WO2014141118A1 - Dérivés d'imidazo[4,5-c]quinoléine et leurs utilisations - Google Patents

Dérivés d'imidazo[4,5-c]quinoléine et leurs utilisations Download PDF

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WO2014141118A1
WO2014141118A1 PCT/IB2014/059719 IB2014059719W WO2014141118A1 WO 2014141118 A1 WO2014141118 A1 WO 2014141118A1 IB 2014059719 W IB2014059719 W IB 2014059719W WO 2014141118 A1 WO2014141118 A1 WO 2014141118A1
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alkyl
phenyl
quinolin
imidazo
methyl
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PCT/IB2014/059719
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English (en)
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Sanjay Kumar
Rajiv Sharma
Vijaykumar Bhagwan DEORE
Nilambari Nilkanth Yewalkar
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Piramal Enterprises Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to substituted imidazo[4,5-c]quinoline derivatives (referred to herein as compounds of formula (I)), processes for their preparation, pharmaceutical compositions comprising the compounds of formula (I) and their use in the treatment of diseases or disorders mediated by one or more kinases, for instance proliferative diseases or disorders. These compounds can also be used in the treatment of inflammatory disorders, angiogenesis related disorders and bacterial infections.
  • Phosphatidylinositol-3-kinase or phosphoinositol-3-kinase are a family of lipid kinases.
  • the PI3K family is composed of three classes, viz., Class I, II and III.
  • Class III PI3K enzymes phosphorylate PI (phosphatidylinositol) alone, while, Class II PI3K enzymes phosphorylate both PI and PI 4-phosphate [PI(4)P].
  • Class I PI3K enzymes phosphorylate PI, PI(4)P and PI 4,5-bisphosphate [PI(4, 5)P 2 ].
  • Class I PBKs are further divided into two groups, class IA and class IB, in terms of their activation mechanism.
  • Class IA PBKs is composed of pi 10a, ⁇ ⁇ and ⁇ ⁇ subtypes and are generally activated in response to growth factor-stimulation of receptor tyrosine kinases.
  • Class IB is composed of pi 10y alone.
  • PI3K phosphoinositide 3-kinase
  • Somatic aberrations of PBK-Akt-mTOR phosphoinositide 3- kinase-Protein Kinase B -mammalian target of rapamycin
  • Phosphatase and tensin homolog PTEN
  • PTEN a tumor suppressor gene is homozygously mutated in a variety of human cancers.
  • PTEN/MMAC antagonizes PI3K signaling and can therefore be seen as a counterpart of the PI3K oncogene.
  • PTEN is second only to p53 as the most frequently deleted tumor suppressor gene in human cancers.
  • PI3K-Akt pathway suppresses coagulation and inflammation.
  • the compounds that are PI3K and/or mTOR inhibitors find use in the treatment of cancers, autoimmune and inflammatory diseases and disorders.
  • Protein kinases play important roles in regulating most cellular functions such as proliferation, cell cycle, cell metabolism, survival, apoptosis, DNA damage repair, cell motility and response to the microenvironment. Protein kinases can be divided into broad groups based upon the identity of the amino acid(s) (serine/threonine, tyrosine, lysine, and histidine) that they target.
  • DNA-PK DNA-dependent protein kinase
  • ALK1 activin receptor-like kinase 1 also known as ACVRL1
  • ALK2 activin A receptor, type I
  • ACVR1 also known as ACVR1
  • CLK1 CDC-like kinase 1
  • CLK4 CDC-like kinase 4
  • RIPK2 receptor-interacting serine/threonine-protein kinase 2
  • ALK Activin Like Kinase
  • PI3K isoforms control inflammation at many levels, from the generation of inflammatory cells to the migration and function of these cells. More specifically, the gamma and delta isoforms of PI3K underpin the inflammatory responses. Genetic targeting of ⁇ 3 ⁇ ( ⁇ ⁇ ) and ⁇ ( ⁇ ⁇ ) in mice has underlined a central role of these PI3K isoforms in inflammation and allergy, as they modulate chemotaxis of leukocytes and degranulation in mast cells. Proof-of-concept molecules such as CZC24832 selective for ⁇ have already successfully alleviated disease progress in models of inflammation.
  • kinases such as PI3K, mTOR, ALK and DNA-PK
  • inhibition of one or more kinases can be considered as a promising targeted therapies for the treatment of cancer, angiogenic disorders, inflammatory disorders or any disorders mediated by any one or more of the said kinases.
  • Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries. About 12.7 million cancer cases and 7.6 million cancer deaths (around 13% of all deaths) are estimated to have occurred in 2008 worldwide. About 5% to 10 % of cancers are strongly hereditary. However, most cancers do not result from inherited genes but from damage to genes as a result from internal factors or external factors.
  • Angiogenesis is the process of forming new blood vessels and is critical in many normal and abnormal physiological states. Angiogenesis is normally observed in wound healing, fetal and embryonic development and formation of corpus luteum, endometrium and placenta. However, angiogenesis is also the fundamental step in the transition of tumors from a dormant state to a malignant state. In diseases like cancer, the body loses the ability to maintain balanced angiogenesis. New blood vessels feed diseased tissues, destroying normal tissues and sometimes are involved in tumor metastasis. Hence, anti-angiogenic agents are a very promising class of drugs to block or slow the cancer growth.
  • WO2006/122806 describes imidazoquinolines as lipid kinase inhibitors that are used alone or in combination with one or more other pharmaceutically active compounds for the treatment of an inflammatory or obstructive airway disease such as asthma or a proliferative disease such as a tumor disease.
  • WO2012/007926 and WO201/2077031 describe imidazoquinoline derivatives useful in the treatment of proliferative diseases, inflammatory diseases and angiogenesis related disorders.
  • TNF-oc has been implicated as a mediator in several diseases such as inflammatory bowel disease, inflammation, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non- rheumatoid arthritis, osteoporosis/bone resorption, Crohn's disease, allergic asthma, septic shock, endotoxic shock, ischemia-reperfusion injury, multiple sclerosis, sepsis, chronic recurrent uveitis, ulcerative colitis and the like.
  • Much research has been conducted to study the effect of TNF- and anti-TNF-oc therapies. Studies in the area of cancer have shown that with TNF-oc therapy it is important to balance the cytotoxicity and systemic toxicity of the potential drug candidates.
  • Monoclonal antibody drugs such as Infliximab, Etanercept and Adalimumab are useful as anti-inflammatory agents, but have drawbacks such as route of administration (only parenteral), high cost and activation of latent tuberculosis (Rheumatology, 2007, 46(5), 887- 888; Clin. Infect. Dis., 2004, 39, 295-299 and Ann. Rheum. Dis., 2005, 64, iv2-iv-14).
  • route of administration only parenteral
  • the present invention relates to a compound of formula (I) (as described herein) in all its isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, an N-oxide or a carboxylic acid isostere thereof.
  • the present invention relates to processes for the preparation of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method of inhibiting activity of one or more kinases selected from PI3 kinase, mTOR or ALK-1 comprising contacting the said kinase with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method for the treatment of a disease mediated by a kinase selected from PI3 kinase (PI3K), mTOR or ALK- 1, comprising administering to a subject in need thereof; a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a kinase selected from PI3 kinase (PI3K), mTOR or ALK- 1
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof ; for use in the treatment of a disease mediated by a kinase selected from PI3 kinase (PI3K), mTOR or ALK-1.
  • a kinase selected from PI3 kinase (PI3K), mTOR or ALK-1.
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof ; for use in the treatment of a proliferative disease or disorder, mediated by a kinase selected from PI3 kinase (PI3K), mTOR and ALKl or combinations thereof.
  • a kinase selected from PI3 kinase (PI3K), mTOR and ALKl or combinations thereof.
  • the present invention relates to use of the compound of formula (I), for the manufacture of a medicament for the treatment of diseases mediated by PI3 kinase (PI3K), mTOR or ALK-1.
  • PI3K PI3 kinase
  • mTOR PI3 kinase
  • ALK-1 PI3 kinase
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, adjuvant or a vehicle.
  • the present invention relates to a compound of formula (I),
  • Ring A is (C6-Ci4)aryl or heteroaryl
  • X 2 is O or NR y ;
  • Rj is hydrogen, CN, -NR a R b , -OR a or (d-C 6 ) alkyl, wherein (Ci-C 6 ) alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of CN, -NR a R b , nitro, halogen, -OR a , -COOH, -C(0)0-(C C 6 ) alkyl and - P(0)(OR a )(OR a );
  • R2 at each occurrence is independently selected from the group consisting of halogen
  • R3 is hydrogen or (Ci-Ce)alkyl
  • R 4 is halogen, (C6-Ci4)aryl or heteroaryl; wherein each of the aryl and heteroaryl is unsubstituted or substituted with one or more groups selected from R « ;
  • R x is nitro, CN, -C(0)0(C ! -C 6 )alkyl or (Q-Ce ⁇ lkyl, wherein (Q-Ce kyl is unsubstituted or substituted with CN or -NR a R b ;
  • R y is hydrogen, (d-C 6 ) alkyl, -C(0)0-(C ! -C 6 )alkyl or -S(0) 2 -(C 1 -C 6 )alkyl;
  • R41 at each occurrence is independently selected from the group consisting of hydrogen, halogen, -OR a , CN, -NR a R b , -NR a COR b , -COOR a , -CONR a R b , halo-(C ! -C 6 )alkyl and (C ! -C 6 )alkyl;
  • R a and R b at each occurrence are independently selected from hydrogen and (Ci- C6)alkyl
  • p is an integer from 0 to 4.
  • substitution or “substituted by” or “substituted with” includes the implicit proviso that such substitution is in accordance with the permitted valence of the substituted atom and the substituent, as well as represents a stable compound, which does not readily undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • halo or halogen as used herein refers to an atom selected from fluorine (F), chlorine (CI), bromine (Br) or iodine (I).
  • alkyl refers to the radical of saturated aliphatic groups, including straight or branched-chain containing from 1 to 10 carbon atoms i.e. (Ci-Cio)alkyl group, for example, 1 to 6 carbons atoms ((Ci-Ce)alkyl group).
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, 1-methylbutyl, sec-butyl, teri-butyl, pentyl, neo-pentyl, «-hexyl, and n- decyl.
  • the alkyl groups may be unsubstituted or substituted with one or more substituents, for instance, from one to five identical or different substituents, for example, (Ci-Ce)alkyl, (C 2 -Cs)alkenyl, (C 2 -Cs)alkynyl, halogen, halo(Ci- C 6 )alkyl, hydroxy, (C 6 -Cio)aryl, heteroaryl, CN, nitro, -NR a R b , -OR a , -C(0)OR a or - P(0)(OR a )(OR a ); wherein R a and R b are as defined above.
  • substituents for instance, from one to five identical or different substituents, for example, (Ci-Ce)alkyl, (C 2 -Cs)alkenyl, (C 2 -Cs)alkynyl, halogen, halo(Ci- C 6 )al
  • halo(Ci-C6)alkyl refers to, alkyl radical which is substituted by one or more halogen atoms (F, CI, Br or I).
  • halo(Ci-Ce)alkyl include, but not limited to, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl and trichloromethyl.
  • the halo(Ci- C6)alkyl group may be unsubstituted or substituted with one or more substituents, for instance, halogen, CN, hydroxy, amino or nitro.
  • substituted halo(Ci-Ce)alkyl examples include but not limited to l,l-difluoropropan-2-ol, 3-amino-l,l-difluoro-2-propanol and 3- chloro-2-methylpropanenitrile.
  • aryl or "(C 6 -Ci4) aryl” as used herein refers to a monocyclic or polycyclic hydrocarbon group having up to 14 ring carbon atoms, preferably up to 10 ring carbon atoms, more preferably up to 6 ring carbon atoms in which at least one carbocyclic ring is present that has a conjugated ⁇ electron system.
  • aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl and the like.
  • Aryl residues can be bonded via any desired position, and in substituted aryl residues, the substituents can be located in any desired position.
  • aryl group may be unsubstituted or substituted with one or more substituents independently selected from (Ci-Ce)alkyl, (C 2 -Cs)alkenyl, (C 2 - C 8 )alkynyl, halogen, halo(d-C 6 ) alkyl, hydroxy, -0(C C 6 ) alkyl, -0-(halo(Ci-C 6 )alkyl), (C 6 - Cio)aryl, -0(C 6 -Cio)aryl, heteroaryl, CN, nitro, -C(0)R a , -NR a R b , and -OR a ; wherein R a and R b are as defined above.
  • heteroaryl refers to an aromatic heterocyclic ring system containing 5 to 20 ring atoms, suitably 5 to 10 ring atoms, which may be a monocyclic or polycyclic, fused together or linked covalently.
  • the rings may contain from 1 to 4 heteroatoms independently selected from N, O and S.
  • An example of heteroaryl includes "nitrogen containing heteroaryl", which refers to an aromatic heterocyclic ring system, wherein at least one of the ring atom is nitrogen.
  • the ring system may contain additional 1 to 4 heteroatoms independently selected from N, O and S.
  • the heteroaryl can be 6 to 10 membered nitrogen containing heteroaryl or 5 or 6- membered nitrogen containing heteroaryl.
  • the nitrogen atom or sulfur atom of the heteroaryl ring may be oxidized or the nitrogen atom of the heteroaryl ring may be quaternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the any suitable position in the imidazo[4,5-c]quinoline core.
  • heteroaryl examples include, but are not limited to, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, lH-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, phthalazinyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, indolizinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, furopyr
  • heteroaryl groups may be C-attached or N-attached (where such is possible).
  • a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C- attached).
  • the oxidized form of the ring nitrogen and sulfur atom contained in the heteroaryl to provide the corresponding N-oxide, S-oxide or S,S-dioxide is also encompassed in the scope of the present invention.
  • the heteroaryl group may be unsubstituted or substituted with one or more substituents independently selected from (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2- C 8 )alkynyl, halogen, halo(C C 6 ) alkyl, hydroxy, -0(d-C6)alkyl, -0-(halo(C 1 -C 6 )alkyl), (C 6 - Cio)aryl, heteroaryl, CN, nitro, -C(0)R a , -OR a and -NR a R b ; wherein R a and R b are as defined above.
  • compound of the present invention includes compounds of formula (I) and stereoisomers, tautomers, solvates, polymorphs, N-oxides and pharmaceutically acceptable salts thereof; unless indicated otherwise.
  • stereoisomer or “stereoisomeric” as used herein refers to all isomers of individual compounds 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 syn/anti or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, individual diastereoisomers, or enantiomers, or may exist as geometric isomers, with all isomeric forms of said compounds being included in the present invention.
  • tautomer or “tautomeric” as used herein 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 and imine-enamine tautomers.
  • salts as used herein includes salts of the compounds of formula (I) which are prepared by treating said compounds with a suitable acid or a base, depending on the particular substituents found on the compounds described herein.
  • N-oxide refers to the oxide of the nitrogen atom of nitrogen-containing heteroaryl. N-oxide can be formed in presence of an oxidizing agent for example peroxide such as m-chloro-perbenzoic acid or hydrogen peroxide.
  • an oxidizing agent for example peroxide such as m-chloro-perbenzoic acid or hydrogen peroxide.
  • 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 present invention, a compound of formula I) in the crystal lattice.
  • the present invention also includes within its scope all isotopically labeled forms of compounds of formula (I), wherein one or more atoms of 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 invention. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as 2 H and 3 H, carbon such as 11 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
  • diseases or disorders mediated by a kinase selected from the group consisting of PI3 kinase, mTOR and ALK-1 or combination of said kinases refer to the diseases or disorders which is characterized by abnormal PI3 kinase or mTOR kinase or ALK 1 activity or a combination of abnormal activity of all the three kinases.
  • terapéuticaally effective amount refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder.
  • treat means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.
  • a disease e.g., a disease or disorder delineated herein
  • Disease means any condition or disorder that damage or interferes with the normal function of a cell, tissue, or organ.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • 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 as well as human.
  • PI3K and/or mTOR inhibitors refer to the compounds which inhibit PI3K or mTOR or both PI3K and mTOR.
  • tumor refers to an abnormal growth of tissue resulting from uncontrolled, progressive multiplication of cells.
  • a tumor can be benign or malignant.
  • the present invention provides a compound of formula (I), wherein ring A is phenyl or 5 or 6-membered nitrogen containing heteroaryl.
  • Another embodiment of the present invention is a compound of formula (I), wherein ring A is phenyl.
  • Another embodiment is a compound of formula (I), wherein ring A is phenyl; R2 is halogen and p is an integer from 0 to 4.
  • Another embodiment is a compound of formula (I), wherein ring A is 5 or 6- membered nitrogen containing heteroaryl.
  • Another embodiment is a compound of formula (I), wherein ring A is 5 or 6- membered nitrogen containing heteroaryl selected from pyrrolyl, thiazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl.
  • Another embodiment is a compound of formula (I), wherein ring A is pyridyl.
  • Another embodiment is a compound of formula (I), wherein ring A is 3-pyridyl.
  • Another embodiment of the present invention is a compound of formula (I), wherein ring A is phenyl or pyridyl.
  • Another embodiment is a compound of formula (I), wherein Xj is O or N(CN)
  • Another embodiment is a compound of formula (I), wherein Xj is O.
  • Another embodiment is a compound of formula (I), wherein Xj is N(CN).
  • Another embodiment is a compound of formula (I), wherein X2 is O.
  • Another embodiment is a compound of formula (I), wherein X2 is NR y , wherein R y is hydrogen, (Q-Ce ⁇ lkyl, -C(0)0-(C 1 -C 6 )alkyl or -S(0) 2 -(C 1 -C 6 )alkyl.
  • Another embodiment is a compound of formula (I), wherein X2 is NR y , wherein R y is hydrogen, -C(0)0-C(CH 3 ) 3 or -S(0) 2 -CH 3 .
  • Another embodiment is a compound of formula (I), wherein X 2 is -O- or -NR y , wherein R y is hydrogen, -C(0)OC(CH 3 ) 3 or -S(0) 2 CH 3 .
  • Another embodiment is a compound of formula (I), wherein Rj is hydrogen, -OR a or (C C ) alkyl, wherein (Q-Ce ⁇ lkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of -OR a , -C(0)0-(Ci-Ce)alkyl and - COOH, wherein R a is hydrogen or (Ci-C6)alkyl.
  • Another embodiment is a compound of formula (I), wherein Rj is selected from hydrogen, -OCH 3 or (Ci-Ce) alkyl, wherein (Ci-C ) alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of hydroxy, -C(0)0- CH2CH 3 and -COOH.
  • Another embodiment is a compound of formula (I), wherein R2 is halogen or (Ci-C 6 ) alkyl, wherein (Ci-Ce)alkyl is unsubstituted or substituted with halogen or CN.
  • Another embodiment is a compound of formula (I), wherein R3 is hydrogen or methyl.
  • Another embodiment is a compound of formula (I), wherein R3 is hydrogen.
  • Another embodiment is a compound of formula (I), wherein R3 is methyl.
  • Another embodiment is a compound of formula (I), wherein R 4 is halogen.
  • Another embodiment is a compound of formula (I), wherein R ⁇ is phenyl or 6 to 10 membered nitrogen containing heteroaryl, wherein phenyl and the heteroaryl is unsubstituted or substituted with one or more groups selected from R 41 .
  • R 4 is phenyl, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -OR a , CN, -NR a R b , -NR a COR b , -COOR a , -CONR a R b , halo-(Ci-Ce) alkyl and (Ci-Ce)alkyl, wherein R a and R b at each occurrence are independently selected from hydrogen and (Ci-C6)alkyl.
  • R 4 is phenyl, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -OR a , -NR a R b , COOR a , halo-(Ci-C 6 )alkyl and (Ci-C 6 )alkyl, wherein R a and R b at each occurrence are independently selected from hydrogen and (Ci-C6)alkyl.
  • Another embodiment is a compound of formula (I), wherein R 4 is phenyl, which is unsubstituted or substituted with one or more groups independently selected from -OR a , and - COOR a ; wherein R a at each occurrence is independently selected from hydrogen and (Q- C 6 )alkyl.
  • R ⁇ is 6 to 10 membered heteroaryl, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -OR a , CN, -NR a R b , -NR a COR b , -COOR a , - CONR a R b , halo-(Ci-C 6 )alkyl and (C 1 -C 6 )alkyl.
  • R4 is 6 to 10 membered nitrogen containing heteroaryl, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -OR a , CN, -NR a R b , -NR a COR b , -COORa, -CONRaRb, halo-(Ci-C 6 )alkyl and (Ci-C6)alkyl.
  • Another embodiment is a compound of formula (I), wherein R4 is 6 to 10 membered nitrogen containing heteroaryl, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -OR a , -NR a Rb, halo-(Ci- C6)alkyl and (Ci-Ce)alkyl, wherein R a and Rb at each occurrence are independently selected from hydrogen and (Ci-C6)alkyl.
  • Another embodiment is a compound of formula (I), wherein R 4 is pyridyl, indolyl or quinolinyl, wherein each of pyridyl, indolyl and quinolinyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -NR a Rb, halo-(Ci-C6)alkyl, -OR a and (Ci-C6)alkyl, wherein R a and Rb at each occurrence are independently selected from hydrogen and (Ci-C6)alkyl.
  • R ⁇ is pyridyl, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -OR a , CN, -NR a R b , -NR a COR b , -COOR a , -CONR a R b , halo-(C C 6 )alkyl and (C 1 -C 6 )alkyl.
  • Another embodiment is a compound of formula (I), wherein R ⁇ is pyridyl, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -OR a , -NR a Rb, halo-(Ci-Ce)alkyl and (Ci-Ce)alkyl, wherein R a and Rb at each occurrence are independently selected from hydrogen and (Ci-C6)alkyl.
  • R 4 is 3-pyridyl, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -OR a , CN, -NR a R b , -NR a COR b , -COOR a , -CONR a R b , halo-(C
  • Another embodiment is a compound of formula (I), wherein R4 is pyridyl, which is
  • R 4 n, R 4 i 2 and R 41 3 is independently selected from the group consisting of hydrogen, halogen, -OR a , CN, -NR a R b , -NR a COR b , -COOR a , -CONR a R b , halo-(Ci-C 6 )alkyl and (Ci- C6)alkyl, wherein R a and R b at each occurrence are independently selected from hydrogen and (Ci-C 6 )alkyl.
  • R ⁇ is pyridyl, which is unsubstituted or substituted, represented by structural formula , wherein each of R411, R412 and R ⁇ is independently selected from the group consisting of hydrogen, halogen, -0-(d-C 6 )alkyl, (C 1 -C 6 )alkyl, -NH 2 , -NH-(d-C 6 )alkyl, -N[(C 1 -C 6 )alkyl] 2 and halo- (Ci-C 6 )alkyl.
  • Another embodiment is a compound of formula (I), wherein R4 is pyridyl, which is
  • R411, R412 and R 41 3 is independently selected from the group consisting of hydrogen, F, -OCH3, -CH 3 -NH 2 , -NH-CH3, -N(CH 3 ) 2 and -CF 3 .
  • Another embodiment is a co ), wherein R4 is substituted pyridyl,
  • R 411 is -NH 2 ;
  • R412 and R 41 3 are independently selected from the group consisting of hydrogen, halogen, -0-(Ci-C6)alkyl, (C 1 -C 6 )alkyl, -NH 2 , -NH-(C 1 -C 6 )alkyl, -N[(C 1 -C 6 )alkyl] 2 and halo-(C 1 -C 6 )alkyl.
  • Another embodiment is a compound of formula (I), wherein R4 is substituted pyridyl,
  • R4 J3 is -CF 3 ; and R4n and
  • R4i 2 are independently selected from the group consisting of hydrogen, halogen, -0-(Cr C 6 )alkyl, (C 1 -C 6 )alkyl, -NH 2 , -NH-(C ! -C 6 )alkyl, -N[(C 1 -C 6 )alkyl] 2 and halo-(C 1 -C 6 )alkyl.
  • Another embodiment is a compound of formula (I), wherein R 4 is substituted pyridyl,
  • R 411 is -NH 2 and R4 J3 is -
  • CF 3 and R4 12 is selected from hydrogen, halogen, -0-(Ci-C6)alkyl, (Ci-C6)alkyl, -NH 2 , -NH- Ci-Ce-alkyl, -N[(Ci-C 6 )alkyl] 2 and halo-(Ci-C 6 )alkyl.
  • Another embodiment is a compound of formula (I), wherein R4 is substituted pyridyl,
  • R 411 is -NH 2
  • R4 J3 is -CF 3 1 2 is hydrogen.
  • Another embodiment is a compound of formula (I), wherein R 4 is unsubstituted
  • ⁇ indicates the point of attachment.
  • Another embodiment is a compound of formula (I), wherein R 4 is quinolinyl, which is unsubstituted or substituted with one or more groups selected from R 41 .
  • Another embodiment is a compound of formula (I), wherein R 4 is indolyl, which is unsubstituted or substituted with one or more groups selected from R 41 .
  • Another embodiment is a compound of formula (I), wherein Ring A is phenyl or 5- or
  • Ri is hydrogen, CN, -NR a R b , - OR a or (Ci-C6)alkyl, wherein (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of CN, -NR a R , nitro, halogen, - ORa, -COOH, -C(0)0-(Ci-C 6 )alkyl and -P(0)(OR a )(OR a );
  • R 2 is halogen, CN, -NR a R b , or (Ci-C6)alkyl, wherein (Ci-C6)alkyl is unsubstituted or substituted by halogen or CN;
  • R 3 is hydrogen or (Ci-Ce)alkyl;
  • R ⁇ is phenyl or 6 to 10 membered nitrogen containing heteroaryl, wherein phenyl
  • Ring A is phenyl or 5- or 6-membered nitrogen containing heteroaryl
  • Xj is O
  • X2 is NR y
  • R y is hydrogen, (Q- C 6 )alkyl, -C(0)0-(Ci-C 6 )alkyl or -S(0) 2 -(Ci-C 6 )alkyl
  • Rj is hydrogen, CN, -NR a R b , -OR a or (Ci-C6)alkyl, wherein (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of CN, -NR a R b , nitro, halogen, -OR a , - COOH, -C(0)0-(d-C 6 )alkyl and -P(0)(OR a )(OR a ); R 2 is halogen, CN, -NR a R
  • Ring A is selected from phenyl or 5- or 6-membered nitrogen containing heteroaryl;
  • X2 is NR y , wherein R y is hydrogen, (Q-Ce ⁇ lkyl, -C(0)0-(C !
  • Rj is hydrogen, CN, -NR a R b , -OR a or (Ci-C6)alkyl, wherein (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of CN, -NR a R b , nitro, halogen, -OR a , -COOH, -C(0)0-(d-C 6 )alkyl or -P(0)(OR a )(OR a ); R 2 is halogen, CN, -NR a R b , or (Ci-C6)alkyl, wherein (Ci-Ce)alkyl is unsubstituted or substituted by halogen or CN; R3 is hydrogen or (Ci-Ce)alkyl; R 4 is phenyl or 6 to 10 membered nitrogen
  • Ri is hydrogen, CN, -NR a R b , -OR a or (Ci-C6)alkyl, wherein (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of CN, -NR a R b , nitro, halogen, -OR a , -COOH, -C(0)0-(Ci-Ce)alkyl and -P(0)(OR a )(OR a );
  • R 2 is halogen, CN, -NR a R b , or (Ci-C6)alkyl, wherein (Ci-Ce)alkyl is unsubstituted or substituted by halogen or CN;
  • R 3 is hydrogen or (Cj-C6)
  • Another embodiment is a compound of formula (I), wherein Ring A is phenyl; Xj is
  • Ri is hydrogen, -0(Ci-Ce)alkyl or (Ci-C6)alkyl, wherein (Ci-C6)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of hydroxy, -COOH and -C(0)0-(Ci-Ce)alkyl;
  • R2 is halogen or (Ci-C6)alkyl, wherein (Ci-Ce)alkyl is unsubstituted or substituted by halogen or CN;
  • R 3 is hydrogen or (Ci- C6)alkyl;
  • R4 is phenyl, pyridyl, indolyl or quinolinyl, wherein each of phenyl, pyridyl, indolyl and quinolinyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -OR a, CN, -NR a R b
  • -COOR a -CONR a R b , halo-(Ci-C 6 )alkyl and (Ci-C 6 )alkyl and R a and R b at each occurrence are independently selected from hydrogen and (Ci-Ce)alkyl; and p is an integer from 0 to 4.
  • R 2 is halogen, CN, -NR a R b , or (C 1 -C 6 )alkyl, wherein (Q- C6)alkyl is unsubstituted or substituted by halogen or CN;
  • R 3 is hydrogen or methyl;
  • R 4 is pyridyl, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -NR a Rb, halo-(Ci-Ce)alkyl, -OR a and (Ci-C6)alkyl, wherein R a and R b at each occurrence are independently selected from hydrogen and (Q- C 6 )alkyl.
  • Another embodiment of the present invention is a compound of formula (I),
  • Ring A is phenyl or 5 or 6-membered nitrogen containing heteroaryl
  • X ! is O or NR X ;
  • X 2 is O or NR y ;
  • Rj is hydrogen, CN, -NR a R b , -OR a or (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of CN, -NR a R b , nitro, halogen, -OR a , -COOH, -C(0)0-(Ci-C 6 )alkyl and - P(0)(OR a )(OR a );
  • R2 is halogen, CN, -NR a R b , or (Ci-Ce)alkyl wherein (Ci-C6)alkyl is unsubstituted or substituted by halogen or CN;
  • R 3 is hydrogen or (Ci-Ce)alkyl
  • R 4 is halogen, (C6-Ci 4 )aryl or heteroaryl; wherein aryl or the heteroaryl is unsubstituted or substituted with one or more groups selected from R 41 ;
  • R x is CN
  • R y is selected from hydrogen, (Ci-C 6 )alkyl, -C(0)0-(Ci-C 6 )alkyl or -S(0) 2 -(Ci- C 6 )alkyl;
  • R41 at each occurrence is independently selected from the group consisting of halogen, -OR a , CN, -NR a R b , -NR a COR b , -COOR a , -CONR a R b , halo-(Ci-C 6 )alkyl and (Ci- C 6 )alkyl;
  • R a and R b at each occurrence are independently selected from hydrogen and (Ci-
  • p is an integer from 0 to 4.
  • p is 0.
  • Representative compounds, encompassed in accordance with the present invention include:
  • the compounds of formula (I) can be prepared using various procedures; one such procedure is depicted in the Scheme I below. Those with skill in the art will appreciate that the specific starting compounds; reagents, such as bases, solvents and coupling agents; and temperature conditions etc. identified in the Schemes can be altered to prepare compounds encompassed by the present invention. Further, the procedures for the preparation of the intermediates used in the synthesis of the compounds of formula (I) are illustrated in the following Schemes A and B. In Scheme A, a process for the preparation of the compounds of formula (le) which constitute key intermediates of the compounds of formula (I) is illustrated. For ease of reference, the compounds referred to in the following scheme A are designated as compound(s) (la), (lb), (lc), (Id) and (le) respectively.
  • X2 is O or NR y, wherein R y is -C(0)0-(Ci-C6)alkyl; and R2, p and ring A are as defined in any one of the above embodiments.
  • the compound of formula (lb) (wherein X2 is -O- or NR y , wherein R y is -C(0)0-(Ci-Ce) alkyl) can be prepared by reacting the compound of formula (la) (wherein X2 is O or NR y , wherein R y is -C(0)0-(Ci-C6)alkyl) with carbalkoxymethylene triphenylphosphorane such as carbethoxymethylene triphenylphosphorane in the presence of a solvent such as dichloromethane or toluene, at a temperature ranging from about 25 °C to about 110 °C.
  • a solvent such as dichloromethane or toluene
  • the resulting compound of formula (lb) can be treated with boronic acid derivative of formula (lc) (wherein R2, p and ring A are as defined in any one of the above embodiments), at a temperature ranging from about 20 °C to about 100 °C, in the presence of a catalyst such as cyciooctadiene rhodium chloride dimer and a base such as potassium hydroxide or potassium carbonate to obtain a compound of formula (Id),
  • the resulting compound of formula (Id) can be subjected to reduction in the presence of a reducing agent such as ammonium formate/palladium on carbon (10%) or stannous chloride and an alcoholic solvent such as of Hanoi to obtain a compound of formula (le) (wherein X2 is O or NR y , wherein R y is -C(0)0-(Ci-Ce)alkyl and R2, p and ring A are as defined in any one of the above embodiments).
  • Scheme B a process for the preparation of the compounds of formula (2e) which constitute key intermediates of the compounds of formula (I) is illustrated.
  • the compounds referred to in the following scheme B are designated as compound(s) (2a), (2b), (2c), (2d) and (2e) respectively.
  • X2 is O; hal is halogen such as bromine or fluorine; and Rj, R2, p and ring A are as defined in any one of the above embodiments.
  • the compound of formula (2b) can be prepared by reacting the compound of formula (2a) with a compound of formula: [EtOC(0)]2CHRi (wherein Rj is as defined in any one of the above embodiments), which encompasses the specific compounds such as diethylmalonate diethylmethylmalonate, diethylcyanomalonate, diethylaminomalonate and diethylmethoxymalonate; in the presence of a base such as sodium hydride and a solvent such as dimethylformamide at a temperature range from 0 °C to 25 °C.
  • a base such as sodium hydride
  • a solvent such as dimethylformamide
  • the resulting compound of formula (2b) can be subjected to reduction in the presence of a reducing agent such as lithium aluminum hydride and a solvent such as tetratiydrofuran to form, a compound of formula (2c).
  • a reducing agent such as lithium aluminum hydride and a solvent such as tetratiydrofuran
  • the resulting compound of formula (2c) can be subjected to cyclization in the presence of a reagent such as tosyl chloride, a reducing agent such as butyl lithium and a solvent such as tetratiydrofuran to form a compound of formula (2d).
  • the resulting compound of formula (2d) can be subjected to reduction in the presence of a reducing agent such as ammonium formate in palladium on carbon to obtain a compound of formula (2,e) (wherein X2 is O; and Rj, R2, p and ring A are as defined in any one of the above embodiments).
  • a reducing agent such as ammonium formate in palladium on carbon
  • Xi is O or N(CN); X2 is O; Ri, R2, R3, R4, p and ring A are as defined above in any one of the above embodiments; or
  • Xj is O or N(CN);
  • X 2 is -N(R y ), wherein R y is -C(0)0-(C ! -C 6 )alkyl, Rj is -CH2C(0)0-(Ci-C 6 )alkyl; R2, R 3 , R 4 , p and ring A are as defined above in any one of the above embodiments.
  • the compound of formula 1 can be treated with phosphorus oxy chloride at a temperature of about 120 °C to obtain the compound of formula (2).
  • X2 is O; Ri, R2, p and ring A are as defined above in any one of the above embodiments; or
  • X 2 is -N(R y ), wherein R y is -C(0)0-C C 6 alkyl, Rj is -CH 2 C(0)0-C 1 -C 6 alkyl, R 2 , p and ring A are as defined above in any one of the above embodiments.
  • the resulting compound of formula (3) (a nitro-quinolinol) is subjected to catalytic reduction to obtain a compound of formula (4) (quinoline-diamine compound).
  • the resulting compound of formula (4) can be reacted with a reagent such as trichloromethylchloroformate or triphosgene in the presence of a base such as triethylamine or trimethylamine in a solvent such as dichloromethane or chloroform at a temperature of about 0°C to 25 °C to obtain a compound of formula (5) (wherein Xj is O).
  • a reagent such as dimethyl cyanocarbonimidodithioate or dipheny! n-cyanocarbonimidate in presence of a base such as cesium carbonate and a solvent such as dimethylformamide to obtain a compound of formula (5), wherein Xj is N(CN).
  • the resulting compound of formula (5) can be treated with a compound of formula: R3-halogen (wherein R3 is as defined for the compounds of formula (I)), in the presence of a base such as sodium hydride and a solvent such as dimethylformamide at a temperature of 25 °C to obtain a compound of formula (6).
  • the resulting compound of formula (6) can be treated with a compound of formula: R4-B(OH) 2 in the presence of a coupling agent such as palladium dichlorobistriphenylphosphine and a base such as sodium carbonate or potassium carbonate at a temperature of about 100 °C to 120 °C to obtain a compound of formula (I) (wherein (i) Xj is O or N(CN); X 2 is O; Rj, R 2 , R3, R4, p and ring A are as defined in any one of the above embodiments; or (ii) Xi is O or N(CN); X 2 is -N(R y ), wherein R y is -C(0)0-Ci-C6 alkyl, Rj is -CH 2 C(0)0-Ci-C 6 alkyl, R 2 , R3, R4, p and ring A are as defined above in any one of the above embodiments).
  • a coupling agent such as palladium dichlorobistripheny
  • the compound of formula (I), wherein Xj is O or N(CN); X2 is -N(R y ), wherein R y is -C(0)0-(Ci-C 6 )alkyl, 3 ⁇ 4 is -CH 2 C(0)0-(Ci-C 6 )alkyl, R 2 , R 3 , R4, p and ring A are as defined in any one of the above embodiments, can be treated with an acid such as trifluoroacetic acid in a solvent such as dichloromethane to obtain a compound of formula (I), wherein Xj is O or N(CN); X 2 is -N(R y ), wherein R y is hydrogen, Rj is -CH 2 C(0)0-(C 1 -C 6 )alkyl, R 2 , R 3 , R4, p and ring A are as defined above in any one of the above embodiments.
  • the compound of formula (I), wherein Xj is O or N(CN); X 2 is -N(R y ), wherein R y is hydrogen, Ri is -CH 2 C(0)0-(Ci-Ce)alkyl, R 2 , R3, R4, p and ring A are as defined in any one of the above embodiments, can be treated with a sulfonating agent such as (Ci-Ce)alkyl- S(0) 2 C1 in the presence of a base such as triethylamine and a solvent such as dichloromethane to obtain a compound of formula (I), wherein Xj is O or N(CN); X 2 is - N(Ry), wherein R y is -S(0) 2 -(Ci-C 6 ) alkyl, Ri is -CH 2 C(0)0-(Ci-C 6 )alkyl, R 2 , R 3 , R4, p and ring A are as defined above in any one of the above embodiments.
  • the compounds of formula (I), wherein Ri is -CH 2 C(0)0-(Ci-Ce)alkyl, can be treated with a base such as lithium hydroxide in a solvent such as tetrahydrofuran, methanol or a mixture thereof, to obtain a compound of formula (I), wherein Rj is -CH 2 C(0)OH.
  • the present invention also encompasses certain intermediates formed in the process of preparation of a compound of formula (I) and its pharmaceutically acceptable salt.
  • Xj is O or N(CN); X 2 is O; Ri, R 2 , R3, R4, P and ring A are as defined for formula
  • Xj is O or N(CN);
  • X 2 is -N(R y ), wherein R y is -C(0)0-(C 1 -C 6 )alkyl, Rj is -CH2C(0)0-(Ci-C6)alkyl, R2, R3, R4, p and ring A are as defined for formula (I), comprising the steps:
  • X2 is O; Ri, R2, p and ring A are as defined in any one of the above embodiments; or
  • X 2 is -N(R y ), wherein R y is -C(0)0-C C 6 alkyl, Rj is -CH2C(0)0-C ! -C 6 alkyl, R 2 , p and ring A are as defined for formula (I);
  • X2 is O; Ri, R2, p and ring A are as defined for formula (I); or (ii) X2 is -N(R y ), wherein R y is -C(0)0-C C 6 alkyl, Rj is -CH 2 C(0)0-C 1 -C 6 alkyl, R 2 , p and ring A are as defined for formula (I);
  • Xj is O or N(CN); X2 is O; Ri, R2, R 3 , p and ring A are as defined for formula (I); or (ii) Xj is O OR N(CN); X 2 is -N(R y ), wherein R y is -C(0)0-C C 6 alkyl, Rj is - CH2C(0)0-Ci-C 6 alkyl; R2, R 3 , p and ring A are as defined for formula (I);
  • X 2 is -N(R y ), wherein R y is -S(0) 2 -(Ci-C 6 )alkyl, Ri is - CH 2 C(0)0-(Ci-Ce)alkyl, R 2 , R3, R ⁇ , p and ring A are as defined for formula (I).
  • the compounds of formula (I), wherein Rj is -CH 2 C(0)0-(Ci-Ce)alkyl is subjected to hydrolysis to obtain a compound of formula (I), wherein Ri is -CH 2 C(0)OH.
  • the process for the preparation of the compounds of formula (I), described herein may involve a further step of converting the compound of formula (I) to a pharmaceutically acceptable salt and/or a solvate and/or a prodrug.
  • Isotopically labeled forms of the 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 experimental section by using an appropriate isotopically labeled reagent in place of the corresponding non-labeled reagent.
  • the compounds of formula (I) in their free base form are converted to their corresponding pharmaceutically acceptable salts.
  • the compounds of the present invention represented by formula (I), which contain acidic groups, may be converted into salts with pharmaceutically acceptable bases.
  • Such salts include, but are not limited to, alkali metal salts, like lithium, sodium and potassium salts; alkaline earth metal salts like calcium and magnesium salts; ammonium salts; [tris(hydroxymethyl)aminomethane], trimethylamine salts and diethylamine salts; salts with amino acids such as lysine, arginine and guanidine and salts with N,N-Dimethylimidodicarbonimidic diamide (metformin).
  • the compounds of the present invention represented by formula (I), which contain one or more basic groups, i.e. groups which can be protonated, can form an addition salt with an inorganic or organic acid.
  • suitable acid addition salts include but are not limited to, hydrochlorides, hydrobromides, hydrofluorides, nitrates, acetates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, cinnamates, citrates, ethanesulfonates, fumarates, glucuronates, glutamates, glycolates, ketoglutarates, lactates, maleates, malonates, mesylates, oxalates, palmoates, perchlorates, phosphates, picrates, salicylates, succinates, sulfamates, sulfates, tartrates, tosylates and other acids known to the person skilled in the art.
  • Another embodiment is a compound of formula (I), wherein the pharmaceutically acceptable salt is selected from (a) an inorganic acid addition salt selected from hydrochloride, sulphate, phosphate and nitrate, and (b) an organic acid addition salt selected from acetate, maleate, tartarate, citrate, mesylate, besylate, tosylate and cinnamate.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the subject compound i.e. the compound of formula (I), which contains a basic or an acidic moiety, by conventional chemical methods.
  • the salts can be prepared by treating the compound of formula (I) in its free base or acid form with an appropriate amount of the desired salt-forming inorganic or organic acid or a base in a suitable solvent or dispersant, or by cation or anion exchange.
  • suitable solvents used for preparing pharmaceutically acceptable salts of the compounds of Formula (I) include , for example, ethyl acetate, ether, alcohols, acetone, tetrahydrofuran, dioxane or mixtures of these solvents. These salts can also be used for purification of the compounds obtained.
  • polymorphs of compounds of formula (I) within the scope of the present invention.
  • Various polymorphs of the compounds of formula (I), forming part of this invention can be prepared by crystallization of the compounds of formula (I) under different conditions. The different conditions are, for example, using different solvents that are commonly used 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 infrared spectroscopy (IR), solid probe nuclear magnetic resonance (NMR) spectroscopy, differential scanning calorimetry (DSC), powder x-ray diffraction or such other techniques.
  • IR infrared spectroscopy
  • NMR nuclear magnetic resonance
  • DSC differential scanning calorimetry
  • the compounds of the present invention can be used for the treatment of proliferative diseases or disorders in a subject, comprising the step of administering to said subject a therapeutically effective amount of a compound of this invention or a pharmaceutically acceptable salt of the said compound or a composition of this invention.
  • compounds of the present invention can be used to treat tumor cells, and thereby assist in reducing the size of a tumor.
  • the compounds of the present invention can be used for the treatment of inflammatory diseases in a subject, comprising the step of administering to said subject a therapeutically effective amount of a compound of this invention or a pharmaceutically acceptable salt of the said compound or a composition of this invention.
  • Compounds of the present invention can be used for the treatment of angiogenesis related disorders.
  • Compounds of the present invention inhibit one or more kinases including, PI3K, mTOR and ALK1, thus having utility in the treatment of diseases or disorders, which reciprocates to the inhibition of the activity of the said kinases.
  • compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of proliferative diseases, inflammation and angiogenesis related disorders.
  • compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a proliferative disease or disorder mediated by a kinase selected from the group consisting of phosphatidylinositol 3 kinase (PI3 K), mammalian target of rapamycin (mTOR) and activin receptor-like kinase 1(ALK1) or combinations thereof.
  • a kinase selected from the group consisting of phosphatidylinositol 3 kinase (PI3 K), mammalian target of rapamycin (mTOR) and activin receptor-like kinase 1(ALK1) or combinations thereof.
  • compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a diseases or disorders mediated by a PI3 kinase.
  • a method for the treatment of diseases or disorders mediated by a kinase selected from the group consisting of PI3 kinase, mTOR and ALK-1 or combinations thereof comprising administering to a subject in need thereof; a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of diseases or disorders mediated by PI3 kinase comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of proliferative diseases, inflammatory diseases or angiogenesis related disorders mediated by a kinase selected from the group consisting of PI3 kinase, mTOR and ALK-1 or combination of said kinases comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of proliferative diseases, inflammatory diseases or angiogenesis related disorders mediated by PI3 kinase comprising administering to a subject in need thereof; a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of proliferative diseases or disorders mediated by a kinase selected from the group consisting of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin (mTOR) and activin receptor-like kinase 1 (ALK-1) or a combination of said kinases, comprising administering to a subject in need thereof; a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • PI3K phosphatidylinositol 3 kinase
  • mTOR mammalian target of rapamycin
  • ALK-1 activin receptor-like kinase 1
  • a method for the treatment of proliferative diseases or disorders mediated by PI3 kinase comprising administering to a subject in need thereof; a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of inhibiting the activity of one or more kinases selected from a group consisting of PI3 kinase, mTOR and ALK-1 comprising contacting the said kinase with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the proliferative disease mediated by a kinase selected from the group consisting of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin (mTOR) and activin receptor-like kinase 1 (ALK-1) or a combination of said kinases is cancer.
  • the cancer is solid cancer or hematological cancer.
  • the cancer is selected from the group consisting of leukemia such as acute lymphocytic leukemia; acute myeloid leukemia; adult acute myeloid leukemia; acute lymphoblastic leukemia; chronic lymphocytic leukemia; chronic myeloid leukemia; hairy cell leukemia, lung cancer including non-small- cell lung cancer and small-cell lung cancer, brain tumors such as brain stem glioma; glioblastoma; astrocytoma including cerebellar astrocytoma and cerebral astrocytoma, visual pathway and hypothalamic glioma; supratentorial primitive neuroectodermal and pineal tumors; medulloblastoma, lymphoma such as primary central nervous system lymphoma; non-Hodgkin's lymphoma particularly mantle cell lymphoma, Hodgkin's disease, liver cancer such as hepatocellular carcinoma, kidney cancer such as renal cell carcinoma and Wilms' tumor
  • the cancer is selected from the group consisting of leukemia, lung cancer, brain tumors, Hodgkin's disease, liver cancer, kidney cancer, bladder cancer, breast cancer, endometrial cancer, head and neck cancer, lymphoma, melanoma, cervical cancer, thyroid cancer, gastric cancer, germ cell tumor, cholangiocarcinoma, extracranial cancer, sarcoma, mesothelioma, malignant fibrous histiocytoma of bone, retinoblastoma, esophageal cancer, multiple myeloma, oral cancer, pancreatic cancer, neuroblastoma, skin cancer, ovarian cancer, recurrent ovarian cancer, prostate cancer, testicular cancer, colorectal cancer, lymphoproliferative disease, refractory multiple myeloma, cancer of urinary tract, resistant multiple myeloma and myeloproliferative disorder.
  • the cancer is selected from the group consisting of breast cancer, prostate cancer, pancreatic cancer, lung cancer (non-small-cell lung cancer and small-cell lung cancer), head and neck cancer, ovarian cancer, colon cancer, rectal cancer, kidney cancer, gastric cancer, non-Hodgkin's lymphoma, primary central nervous system lymphoma, glioblastoma and astrocytoma.
  • a method for the treatment of inflammatory diseases or disorders comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of diseases mediated by TNF-a or IL-6 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of inflammatory diseases or disorders mediated by PI3 kinase and/or mTOR comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the inflammatory diseases or disorders are selected from the group consisting of rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, chronic non-rheumatoid arthritis, osteoporosis, septic shock, psoriasis and atherosclerosis or a combination of said inflammatory diseases or disorders.
  • a method for the treatment of angiogenesis related disorders mediated by one or more kinases comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of angiogenesis related disorders mediated by vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • the angiogenesis related disorder is an inflammatory disorder.
  • the inflammatory disorder which is an angiogenesis related disorder is selected from the group consisting of immune and nonimmune inflammation, chronic articular rheumatism, disorders associated with inappropriate or inopportune invasion of vessels such as diabetic retinopathy, neovascular glaucoma, capillary proliferation in atherosclerotic plaques and osteoporosis.
  • the angiogenesis related disorder is selected from the group consisting of solid tumor, solid tumor metastasis, angiofibroma, retrolental fibroplasia, hemangioma or Kaposi's sarcoma.
  • a compound of formula (I) can be employed as a sole therapy or in combination with one or more further therapeutic agents for the treatment of indications described herein, such as cancer.
  • a compound of formula (I) can be administered either simultaneously or before or after the other therapeutic agent, either separately by the same or different route of administration, or together in the same pharmaceutical formulation.
  • compositions according to the invention are prepared in a manner known per se and familiar to one skilled in the art.
  • Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compounds of formula (I), and/or their physiologically tolerable salts.
  • Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compounds of formula (I), and/or their physiologically tolerable salts.
  • Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compounds of formula (I), and/or their physiologically tolerable salts.
  • 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 for 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 preparations or compositions normally contain about 1 to 99 , for example, about 5 to 70%, or from about 5 to about 30 % by weight of the compound of the formula (I) or pharmaceutically acceptable salt thereof.
  • the amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, as the active ingredient in the pharmaceutical preparations normally ranges from about 1 to 1000 mg.
  • the dose of the compounds of this invention can cover a wide range.
  • the dose to be administered daily is to be selected so as to produce the desired therapeutic effect.
  • a suitable dose is about 0.1 mg/kg to 50 mg/kg of the compound of formula (I) or pharmaceutically acceptable salt thereof, for example, about 1 mg/kg to 25 mg/kg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, with the typical dose being about 1 mg/kg to 10 mg/kg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. If required, higher or lower daily doses can also be administered.
  • Actual dosage levels of the compounds of formula (I) which are the active ingredients contained in the pharmaceutical compositions of this 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 subject (patient).
  • the pharmaceutical composition can be administered orally, for example in the form of pills, tablets, coated tablets, lozenges, capsules, dispersible powders or granules, suspensions, emulsions, syrups 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 solutions or ointments or transdermally, for example in the form of transdermal patches, or in other ways, for example in the form of aerosols, nasal sprays or nasal drops.
  • the selected dosage level will depend upon a variety of factors including the therapeutic activity of the specific compound of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and /or materials used in combination with the particular compounds employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • the pharmaceutical preparations or compositions can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. They can also contain one or more compounds of formula (I) and/or their pharmaceutically acceptable salts. Furthermore, in addition to at least one compound of formula (I) and/or its pharmaceutically acceptable salt, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.
  • additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. They can also contain one or more compounds of formula (I) and/or their pharmaceutically acceptable salts.
  • the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.
  • pharmaceutically acceptable it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (i) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient or carrier.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof and at least one further pharmaceutically active compound, together with a pharmaceutically acceptable excipient or carrier.
  • a therapeutically or prophylactically active compound in combination with one or more compounds of formula (I) for treatment of cancer can be selected from, but not limited to, one or more of the following groups: (i) Kinase inhibitors such as gefitinib, erlotinib, lapatinib, bevacizumab, avastin, sorafenib, Bcr-Abl kinase inhibitors, such as imitinib and nilotinib or LY- 317615 (Eli Lilly and Co.) (ii) Alkylating agents such as mitomycin C, busulfan, oxaliplatin, cisplatin, carboplatin, procarbazine or dacarbazine (iii) Antimetabolites such as methotrexate, mercaptopurine, thioguanine, fludarabine phosphate, fluorouracil, vinblastine, vincristine, gemcitabine or paclitaxel (i
  • Nomenclature of the compounds exemplified in the present invention was derived from Chemdraw Ultra version 9.0.1 CambridgeSoft Corporation, Cambridge.
  • Reagents were purchased from commercial suppliers such as Labex Corporation, India; Spectrochem Ltd., India; Combi-Blocks Inc., CA, Clairvoyant Chemicals, India Avra Synthesis, India and Sigma Aldrich Chemical company and were are used as such.
  • Step 1 N,N-Dibenzyl-4-bromoaniline
  • Step 2 3-(4-(Dibenzylamino)phenyl) oxetan-3-ol
  • Butyl Lithium (248 mmol, 1.6M) was added drop wise to a cold solution (-78 °C) of N,N- dibenzyl-4-bromoaniline (compound of step 1, 99 mmol) in dry THF under nitrogen atmosphere. The temperature was maintained for 1 hour. Oxetan-3-one (109 mmol) was added and the reaction mixture was stirred at RT for 2 hours. After completion of the reaction, the reaction mixture was quenched with saturated solution of ammonium chloride, stirred for 15 minutes. The organic layer was separated, dried over sodium sulfate and evaporated. The title compound obtained as residue was purified (silica gel column, 25% EtOAc: 75% petroleum ether as eluent).
  • N, N-dibenzyl-4-(3-methoxyoxetan-3-yl)aniline (22.26 mmol) was dissolved in MeOH and CHCI 3 and subjected to hydrogenation at hydrogen pressure of 300 psi and temperature of 50 °C for 5 hours in hydrogenation apparatus in presence of Pearlman's catalyst (2.226 mmol). After completion of the reaction, the reaction mixture was filtered and the residue was washed with metahnol. The filtrate was evaporated and the crude mass was purified (silica gel column, 3% MeOH: 97% CHC1 3 as eluent).
  • Example 1 Ethyl 2-(3-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro- lH-imidazo[4,5-c]quinolin- 1 -yl) phenyl)oxetan-3-yl)acetate
  • Step 1 Ethyl 2-(3-(4-(6-bromo-3-nitroquinolin-4-ylamino)phenyl)oxetan-3-yl)acetate
  • Ethyl 2-(3-(4-aminophenyl)oxetan-3-yl)acetate (Intermediate 3, 23.38 mmol) was added to a solution of 6-bromo-4-chloro-3-nitro-quinoline (Intermediate 11, 23.38 mmol) and sodium carbonate (28.1 mmol) in dry DMF and the resulting reaction mixture was stirred for 18 hours. After completion of the reaction, water was added and the reaction mixture was filtered. The residue was washed with water to obtain the title compound acid free.
  • Step 2 Ethyl 2-(3-(4-(3-amino-6-bromoquinolin-4-ylamino)phenyl) oxetan-3-yl)acetate
  • Step 3 Ethyl 2-(3-(4-(8-bromo-2-oxo-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l- yl)phenyl) oxetan-3-yl)acetate
  • Triethylamine (12.27 mmol) was added to a solution of ethyl 2-(3-(4-(3-amino-6- bromoquinolin-4-ylamino)phenyl) oxetan-3-yl)acetate (compound of step 2, 1.53 mmol) in dry DCM.
  • the reaction mixture was cooled to 0 °C, triphosgene (1.53 mmol) dissolved in DCM was added slowly and stirred for 2 hours. After completion of the reaction, DCM was added and washed with water. Aqueous layer was extracted with DCM.
  • Step 4 Ethyl 2-(3-(4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- c]quinolin- 1 -yl) phenyl)oxetan-3-yl)acetate
  • Step 5 Ethyl 2-(3-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro- lH-imidazo[4,5-c]quinolin- 1 -yl) phenyl)oxetan-3-yl)acetate
  • Step 1 6-Bromo-N-(4-(3-methyloxetan-3-yl)phenyl)-3-nitroquinolin-4-amine
  • Step 2 6-Bromo-N 4 -(4-(3-methyloxetan-3-yl)phenyl)quinoline-3,4-diamine
  • Step 3 8-Bromo-l-(4-(3-methyloxetan-3-yl)phenyl)-lH-imidazo[4,5-c]quinolin-2(3H)- one
  • Triethylamine (5.46 mmol) was added to a solution of 6-bromo-N 4 -(4-(3-methyloxetan-3- yl)phenyl)quinoline-3,4-diamine (compound of step 2, 0.781 mmol) in dry DCM. Reaction mixture was cooled to 0 °C. Triphosgene (0.781 mmol) solution in DCM was added to the reaction mixture slowly and stirred for 2 hours. After completion of the reaction, DCM was added and washed with water. The aqueous layer was partitioned with DCM.
  • Step 4 8-Bromo-3-methyl-l-(4-(3-methyloxetan-3-yl)phenyl)-lH-imidazo [4,5- c]quinolin-2(3H)-one
  • Step 5 8-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-l-(4-(3-methyloxetan-
  • Example 3 Ethyl 2-(3-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro- lH-imidazo[4,5-c]quinolin- 1 -yl)phenyl)azetidin-3-yl)acetate
  • Step 1 teri-Butyl 3-(4-((6-bromo-3-nitroquinolin-4-yl)amino)phenyl)-3-(2-ethoxy-2- oxoethyl)azetidine- 1 -carboxylate
  • 6-bromo-4-chloro-3-nitroquinoline (Intermediate 11, 2.087 mmol) and teri-butyl 3-(4- aminophenyl)-3-(2-ethoxy-2-oxoethyl)azetidine-l -carboxylate (Intermediate 10, 2.087 mmol) are dissolved in acetic acid (2 mL) and stirred over night. After completion of the reaction, water was added and yellow precipitate so obtained was filtered. The residue was washed with water and dried to obtain the title compound.
  • Step 2 teri-Butyl 3-(4-((3-amino-6-bromoquinolin-4-yl)amino)phenyl)-3-(2-ethoxy-2- oxoethyl)azetidine- 1 -carboxylate
  • Step 3 teri-Butyl 3-(4-(8-bromo-2-oxo-2,3-dihydro-lH-irnidazo[4,5-c]quinolin-l- yl)phenyl)-3-(2-ethoxy-2-oxoethyl)azetidine- 1 -carboxylate
  • Step 4 teri-Butyl 3-(4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- c]quinolin- 1 -yl)phenyl)-3-(2-ethoxy-2-oxoethyl)azetidine- 1 -carboxylate
  • Step 5 teri-Butyl 3-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-2-oxo-
  • Potassium carbonate was added to a solution of teri-Butyl 3-(4-(8-bromo-3-methyl-2-oxo- 2,3-dihydro-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)-3-(2-ethoxy-2-oxoethyl)azetidine-l- carboxylate (compound of step 4, 1.176 mmol) and 5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (1.763 mmol) in dioxane.
  • Step 6 Ethyl 2-(3-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro- lH-imidazo[4,5-c]quinolin- 1 -yl)phenyl)azetidin-3-yl)acetate
  • Trifluoroacetic acid (1.182 mmol) was added to a solution of teri-butyl 3-(4-(8-(6-amino-5- (trifluoromethyl)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l- yl)phenyl)-3-(2-ethoxy-2-oxoethyl)azetidine-l -carboxylate (compound of step 5, 0.118 mmol) in DCM (5 mL) and stirred over night at RT.
  • Example 4 2-(3-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro- lH-imidazo[4,5-c]quinolin- 1 -yl)phenyl)- 1 -(teri-butoxycarbonyl)azetidin-3-yl)acetic acid
  • Example 5 Ethyl 2-(3-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro- lH-imidazo[4,5-c]quinolin- 1 -yl)phenyl)- 1 -(methylsulfonyl)azetidin-3-yl)acetate Triethylamine (0.078 mmol) was added to a solution of ethyl 2-(3-(4-(8-(6-amino-5- (trifluoromethyl)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l- yl)phenyl)azetidin-3-yl)acetate (compound of Example 3, 0.052 mmol) in THF (2 mL), followed by the addition of methylsulfonyl chloride
  • reaction mixture was stirred at RT for 30 minutes. After completion of the reaction, DCM (5 mL) was added and the reaction mixture was quenched with water. The organic layer was separated and aqueous layer was partitioned with DCM. The organic layers were combined, dried over sodium sulfate, concentrated and purified (silica gel column, MeOH/CHCk, as eluent).
  • Example 7 Ethyl 2-(3-(4-(3-methyl-2-oxo-8-(pyridin-3-yl)-2,3-dihydro-lH-imidazo[4,5- c]quinolin- 1 -yl)phenyl)oxetan-3-yl)acetate
  • Step 1 Ethyl 2-(3-(4-(8-(6-amino-5-methylpyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5-c]quinolin-l-yl)phenyl)oxetan-3-yl)acetate
  • Step 2 8-(6-amino-5-methylpyridin-3-yl)-l-(4-(3-(2-hydroxyethyl)oxetan-3- yl)phenyl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)-one
  • Example 12 Ethyl 2-(3-(4-(8-(lH-indol-6-yl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- c]quinolin- 1 -yl)phenyl)oxetan-3-yl)acetate
  • Lithium hydroxide (1.5 M, 0.679 mmol) was added to a solution of ethyl 2-(3-(4-(8-(2,6- difluoropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l- yl)phenyl)oxetan-3-yl)acetate (Compound of Example 11, 0.113 mmol) in THF: MeOH (4: 1) at RT and stirred for 5 hours. The reaction mixture was concentrated and triturated with saturated solution of ammonium chloride. The compound was extracted with EtOAc. The EtOAc layer was dried over sodium sulfate and concentrated to obtain the title compound.
  • Example 14 Ethyl 2-(3-(4-(3-methyl-2-oxo-8-(5-(trifluoromethyl)pyridin-3-yl)-2,3-dihydro- 1 H-imidazo [4, 5 -c] quinolin- 1 -yl)phenyl)oxetan-3 -yl)acetate
  • the reaction mixture was degassed using argon, followed by addition of tetrakis(triphenylphosphine)-palladium (0) (0.013 mmol).
  • the reaction mixture was heated at 110 °C for 8 minutes in microwave. After completion of the reaction, the solvent was evaporated and EtOAC was added to the residue. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate.
  • Example 22 ieri-Butyl 3-(2-ethoxy-2-oxoethyl)-3-(4-(3-methyl-2-oxo-8-(pyridin-3-yl)-2,3- dihydro- lH-imidazo[4,5-c]quinolin- 1 -yl)phenyl)azetidine- 1 -carboxylate
  • the reaction mixture was degassed using argon, followed by addition of tetrakis(triphenylphosphine)- palladium (0) (0.04 mmol).
  • the reaction mixture was heated at 110 °C for 8 minutes in microwave. After completion of the reaction, the solvent was evaporated and EtOAC was added to the residue.
  • the reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was dried over anhydrous Na 2 S0 4 and purified (silica gel column, 5% methanol in chloroform as eluent) to obtain the title compound.
  • Example 23 teri-butyl 3-(2-ethoxy-2-oxoethyl)-3-(4-(8-(6-methoxypyridin-3-yl)-3-methyl- 2-oxo-2,3-dihydro- lH-imidazo[4,5-c]quinolin- 1 -yl)phenyl)azetidine- 1 -carboxylate teri-Butyl 3-(4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l- yl)phenyl)-3-(2-ethoxy-2-oxoethyl)azetidine-l -carboxylate (compound of step 4 of Example 3, 0.168 mmol), 2-methoxy-5-pyridineboronic acid (0.252 mmol) was dissolved in dioxane : water (2: 1 mL) and K2CO 3 (0.504 mmol)
  • reaction mixture was degassed using argon, followed by addition of tetrakis(triphenylphosphine)palladium (0) (0.04 mmol).
  • the reaction mixture was heated at 110 °C for 8 minutes in microwave and the reaction was monitored by TLC.
  • dioxane was removed under high vacuum and the residue was diluted with ethyl acetate (25 mL).
  • the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate.
  • the organic layer was dried over anhydrous Na 2 S0 4 and purified (silica gel column, 5% methanol in chloroform as eluent) to obtain the title compound.
  • Example 27 8-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-l-(4-(3-methoxyoxetan-3- yl)phenyl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)-one
  • Step 1 6-Bromo-N-(4-(3-methoxyoxetan-3-yl)phenyl)-3-nitroquinolin-4-amine 4-(3-methoxyoxetan-3-yl)aniline (Intermediate 12 , 7.23 mmol) was added to a solution of 6- bromo-4-chloro-3-nitroquinoline (Intermediate 11, 7.23 mmol) and Na2CC>3 (14.46 mmol) in dry DMF and the resulting reaction mixture was stirred for 3 hours.
  • Step 2 6-Bromo-N 4 -(4-(3-methoxyoxetan-3-yl)phenyl)quinoline-3,4-diamine Stannous Chloride (32.5 mmol) was added to a suspension of 6-bromo-N-(4-(3- methoxyoxetan-3-yl)phenyl)-3-nitroquinolin-4-amine (3.62 mmol) in EtOAc and the reaction mixture was stirred at RT for 2 hours. After completion of the reaction, EtOAc was added and quenched with 10 M NaOH. The organic layer was separated, concentrated and purified (silica gel column, MeOH/ CHCI 3 as eluent) to obtain the title compound
  • Step 3 8-Bromo-l-(4-(3-methoxyoxetan-3-yl)phenyl)-lH-imidazo[4,5-c]quinolin- 2(3H)-one
  • Triethylamine (35.5 mmol) was added to a solution of 6-bromo-N 4 -(4-(3-methoxyoxetan-3- yl)phenyl)quinoline-3,4-diamine (compound of step 2, 3.55 mmol) in dry dichloromethane.
  • the reaction mixture was cooled to 0 °C, triphosgene (3.90 mmol) dissolved in DCM was added slowly and stirred for 2 hours. After completion of the reaction, DCM was added and washed with water. Aqueous layer was extracted with DCM. The organic layer was dried over sodium sulfate, concentrated and purified (silica gel column, MeOH/CHCi 3 as eluent) to obtain the title compound.
  • Step 4 8-bromo-l-(4-(3-methoxyoxetan-3-yl)phenyl)-3-methyl-lH-imidazo[4,5- c]quinolin-2(3H)-one
  • Step 5 8-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-l-(4-(3-methoxyoxetan-3- yl)phenyl)-3-methyl-lH-imidazo[4,5-c]quinolin-2(3H)-one
  • reaction mixture was diluted with EtOAc and washed with water and brine.
  • the solvent was evaporated to obtain solid residue, which was purified by column chromatography (silica gel, 1.5% MeOH in 99.5% CHC1 3 ) to obtain the title compound.
  • Example 28 Ethyl 2-(3-(4-(8-(6-amino-5-(trifluoromemyl)pyridin-3-yl)-2-(cyanoimino)-3- methyl-2, 3 -dihydro- 1 H-imidazo [4, 5 -c] quinolin- 1 -yl)phenyl)oxetan-3 -yl)acetate
  • Step 1 Ethyl 2-(3-(4-(8-bromo-2-(cyanoimino)-2,3-dihydro-lH-imidazo[4,5- c]quinolin- 1 -yl)phenyl)oxetan-3-yl)acetate
  • Step 2 Ethyl 2-(3-(4-(8-bromo-2-(cyanoimino)-3-methyl-2,3-dihydro-lH- imidazo[4,5-c]quinolin-l-yl)phenyl)oxetan-3-yl)acetate
  • Step 3 Ethyl 2-(3-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(cyanoimino)-3- methyl-2, 3 -dihydro- 1 H-imidazo [4, 5 -c] quinolin- 1 -yl)phenyl)oxetan-3 -yl)acetate
  • Example 29 Ethyl 2-(3-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(cyanoimino)-2,3- dihydro- lH-imidazo[4,5-c]quinolin- 1 -yl)phenyl)oxetan-3-yl)acetate
  • Example 30 teri-Butyl 3-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(cyanoimino)-3- methyl-2, 3 -dihydro- 1 H-imidazo [4, 5 -c] quinolin- 1 -yl)phenyl)-3 -(2-ethoxy-2- oxoethyl)azetidine- 1 -carboxylate
  • Step 1 teri-Butyl 3-(4-(8-bromo-2-(cyanoimino)-2,3-dihydro-lH-imidazo[4,5- c]quinolin- 1 -yl)phenyl)-3-(2-ethoxy-2-oxoethyl)azetidine- 1 -carboxylate
  • Step 2 teri-Butyl 3-(4-(8-bromo-2-(cyanoimino)-3-methyl-2,3-dihydro-lH- imidazo[4,5-c]quinolin-l-yl)phenyl)-3-(2-ethoxy-2-oxoethyl)azetidine-l-carboxylate NaH (0.691 mmol, 60%) was added slowly to the cool solution of teri-butyl 3-(4-(8-bromo-2- (cyanoimino)-2 -dmydro-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)-3-(2-ethoxy-2-oxoethyl)- azetidine-l-carboxylate (compound of step 1, 0.413 mmol) in DMF (3 mL).
  • reaction mixture was maintained at 0 °C until the complete addition of NaH.
  • the reaction mixture was stirred for 30 minutes, followed by the addition of methyl iodide (0.691 mmol).
  • the reaction mixture was further stirred at RT for 1 hour.
  • the solvent was evaporated and the reaction mass was extracted with ethyl acetate.
  • the organic layer was dried over Na 2 S0 4 , concentrated and purified using column chromatography (silica gel column, 5% MeOH: CHC1 3 as eluent).
  • Step 3 teri-Butyl 3-(4-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(cyanoimino)-
  • Tetrakis(triphenylphosphine)palladium (0) (0.08 mmol) was added to the reaction mixture degassed in an inert atmosphere. The reaction mixture was heated at 110 °C for 8 minutes in microwave. After the completion of the reaction, dioxane was evaporated and EtOAc was added to the residue. The reaction was quenched with water and the aqueous layer was partitioned with EtOAc. The organic layer was separated, dried over anhydrous Na 2 S0 4 , concentrated and purified using column chromatography (silicagel column, 5% MeOH: Chloroform as eluent).
  • reaction mixture was heated at 110 °C for 8 minutes in microwave and reaction was monitored by thin layer chromatography. After completion of reaction, DMF was removed and the residue was dissolved in ethyl acetate (25 mL). Water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na 2 S0 4 , concentrated and purified by column chromatography (silica gel column, 5% MeOH and CHC1 3 as eluent).
  • Step 6 6-Bromo-N-(6-(3-methyloxetan-3-yl)pyridin-3-yl)-3-nitroquinolin-4-amine
  • a solution of 6-(3-methyloxetan-3-yl)pyridin-3-amine (compound of step 5, 1.705 mmol) in dry DMF was stirred followed by the addition of sodium bicarbonate (2.04 mmol).
  • the reaction mixture was further stirred for 5 minutes at RT.
  • 6-Bromo-4-chloro-3-nitroquinoline (Intermediate 11, 1.705 mmol) was added to the reaction mixture and the reaction mixture was further stirred for 2 hours. After completion of reaction, the reaction mixture was poured in water and the yellow solid obtained was filtered and dried to obtain the title compound.
  • Step 7 6-Bromo-N 4 -(6-(3-methyloxetan-3-yl)pyridin-3-yl)quinoline-3,4-diamine
  • Stannous chloride dihydrate (9.6 mmol) was added to the suspension of 6-bromo-N-(6-(3- methyloxetan-3-yl)pyridin-3-yl)-3-nitroquinolin-4-amine (Compound of step 6, 2.4 mmol) in ethyl acetate.
  • the reaction mixture was stirred at RT for 2 hours. After completion of reaction, the reaction mixture was diluted with ethyl acetate and quenched with NaOH solution (10 M).
  • Step 8 8-Bromo-l-(6-(3-methyloxetan-3-yl)pyridin-3-yl)-lH-imidazo[4,5-c]quinolin- 2(3H)-one
  • Triethylamine (7.9 mmol) was added to a solution of 6-bromo-N 4 -(6-(3-methyloxetan-3- yl)pyridin-3-yl)quinoline-3,4-diamine (compound of step 7, 1.29 mmol) in dry dichloromethane.
  • the reaction mixture was cooled to 0 °C followed by addition of triphosgene (1.29 mmol) solution in dichloromethane.
  • the reaction mixture was stirred for 2 hours. After completion of reaction, the mixture was diluted with dichloromethane and washed with water.
  • Step 9 8-Bromo-3-methyl-l-(6-(3-methyloxetan-3-yl)pyridin-3-yl)-lH-imidazo[4,5- c]quinolin-2(3H)-one
  • Step 10 8-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-l-(6-(3- methyloxetan-3-yl)pyridin-3-yl)-lH-imidazo[4,5-c]quinolin-2(3H)-one
  • reaction mixture was cooled, diluted with water and extracted with ethyl acetate.
  • organic layer was dried over sodium sulfate, concentrated and purified (silicagel column, MeOH/chloroform as eluent) to obtain the title compound.
  • Step 1 N-(8-Bromo-l-(6-(3-methyloxetan-3-yl)pyridin-3-yl)-lH-imidazo[4,5- c]quinolin-2(3H)-ylidene)cyanamide
  • Step 2 N-(8-Bromo-3-methyl-l-(6-(3-methyloxetan-3-yl)pyridin-3-yl)-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide
  • Step 3 N-(8-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-l-(6-(3- methyloxetan-3-yl)pyridin-3-yl)-lH-imidazo[4,5-c]quinolin-2(3H)- ylidene) cyanamide
  • a reaction mixture of N-(8-bromo-3-methyl-l-(6-(3-methyloxetan-3-yl)pyridin-3-yl)-lH- imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide compound of step 2, 0.062 mmol
  • 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine 0.093 mmol
  • the efficacy of the present compounds can be determined by a number of pharmacological assays well known in the art, such as those described below.
  • the exemplified pharmacological assays, which follow herein, have been carried out with the compounds of the present invention.
  • Example 34 Protocol for kinase assay (PBKoc)
  • the assay was designed as in the reference, Journal of Biomolecular Screening, 2002, 7, 5, 441-450, the disclosure of which is incorporated by reference for the teaching of the assay.
  • the pi 10a biochemical assay was performed using a radioactive assay measuring the incorporation of 32 P into the pi 10a substrate, phosphatidylinositol (PI).
  • PI phosphatidylinositol
  • the reaction was performed in a 96-well MaxiSorp plates. Plates were pre-coated with 4 ⁇ g/well of a 1: 1 ratio of phosphatidylinositol (PI: Avanti #840042C) and phosphatidylserine (PS: Avanti #840032C) diluted in CHCI 3 .
  • Equal amount of pi 10a (Upstate Millipore) protein was added to each well, containing 25 ⁇ reaction buffer (50 mM MOPSO, pH 7.0, 100 mM NaCl, 4 mM MgCl 2 , 0.1% (w/v) BSA) whereas, for negative control, only reaction buffer was added.
  • reaction buffer 50 mM MOPSO, pH 7.0, 100 mM NaCl, 4 mM MgCl 2 , 0.1% (w/v) BSA
  • Compounds of the present invention dissolved in DMSO were treated at nine-point dose responses (0.3, 1, 3, 6, 10, 30, 60, 100 and 300 nM). Reactions were initiated by the addition of 25 ⁇ ATP solution (Sigma, USA) containing 50 ⁇ /mL [ ⁇ - 32 P]-ATP and incubated at RT for 2 hours with gentle shaking.
  • T c pm P-cpm in presence of compounds of the present invention
  • the assay was designed as in the reference, Anticancer Drugs, 2002, 13, 1-8, the disclosure of which is incorporated by reference for the teaching of the assay.

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Abstract

La présente invention concerne des dérivés d'imidazo[4,5-c]quinoléine substitués représentés par la formule de composés (I), leurs procédés de préparation, des compositions pharmaceutiques contenant lesdits composés et leur utilisation dans le traitement des maladies et troubles entraînés par une ou plusieurs kinases (kinase P13, mTOR et ALK-1 par exemple) et dans le traitement de maladies ou de troubles particulièrement proliférants comme le cancer. Les composés de la formule (I) peuvent également être utilisés dans le traitement des troubles liés aux inflammations et à l'angiogenèse ainsi que dans le traitement des infections bactériennes.
PCT/IB2014/059719 2013-03-14 2014-03-13 Dérivés d'imidazo[4,5-c]quinoléine et leurs utilisations WO2014141118A1 (fr)

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WO2012007926A1 (fr) 2010-07-16 2012-01-19 Piramal Life Sciences Limited Dérivés d'imidazoquinoline substitués à titre d'inhibiteurs de kinases
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CN106478558A (zh) * 2016-10-17 2017-03-08 天津雅奥科技发展有限公司 一种4‑羟甲基‑二氢‑呋喃‑2(3h)‑酮的合成方法

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