was prepared reaction of 2-chloro-4-(2-(3-nitrophenyl)-5,6-dihydro-4H- cyclopenta[b]thiophen-3-yl)pyrimidine (compound 43i of Example 43) with 4-morpholinoaniline according to procedure followed for the preparing compound 43j of Example 43.
- N-(4- morpholinophenyl)-4-(2-(3-nitrophenyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)pyrimidin- 2-amine obtained in this reaction step was used in the subsequent reaction step without purification.
- the pharmacological activity of the compounds as multikinase inhibitors can be confirmed by a number of pharmocological assays known in the art.
- the exemplified pharmacological assay, given below, has been carried out with the compounds of the present invention synthesized in the above Examples.
- IGF-1R kinase activity was assayed using a time resolved fluorescence energy transfer (TR-FRET) in vitro kinase assay.
- TR-FRET time resolved fluorescence energy transfer
- IGFR kinase enzyme used for the assay was human IGF-1R purified from a baculovirus expression system using glutathione-sepharose column chromatography. The kinase reaction was conducted in a 384-well plate.
- the reaction buffer (Tris HC1 (50 mM; pH: 7.4), EGTA (1 mM), MgCl 2 (10 mM, DTT (2 mM), Tween-20 (0.01%)) for peptide phosphorylation contained, in final concentrations, human IGF-1R kinase enzyme (0.25 nM), poly GT peptide substrate (50 nM) and ATP (20 ⁇ ).
- test compounds compounds of the present invention
- DMSO dimethyl methyl sulfoxide
- the test compounds were evaluated at various concentrations, their final concentrations in the assay ranging from 40 ⁇ to 40 pM.
- the final concentration of DMSO in the assay was less than 1%.
- IGFR kinase enzyme 2.5 ⁇
- various concentrations of the test compounds 2.5 ⁇
- the kinase reaction was initiated by the addition of ATP (2.5 ⁇ ) followed by incubation for 1 h at 23 °C.
- the kinase reaction was stopped by the addition of EDTA (5 ⁇ ) (final concentration in the assay: 10 mM).
- Europium cryptate-labelled antiphosphotyrosine antibody PY20 (5 ⁇ ) (final concentration in the assay: 2 nM) was added and the mixture was equilibrated for 1 h at 23 °C.
- the intensity of light emission which was indicative of the quantum of substrate phosphorylation by the kinase enzyme was measured at 665 nm using Envision plate reader.
- the ability of the test compounds to inhibit substrate phophorylation which is indicative of the IGF-1R kinase inhibitory activity of the test compounds expressed as IC 50 values was determined by a four-parameter sigmoidal curve in Sigma plot or Graph pad.
- IGF-1R kinase inhibitory activity of the test compounds have been reported in Table 1 below.
- Table 1 IGF-1R inhibitory activity of the test compounds
- the compounds of the present invention exhibited significant IGF-1R kinase inhibitory activity.
- EGFR kinase activity was assayed using a TR-FRET in vitro kinase assay.
- EGFR kinase enzyme used for the assay was human EGFR purified from a baculovirus expression system using glutathione-sepharose column chromatography. The kinase reaction was conducted in a 384-well plate.
- the reaction buffer Tris HC1 (50 mM) (pH 7.4), EGTA (1 mM), MgCl 2 (10 mM), DTT (2 mM), Tween-20 (0.01%)
- peptide phosphorylation contained, in final concentrations, human EGFR kinase enzyme (1 nM), peptide substrate (50 nM) and ATP (20 ⁇ ).
- test compounds compounds of the present invention
- DMSO DMSO
- EGFR kinase enzyme 1 nM, 2.5 ⁇
- various concentrations of the test compounds 40 ⁇ to 40 pM, 2.5 ⁇
- the kinase reaction was initiated by the addition of ATP followed by incubation for 1 h at 23 °C.
- the kinase reaction was stopped by the addition of EDTA (5 ⁇ ) (final concentration in the assay: 10 mM).
- Europium- labelled PT66 antibody (5 ⁇ ) (final concentration in the assay: 2 nM) was added and the mixture was equilibrated for 1 h at 23 °C.
- the intensity of light emission which was indicative of the quantum of substrate phosphorylation by the kinase enzyme was measured at 665 nm using Envision plate reader.
- the ability of the test compounds to inhibit substrate phophorylation which is indicative of the EGFR kinase inhibitory activity of the test compounds expressed as IC 50 values was determined by a four-parameter sigmoidal curve in Sigma plot or Graph pad. Results: EFGR kinase inhibitory activity of the test compounds have been reported in Table 2 below.
- +++ indicates the IC 50 values ranging from 0.1 nM to 100 nM
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Abstract
La présente invention concerne des composés de formule (I), leurs formes isotopiques, leurs formes stéréoisomériques, leurs formes tautomères, leurs sels pharmaceutiquement acceptables, leurs solvates pharmaceutiquement acceptables, leurs promédicaments, leurs polymorphes ou leurs N-oxydes. La présente invention concerne également des procédés de préparation des composés de formule (I) et des compositions pharmaceutiques comprenant les composés de formule (I). Les composés et leurs compositions pharmaceutiques sont des inhibiteurs de multikinase et sont utiles dans le traitement de troubles prolifératifs tels que les cancers. (Formule (1)
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WO2007123892A2 (fr) * | 2006-04-17 | 2007-11-01 | Arqule Inc. | Inhibiteurs raf et leurs utilisations |
WO2009070516A1 (fr) * | 2007-11-27 | 2009-06-04 | Abbott Laboratories | Dérivés d'imido-thiazole en tant qu'inhibiteurs de protéines kinases |
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WO2007123892A2 (fr) * | 2006-04-17 | 2007-11-01 | Arqule Inc. | Inhibiteurs raf et leurs utilisations |
WO2009070516A1 (fr) * | 2007-11-27 | 2009-06-04 | Abbott Laboratories | Dérivés d'imido-thiazole en tant qu'inhibiteurs de protéines kinases |
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CN113166136A (zh) * | 2018-12-19 | 2021-07-23 | 益方生物科技(上海)股份有限公司 | C端src激酶抑制剂 |
EP3898622A4 (fr) * | 2018-12-19 | 2022-08-10 | InventisBio Co., Ltd. | Inhibiteurs de kinase src c-terminale |
CN113166136B (zh) * | 2018-12-19 | 2024-03-01 | 益方生物科技(上海)股份有限公司 | C端src激酶抑制剂 |
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