WO2001025238A2 - Heterocyclic compounds useful as inhibitors of tyrosine kinases - Google Patents

Heterocyclic compounds useful as inhibitors of tyrosine kinases Download PDF

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WO2001025238A2
WO2001025238A2 PCT/US2000/027444 US0027444W WO0125238A2 WO 2001025238 A2 WO2001025238 A2 WO 2001025238A2 US 0027444 W US0027444 W US 0027444W WO 0125238 A2 WO0125238 A2 WO 0125238A2
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alkyl
optionally substituted
alkoxy
nrι
phenyl
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PCT/US2000/027444
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French (fr)
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WO2001025238A3 (en
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Roger John Snow
Mario Gustavo Cardozo
Daniel Goldberg
Abdelhakim Hammach
Tina Morwick
Neil Moss
Usha R. Patel
Anthony S. Prokopowicz, Iii
Hidenori Takahashi
Matt Aaron Tschantz
Xiao-Jun Wang
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Boehringer Ingelheim Pharmaceuticals, Inc.
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Priority to MXPA02003364A priority Critical patent/MXPA02003364A/en
Priority to AT00968713T priority patent/ATE277044T1/en
Priority to CA2384378A priority patent/CA2384378C/en
Priority to JP2001528182A priority patent/JP5036112B2/en
Priority to DE60014130T priority patent/DE60014130T2/en
Priority to EP00968713A priority patent/EP1222187B1/en
Publication of WO2001025238A2 publication Critical patent/WO2001025238A2/en
Publication of WO2001025238A3 publication Critical patent/WO2001025238A3/en

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    • 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
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    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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    • 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

Definitions

  • This invention relates to substituted compounds of formula (I):
  • Arj, R a , R 4 , R 5 , X and Y are defined below, which are useful as inhibitors of certain protein tyrosine kinases and are thus useful for treating diseases resulting from inappropriate cell proliferation, which include autoimmune diseases, chronic inflammatory diseases, allergic diseases, transplant rejection and cancer.
  • This invention also relates to processes for preparing these compounds and to pharmaceutical compositions comprising these compounds.
  • Tyrosine kinases play an essential role in the regulation of cell signaling and cell proliferation by phosphorylating tyrosine residues of peptides and proteins. Inappropriate activation of tyrosine kinases is known to be involved in a variety of disease states, including immunologic and oncologic disorders.
  • T cells play an important role in regulating the immune response (F. Powrie and R.L. Coffman, Immunol. Today, 1993, 14, 270). Activation of T cells is often the initiating event in many inflammatory and autoimmune diseases. In addition to their role in immune surveillance, T cells can become autoreactive by recognizing self-antigens and thereby cause autoimmune disease such as rheumatoid arthritis and inflammatory bowel disease.
  • T cell receptor is the antigen-specific component of the T cell and is activated when the receptor is engaged with foreign or self-antigenic peptides.
  • TCR enzyme-mediated signal transduction cascades is initiated which results in the production of pro-inflammatory cytokines such as interleukin-2 (IL- 2).
  • IL-2 interleukin-2
  • IL-2 The release of IL-2 is critically important since this lymphokine is required for T- lymphocyte proliferation, differentiation, and effector function. Clinical studies have shown that interference with IL-2 activity effectively suppresses immune response in vivo (T.A. Waldmann, Immunol. Today, 1993, 14, 270). Accordingly, agents which inhibit T- lymphocyte activation and subsequent IL-2 production, or block the activity of IL-2 are therapeutically useful for selectively suppressing immune response in a patient in need of such immunosuppression.
  • the eight members ofthe src family of tyrosine kinases are src, lck, fyn, lyn, hck, fgr, blk and yes (J.B. Bolen, J.S. Brugge, Ann. Rev. Immunol, 1997, 15, 371). These can be divided into 2 groups based on their pattern of tissue expression. Src, fyn and yes have a broad distribution while expression of lck, lyn, hck, fgr, and blk is largely limited to hemopoietic cells.
  • the therapeutic effects of inhibiting kinases ofthe src family can be ascertained by linking functional defects seen in gene disruption studies in mice.
  • Src(-/-) mice had severe abnormalities in bone remodeling. Inhibition of src may therefore be useful in treating osteoporosis.
  • Lck(-/-) mice display a complete lack of CD4+ cells and are unable to mount antigen-dependent immune responses.
  • a kinase of particular interest is p561ck, which is only expressed in T-cells.
  • the tyrosine kinase p561ck is a required element to initiate the activation response from the TCR intracellular domains to other signaling proteins.
  • T cells which lack the p561ck protein are unable to signal through the T cell receptor (D.B. Straus and A. Weiss, Cell, 1992, 70, 585).
  • Transfection of p561ck back into these cell lines restores TCR responsiveness.
  • inactivation ofthe p561ck gene leads to lack of proper thymocyte development (T.J. Molina et al, Nature, 1992, 357, 161).
  • p561ck plays a crucial role in T cell maturation and antigen-induced T-cell activation. Therefore, an agent blocking p561ck would effectively block T cell function, act as an immunosuppressive agent and have potential utility in autoimmune diseases, for example rheumatoid arthritis, multiple sclerosis, lupus, transplant rejection and allergic diseases (J.H. Hanke et al., Inflamm. Res., 1995, 44, 357).
  • Inhibitors of other members ofthe src family of non-receptor tyrosine kinases are also useful for treating various disease states.
  • Src is present in osteoclasts, and is important in bone remodeling.
  • inactivation of p60src diminishes bone resorption by osteoclasts (P. Soriano et al., Cell 1991, 64, 693, B.F. Boyce et al. J. Clin. Invest 1992, 90, 1622), it is therefore possible that inhibitors ofthe kinase activity of p60src are useful in the treatment of osteoporosis, Paget's disease and inflammation of bones and joints.
  • Src kinases have been found to be activated in tumors, including breast and colon cancers, melanoma and sarcoma.
  • tumors including breast and colon cancers, melanoma and sarcoma.
  • a number of primary tumors and tumor cell lines from patients with breast cancer, colon cancer, melanoma and sarcoma have been shown to have elevated src kinase activity, and activating src mutations are seen in some advanced colon cancers.
  • Inhibitors of src kinase had significant antiproliferative activity against cancer cell lines (M.M. Moasser et al., Cancer Res., 1999, 59, 6145) and inhibited the transformation of cells to an oncogenic phenotype (R. Kami et al., Oncogene, 1999, 18, 4654) suggesting that src kinase inhibitors may be useful anti- cancer agents.
  • src family kinases participate in signal transduction in several cell types.
  • fyn like lck, is involved in T-cell activation.
  • Hck and fgr are involved in Fc gamma receptor mediated oxidative burst of neutrophils.
  • Src and lyn are believed to be important in Fc epsilon induced degranulation of mast cells, and so may play a role in asthma and other allergic diseases.
  • the kinase lyn is known to be involved in the cellular response to DNA damage induced by UV light (T. Hiwasa, FEBS Lett. 1999, 444, 173) or ionizing radiation (S. Kumar, J. Biol Chem, 1998, 273, 25654). Inhibitors of lyn kinase may thus be useful as potentiators in radiation therapy.
  • Platelet derived growth factor is a potent mitogen for smooth muscle cells. Its receptor (PDGFR) is a member of the receptor tyrosine kinase family (L. Claesson- Welsh, J. Biol Chem, 1994, 269, 32023). PDGF is involved in atherosclerosis and restenosis (K.E. Bornfeldt, Trends Cardiovasc. Med., 1996, 6, 143). In addition, receptor tyrosine kinases including PDGFR kinase have been implicated as contributing factors in cancer (A. Levitzki and A. Gazit, Science, 1995, 267, 1782) including ovarian (M.B.
  • Inhibitors of PDGFR kinase are thus useful in the treatment of fibrotic diseases, restenosis and PDGF-dependent tumors. Reports have appeared in the literature of agents that inhibit the kinase activity of p561ck kinase and thus inhibit T cell activation. These include the natural product lavendustin A, and analogs (M.S. Smyth, J. Med.
  • U.S. Pat. No. 4,176,184 discloses imidazoisoquinoline-diones, which are described as being useful as cardiotonics, hypotensives, antithrombotics and antiarrhythmics.
  • DE 3410168 Al discloses imidazoisoquinoline-dione derivatives, these compounds are described as being useful as cardiotonic agents in which the substituent on the fused imidazole ring is a pyridine ring bridged to the imidazole carbon by a -C 4 alkyl group, a vinyl group or a chemical bond.
  • EP 322 746 Al discloses heterocyclic lactam derivatives described as being useful as cardiotonic agents, antihypertensive agents and vasodilators.
  • the compounds of the present invention represent a novel structural class, which is distinct from previously reported tyrosine kinase inhibitors.
  • diseases and pathological conditions mediated by src-family tyrosine kinases and PDGFR kinase such as autoimmune diseases, transplant rejection, psoriasis, osteoporosis, Paget's disease, cancer, including src-dependent tumors and PDGF-dependent tumors, atherosclerosis, restenosis and allergic diseases, using the novel compounds ofthe invention.
  • a ⁇ ⁇ is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more R ⁇ , R 2 and
  • X is NH, N-C ⁇ . 3 alkyl, N-cyclopropyl, S or O;
  • R a is H, d-ioalkyl, C 2 . 10 alkenyl or C 2 . 10 alkynyl, each of which may be branched or cyclic; or R a is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more C ⁇ . 6 alkyl, . 6 alkoxy, halogen, OH, oxo, NRioR ⁇ , aryl or heteroaryl, each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, C ⁇ . 3 alkyl, Cj.
  • Rj and R 2 are the same or different and selected from H, halogen, CN, NO 2 , C MO branched or unbranched saturated or unsaturated alkyl, CM O branched or unbranched alkoxy, C MO branched or unbranched acyl, C O branched or unbranched acyloxy, C MO branched or unbranched alkylthio, aminosulfonyl, di-(C ⁇ _ 3 )alkylaminosulfonyl, NR 10 R11, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned Ri and R are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH,
  • R 3 is H, halogen, OH, (CH 2 ) n NR ⁇ 0 Rn, CONR 10 Rn, (CH 2 ) n CO 2 R 12 ; C ⁇ - 3 alkyl optionally substituted with OH, C 1 . 3 alkoxy optionally halogenated or C ⁇ alkylthio;
  • R ⁇ is C ⁇ . 3 alkyl or H
  • R 7 is C ⁇ . 6 alkyl branched or unbranched or H
  • R 8 is H, C ⁇ . 6 alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or C u3 alkoxy
  • R 8 is (CH 2 ) m NR ⁇ 0 Rn, (CH 2 ) m NR ⁇ 0 COR ⁇ 2 , (CH 2 ) n CO 2 R ⁇ 2 , (CH 2 ) n CONR ⁇ oR ⁇
  • R 8 is phenyl or heteroaryl, each being optionally substituted with C ⁇ _ 3 alkyl, C ⁇ . 3 alkoxy, OH, -SO 3 H or halogen;
  • R is H, CN or CONRjoRn; or R 9 is Ci.ioalkyl branched or unbranched, C 3 - ⁇ ocycloalkyl, C 5 . 7 cycloalkenyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl each being optionally substituted with one or more C M ocycloalkyl, C 3 . ⁇ 0 cycloalkylidene, C . cycloalkenyl, halogen, OH, oxo, CN, C ⁇ .
  • R JO and R ⁇ may be the same or different and are each independently selected from H, OH, Cu 3 alkoxy, C ⁇ . 6 alkyl branched or unbranched, C 3 . 8 cycloalkyl, aryl, arylC ⁇ . 3 alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylC ⁇ alkyl or heteroaryl are optionally substituted with OH, C ⁇ . 3 alkoxy, CN, NO 2 , C ⁇ . 3 acyloxy, CO 2 R 12 , NR ⁇ 3 R 14 , O(CH 2 ) 2 .
  • R 12 is H, C ⁇ _ 6 alkyl or C 3 . 8 cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C ⁇ alkoxy or NR ⁇ 3 R 14 ; or R ⁇ 2 is phenyl or heterocycle, optionally substituted with one to three groups selected from C ⁇ . 3 alkyl, C ⁇ _ 3 alkoxy, halogen, (CH 2 ) m NR ⁇ 0 R ⁇ , (CH 2 ) conflictCONR ⁇ oRn and O(CH 2 ) M NR 10 R ⁇ 1;
  • R ⁇ 3 and R ⁇ 4 are each independently selected from H and C ⁇ . 6 alkyl optionally substituted with C ⁇ - 3 alkoxy, OH or phenyl; or R 1 and R ⁇ 4 together form a chain completing a ring, said chain is (CH 2 ) 4 . 5 or
  • R ⁇ 5 is H or . 3 alkyl
  • each ofthe above Ari are optionally substituted by one or more Ri, R 2 and R ;
  • R a is H, Ci- ⁇ alkyl, C 2 . 5 alkenyl, C 2 . 5 alkynyl, phenyl or heteroaryl selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; each Rg being optionally substituted with one or more phenyl, halogen, C ⁇ - alkyl, C ⁇ - 3 alkoxy, OH, oxo, or NR 10 R ⁇ ; wherein Ra is at the 4- position;
  • R ⁇ and R 2 are as hereinabove defined;
  • R 3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
  • R$ is H, C ⁇ - 3 alkyl branched or unbranched, saturated or unsaturated, optionally substituted with OH; or Rs is (CH 2 ) 2 . 3 NR 10 Rn, (CH 2 ) n CO 2 R 12 or (CH 2 ) n CONR 10 Rn; R 9 is CN or CONRioRii; or R 9 is C ⁇ . 3 alkyl branched or unbranched, C 2 ⁇ alkenyl, C 2 - 4 alkynyl each being optionally substituted with one or more C 5 . 7 cycloalkyl, C 5 . 7 cycloalkylidene, C 5 . 7 cycloalkenyl,OH, CN, C ⁇ .
  • R is aryl,heteroaryl or heterocycle, each optionally substituted with one to three groups selected from Cj. 3 alkyl optionally substituted with phenyl or C ⁇ . 3 alkoxy, halogen, CN, oxo, (CH 2 ) n NR ⁇ oR ⁇ , (CH 2 ) n CO 2 R ⁇ 2 ; (CH 2 ) n CONR 10 Rn and O(CH 2 ) 2 . 4 NR 10 R U ;
  • R ⁇ and R 9 together form a saturated or unsaturated 5 or 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by C ⁇ . 3 alkyl or OH, or optionally spiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3 dioxolane group or 1,3 dithiolane group optionally substituted by C ⁇ . 3 alkyl, C ⁇ . 3 alkoxy, OH or (CH 2 ) n NR 10 Rn;
  • R 10 and Rn may be the same or different and are each independently selected from H, OH, d. 3 alkoxy, C ⁇ - 6 alkyl branched or unbranched, C . 8 cycloalkyl, benzyl and phenyl; wherein said alkyl, cycloalkyl, benzyl or phenyl are optionally substituted with OH, C ⁇ . 3 alkoxy, C ⁇ . 3 acyloxy, CN, NO 2 , CO 2 R ]2 , NR ⁇ 3 R ⁇ 4 , O(CH 2 ) 2 . 4 NR 13 R H or phenyl;
  • R 12 is H, C ⁇ . 6 alkyl or C 5 . cycloalkyl, each optionally substituted with phenyl, OH, Ci- 3 alkoxy or NR ⁇ 3 R ⁇ 4 ; or Rj 2 is phenyl or heterocycle, each optionally substituted with one to three groups selected from C ⁇ . 3 alkyl, C ⁇ . alkoxy, halogen, (CH ) m NR ⁇ oRn, (CH 2 ) n CONRioRii and O(CH 2 ) 2 - 4 NR 10 Rn;
  • R1 3 and R 14 are each independently selected from H and d- 6 alkyl optionally substituted with C ⁇ . 3 alkoxy, OH or phenyl;
  • R ⁇ 3 and R ⁇ 4 together form a chain completing a ring, said chain is (CH ) 4 . 5 or (CH 2 ) 2 O(CH 2 ) 2 ;
  • R ]5 is H.
  • Ari is phenyl, or pyridyl, wherein each is optionally substituted by one or more
  • X is NH or N-CH 3 ;
  • Y is NH
  • R a is H, hydroxyC ⁇ . 2 alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C 3 . 5 alkynyl substituted by C ⁇ . 3 alkoxy or phenyl;
  • Ri and R 2 are the same or different and selected from: H, halogen, C ⁇ . 3 alkyl, wherein the C ⁇ - 3 alkyl are optionally partially or fully halogenated, NO 2 , NR ⁇ 3 R ⁇ 4 ;
  • R 3 is H, halogen, methoxy or methyl; R 4 and R 5 together complete a fused ring of formula B;
  • Rs is H, C ⁇ . 3 alkyl optionally substituted with OH; or R 8 is (CH 2 ) 2 . 3 NR ⁇ 0 Rn or CO 2 R ⁇ 2 ;
  • R 9 is aryl or heteroaryl optionally substituted with one to three groups selected from C ⁇ . 3 alkyl optionally substituted with phenyl, C ⁇ . 3 alkoxy, halogen, amino or CONH 2 ;
  • R 8 and R together form a cyclopentene ring spiro-fused to a 1,3 dioxolane group, said 1,3 dioxolane group being optionally substituted by C ⁇ . 3 alkyl, C ⁇ _ 3 alkoxy, OH or (CH 2 ) n NR 10 Rn;
  • Rio and Ri ⁇ may be the same or different and are each independently selected from H, OH, C ⁇ _ 3 alkoxy, C ⁇ . 3 alkyl branched or unbranched, C 5 . cycloalkyl or phenyl, wherein said alkyl, cycloalkyl or phenyl are optionally substituted with OH, C ⁇ . 3 alkoxy, Ci. 3 acyloxy, NO 2 , CO 2 R ]2 , NR ⁇ 3 R ⁇ 4 , O(CH 2 ) M NR ⁇ 3 R 14 or phenyl;
  • R ⁇ 2 is H, C ⁇ . 3 alkyl or C 5 . 7 cycloalkyl, each optionally substituted with phenyl, OH, Ci. 3 alkoxy or NRj 3 R ⁇ 4 ; or R ⁇ 2 is phenyl or is a saturated, 4- to 6-membered nitrogen- containing heterocycle, each optionally substituted with one to three groups selected from d. 3 alkyl, C ⁇ _ 3 alkoxy, halogen, (CH 2 ) m NR 10 Rn, (CH 2 ) n CONR ⁇ 0 Rn and O(CH 2 ) 2 .
  • R ⁇ 3 and R ⁇ 4 are each independently selected from H and C ⁇ _ alkyl optionally substituted with d- 3 alkoxy or OH; or Rj 3 and Rj 4 together form a chain completing a ring, said chain is (CH ) 4 . 5 or
  • Ari is phenyl
  • R a is H or hydroxymethyl
  • Ri and R 2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO 2 and NH 2 ;
  • R 3 is H, chloro, fluoro, bromo or methoxy
  • Rio and Rn may be the same or different and are each independently selected from H, OH, methoxy, C ⁇ . 3 alkyl branched or unbranched or C 5 . 7 cycloalkyl, wherein said alkyl or cycloalkyl are optionally substituted with OH, NR ⁇ 3 R ⁇ 4 or phenyl;
  • R ⁇ 2 is C ⁇ . alkyl optionally substituted with morpholino; or R ⁇ 2 is phenyl or is azetidinyl, pyrrolidinyl or piperidinyl, each optionally substituted with one to three groups selected from C ⁇ . 3 alkyl, C ⁇ . 3 alkoxy and halogen.
  • the invention provides novel compounds ofthe formula I:
  • Ari is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocyle is optionally substituted by one or more Rj, R 2 and R3;
  • X is NH, N-Ci. 3 alkyl, N-cyclopropyl, S or O;
  • Y is NR1 5 , S or O;
  • R a is H, Ci-ioalkyl, C 2 . ⁇ oalkenyl or C 2 . ⁇ oalkynyl, each of which may be branched or cyclic; or R a is aryl or heteroaryl; wherein each R a is independently optionally substituted with one or more C ⁇ - 3 alkyl, C ⁇ . 6 alkoxy, halogen, OH, oxo, NRioRn, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, C ⁇ . alkyl, C ⁇ . 3 alkoxy, hydroxyC ⁇ . 3 alkyl and (CH 2 ) m NR ⁇ oRn; and wherein R a is attached at the 4- or 5- position;
  • Ri and R 2 are the same or different and selected from H, halogen, CN, NO 2 , C ⁇ -1 0 branched or unbranched saturated or unsaturated alkyl, Ci.10 branched or unbranched alkoxy, d-io branched or unbranched acyl, d_ ⁇ o branched or unbranched acyloxy, Cj.io branched or unbranched alkylthio, aminosulfonyl, di-(C ⁇ .
  • Ri and R 2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, C ⁇ - 6 branched or unbranched alkyl, C 3 . cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C ⁇ . )alkylaminocarbonyl;
  • R 3 is H, halogen, OH, (CH 2 ) n NR ⁇ 0 Rn, (CH 2 ) n CO 2 R 12 ; C ⁇ . 3 alkyl optionally substituted with OH, C ⁇ - 3 alkoxy optionally halogenated or C ⁇ . 3 alkylthio;
  • R ⁇ is C ⁇ - alkyl or H
  • R 7 is C ⁇ . 6 alkyl branched or unbranched or H
  • R 8 is H, C ⁇ -6 alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or C ⁇ . 3 alkoxy; or R 8 is (CH 2 ) m NR ⁇ 0 Rn, (CH 2 ) m NR ⁇ 0 COR ⁇ 2 , (CH 2 ) n CO Ri 2 , (CH 2 ) n CONR ⁇ oRn; or Rs is phenyl or heteroaryl, each being optionally substituted with C ⁇ . 3 alkyl, C ⁇ . 3 alkoxy, OH, -SO 3 H or halogen;
  • R is H; or R is Ci-ioalkyl branched or unbranched, C 3 . ⁇ o cycloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl each being optionally substituted with one or more halogen, OH, oxo, CN, C ⁇ . 3 alkoxy, NRioRn, NR ⁇ 0 COR] 2 , SR ]2 , CONR10R11, CO 2 R ⁇ 2 , aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with C ⁇ . 3 alkyl, C ⁇ .
  • R 9 is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to three groups selected from C ⁇ . 3 alkyl optionally substituted with phenyl, Ci- 3 alkoxy, halogen, (CH 2 ) n NR ⁇ 0 Rn, (CH 2 ) n CO 2 R ⁇ 2 ; (CH 2 ) n CONR ⁇ 0 Rn and O(CH 2 ) 2 .
  • R 8 and R together form a saturated or unsaturated 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two OH, oxo or (CH 2 ) n NR 10 Rn;
  • Rio and Ri i may be the same or different and are each independently selected from H, OH, C ⁇ . 3 alkoxy, C ⁇ . 6 alkyl branched or unbranched, C 3 . 8 cycloalkyl, aryl, arylC]. 3 alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylC ⁇ . 3 alkyl or heteroaryl are optionally substituted with OH, C ⁇ . 3 alkoxy, C ⁇ - 3 acyloxy, CO 2 R ⁇ 2 , NR ⁇ 3 R ⁇ 4 , O(CH 2 ) 2 . 4 NR 13 R 14 , aryl or heteroaryl;
  • R ⁇ 2 is H, C ⁇ _ 6 alkyl or C 3 . 8 cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C ⁇ . 3 alkoxy or NR ⁇ 3 Rj 4 ; or R ]2 is phenyl, optionally substituted with one to three groups selected from C ⁇ . 3 alkyl, C ⁇ - 3 alkoxy, halogen, (CH 2 ) m NR ⁇ oRn, (CH 2 ) n CONRioRn and O(CH 2 ) 2 ⁇ NR, 0 Rn ; R ⁇ 3 and R ⁇ are each independently selected from H and C ⁇ . 6 alkyl optionally substituted with C].
  • 3 alkoxy, OH or phenyl; or R ⁇ 3 and R] 4 together form a chain completing a ring, said chain is (CH 2 ) 4 . 5 or (CH 2 ) 2 O(CH 2 ) 2 ;
  • R 15 is H or C ⁇ . 3 alkyl
  • Ari is a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl; b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, cycloheptenyl; c) phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl; d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, qui
  • each ofthe above Ari are optionally substituted by one or more Ri, R and R 3 as hereinabove defined;
  • R a is H, C ⁇ - 6 alkyl, C 2 . 5 alkenyl, C 2 . 5 alkynyl, phenyl or heteroaryl selected from: pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; each R a being optionally substituted with one or more phenyl, halogen, C ⁇ . 3 alkyl, C ⁇ _ 3 alkoxy, OH, oxo, or NRioR ; wherein Ra is at the 4- position;
  • R 3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
  • Rs is H, C ⁇ - 3 alkyl branched or unbranched, saturated or unsaturated, optionally substituted with OH; or Rs is (CH 2 ) 2 . 3 NR ⁇ 0 Rn, (CH 2 ) n CO 2 R ⁇ 2 or (CH 2 ) n CONR ⁇ 0 Rn;
  • R 9 is C ⁇ _ 3 alkyl branched or unbranched, C 2 . 4 alkenyl, C - 4 alkynyl each being optionally substituted with one or more OH, CN, NRioRn, CONRioRn, CO 2 R ⁇ 2 , aryl or heteroaryl; wherein each aryl or heteroaryl is optionally substituted with C ⁇ . 3 alkyl, C ⁇ _ 3 alkoxy, halogen, (CH 2 ) n NR ⁇ 0 Rn or O(CH 2 ) M NR ⁇ 0 Rn; or R 9 is aryl or heteroaryl optionally substituted with one to three groups selected from C]. 3 alkyl optionally substituted with phenyl, C ⁇ .
  • R 8 and R 9 together form a saturated or unsaturated 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by OH;
  • Rio and Rn may be the same or different and are each independently selected from H, OH, C ⁇ - 3 alkoxy, C ⁇ . 6 alkyl branched or unbranched, C . 8 cycloalkyl, benzyl and phenyl; wherein said alkyl, cycloalkyl, benzyl or phenyl are optionally substituted with OH, Ci- 3 alkoxy, C ⁇ _ 3 acyloxy, CO 2 R ⁇ 2 , NR i R ⁇ 4 , O(CH 2 ) 2 . 4 NR ⁇ 3 R ⁇ 4 or phenyl;
  • R ⁇ 2 is H or C ⁇ . 6 alkyl optionally substituted with phenyl, OH, C ⁇ - 3 alkoxy or NR ⁇ 3 R ⁇ 4 ;
  • Ri 3 and Rj 4 are each independently selected from H and C ⁇ . 6 alkyl optionally substituted with C ⁇ - 3 alkoxy, OH or phenyl;
  • R 13 and R ⁇ 4 together form a chain completing a ring, said chain is (CH 2 ) 4 . 5 or (CH 2 ) 2 O(CH 2 ) 2 ;
  • R ⁇ 5 is H.
  • Ari is phenyl, or pyridyl
  • X is NH or N-CH 3 ;
  • Y is NH and R a is H, hydroxyC ⁇ . 2 alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo- propyl, vinyl or C 3 . 5 alkynyl substituted by C ⁇ - 3 alkoxy or phenyl;
  • Ri and R 2 are the same or different and selected from: halogen, C 1 . 3 alkyl, wherein the Cj. 3 alkyl are optionally partially or fully halogenated, NO 2 , NR J3 R ⁇ 4 ;
  • R 3 is H, halogen, methoxy or methyl
  • Rs is H, C ⁇ _ 3 alkyl optionally substituted with OH; or R 8 is (CH 2 ) 2 . 3 NR ⁇ 0 Rn or CO 2 R )2 ;
  • R 9 is methyl or C 2 . 3 alkenyl each being optionally substituted with one or more OH, CN, NRioRn, CONRioRn or CO 2 R ⁇ 2 ; or R 9 is heteroaryl optionally substituted with one to three groups selected from C ⁇ . 3 alkyl optionally substituted with phenyl, C ⁇ _ 3 alkoxy, halogen or amino;
  • Rio and Ri 1 may be the same or different and are each independently selected from H, OH, C ⁇ . 3 alkoxy, C ⁇ . 3 alkyl branched or unbranched, optionally substituted with OH, Ci. 3 alkoxy, C ⁇ . 3 acyloxy, CO 2 R ⁇ 2 , NR ⁇ 3 R ⁇ 4 , O(CH 2 ) 2 . 4 NR ⁇ 3 R ⁇ 4 or phenyl;
  • R ⁇ 2 is H or C ⁇ . 3 alkyl optionally substituted with phenyl, OH, C ⁇ _ 3 alkoxy or NR ⁇ 3 R ⁇ 4 ;
  • R ⁇ 3 and R] 4 are each independently selected from H and C ⁇ . 3 alkyl optionally substituted with C ⁇ - 3 alkoxy or OH; or R ⁇ 3 and R ⁇ 4 together form a chain completing a ring, said chain is (CH 2 ) 4 . 5 or (CH 2 ) 2 O(CH 2 ) 2 .
  • compounds of the formula (I) as described immediately above, and wherein:
  • Ari is phenyl
  • R a is H or hydroxymethyl
  • Ri and R 2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO 2 and NH 2 ;
  • R 3 is H, chloro, fluoro, bromo or methoxy
  • Rio and Rn may be the same or different and are each independently selected from H, OH, methoxy, C ⁇ _ 3 alkyl branched or unbranched, optionally substituted with OH, NR )3 R ⁇ 4 or phenyl; or Rio and Ri i together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C ⁇ - 2 alkyl; and
  • R ⁇ 2 is C ⁇ . 3 alkyl optionally substituted with morpholino.
  • X is NH, N-C ⁇ . 3 alkyl, N-cyclopropyl, S or O;
  • R a is H, Ci-ioalkyl, C 2 . ⁇ 0 alkenyl or C 2 . ⁇ 0 alkynyl, each of which may be branched or cyclic; or R a is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more C].
  • Ri and R 2 are the same or different and selected from H, halogen, CN, NO 2 , C MO branched or unbranched saturated or unsaturated alkyl, C MO branched or unbranched alkoxy, C O branched or unbranched acyl, C O branched or unbranched acyloxy, C MO branched or unbranched alkylthio, aminosulfonyl, di-(C ⁇ .
  • Ri and R 2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, C ⁇ . 6 branched or unbranched alkyl, C 3 - 7 cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C ⁇ .
  • R 3 is H, halogen, OH, (CH 2 ) n NR ⁇ 0 Rn, CONR 10 Rn, (CH 2 ) n CO 2 R 12 ; C ⁇ . 3 alkyl optionally substituted with OH, Cj. 3 alkoxy optionally halogenated or C1. 3 alkylthio;
  • R is C ⁇ - 3 alkyl or H
  • R 7 is Ci. 6 alkyl branched or unbranched or H
  • R 8 is H, C ⁇ - 6 alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or C t . 3 alkoxy; or Rs is (CH 2 ) m NR ⁇ 0 Rn, (CH 2 ) m NR] 0 COR ⁇ 2 , (CH 2 ) n CO 2 Ri 2 , (CH 2 ) n CONR 10 Rn or Rs is phenyl or heteroaryl, each being optionally substituted with C ⁇ - 3 alkyl, C ⁇ . 3 alkoxy, OH, -SO 3 H or halogen;
  • R 9 is H, CN or CONRioRni or R 9 is Ci.ioalkyl branched or unbranched, C 3 _ ⁇ ocycloalkyl, C 5 . 7 cycloalkenyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl each being optionally substituted with one or more C 3 - ⁇ ocycloalkyl, C 3 . ⁇ ocycloalkylidene, C .
  • Rio and Rn may be the same or different and are each independently selected from H, OH, C ⁇ _ 3 alkoxy, C ⁇ _ 6 alkyl branched or unbranched, C 3 . 8 cycloalkyl, aryl, arylC ⁇ _ 3 alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylC ⁇ . 3 alkyl or heteroaryl are optionally substituted with OH, C ⁇ . 3 alkoxy, CN, NO 2 , C ⁇ . 3 acyloxy, CO 2 R ⁇ 2 , NR )3 R ⁇ 4 , O(CH 2 ) 2 . 4 NR ⁇ 3 R ⁇ 4 , aryl or heteroaryl;
  • R ⁇ 2 is H, C[. 6 alkyl or C 3 . 8 cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C ⁇ . 3 alkoxy or NR ⁇ 3 R ⁇ 4 ; or R ⁇ 2 is phenyl or heterocycle, optionally substituted with one to three groups selected from C ⁇ _ 3 alkyl, C ⁇ . 3 alkoxy, halogen, (CH 2 ) m NR ⁇ 0 Rn, (CH 2 ) n CONR ⁇ 0 Rn and O(CH 2 ) 2 _ 4 NR ⁇ 0 Rn ; R ⁇ 3 and R ⁇ 4 are each independently selected from H and C ⁇ - 6 alkyl optionally substituted with C ⁇ . 3 alkoxy, OH or phenyl; or Rj 3 and R ⁇ 4 together form a chain completing a ring, said chain is (CH 2 ) 4 . 5 or
  • X is NH or N-CH 3 ;
  • R a is H, hydroxyC ⁇ - 2 alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo- propyl, vinyl or C 3 . 5 alkynyl substituted by C ⁇ _ 3 alkoxy or phenyl; and wherein R a is attached at the 4- position;
  • Ri and R 2 are the same or different and selected from: H, halogen, C ⁇ . 3 alkyl, wherein the d- alkyl is optionally partially or fully halogenated, NO 2 , NR ⁇ R] 4 ;
  • R 3 is H, halogen, methoxy or methyl
  • Rg is H, C ⁇ . 3 alkyl optionally substituted with OH; or R 8 is (CH 2 ) 2 . 3 NR ⁇ 0 Rn or CO 2 R ]2 ; R is CN; or R 9 is methyl, C 2 . 3 alkenyl or C . 3 alkynyl, each being optionally substituted with one or more Cs. 7 cycloalkylidene, C 5 .
  • R 9 is aryl or heteroaryl optionally substituted with one to three groups selected from C].
  • 3 alkyl optionally substituted with phenyl, C ⁇ . 3 alkoxy, halogen, amino or CONH 2 ;
  • R 8 and R 9 together form a cyclopentene ring spiro-fused to a 1,3 dioxolane group, said 1,3 dioxolane group being optionally substituted by C ⁇ _ 3 alkyl, C ⁇ . 3 alkoxy, OH or (CH 2 ) n NR, 0 Rn;
  • Rio and Rn may be the same or different and are each independently selected from H, OH, C ⁇ . alkoxy, C ⁇ _ 3 alkyl branched or unbranched, C 5 . 7 cycloalkyl or phenyl, wherein said alkyl, cycloalkyl or phenyl are optionally substituted with OH, C ⁇ . 3 alkoxy, Ci. 3 acyloxy, NO 2 , CO 2 R ⁇ 2 , NR ⁇ 3 R M , O(CH 2 ) 2 . 4 NR ⁇ 3 R M or phenyl;
  • R ⁇ 2 is H, C ⁇ . 3 alkyl or C 5 . 7 cycloalkyl, each optionally substituted with phenyl, OH, C ⁇ . alkoxy or NR ⁇ 3 R [4 ; or Rj 2 is phenyl or is a saturated, 4- to 6-membered nitrogen- containing heterocycle, each optionally substituted with one to three groups selected from C ⁇ . 3 alkyl, C ⁇ . 3 alkoxy, halogen, (CH 2 ) m NR ⁇ 0 Rn, (CH 2 ) n CONR ⁇ 0 Rn and O(CH 2 ) 2 .
  • R ⁇ 3 and R ⁇ 4 are each independently selected from H and C ⁇ _ 3 alkyl optionally substituted with d. 3 alkoxy or OH; or R ⁇ 3 and R ⁇ 4 together form a chain completing a ring, said chain is (CH 2 ) 4 . 5 or (CH 2 ) 2 O(CH 2 ) 2 .
  • compounds of the formula (la) described immediately above wherein:
  • R a is H or hydroxymethyl
  • Ri and R 2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO 2 and NH 2 ;
  • R 3 is H, chloro, fluoro, bromo or methoxy
  • Rio and Ri ⁇ may be the same or different and are each independently selected from H, OH, methoxy, C ⁇ . 3 alkyl branched or unbranched or C 5 . 7 cycloalkyl, wherein said alkyl or cycloalkyl are optionally substituted with OH, NR ⁇ R ⁇ 4 or phenyl;
  • R ⁇ 2 is C ⁇ - 3 alkyl optionally substituted with morpholino; or R ⁇ 2 is phenyl or is azetidinyl, pyrrolidinyl or piperidinyl, each optionally substituted with one to three groups selected from C ⁇ _ 3 alkyl, C ⁇ . 3 alkoxy and halogen.
  • X is NH, N-Cioalkyl, N-cyclopropyl, S or O;
  • Ra is H, Ci-ioalkyl, C 2 . ⁇ oalkenyl or C 2 . ⁇ oalkynyl, each of which may be branched or cyclic; or R a is aryl or heteroaryl; wherein each R a is independently optionally substituted with one or more C ⁇ . 6 alkoxy, halogen, OH, oxo, NRioRn, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, C ⁇ 3 alkyl, C ⁇ _ alkoxy, hydroxyC ⁇ - 3 alkyl and (CH 2 ) m NR ⁇ oRn; and wherein Ra is attached at the 4- or 5- position;
  • Ri and R 2 are the same or different and selected from H, halogen, CN, NO 2 , C MO branched or unbranched saturated or unsaturated alkyl, C MO branched or unbranched alkoxy, C O branched or unbranched acyl, CM O branched or unbranched acyloxy, C MO branched or unbranched alkylthio, aminosulfonyl, di-(C ⁇ .
  • Ri and R 2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, C ⁇ - 6 branched or unbranched alkyl, C 3 . cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C ⁇ .
  • R 3 is H, halogen, OH, (CH 2 ) ⁇ NR ⁇ 0 Rn, (CH 2 ) n CO 2 R ⁇ 2 ; C ⁇ . 3 alkyl optionally substituted with OH, C ⁇ - 3 alkoxy optionally halogenated or C1.3 alkylthio;
  • R ⁇ is C ⁇ - 3 alkyl or H
  • R is C ⁇ . 6 alkyl branched or unbranched or H
  • Rs is H, C ⁇ - 6 alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or C ⁇ . 3 alkoxy; or Rs is (CH 2 ) m NR ⁇ 0 Rn, (CH 2 ) m NR ⁇ 0 COR ⁇ 2 , (CH 2 ) n CO 2 R ⁇ 2 , (CH 2 ) n CONR ⁇ oRn or R 8 is phenyl or heteroaryl, each being optionally substituted with C ⁇ . 3 alkyl, C ⁇ . 3 alkoxy, OH, -SO 3 H or halogen;
  • R 9 is H; or R 9 is Ci-ioalkyl branched or unbranched, C 3 . ⁇ ocycloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl each being optionally substituted with one or more halogen, OH, oxo, CN, Ci. 3 alkoxy, NRioRn, NR ⁇ 0 COR ⁇ 2 , SRj 2 , CONRioRn, CO 2 R ⁇ 2 , aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with C ⁇ . 3 alkyl, C ⁇ .
  • R is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to three groups selected from C ⁇ . 3 alkyl optionally substituted with phenyl, Ci- 3 alkoxy, halogen, (CH 2 ) n NR ⁇ 0 Rn, (CH 2 ) n CO 2 R, 2 ; (CH 2 ) administratCONR 10 Rii and O(CH 2 ) 2 . 4 NR ⁇ oRn;
  • Rio and Rn may be the same or different and are each independently selected from H, OH, C ⁇ _ 3 alkoxy, C ⁇ _ 6 alkyl branched or unbranched, C 3 . 8 cycloalkyl, aryl, arylC]. 3 alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylC ⁇ . 3 alkyl or heteroaryl are optionally substituted with OH, C ⁇ . 3 alkoxy, C ⁇ . 3 acyloxy, CO 2 R ⁇ 2 , N ⁇ 3 R ⁇ 4 , O(CH 2 ) 2 . 4 NR ⁇ 3 R ⁇ 4 , aryl or heteroaryl;
  • R ⁇ 2 is H, C ⁇ - 6 alkyl or C 3 . 8 cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C ⁇ . 3 alkoxy or NR ⁇ 3 R ⁇ 4 ; or R ⁇ is phenyl, optionally substituted with one to three groups selected from C ⁇ alkyl, d ⁇ alkoxy, halogen, (CH 2 ) m NR ⁇ oR u , (CH 2 ) conflictCONR 10 R ⁇ i and O(CH 2 ) 2 . 4 NR 10 Rn ;
  • Ri 3 and R ⁇ 4 are each independently selected from H and C]. 6 alkyl optionally substituted with C ⁇ . alkoxy, OH or phenyl; or R ⁇ 3 and R ⁇ 4 together form a chain completing a ring, said chain is (CH 2 ) 4 . 5 or (CH 2 ) 2 O(CH 2 ) 2 ; m is 1-4, n is 0-3 and p is 0-2; and
  • X is NH or N-CH 3 ;
  • R a is H, hydroxyCi. 2 alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo- propyl, vinyl or C 3 . 5 alkynyl substituted by C ⁇ . 3 alkoxy or phenyl; and wherein R a is attached at the 4- position;
  • Ri and R 2 are the same or different and selected from: halogen, C ⁇ _ 3 alkyl, wherein the C 1 . 3 alkyl is optionally partially or fully halogenated, NO 2 , NRj 3 R ⁇ 4 ;
  • R 3 is H, halogen, methoxy or methyl
  • Rs is H, C ⁇ . 3 alkyl optionally substituted with OH; or R 8 is (CH 2 ) 2 _ 3 NR ⁇ 0 Rn or CO 2 R ⁇ 2 ;
  • R is methyl or C 2 . 4 alkenyl each being optionally substituted with one or more OH, CN, NRioRn, CONRioRn or CO 2 R ⁇ 2 ; or R 9 is heteroaryl optionally substituted with one to three groups selected from C ⁇ - 3 alkyl optionally substituted with phenyl, C ⁇ . 3 alkoxy, halogen or (CH 2 ) n NR ⁇ oR ⁇ 1 ; Rio and Rn may be the same or different and are each independently selected from H, OH, C ⁇ . 3 alkoxy, C ⁇ . 3 alkyl branched or unbranched, optionally substituted with OH, C ⁇ . alkoxy, C ⁇ . 3 acyloxy, CO 2 R ]2 , NR ⁇ 3 R ⁇ , O(CH 2 ) 2 ⁇ NR )3 R ⁇ 4 or phenyl;
  • R ⁇ 2 is H or C ⁇ . 3 alkyl optionally substituted with phenyl, OH, C ⁇ _ 3 alkoxy or NR ⁇ 3 R ⁇ 4 ;
  • R ⁇ 3 and R ⁇ 4 are each independently selected from H and C ⁇ . 3 alkyl optionally substituted with C ⁇ . 3 alkoxy or OH; or R ⁇ 3 and R ⁇ 4 together form a chain completing a ring, said chain is (CH 2 ) 4 . 5 or (CH 2 ) 2 O(CH 2 ) 2 .
  • R a is H or hydroxymethyl
  • Ri and R 2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO 2 and NH 2 ;
  • R 3 is H, chloro, ffuoro, bromo or methoxy
  • Rio and Rn may be the same or different and are each independently selected from H, OH, methoxy, d. 3 alkyl branched or unbranched, optionally substituted with OH, NR ⁇ 3 R ⁇ 4 or phenyl; or Rio and Ri i together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C ⁇ . 2 alkyl; and R ⁇ 2 is C ⁇ . 3 alkyl optionally substituted with morpholino.
  • intermediate compounds ofthe formula(III) useful in the synthetic schemes and examples set forth below.
  • intermediate compounds ofthe formula(III), representedative examples shown Table 1 below which possess physiological activity.
  • Ari is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more Ri, R 2 and R 3 ;
  • X is NH, N-C ⁇ - 3 alkyl, N,cyclopropyl, S or O;
  • Y is NRis, S or O;
  • R a is H, Ci-ioalkyl, C 2 . ⁇ oalkenyl or C 2 _ ⁇ oalkynyl, each of which may be branched or cyclic; or R a is aryl or heteroaryl; wherein each R a is independently optionally substituted with one or more C ⁇ . 3 alkyl, C ⁇ - 6 alkoxy, halogen, OH, oxo, NRioRn, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, C ⁇ _ 3 alkyl, Cj. alkoxy, hydroxyC ⁇ . 3 alkyl and (CH 2 ) m NR ⁇ oRn; and wherein R a is attached at the 4- or 5- position;
  • Ri and R 2 are the same or different and selected from H, halogen, CN, NO 2 , C MO branched or unbranched saturated or unsaturated alkyl, C MO branched or unbranched alkoxy, C MO branched or unbranched acyl, C MO branched or unbranched acyloxy, C MO branched or unbranched alkylthio, aminosulfonyl, di-(C ⁇ _ 3 )alkylaminosulfonyl, NRioRn, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned Ri and R 2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, - 6 branched or unbranched alkyl, C 3 . 7 cycloalkyl, phenyl, naphthyl, hetero
  • R 3 is H, halogen, OH, (CH 2 ) conflictNR 10 R n , (CH 2 ) n CO 2 R ⁇ 2 ; C ⁇ - 3 alkyl optionally substituted with OH, C ⁇ . 3 alkoxy optionally halogenated or C ⁇ . 3 alkylthio;
  • R is C ⁇ - 6 alkyl branched or unbranched or H
  • Rio and Rn may be the same or different and are each independently selected from H, OH, C ⁇ -3alkoxy, C ⁇ . 6 alkyl branched or unbranched, C 3 . 8 cycloalkyl, aryl, and heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl are optionally substituted with OH, CO 2 R] 2 , NR 13 R 1 4, O(CH 2 ) 2 . 4 NR ⁇ 3 R ⁇ , aryl or heteroaryl;
  • R ⁇ 2 is H, Ci. 6 alkyl or C 3 . 8 cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C ⁇ - 3 alkoxy or NRj 3 R ⁇ 4 ; or R ⁇ 2 is phenyl, optionally substituted with one to three groups selected from C ⁇ _ 3 alkyl, C ⁇ _ 3 alkoxy, halogen, (CH 2 ) m NR, 0 R,i, (CH 2 ) n CONR ⁇ oRn and O(CH 2 ) 2 . 4 NR ⁇ 0 Rn ; R ⁇ and R ⁇ 4 are each independently selected from H and C ⁇ .
  • n 0-3 and p is 0-2.
  • each of the above Ari are optionally substituted by one or more Ri, R 2 and R 3 as hereinabove defined;
  • R a is H, Ci- ⁇ alkyl, C 2 . 5 alkenyl, C 2 . 5 alkynyl, phenyl or heteroaryl selected from: pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; each R a being optionally substituted with one or more phenyl, halogen, C ⁇ . 3 alkyl, C ⁇ _ 3 alkoxy, OH, oxo, or NRioRn; wherein R a is at the 4- position; R 3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
  • Rg is Ci_ 3 aikyl or H
  • R is C ⁇ . 6 alkyl branched or unbranched or H
  • Rio and Rn may be the same or different and are each independently selected from H, OH, C ⁇ - 3 alkoxy, C ⁇ - 6 alkyl branched or unbranched, C 3 . 8 cycloalkyl, benzyl and phenyl; wherein said alkyl, cycloalkyl or phenyl are optionally substituted with OH, C ⁇ . 3 alkoxy, C ⁇ - 3 acyloxy, CO 2 Rj 2 , NR, 3 R i4 , O(CH 2 ) 2 _ 4 NR ⁇ 3 R ⁇ 4 or phenyl;
  • Ri 2 is H or C h alky! optionally substituted with phenyl, OH, C ⁇ . 3 alkoxy or NR ⁇ 3 R ⁇ 4 ;
  • R ⁇ 3 and Rj 4 are each independently selected from H and C ⁇ . 6 alkyl optionally substituted with C ⁇ . 3 alkoxy, OH or phenyl; and or R ⁇ 3 and R ]4 together form a chain completing a ring, said chain is (CH 2 ) 4 . 5 or (CH 2 ) 2 O(CH 2 ) 2 .
  • Ari is phenyl, or pyridyl
  • R a is H, hydroxyC]. 2 alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo- propyl, vinyl or C 3 . 5 alkynyl substituted by C ⁇ _ 3 alkoxy or phenyl;
  • Ri and R 2 are the same or different and selected from: halogen, C ⁇ _ 3 alkyl, wherein the C ⁇ _ 3 alkyl are optionally partially or fully halogenated, NO 2 , NR ⁇ 3 Rj 4 ;
  • R 3 is H, halogen, methoxy or methyl
  • Rio and Rn may be the same or different and are each independently selected from H, OH, C ⁇ . 3 alkoxy, C ⁇ . 3 alkyl branched or unbranched, optionally substituted with OH, C ⁇ . 3 alkoxy, C ⁇ - 3 acyloxy, CO 2 R ⁇ 2 , NR ⁇ 3 R ⁇ , O(CH 2 ) 2 . NR ]3 R ⁇ 4 or phenyl; or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C ⁇ . 3 alkyl, C ⁇ . 3 alkoxy or OH;
  • R ⁇ is H or C ⁇ . 3 alkyl optionally substituted with phenyl, OH, C]. 3 alkoxy or NR ⁇ 3 Rj 4 ;
  • R ⁇ 3 and Rj 4 are each independently selected from H and C]. 3 alkyl optionally substituted with C ⁇ . 3 alkoxy or OH; or R[ 3 and Rj 4 together form a chain completing a ring, said chain is (CH 2 ) 4 . 5 or
  • Ari is phenyl
  • R a is H or hydroxy methyl
  • Ri and R 2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO 2 and NH 2 ;
  • R 3 is H, chloro, fluoro, bromo or methoxy
  • Rio and Rn may be the same or different and are each independently selected from H, OH, methoxy, C ⁇ . 3 alkyl branched or unbranched, optionally substituted with OH, NR ⁇ 3 R ⁇ 4 or phenyl; or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C ⁇ - 2 alkyl; and R ⁇ 2 is C ⁇ - 3 alkyl optionally substituted with morpholino.
  • Any compounds of this invention containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention.
  • Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
  • Some ofthe compounds of the invention can exist in more than one tautomeric form.
  • the invention includes all such tautomers.
  • the compounds ofthe invention are only those which are contemplated to be 'chemically stable' as will be appreciated by those skilled in the art.
  • a compound which would have a 'dangling valency', or a 'carbanion' are not compounds contemplated by the invention.
  • alkoxy is a C ⁇ - 6 alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy.
  • alkyl, alkylene or alkynyl groups shall be understood as being branched or unbranched unless otherwise specified. Other more specific definitions are as follows:
  • halogen as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine.
  • heteroaryl refers to a stable 5-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic aromatic heterocycle radical.
  • Each heterocycle consists of carbon atoms and from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur.
  • the heterocycle may be attached by any atom ofthe cycle, which results in the creation of a stable structure.
  • heteroaryl radicals include, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, 2,4-dioxo-quinazolinyl, imidazo[4,5-c]pyridinyl and indazolyl, or a fused heteroaryl such as cyclopentenopyridine, cyclohexanopyridine
  • heterocycle refers to a stable 4-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated, and is non-aromatic.
  • Each heterocycle consists of carbon atoms and from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur.
  • the heterocycle may be attached by any atom ofthe cycle, which results in the creation of a stable structure.
  • Example "heterocycle” radicals include azetidinyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl,indolinyl, 2,3-dihydrobenzimidazolyl and 2,3-dihydro- lH-imidazo[4,5-c] pyridinyl.
  • nitrogen and “sulfur” and their respective elements symbols include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
  • aryl shall be understood to mean a 6-10 membered aromatic carbocycle, "aryl” includes, for example, phenyl and naphthyl; other terms comprising "aryl” will have the same definition for the aryl component, examples of these moieties include: arylalkyl, aryloxy or arylthio.
  • carbocycle shall be understood to mean a 3-10 membered aromatic or nonaromatic cyclic carbon chain.
  • nonaromatic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl and the like.
  • aromatic carbocycles include the "aryl" compounds as described hereinabove.
  • R can be a Ci-ioalkyl, saturated or unsaturated, branched or unbranched, or R can be "aryl” as defined hereinabove.
  • Acyloxy shall be understood to mean an R- CO 2 - group wherein R is as defined in this paragraph.
  • the invention includes pharmaceutically acceptable derivatives of compounds of the invention.
  • a "pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt or ester of a compound of this invention, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, a pharmacologically active metabolite or pharmacologically active residue thereof.
  • Pharmaceutically acceptable salts ofthe compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.
  • Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C J-C4
  • the compounds of this invention include prodrugs of compounds ofthe invention.
  • Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce a compound of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction, enzymatically, metabolically or otherwise. Specifically, when a prodrug of this invention is administered to a patient, the prodrug may be transformed into a compound of the invention, thereby imparting the desired pharmacological effect.
  • the compounds ofthe invention may be prepared by the methods described below. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitered by thin layer chromatography (TLC) if desired. If desired, intermediates and products may be purified by chromatography on silica gel and/or recrystallization. Starting materials and reagents are either commercially available or may be prepared by one skilled in the art using methods described in the chemical literature.
  • An optionally substituted diamine II is reacted with an aryl isothiocyanate in a suitable solvent such as EtOAc, DMF or THF at about ambient to reflux temperature for about 3 to 24 hr to provide thiourea III.
  • a suitable solvent such as EtOAc, DMF or THF
  • Reaction ofthe thiourea with a suitable activating agent such as 1,3-dicyclohexylcarbodiimide (DCC) or mercuric oxide in a suitable solvent such as THF or DMF at about ambient to reflux temperature provides I or a precursor to I which may undergo further chemical transformation to obtain the desired compound. If desired, one may perform the two steps without isolating the thiourea, by adding DCC or mercuric oxide to the reaction of II and the aryl isothiocyanate.
  • a suitable activating agent such as 1,3-dicyclohexylcarbodiimide (DCC) or mercuric oxide in a suitable solvent such as THF or DMF at about ambient to reflux temperature
  • One may also prepare benzothiazoles (formula I, X S) by Method A, starting with the analogous aminothiophenol. Preferably, one may also use Method B illustrated in Scheme II and described below.
  • an appropriately substituted aniline is reacted with an aryl isothiocyanate as in Method A to provide thiourea V.
  • the starting diamine (II) in Method A may be prepared by reduction of a nitroaniline, for example under hydrogen atmosphere in the presence of a suitable catalyst such as palladium on carbon in a suitable solvent, such as EtOAc or HO Ac.
  • a suitable catalyst such as palladium on carbon in a suitable solvent, such as EtOAc or HO Ac.
  • Method C one may reduce intermediate IX as described above, to the corresponding diamine and form the benzimidazole by Method A prior to formation of the isoquinolinone.
  • reaction with a terminal alkyne in the presence of a suitable catalyst, such as (PPh 3 ) 2 PdCl 2 , and Cul, and a suitable base, such as triethylamine in a solvent such as THF at about ambient temperature provides an alkyne as R a .
  • a suitable catalyst such as (PPh 3 ) 2 PdCl 2 , and Cul
  • a suitable base such as triethylamine in a solvent such as THF at about ambient temperature
  • R a may be obtained by transformation of these R a by methods known to those skilled in the art. Several of these transformations are exemplified below.
  • the compounds ofthe invention are useful in inhibiting the activity of src-family kinases and PDGFR kinase. In doing so, the compounds are effective in blocking disease processes mediated by these kinases. For example, by inhibiting p56 lck, the compounds block downstream signaling events following T cell activation by antigen. Activation of antigen-specific T cells is necessary for the induction and progression of diseases, including autoimmune diseases, allergic diseases and transplant rejection (J.H. Hanke et al., Inflamm. Res., 1995, 44, 357). Therefore the compounds ofthe invention are useful for treating such diseases.
  • rheumatoid arthritis include but are not limited to rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus erythematosus, insulin-dependent diabetes mellitus and asthma.
  • the compounds ofthe invention are useful in treating cancer.
  • the compounds of the invention are useful in treating src-dependent tumors, such as in mammary carcinoma, colon carcinoma, melanoma and sarcoma, and are also useful in treating PDGF-dependent tumors, such as ovarian cancer, prostate cancer and glioblastoma.
  • compounds ofthe invention may also be useful in treating osteoporosis, Paget's disease, bone inflammation and joint inflammation .
  • compounds ofthe invention may also be useful in treating fibrotic diseases, restenosis and atherosclerosis.
  • the compounds ofthe invention may also be useful in enhancing or potentiating the effectiveness of radiation therapy.
  • the compounds ofthe invention may be administered in any conventional dosage form in any conventional manner.
  • Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, rectally, topically or by inhalation.
  • the preferred modes of administration are oral and intravenous.
  • Compositions comprising the compounds ofthe invention for each ofthe aforementioned routes of administration will be apparent to the skilled artisan.
  • one embodiment ofthe invention provides for pharmaceutical compositions including a pharmaceutically effective amount ofthe compounds according to the invention.
  • Such pharmaceutical compositions will include pharmaceutically acceptable carriers and adjuvants as further described below.
  • the compounds of this invention may be administered alone or in combination with adjuvants that enhance stability ofthe inhibitors, facilitate administration of pharmaceutic compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients.
  • combination therapies utilize lower dosages ofthe conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies.
  • Compounds ofthe invention may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition.
  • the compounds may then be administered together in a single dosage form.
  • the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of formula (I) (w/w) or a combination thereof.
  • the optimum percentage (w/w) of a compound of formula(I) may vary and is within the purview of those skilled in the art.
  • the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.
  • dosage forms ofthe compounds of this invention include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art.
  • carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances.
  • Preferred dosage forms include, tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G.
  • Dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific dosage and treatment regimens will depend on factors such as the patient's general health profile, the severity and course ofthe patient's disorder or disposition thereto, and the judgment ofthe treating physician.
  • Example 1 Synthesis of 2-(2,6-Dichlorophenylamino)-6,6-dimethyl-lH,6H- imidazo[4,5-/ ⁇ ]isoquinoline-7,9-dione.
  • Example 3a Synthesis of 2-(2,6-Dichlorophenylamino)-6,7-dimethyl-l,8-dihydro- imidazo [4,5- ⁇ ] isoquinoline-9-one.
  • Example 3b Synthesis of 2-(2,6-Dichlorophenylamino)-6,7-dimethyl-l,8-dihydro- imidazo [4,5- ⁇ ] isoquinoline-9-one (Method C).
  • the thiourea was filtered and washed with EtOAc (850mg, 74%). mp 220°C (dec). A portion ofthe thiourea (490mg, 1.25mmol) was suspended in CHC1 3 (50mL) and treated with a solution of Br 2 (200mg, 1.25mmol) in CHC1 3 (5mL), and the resulting mixture was refluxed for lh. The solvent was evaporated, the residue was suspended in a saturated solution of NaHSO 3 , filtered, then treated analogously with a saturated solution of NaHCO 3 . Purification by silica column chromatography (0 to 5% MeOH in CH 2 C1 2 eluant) yielded the title compound (28 lmg, 58%), mp >300°C, MS (CI) 390 (MH + ).
  • Example 7 Synthesis of 2-(2,6-Dichlorophenylamino)-l,7-dimethyl-6-(2-morpholin- 4-yl-2-oxoethyl)-l,8-dihydro-imidazo[4,5- ⁇ ]isoquinoline-9-one.
  • Example 8 Synthesis of 2-(2,6-Dichlorophenylamino)-l,7-dimethyl-6-(2-morpholin- 4-yl-ethyl)-l,8-dihydro-imidazo[4,5-A]isoquinoline-9-one.
  • Example 9 Synthesis of 2-(2,6-Dichlorophenylamino)-l,7-dimethyl-9-oxo-l,8- dihydro-imidazo[4,5- ⁇ ]isoquinolin-6-yl acetic acid ethyl ester.
  • Example 10 Synthesis 2-(2,6-Dichlorophenylamino)-l,7-dimethyl-6-(2- hydroxyethyI)-l,8-dihydro-imidazo[4,5-A]isoquinoline-9-one.
  • Example 12 Synthesis of 3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro-lH-imidazo[4,5- ⁇ ]isoquinolin-7-yl]-acrylic acid methyl ester.
  • Example 11 12 To a suspension ofthe product of Example 11 (329mg, 0.82mmol) in THF (5mL) was added sequentially, trimethyl phosphonoacetate (164mg, 0.90mmol), lithium hydroxide monohydrate (76mg, 1.8mmol) and water (0.9mL). The blood red solution was stirred for 2h, quenched with water, and the resulting solid was collected and dried in vacuo. Column chromatography (5% MeOH-CH 2 Cl 2 ) provided the title compound (300mg, 80%), mp >300°C; MS (ES) 457, 459 (MH+).
  • Example 13 Synthesis of 3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro-lH-imidazo[4,5- ⁇ ]isoquinolin-7-yl]-propionic acid methyl ester.
  • Example 14 Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-(3-hydroxy- propen-l-yl)-l,8-dihydro-imidazo[4,5-A]isoquinolin-9-one.
  • Example 15 Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-vinyl-l,8- dihydro-imidazo[4,5-A]isoquinoline-9-one.
  • Example 16 Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-(l- hydroxyprop-2-en-l-yl)-l,8-dihydro-imidazo[4,5- ⁇ ]isoquinolin-9-one.
  • Example 17 Synthesis of 2-(2,6-Dichlorophenylamino)-7-(l-acetoxyprop-3-en-l-y ⁇ )- l,6-dimethyl-l,8-dihydro-imidazo[4,5- ⁇ ]isoquinolin-9-one.
  • Example 18 Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-(3- morpholin-4-yl-propen-l-yl)- l,8-dihydro-imidazo[4,5- ⁇ ]-isoquinolin-9-one.
  • Tris(dibenzylideneacetone) dipalladium(O) (1.8mg, 0.002mmol) and triphenylphosphine (1.6mg, 0.006mmol) were stirred in THF (0.5ml) for 20min under inert atmosphere until the red solution turned yellow.
  • THF 0.5ml
  • triethylamine 17.1 ml
  • morpholine 1 l ⁇ L, 0.12mmol
  • Example 19 Synthesis of 7-Benzylaminomethyl-2-(2,6-dichlorophenylamino)-l,6- dimethyl-l,8-dihydro-imidazo[4,5- ⁇ ]-isoquinolin-9-one.
  • Example 20 Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-oxazol-5-yl- 1 ,8-dihydro-imidazo [4,5-A] isoquinolin-9-one.
  • Example 21 Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-(3-methyl- 3H-imidazol-4-yl)-l,8- dihydro-imidazo[4,5-A]isoquinolin-9-one.
  • Example 22 Synthesis of 2-(2,6-Dichlorophenylamino)-l,6,7-trimethyl-4-vinyl-l,8- dihydro-imidazo [4,5- ⁇ ] isoquinoline-9-one.
  • Example 24 Synthesis of 2-(2,6-Dichlorophenylamino)-4-(2- hydroxyethylaminomethyl)-l,6,7-trimethyl-l,8-dihydro-imidazo[4,5- ⁇ ]isoquinoline- 9-one.
  • Example 25 Synthesis of 2-(2,6-DichIorophenylamino)-4-(3-methoxypropyn-l-yl)- l,6,7-trimethyl-l,8-dihydro-imidazo[4,5-A]isoquinoline-9-one.
  • Tin(II) chloride (46.67g, 206.84mmol) was added portionwise to a solution of 2-bromo- 5-nitro benzoic acid (12.71g, 49.9mmol) in dry ethanol (200mL). The mixture was heated at 70°C for 45min, then ethanol was evaporated. The residue was cooled to 0°C, and acetic anhydride (43mL) and pyridine (26mL) were added. The solution was stirred at room temperature for 14h and evaporated. The residue was partitioned between aq. 2M HCl and ethyl acetate (400mL). The organic phase was washed with brine and dried over MgSO 4 . The residue from evaporation was crystallized from water to give 5- acetylamino-2-bromobenzoic acid (12.4 g, 96 %).
  • Example 27 Synthesis of 2-(2,6-Dichlorophenylamino)-3-methyl-5,6,7,8-tetrahydro- 3//-l,3,5-triaza-dicyclopenta[a j /]naphthalen-4-one.
  • Example 28 Synthesis of 7-(3-Aminopropen-l-yl)-2-(2,6-dichlorophenylamino)-l,6- dimethyl-l,8-dihydro-imidazo[4,5- ⁇ ]-isoquinolin-9-one.
  • the inhibition of tyrosine kinases by the compounds ofthe invention was measured with the following assay.
  • ATP Triphosphate
  • Test compounds obtained routinely at 5mg/mL in 100% DMSO were diluted appropriately into complete Kinase assay buffer with 10% DMSO, lO ⁇ l ofthe 6Xcompound solution was distributed into each assay well, the final compound concentration for IC 50 determinations ranged from 200 to l ⁇ g/mL.
  • [ ⁇ 33P]-ATP label was prepared as a 10 Ci/mmol working solution in complete Kinase assay buffer. Protein kinase was initiated by adding 10 to 50 ⁇ g of diluted enzyme stock.
  • Representative compounds from the examples above were evaluated in the tyrosine kinase assay above using PDGFR kinase and were found to have IC 50 's less than 10 ⁇ M.
  • Inactivation of T cells resulting from inhibition ofthe tyrosine kinase p56 lck can be measured by inhibition of IL-2 production in Jurkat cells.
  • 96-well flat bottom plates were coated with anti-CD3, clone UCHT1, (Immunotech cat. # 1304) at 4 ⁇ g/ml in Phosphate Buffered Saline (PBS), 100 ⁇ l/well.
  • PBS Phosphate Buffered Saline
  • the solution was prepared by taking 200 ⁇ l of 200 ⁇ g/ml anti-CD3 stock/ 10ml PBS. The plate was then incubated at 37°C for 2h.
  • Jurkat cells were pelleted and counted.
  • the cells were resuspended at 2.5 x 10 6 cells/ml in RPMI, 10 % FBS (complete media).
  • Test compounds were diluted from a 5mg/ml DMSO stock directly into complete media.
  • the plate was centrifuged at 1500 ⁇ m for 5 min. at room temperature and the supematants were removed.
  • the supematants were tested using R&D Systems Quantikine Human IL-2 Kit (cat.#2050).
  • Samples were diluted 1:5 in RPMI 1640, and 100 ⁇ l/well used in the ELISA.
  • the optical density of each well was determined using a microplate reader set to 450 nm.
  • EC 50 values were determined using Origin (non-linear regression) or SAS by plotting absorbance vs. concentration of compound.

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Abstract

Disclosed are novel compounds of formula (I) wherein Ar1, Ra, R4, R5, X and Y are defined below, which are useful as inhibitors of certain protein tyrosina kinases and are thus useful for treating diseases associated with such kinases, for example, diseases resulting from inappropriate cell proliferation, which include autoimmune diseases, chronic inflammatory diseases, allergic diseases, transplant rejection and cancer. Also disclosed are processes for preparing these compounds, novel intermediates useful in these processes and compositions comprising compounds of formula (I).

Description

HETEROCYCLIC COMPOUNDS USEFUL AS INHIBITORS OF TYROSINE KINASES
Benefit is hereby claimed from U.S. Provisional Application No. 60/157,922, filed October 6, 1999, herein incorporated by reference in its entirety.
Technical Field ofthe Invention
This invention relates to substituted compounds of formula (I):
Figure imgf000002_0001
wherein Arj, Ra, R4, R5, X and Y are defined below, which are useful as inhibitors of certain protein tyrosine kinases and are thus useful for treating diseases resulting from inappropriate cell proliferation, which include autoimmune diseases, chronic inflammatory diseases, allergic diseases, transplant rejection and cancer. This invention also relates to processes for preparing these compounds and to pharmaceutical compositions comprising these compounds. Background ofthe Invention
Tyrosine kinases play an essential role in the regulation of cell signaling and cell proliferation by phosphorylating tyrosine residues of peptides and proteins. Inappropriate activation of tyrosine kinases is known to be involved in a variety of disease states, including immunologic and oncologic disorders.
It has been well established that T cells play an important role in regulating the immune response (F. Powrie and R.L. Coffman, Immunol. Today, 1993, 14, 270). Activation of T cells is often the initiating event in many inflammatory and autoimmune diseases. In addition to their role in immune surveillance, T cells can become autoreactive by recognizing self-antigens and thereby cause autoimmune disease such as rheumatoid arthritis and inflammatory bowel disease.
The T cell receptor (TCR) is the antigen-specific component of the T cell and is activated when the receptor is engaged with foreign or self-antigenic peptides. When the TCR is activated a series of enzyme-mediated signal transduction cascades is initiated which results in the production of pro-inflammatory cytokines such as interleukin-2 (IL- 2).
The release of IL-2 is critically important since this lymphokine is required for T- lymphocyte proliferation, differentiation, and effector function. Clinical studies have shown that interference with IL-2 activity effectively suppresses immune response in vivo (T.A. Waldmann, Immunol. Today, 1993, 14, 270). Accordingly, agents which inhibit T- lymphocyte activation and subsequent IL-2 production, or block the activity of IL-2 are therapeutically useful for selectively suppressing immune response in a patient in need of such immunosuppression.
The eight members ofthe src family of tyrosine kinases are src, lck, fyn, lyn, hck, fgr, blk and yes (J.B. Bolen, J.S. Brugge, Ann. Rev. Immunol, 1997, 15, 371). These can be divided into 2 groups based on their pattern of tissue expression. Src, fyn and yes have a broad distribution while expression of lck, lyn, hck, fgr, and blk is largely limited to hemopoietic cells. The therapeutic effects of inhibiting kinases ofthe src family can be ascertained by linking functional defects seen in gene disruption studies in mice. Src(-/-) mice had severe abnormalities in bone remodeling. Inhibition of src may therefore be useful in treating osteoporosis. Lck(-/-) mice display a complete lack of CD4+ cells and are unable to mount antigen-dependent immune responses.
A kinase of particular interest is p561ck, which is only expressed in T-cells. Within the TCR signal transduction cascade the tyrosine kinase p561ck is a required element to initiate the activation response from the TCR intracellular domains to other signaling proteins. For example, T cells which lack the p561ck protein are unable to signal through the T cell receptor (D.B. Straus and A. Weiss, Cell, 1992, 70, 585). Transfection of p561ck back into these cell lines restores TCR responsiveness. Also, it has been shown in mice that inactivation ofthe p561ck gene leads to lack of proper thymocyte development (T.J. Molina et al, Nature, 1992, 357, 161).
The conclusion drawn from these studies is that p561ck plays a crucial role in T cell maturation and antigen-induced T-cell activation. Therefore, an agent blocking p561ck would effectively block T cell function, act as an immunosuppressive agent and have potential utility in autoimmune diseases, for example rheumatoid arthritis, multiple sclerosis, lupus, transplant rejection and allergic diseases (J.H. Hanke et al., Inflamm. Res., 1995, 44, 357).
Inhibitors of other members ofthe src family of non-receptor tyrosine kinases are also useful for treating various disease states. Src is present in osteoclasts, and is important in bone remodeling. For example, inactivation of p60src diminishes bone resorption by osteoclasts (P. Soriano et al., Cell 1991, 64, 693, B.F. Boyce et al. J. Clin. Invest 1992, 90, 1622), it is therefore possible that inhibitors ofthe kinase activity of p60src are useful in the treatment of osteoporosis, Paget's disease and inflammation of bones and joints. Src kinases have been found to be activated in tumors, including breast and colon cancers, melanoma and sarcoma. For example, a number of primary tumors and tumor cell lines from patients with breast cancer, colon cancer, melanoma and sarcoma have been shown to have elevated src kinase activity, and activating src mutations are seen in some advanced colon cancers. Inhibitors of src kinase had significant antiproliferative activity against cancer cell lines (M.M. Moasser et al., Cancer Res., 1999, 59, 6145) and inhibited the transformation of cells to an oncogenic phenotype (R. Kami et al., Oncogene, 1999, 18, 4654) suggesting that src kinase inhibitors may be useful anti- cancer agents.
In addition, src family kinases participate in signal transduction in several cell types. For example, fyn, like lck, is involved in T-cell activation. Hck and fgr are involved in Fc gamma receptor mediated oxidative burst of neutrophils. Src and lyn are believed to be important in Fc epsilon induced degranulation of mast cells, and so may play a role in asthma and other allergic diseases. The kinase lyn is known to be involved in the cellular response to DNA damage induced by UV light (T. Hiwasa, FEBS Lett. 1999, 444, 173) or ionizing radiation (S. Kumar, J. Biol Chem, 1998, 273, 25654). Inhibitors of lyn kinase may thus be useful as potentiators in radiation therapy.
Platelet derived growth factor is a potent mitogen for smooth muscle cells. Its receptor (PDGFR) is a member of the receptor tyrosine kinase family (L. Claesson- Welsh, J. Biol Chem, 1994, 269, 32023). PDGF is involved in atherosclerosis and restenosis (K.E. Bornfeldt, Trends Cardiovasc. Med., 1996, 6, 143). In addition, receptor tyrosine kinases including PDGFR kinase have been implicated as contributing factors in cancer (A. Levitzki and A. Gazit, Science, 1995, 267, 1782) including ovarian (M.B. Dabrow et al., Gynecologic Oncology, 1998, 71, 29) and prostate (S.M. Sintich et al., Endocrinology, 1999, 140, 3411) cancers and glioblastoma (B.J. Silver, BioFactors, 1992 3, 217). Inhibitors of PDGFR kinase are thus useful in the treatment of fibrotic diseases, restenosis and PDGF-dependent tumors. Reports have appeared in the literature of agents that inhibit the kinase activity of p561ck kinase and thus inhibit T cell activation. These include the natural product lavendustin A, and analogs (M.S. Smyth, J. Med. Chem., 1993, 36, 3010), the natural product damnacanthal (C.R. Faltynek et al., Biochemistry, 1995, 34, 12404), and a 1-methoxy agroclavine isolated from a fungal extract (R. Padmanabha et al. Bioorganic and Med. Chem. Letters, 1998, 8, 569). Other inhibitors reported include WIN 61651 (J. Enzyme Inhibition, 1995, 9, 111) pyrazolopyrimidines PP1 and PP2 (Hanke et al. J. Biol Chem, 1996, 271, 695) and indanone and indandione derivatives (J.L. Bullington et al., Bioorganic and Med. Chem. Letters, 1998, 8, 2489).
A.P. Spader et al. (WO 98/54157, 1998) describe quinoline and quinoxaline compounds that inhibit p561ck and PDGFR kinase. Fused polycyclic 2-aminopyrimidine derivatives that inhibit p561ck are reported by J.M. Davis et al. (WO 98/28281, 1998). J. Das et al. claim a series of benzothiazole amides as inhibitors of lck and other src family kinases (WO 99/24035 , 1999) . Inhibitors of PDGFR kinase and src-family kinases were reviewed by H.D.H. Showalter, A.j. Kraker, Pharmacol. Ther., 1997, 76, 55. Several patents on inhibitors of lck are reviewed in P.M. Traxler, Exp. Opin. Ther. Patents, 1997, 7, 571, and P.M. Traxler, Exp. Opin. Ther. Patents, 1998, 8, 1599.
U.S. Pat. No. 4,176,184 discloses imidazoisoquinoline-diones, which are described as being useful as cardiotonics, hypotensives, antithrombotics and antiarrhythmics. DE 3410168 Al discloses imidazoisoquinoline-dione derivatives, these compounds are described as being useful as cardiotonic agents in which the substituent on the fused imidazole ring is a pyridine ring bridged to the imidazole carbon by a -C4 alkyl group, a vinyl group or a chemical bond. EP 322 746 Al discloses heterocyclic lactam derivatives described as being useful as cardiotonic agents, antihypertensive agents and vasodilators.
The compounds of the present invention represent a novel structural class, which is distinct from previously reported tyrosine kinase inhibitors. Brief Summary ofthe Invention
The work cited above supports the principle that inhibition ofthe kinases mentioned above will be beneficial in the treatment of various disease states.
It is therefore an object ofthe invention to provide novel compounds which inhibit PDGFR kinase and the src-family kinases including lck, src, fyn, lyn, hck, fgr, blk and yes.
It is a further object ofthe invention to provide methods for treating diseases and pathological conditions mediated by src-family tyrosine kinases and PDGFR kinase such as autoimmune diseases, transplant rejection, psoriasis, osteoporosis, Paget's disease, cancer, including src-dependent tumors and PDGF-dependent tumors, atherosclerosis, restenosis and allergic diseases, using the novel compounds ofthe invention.
It is yet a further object ofthe invention to provide processes of preparation ofthe above- mentioned novel compounds and pharmaceutical compositions comprising the same.
Detailed Description ofthe Invention
The src-family tyrosine kinases and PDGFR kinase discussed above exhibit some homology in their amino acid structure. It is contemplated that due to structural differences between individual src-family kinases and PDGFR kinase, different compounds ofthe invention may have different inhibitory potencies against individual tyrosine kinases. Thus some of compounds ofthe invention may also be expected to be most effective in treating diseases mediated by tyrosine kinases that they inhibit most potently. Particular compounds disclosed herein have been shown to be active inhibitors of p561ck kinase, p60src kinase and PDGFR kinase. See the section entitled "Assessment of Biological Properties" disclosed herein.
In its broadest generic aspect, the invention provides novel compounds ofthe formula I:
Figure imgf000008_0001
wherein:
Aτ\ is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more R\, R2 and
X is NH, N-Cι.3alkyl, N-cyclopropyl, S or O;
Figure imgf000008_0002
Ra is H, d-ioalkyl, C2.10alkenyl or C2.10alkynyl, each of which may be branched or cyclic; or Ra is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more Cι.6alkyl, .6 alkoxy, halogen, OH, oxo, NRioRπ, aryl or heteroaryl, each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, Cι.3alkyl, Cj.3alkoxy, hydroxyCι-3alkyl and (CH2)mNRι0Rπ; and wherein Ra is attached at the 4- or 5- position; Rj and R2 are the same or different and selected from H, halogen, CN, NO2, CMO branched or unbranched saturated or unsaturated alkyl, CMO branched or unbranched alkoxy, CMO branched or unbranched acyl, C O branched or unbranched acyloxy, CMO branched or unbranched alkylthio, aminosulfonyl, di-(Cι_3)alkylaminosulfonyl, NR10R11, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned Ri and R are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, Cι-6 branched or unbranched alkyl, C .7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(Cι.3)alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2)nNRι0Rn, CONR10Rn, (CH2)nCO2R12; Cι-3alkyl optionally substituted with OH, C1.3 alkoxy optionally halogenated or Cμ alkylthio;
R4 and R5 together with the atoms to which they are attached complete a fused ring system ofthe formulas A or B:
Figure imgf000009_0001
Rό is Cι.3alkyl or H;
R7 is Cι.6alkyl branched or unbranched or H; R8 is H, Cι.6alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or Cu3alkoxy; or R8 is (CH2)mNRι0Rn, (CH2)mNRι0CORι2, (CH2)nCO2Rι2, (CH2)nCONRιoRιι; or R8 is phenyl or heteroaryl, each being optionally substituted with Cι_3alkyl, Cι.3alkoxy, OH, -SO3H or halogen;
R is H, CN or CONRjoRn; or R9 is Ci.ioalkyl branched or unbranched, C3-ιocycloalkyl, C5.7cycloalkenyl, C2.6 alkenyl, C2.6 alkynyl each being optionally substituted with one or more CMocycloalkyl, C3.ι0cycloalkylidene, C . cycloalkenyl, halogen, OH, oxo, CN, C\. 3alkoxy, Cι-3acyloxy, NRio n, NR10CONR10Rn, NRι0C(=NR10)NR,oRιι, NR10COR12, NR10S(O)PR12, SR12, CONR10Rn, CO2R12, C(R10)=NNR,oR11,
C(Rιo)-NNR10CONRιoRιι, aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with Cι. alkyl, Cι- alkoxy, halogen, (CH2)„NR,oRn or O(CH2)2^NRI0Rn;
or R9 is aryl, heteroaryl, or heterocycle, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three groups selected from Q^alkyl optionally substituted with phenyl or NR1oC(=NRιo)NR1oRn, C^alkoxy, halogen, CN, oxo, (CH2)„NRιoRιι, (CH2)nCO2R12; (CH2)„CONR10Rπ and O(CH2)2_4NR10Rn;
or Rs and R together form a saturated or unsaturated 5 or 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two Cι. alkyl, OH, oxo or (CH2)nNRιoRn, or optionally spiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3 dioxolane group or 1,3 dithiolane group optionally substituted by Cι.6alkyl, d.6alkoxy, OH or (CH2)nNRι0Rn;
RJO and Rπ may be the same or different and are each independently selected from H, OH, Cu3alkoxy, Cι.6alkyl branched or unbranched, C3.8cycloalkyl, aryl, arylCι.3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylC^alkyl or heteroaryl are optionally substituted with OH, Cι.3alkoxy, CN, NO2, Cι.3acyloxy, CO2R12, NRι3R14, O(CH2)2. 4NR1 Rι4, aryl or heteroaryl; or R^ and Rn together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p, and NR13; and wherein said ring is optionally substituted by Cj.3 alkyl, Ci. 3alkoxy, OH, -(CH2)nNRι3Rι4, CONRι3Rι4 or NRι3COR]4;
R12 is H, Cι_6alkyl or C3.8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C^alkoxy or NRι3R14; or Rι2 is phenyl or heterocycle, optionally substituted with one to three groups selected from Cι.3alkyl, Cι_3alkoxy, halogen, (CH2)mNRι0Rπ, (CH2)„CONRιoRn and O(CH2)MNR10Rι1;
Rι3 and Rι4 are each independently selected from H and Cι.6 alkyl optionally substituted with Cι-3alkoxy, OH or phenyl; or R1 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or
(CH2)2O(CH2)2;
Rι5 is H or .3 alkyl;
m is 1-4; n is 0-3 and p is 0-2; and
the pharmaceutically acceptable acid or salt derivatives thereof.
In one embodiment ofthe invention, there are provided compounds ofthe formula (I) described above, wherein:
a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl; b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, cycloheptenyl; c) phenyl, naphthyl; indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl; d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl,or a fused heteroaryl selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or e) a heterocycle selected from pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl;
wherein each ofthe above Ari are optionally substituted by one or more Ri, R2 and R ;
Ra is H, Ci-βalkyl, C2.5alkenyl, C2.5alkynyl, phenyl or heteroaryl selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; each Rg being optionally substituted with one or more phenyl, halogen, Cι- alkyl, Cι-3 alkoxy, OH, oxo, or NR10Rπ; wherein Ra is at the 4- position;
R\ and R2 are as hereinabove defined;
R3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
R$ is H, Cι-3alkyl branched or unbranched, saturated or unsaturated, optionally substituted with OH; or Rs is (CH2)2.3NR10Rn, (CH2)nCO2R12 or (CH2)nCONR10Rn; R9 is CN or CONRioRii; or R9 is Cι.3alkyl branched or unbranched, C2^ alkenyl, C2-4alkynyl each being optionally substituted with one or more C5.7cycloalkyl, C5.7 cycloalkylidene, C5.7cycloalkenyl,OH, CN, Cι.3acyloxy, NRIORM, NRι0CONRι0Rιι, NR,0C(=NRιo)NR10Rιι5 NRι0COR12, NR10S(O)PR12, CONR10Rn, CO2R12,
C(R10)=NNRιoRιι, C(Rιo)=NNR1oCONRι0Rπ, aryl or heteroaryl; wherein each aryl or heteroaryl is optionally substituted with d.3alkyl, Cι-3alkoxy, halogen, (CH2)nNR]oRι ι or O(CH2)2.4NR10Rπ;
or R is aryl,heteroaryl or heterocycle, each optionally substituted with one to three groups selected from Cj.3alkyl optionally substituted with phenyl or
Figure imgf000013_0001
Cι.3alkoxy, halogen, CN, oxo, (CH2)nNRιoRιι, (CH2)nCO2Rι2; (CH2)nCONR10Rn and O(CH2)2.4NR10RU;
or Rδ and R9 together form a saturated or unsaturated 5 or 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by Cι.3alkyl or OH, or optionally spiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3 dioxolane group or 1,3 dithiolane group optionally substituted by Cι.3alkyl, Cι.3alkoxy, OH or (CH2)nNR10Rn;
R10 and Rn may be the same or different and are each independently selected from H, OH, d.3alkoxy, Cι-6alkyl branched or unbranched, C .8cycloalkyl, benzyl and phenyl; wherein said alkyl, cycloalkyl, benzyl or phenyl are optionally substituted with OH, C\. 3alkoxy, Cι.3acyloxy, CN, NO2, CO2R]2, NRι3Rι4, O(CH2)2.4NR13RH or phenyl;
or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι-3 alkyl, Cι.3alkoxy, OH, -(CH2)nNRι3Rι4, CONRι3RH or NR13COR14;;
R12 is H, Cι.6alkyl or C5. cycloalkyl, each optionally substituted with phenyl, OH, Ci- 3alkoxy or NRι3Rι4; or Rj2 is phenyl or heterocycle, each optionally substituted with one to three groups selected from Cι.3alkyl, Cι. alkoxy, halogen, (CH )mNRιoRn, (CH2)nCONRioRii and O(CH2)2-4NR10Rn;
R13 and R14 are each independently selected from H and d-6 alkyl optionally substituted with Cι.3alkoxy, OH or phenyl;
or Rι3 and Rι4 together form a chain completing a ring, said chain is (CH )4.5 or (CH2)2O(CH2)2; and
R]5 is H.
In another embodiment, there are provided compounds ofthe formula (I) described immediately above, wherein:
Ari is phenyl, or pyridyl, wherein each is optionally substituted by one or more
Ri, R and R as defined below;
X is NH or N-CH3;
Y is NH and
Ra is H, hydroxyCι.2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C3.5alkynyl substituted by Cι.3alkoxy or phenyl;
Ri and R2 are the same or different and selected from: H, halogen, Cι.3 alkyl, wherein the Cι-3 alkyl are optionally partially or fully halogenated, NO2, NRι3Rι4;
R3 is H, halogen, methoxy or methyl; R4 and R5 together complete a fused ring of formula B;
Rs is H, Cι.3alkyl optionally substituted with OH; or R8 is (CH2)2.3NRι0Rn or CO2Rι2;
R9 is CN; or R9 is methyl, C2.3 alkenyl or C2.3 alkynyl, each being optionally substituted with one or more C5.7 cycloalkylidene, C5. cycloalkenyl, OH, CN, NR10R11, NRioCONRioR , NRι0COR,2, NRι0S(O)pRι2, CONR10Rn, CO2Rι2, C(Rι0)=NNRι0Rn or heteroaryl;
or R9 is aryl or heteroaryl optionally substituted with one to three groups selected from Cι.3alkyl optionally substituted with phenyl, Cι.3alkoxy, halogen, amino or CONH2;
or R8 and R together form a cyclopentene ring spiro-fused to a 1,3 dioxolane group, said 1,3 dioxolane group being optionally substituted by Cι.3alkyl, Cι_3alkoxy, OH or (CH2)nNR10Rn;
Rio and Ri ι may be the same or different and are each independently selected from H, OH, Cι_3alkoxy, Cι.3alkyl branched or unbranched, C5. cycloalkyl or phenyl, wherein said alkyl, cycloalkyl or phenyl are optionally substituted with OH, Cι.3alkoxy, Ci. 3acyloxy, NO2, CO2R]2, NRι3Rι4, O(CH2)MNRι3R14 or phenyl;
or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1.3 alkyl, Cι_3alkoxy,OH, (CH2)nNRι3R14, CONR]3Rι4 or NR,3CORι4;
Rι2 is H, Cι.3alkyl or C5.7cycloalkyl, each optionally substituted with phenyl, OH, Ci. 3alkoxy or NRj3Rι4; or Rι2 is phenyl or is a saturated, 4- to 6-membered nitrogen- containing heterocycle, each optionally substituted with one to three groups selected from d.3alkyl, Cι_3alkoxy, halogen, (CH2)mNR10Rn, (CH2)nCONRι0Rn and O(CH2)2. Rι3 and Rι4 are each independently selected from H and Cι_ alkyl optionally substituted with d-3alkoxy or OH; or Rj3 and Rj4 together form a chain completing a ring, said chain is (CH )4.5 or
(CH2)2O(CH2)2.
In yet another embodiment, there are provided compounds ofthe formula (I) described immediately above, wherein:
Ari is phenyl;
Ra is H or hydroxymethyl;
Ri and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy;
Rio and Rn may be the same or different and are each independently selected from H, OH, methoxy, Cι.3alkyl branched or unbranched or C5.7cycloalkyl, wherein said alkyl or cycloalkyl are optionally substituted with OH, NRι3Rι4 or phenyl;
or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι.2 alkyl, NRι3Rι4, CONRι3Rι4 or NRj3CORι ; and
Rι2 is Cι. alkyl optionally substituted with morpholino; or Rι2 is phenyl or is azetidinyl, pyrrolidinyl or piperidinyl, each optionally substituted with one to three groups selected from Cι.3alkyl, Cι.3alkoxy and halogen. In another subgeneric aspect, the invention provides novel compounds ofthe formula I:
Figure imgf000017_0001
(I)
wherein:
Ari is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocyle is optionally substituted by one or more Rj, R2 and R3;
X is NH, N-Ci.3alkyl, N-cyclopropyl, S or O;
Y is NR15, S or O;
Ra is H, Ci-ioalkyl, C2.ιoalkenyl or C2.ιoalkynyl, each of which may be branched or cyclic; or Ra is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more Cι-3alkyl, Cι.6 alkoxy, halogen, OH, oxo, NRioRn, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, Cι. alkyl, Cι.3alkoxy, hydroxyCι.3alkyl and (CH2)mNRιoRn; and wherein Ra is attached at the 4- or 5- position;
Ri and R2 are the same or different and selected from H, halogen, CN, NO2, Cι-10 branched or unbranched saturated or unsaturated alkyl, Ci.10 branched or unbranched alkoxy, d-io branched or unbranched acyl, d_ιo branched or unbranched acyloxy, Cj.io branched or unbranched alkylthio, aminosulfonyl, di-(Cι.3)alkylaminosulfonyl, NRioRn, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the above mentioned Ri and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, Cι-6 branched or unbranched alkyl, C3. cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(Cι. )alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2)nNRι0Rn, (CH2)nCO2R12; Cι.3alkyl optionally substituted with OH, Cι-3 alkoxy optionally halogenated or Cι.3 alkylthio;
Ri and R5 together with the atoms to which they are attached complete a fused ring system ofthe formulas A or B:
Figure imgf000018_0001
Rβ is Cι- alkyl or H;
R7 is Cι.6alkyl branched or unbranched or H;
R8 is H, Cι-6 alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or Cι.3alkoxy; or R8 is (CH2)mNRι0Rn, (CH2)mNRι0CORι2, (CH2)nCO Ri2, (CH2)nCONRιoRn; or Rs is phenyl or heteroaryl, each being optionally substituted with Cι.3alkyl, Cι.3alkoxy, OH, -SO3H or halogen;
R is H; or R is Ci-ioalkyl branched or unbranched, C3.ιo cycloalkyl, C2.6 alkenyl, C2.6 alkynyl each being optionally substituted with one or more halogen, OH, oxo, CN, C\. 3alkoxy, NRioRn, NRι0COR]2, SR]2, CONR10R11, CO2Rι2, aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with Cι.3alkyl, Cι.3alkoxy, halogen, (CH2)nNRι0Rn or O(CH2)2.4NRι0Rn; or R9 is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to three groups selected from Cι.3alkyl optionally substituted with phenyl, Ci- 3alkoxy, halogen, (CH2)nNRι0Rn, (CH2)nCO2Rι2; (CH2)nCONRι0Rn and O(CH2)2.
or R8 and R together form a saturated or unsaturated 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two OH, oxo or (CH2)nNR10Rn;
Rio and Ri i may be the same or different and are each independently selected from H, OH, Cι.3alkoxy, Cι.6alkyl branched or unbranched, C3.8cycloalkyl, aryl, arylC].3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylCι.3alkyl or heteroaryl are optionally substituted with OH, Cι.3alkoxy, Cι-3acyloxy, CO2Rι2, NRι3Rι4, O(CH2)2.4NR13R14, aryl or heteroaryl;
or Rio and Rn together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p, and NRι3; and wherein said ring is optionally substituted by C1.3 alkyl, C\. 3alkoxy, OH or -(CH2)nNRι3Rι4;
Rι2 is H, Cι_6alkyl or C3.8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, Cι.3alkoxy or NRι3Rj4; or R]2 is phenyl, optionally substituted with one to three groups selected from Cι.3alkyl, Cι-3alkoxy, halogen, (CH2)mNRιoRn, (CH2)nCONRioRn and O(CH2)2^NR,0Rn; Rι3 and Rι are each independently selected from H and Cι.6 alkyl optionally substituted with C].3alkoxy, OH or phenyl; or Rι3 and R]4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2;
R15 is H or Cι.3 alkyl;
m is 1-4, n is 0-3 and p is 0-2; and
the pharmaceutically acceptable acid or salt derivatives thereof.
In one embodiment ofthe invention, there are provided compounds ofthe formula (I) as described immediately above, and wherein:
Ari is a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl; b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, cycloheptenyl; c) phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl; d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl.or a fused heteroaryl selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or e) a heterocycle selected from: pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl;
wherein each ofthe above Ari are optionally substituted by one or more Ri, R and R3 as hereinabove defined;
Ra is H, Cι-6 alkyl, C2.5 alkenyl, C2.5 alkynyl, phenyl or heteroaryl selected from: pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; each Ra being optionally substituted with one or more phenyl, halogen, Cι.3alkyl, Cι_3 alkoxy, OH, oxo, or NRioR ; wherein Ra is at the 4- position;
R3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
Rs is H, Cι-3alkyl branched or unbranched, saturated or unsaturated, optionally substituted with OH; or Rs is (CH2)2.3NRι0Rn, (CH2)nCO2Rι2 or (CH2)nCONRι0Rn;
R9 is Cι_3alkyl branched or unbranched, C2.4 alkenyl, C -4alkynyl each being optionally substituted with one or more OH, CN, NRioRn, CONRioRn, CO2Rι2, aryl or heteroaryl; wherein each aryl or heteroaryl is optionally substituted with Cι.3alkyl, Cι_3alkoxy, halogen, (CH2)nNRι0Rn or O(CH2)MNRι0Rn; or R9 is aryl or heteroaryl optionally substituted with one to three groups selected from C].3alkyl optionally substituted with phenyl, Cι.3alkoxy, halogen, (CH2)nNRιoRn, (CH2)nCO2R,2; (CH2)nCONRιoRn and O(CH2)MNRι0Rn; or R8 and R9 together form a saturated or unsaturated 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by OH;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι-3alkoxy, Cι.6alkyl branched or unbranched, C .8cycloalkyl, benzyl and phenyl; wherein said alkyl, cycloalkyl, benzyl or phenyl are optionally substituted with OH, Ci- 3alkoxy, Cι_3acyloxy, CO2Rι2, NRi Rι4, O(CH2)2.4NRι3Rι4 or phenyl;
or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C].3 alkyl, Cι.3alkoxy, OH or -(CH2)nNRι3Rι4;
Rι2 is H or Cι.6alkyl optionally substituted with phenyl, OH, Cι-3alkoxy or NRι3Rι4;
Ri3 and Rj4 are each independently selected from H and Cι.6 alkyl optionally substituted with Cι-3alkoxy, OH or phenyl;
or R13 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2; and
Rι5 is H.
In another embodiment ofthe invention, there are provided compounds ofthe formula (I) as described immediately above, and wherein:
Ari is phenyl, or pyridyl;
X is NH or N-CH3; Y is NH and Ra is H, hydroxyCι.2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo- propyl, vinyl or C3.5alkynyl substituted by Cι-3alkoxy or phenyl;
Ri and R2 are the same or different and selected from: halogen, C1.3 alkyl, wherein the Cj.3 alkyl are optionally partially or fully halogenated, NO2, NRJ3Rι4;
R3 is H, halogen, methoxy or methyl;
R4 and R5 together complete a fused ring of formula B;
Rs is H, Cι_3alkyl optionally substituted with OH; or R8 is (CH2)2.3NRι0Rn or CO2R)2;
R9 is methyl or C2.3 alkenyl each being optionally substituted with one or more OH, CN, NRioRn, CONRioRn or CO2Rι2; or R9 is heteroaryl optionally substituted with one to three groups selected from Cι.3alkyl optionally substituted with phenyl, Cι_3alkoxy, halogen or amino;
Rio and Ri 1 may be the same or different and are each independently selected from H, OH, Cι.3alkoxy, Cι.3alkyl branched or unbranched, optionally substituted with OH, Ci. 3alkoxy, Cι.3acyloxy, CO2Rι2, NRι3Rι4, O(CH2)2.4NRι3Rι4 or phenyl;
or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι.3 alkyl, Cι. alkoxy or OH;
Rι2 is H or Cι.3alkyl optionally substituted with phenyl, OH, Cι_3alkoxy or NRι3Rι4;
Rι3 and R]4 are each independently selected from H and Cι.3alkyl optionally substituted with Cι-3alkoxy or OH; or Rι3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2. In yet another embodiment ofthe invention there are provided compounds of the formula (I) as described immediately above, and wherein:
Ari is phenyl;
Ra is H or hydroxymethyl;
Ri and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy;
Rio and Rn may be the same or different and are each independently selected from H, OH, methoxy, Cι_3alkyl branched or unbranched, optionally substituted with OH, NR)3Rι4 or phenyl; or Rio and Ri i together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι-2 alkyl; and
Rι2 is Cι.3alkyl optionally substituted with morpholino.
In still another embodiment ofthe invention there are provided compounds ofthe formula (la):
Figure imgf000025_0001
wherein:
X is NH, N-Cι.3alkyl, N-cyclopropyl, S or O;
Ra is H, Ci-ioalkyl, C2.ι0alkenyl or C2.ι0alkynyl, each of which may be branched or cyclic; or Ra is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more C].6alkyl, Cι_6 alkoxy, halogen, OH, oxo, NRioRn, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, Cι.3alkyl, Cj. 3alkoxy, hydroxyCι.3alkyl and (CH2)mNRιoRn; and wherein Ra is attached at the 4- or 5- position;
Ri and R2 are the same or different and selected from H, halogen, CN, NO2, CMO branched or unbranched saturated or unsaturated alkyl, CMO branched or unbranched alkoxy, C O branched or unbranched acyl, C O branched or unbranched acyloxy, CMO branched or unbranched alkylthio, aminosulfonyl, di-(Cι.3)alkylaminosulfonyl, NRioRn, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned Ri and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, Cι.6 branched or unbranched alkyl, C3-7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(Cι. )alkylaminocarbonyl; R3 is H, halogen, OH, (CH2)nNRι0Rn, CONR10Rn, (CH2)nCO2R12; Cι.3alkyl optionally substituted with OH, Cj.3 alkoxy optionally halogenated or C1.3 alkylthio;
R4 and R5 together with the atoms to which they are attached complete a fused ring system of the formulas A or B:
Figure imgf000026_0001
B
R is Cι-3alkyl or H;
R7 is Ci.6alkyl branched or unbranched or H;
R8 is H, Cι-6alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or Ct.3alkoxy; or Rs is (CH2)mNRι0Rn, (CH2)mNR]0CORι2, (CH2)nCO2Ri2, (CH2)nCONR10Rn or Rs is phenyl or heteroaryl, each being optionally substituted with Cι-3alkyl, Cι.3alkoxy, OH, -SO3H or halogen;
R9 is H, CN or CONRioRni or R9 is Ci.ioalkyl branched or unbranched, C3_ιocycloalkyl, C5.7cycloalkenyl, C2.6 alkenyl, C2.6 alkynyl each being optionally substituted with one or more C3-ιocycloalkyl, C3.ιocycloalkylidene, C .7cycloalkenyl, halogen, OH, oxo, CN, Ci- 3alkoxy, Cι-3acyloxy, NR,0Rn, NRι0CONR,0Rιι, NRIOC(=NRιo)NR1oRn, NR10CORι2, NRioS(O)pRi2, SR12, CONR10R,ι, CO2R,2, C(R10)=NNR,0Rn, C(Rιo)=NNRιoCONRιoRn, aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with Cι.3alkyl, Cι_3alkoxy, halogen, (CH2)nNR,0Rn or O(CH2)MNRι0Rn;
or R is aryl, heteroaryl, or heterocycle, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three groups selected from Cι. alkyl optionally substituted with phenyl or NRιoC(=NRι0)NRιoRn, Cι. alkoxy, halogen, CN, oxo, (CH2)nNR,oR,ι, (CH2)nCO2Rι2; (CH2)nCONR,0R,, and O(CH2)MNR10Rn;
or Rs and R9 together form a saturated or unsaturated 5 or 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two Cι.3alkyl, OH, oxo or (CH2)nNRιoRn» or optionally spiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3 dioxolane group or 1,3 dithiolane group optionally substituted by Cι-6alkyl, Cι.6alkoxy, OH or (CH2)nNRι0Rn;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι_3alkoxy, Cι_6alkyl branched or unbranched, C3.8cycloalkyl, aryl, arylCι_3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylCι.3alkyl or heteroaryl are optionally substituted with OH, Cι.3alkoxy, CN, NO2, Cι.3acyloxy, CO2Rι2, NR)3Rι4, O(CH2)2. 4NRι3Rι4, aryl or heteroaryl;
or Rio and Rn together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p, and NRι3; and wherein said ring is optionally substituted by Cι.3 alkyl, Ci- 3alkoxy, OH, -(CH2)nNRι3Rι4, CONRι3R]4 orNRi3CORM;
Rι2 is H, C[.6alkyl or C3.8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, Cι.3alkoxy or NRι3Rι4; or Rι2 is phenyl or heterocycle, optionally substituted with one to three groups selected from Cι_3alkyl, Cι.3alkoxy, halogen, (CH2)mNRι0Rn, (CH2)nCONRι0Rn and O(CH2)2_4NRι0Rn; Rι3 and Rι4 are each independently selected from H and Cι-6 alkyl optionally substituted with Cι.3alkoxy, OH or phenyl; or Rj3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or
(CH2)2O(CH2)2;
m is 1-4, n is 0-3 and p is 0-2; and
the pharmaceutically acceptable acid or salt derivatives thereof.
In another embodiment ofthe invention, there are provided compounds ofthe formula (la) as described above, wherein:
X is NH or N-CH3;
Ra is H, hydroxyCι-2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo- propyl, vinyl or C3.5alkynyl substituted by Cι_3alkoxy or phenyl; and wherein Ra is attached at the 4- position;
Ri and R2 are the same or different and selected from: H, halogen, Cι.3 alkyl, wherein the d- alkyl is optionally partially or fully halogenated, NO2, NRι R]4;
R3 is H, halogen, methoxy or methyl;
» and R5 together complete a fused ring of formula B;
Rg is H, Cι.3alkyl optionally substituted with OH; or R8 is (CH2)2.3NRι0Rn or CO2R]2; R is CN; or R9 is methyl, C2.3 alkenyl or C .3 alkynyl, each being optionally substituted with one or more Cs.7 cycloalkylidene, C5.7cycloalkenyl, OH, CN, NRioRn, NR,oCONRιoRn, , NR10CORι2, NR10S(O)pRι2, CONR10Rn, CO2R,2> C(R,o)=NNRι0Rn or heteroaryl;
or R9 is aryl or heteroaryl optionally substituted with one to three groups selected from C].3alkyl optionally substituted with phenyl, Cι.3alkoxy, halogen, amino or CONH2;
or R8 and R9 together form a cyclopentene ring spiro-fused to a 1,3 dioxolane group, said 1,3 dioxolane group being optionally substituted by Cι_3alkyl, Cι.3alkoxy, OH or (CH2)nNR,0Rn;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι. alkoxy, Cι_3alkyl branched or unbranched, C5.7cycloalkyl or phenyl, wherein said alkyl, cycloalkyl or phenyl are optionally substituted with OH, Cι.3alkoxy, Ci. 3acyloxy, NO2, CO2Rι2, NRι3RM, O(CH2)2.4NRι3RM or phenyl;
or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1.3 alkyl, Cι-3alkoxy,OH, (CH2)nNRι3Rι4, CONRι3R]4 or NRι3CORH;
Rι2 is H, Cι.3alkyl or C5.7cycloalkyl, each optionally substituted with phenyl, OH, C\. alkoxy or NRι3R[4; or Rj2 is phenyl or is a saturated, 4- to 6-membered nitrogen- containing heterocycle, each optionally substituted with one to three groups selected from Cι.3alkyl, Cι.3alkoxy, halogen, (CH2)mNRι0Rn, (CH2)nCONRι0Rn and O(CH2)2.
4NRιoRιi;
Rι3 and Rι4 are each independently selected from H and Cι_3alkyl optionally substituted with d.3alkoxy or OH; or Rι3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2. In yet another embodiment ofthe present invention, there are provided compounds of the formula (la) described immediately above, wherein:
Ra is H or hydroxymethyl;
Ri and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy;
Rio and Ri ι may be the same or different and are each independently selected from H, OH, methoxy, Cι.3alkyl branched or unbranched or C5.7cycloalkyl, wherein said alkyl or cycloalkyl are optionally substituted with OH, NRι Rι4 or phenyl;
or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by d.2 alkyl, NRι3Rι4, CONRι3Rι4 or NRι3CORι4; and
Rι2 is Cι-3alkyl optionally substituted with morpholino; or Rι2 is phenyl or is azetidinyl, pyrrolidinyl or piperidinyl, each optionally substituted with one to three groups selected from Cι_3alkyl, Cι.3alkoxy and halogen.
In still another subgeneric embodiment ofthe invention there are provided compounds of the formula (la):
Figure imgf000031_0001
wherein:
X is NH, N-Cioalkyl, N-cyclopropyl, S or O;
Ra is H, Ci-ioalkyl, C2.ιoalkenyl or C2.ιoalkynyl, each of which may be branched or cyclic; or Ra is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more Cι.6 alkoxy, halogen, OH, oxo, NRioRn, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, Cμ3alkyl, Cι_ alkoxy, hydroxyCι-3alkyl and (CH2)mNRιoRn; and wherein Ra is attached at the 4- or 5- position;
Ri and R2 are the same or different and selected from H, halogen, CN, NO2, CMO branched or unbranched saturated or unsaturated alkyl, CMO branched or unbranched alkoxy, C O branched or unbranched acyl, CMO branched or unbranched acyloxy, CMO branched or unbranched alkylthio, aminosulfonyl, di-(Cι.3)alkylaminosulfonyl, NRioRn, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the above mentioned Ri and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, Cι-6 branched or unbranched alkyl, C3. cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(Cι.3)alkylaminocarbonyl; R3 is H, halogen, OH, (CH2)πNRι0Rn, (CH2)nCO2Rι2; Cι.3alkyl optionally substituted with OH, Cι-3 alkoxy optionally halogenated or C1.3 alkylthio;
; and R5 together with the atoms to which they are attached complete a fused ring system ofthe formulas A or B:
Figure imgf000032_0001
A B
Rό is Cι-3alkyl or H;
R is Cι.6alkyl branched or unbranched or H;
Rs is H, Cι-6alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or Cι.3alkoxy; or Rs is (CH2)mNRι0Rn, (CH2)mNRι0CORι2, (CH2)nCO2Rι2, (CH2)nCONRιoRn or R8 is phenyl or heteroaryl, each being optionally substituted with Cι.3alkyl, Cι.3alkoxy, OH, -SO3H or halogen;
R9 is H; or R9 is Ci-ioalkyl branched or unbranched, C3.ιocycloalkyl, C2.6 alkenyl, C2. 6alkynyl each being optionally substituted with one or more halogen, OH, oxo, CN, Ci. 3alkoxy, NRioRn, NRι0CORι2, SRj2, CONRioRn, CO2Rι2, aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with Cι.3alkyl, Cι.3alkoxy, halogen, (CH2)nNR)0Ri 1 or O(CH2)2.4NRι0Rn; or R is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to three groups selected from Cι.3alkyl optionally substituted with phenyl, Ci- 3alkoxy, halogen, (CH2)nNRι0Rn, (CH2)nCO2R,2; (CH2)„CONR10Rii and O(CH2)2. 4NRιoRn;
or Rs and R together form a saturated or unsaturated 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two OH, oxo or (CH2)nNR,0Rn;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι_3alkoxy, Cι_6alkyl branched or unbranched, C3.8cycloalkyl, aryl, arylC].3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylCι.3alkyl or heteroaryl are optionally substituted with OH, Cι.3alkoxy, Cι.3acyloxy, CO2Rι2, N ι3Rι4, O(CH2)2.4NRι3Rι4, aryl or heteroaryl;
or Rio and Rn together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p and NRι3; and wherein said ring is optionally substituted by Cι.3 alkyl, Ci. 3alkoxy, OH or -(CH2)nNRι3Rι4;
Rι2 is H, Cι-6alkyl or C3.8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, Cι.3alkoxy or NRι3Rι4; or Rι is phenyl, optionally substituted with one to three groups selected from C^alkyl, d^alkoxy, halogen, (CH2)mNRιoRu, (CH2)„CONR10Rι i and O(CH2)2.4NR10Rn;
Ri3 and Rι4 are each independently selected from H and C].6 alkyl optionally substituted with Cι. alkoxy, OH or phenyl; or Rι3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2; m is 1-4, n is 0-3 and p is 0-2; and
the pharmaceutically acceptable acid or salt derivatives thereof.
In another embodiment ofthe invention there are provided compounds ofthe formula (la) as described immediately above, and wherein:
X is NH or N-CH3;
Ra is H, hydroxyCi.2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo- propyl, vinyl or C3.5alkynyl substituted by Cι.3alkoxy or phenyl; and wherein Ra is attached at the 4- position;
Ri and R2 are the same or different and selected from: halogen, Cι_3 alkyl, wherein the C1.3 alkyl is optionally partially or fully halogenated, NO2, NRj3Rι4;
R3 is H, halogen, methoxy or methyl;
Rt and R5 together complete a fused ring of formula B;
Rs is H, Cι.3alkyl optionally substituted with OH; or R8 is (CH2)2_3NRι0Rn or CO2Rι2;
R is methyl or C2.4 alkenyl each being optionally substituted with one or more OH, CN, NRioRn, CONRioRn or CO2Rι2; or R9 is heteroaryl optionally substituted with one to three groups selected from Cι-3alkyl optionally substituted with phenyl, Cι.3alkoxy, halogen or (CH2)nNRιoRι 1 ; Rio and Rn may be the same or different and are each independently selected from H, OH, Cι.3alkoxy, Cι.3alkyl branched or unbranched, optionally substituted with OH, C\. alkoxy, Cι.3acyloxy, CO2R]2, NRι3Rι , O(CH2)2^NR)3Rι4 or phenyl;
or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι. alkyl, Cι.3alkoxy or OH;
Rι2 is H or Cι.3alkyl optionally substituted with phenyl, OH, Cι_3alkoxy or NRι3Rι4;
Rι3 and Rι4 are each independently selected from H and Cι.3alkyl optionally substituted with Cι.3alkoxy or OH; or Rι3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2.
In still a further embodiment ofthe invention there are provided compounds ofthe formula (la) as described immediately above, and wherein:
Ra is H or hydroxymethyl;
Ri and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, ffuoro, bromo or methoxy;
Rio and Rn may be the same or different and are each independently selected from H, OH, methoxy, d.3alkyl branched or unbranched, optionally substituted with OH, NRι3Rι4 or phenyl; or Rio and Ri i together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι.2 alkyl; and Rι2 is Cι.3alkyl optionally substituted with morpholino.
In another aspect ofthe invention, there are provided intermediate compounds ofthe formula(III) useful in the synthetic schemes and examples set forth below. In yet another aspect ofthe invention are particular intermediate compounds ofthe formula(III), (representative examples shown Table 1 below) which possess physiological activity.
In their broadest generic aspect, intermediate compounds described above are represented by the formula (III):
Figure imgf000036_0001
wherein:
Ari is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more Ri, R2 and R3;
X is NH, N-Cι-3alkyl, N,cyclopropyl, S or O;
Y is NRis, S or O; Ra is H, Ci-ioalkyl, C2.ιoalkenyl or C2_ιoalkynyl, each of which may be branched or cyclic; or Ra is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more Cι.3alkyl, Cι-6 alkoxy, halogen, OH, oxo, NRioRn, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, Cι_3alkyl, Cj. alkoxy, hydroxyCι.3 alkyl and (CH2)mNRιoRn; and wherein Ra is attached at the 4- or 5- position;
Ri and R2 are the same or different and selected from H, halogen, CN, NO2, CMO branched or unbranched saturated or unsaturated alkyl, CMO branched or unbranched alkoxy, CMO branched or unbranched acyl, CMO branched or unbranched acyloxy, CMO branched or unbranched alkylthio, aminosulfonyl, di-(Cι_3)alkylaminosulfonyl, NRioRn, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned Ri and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, -6 branched or unbranched alkyl, C3.7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(Cι-3)alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2)„NR10Rn, (CH2)nCO2Rι2; Cι-3alkyl optionally substituted with OH, Cι.3 alkoxy optionally halogenated or Cι.3 alkylthio;
R4 and R5 together with the atoms to which they are attached complete a fused ring system ofthe formula C:
Figure imgf000038_0001
Figure imgf000038_0002
R is Cι-6alkyl branched or unbranched or H;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι-3alkoxy, Cι.6alkyl branched or unbranched, C3.8cycloalkyl, aryl,
Figure imgf000038_0003
and heteroaryl; wherein said alkyl, cycloalkyl, aryl,
Figure imgf000038_0004
or heteroaryl are optionally substituted with OH,
Figure imgf000038_0005
CO2R]2, NR13R14, O(CH2)2.4NRι3Rι , aryl or heteroaryl;
or Rio and Rn together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p and NR]3; and wherein said ring is optionally substituted by d.3 alkyl, d. 3alkoxy, OH or -(CH2)nNRι3Rι4;
Rι2 is H, Ci.6alkyl or C3.8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, Cι-3alkoxy or NRj3Rι4; or Rι2 is phenyl, optionally substituted with one to three groups selected from Cι_3alkyl, Cι_3alkoxy, halogen, (CH2)mNR,0R,i, (CH2)nCONRιoRn and O(CH2)2.4NRι0Rn; Rι and Rι4 are each independently selected from H and Cι.6 alkyl optionally substituted with alkoxy, OH or phenyl; or R)3 and Rι4 together form a chain completing a ring, said chain is (CH2) .5 or (CH2)2O(CH2)2; and
m is 1-4, n is 0-3 and p is 0-2.
One embodiment of the compounds of formula(III) are those wherein:
Ari is
a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl; b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, cycloheptenyl; c) phenyl, naphthyl; indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl; d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl, or a fused heteroaryl selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or e) a heterocycle selected from: pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl;
wherein each of the above Ari are optionally substituted by one or more Ri, R2 and R3 as hereinabove defined;
Ra is H, Ci-βalkyl, C2.5alkenyl, C2.5alkynyl, phenyl or heteroaryl selected from: pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; each Ra being optionally substituted with one or more phenyl, halogen, Cι.3alkyl, Cι_3 alkoxy, OH, oxo, or NRioRn; wherein Ra is at the 4- position; R3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
Rg is Ci_3aikyl or H;
R is Cι.6alkyl branched or unbranched or H;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι-3alkoxy, Cι-6alkyl branched or unbranched, C3.8cycloalkyl, benzyl and phenyl; wherein said alkyl, cycloalkyl or phenyl are optionally substituted with OH, Cι.3alkoxy, Cι-3acyloxy, CO2Rj2, NR,3Ri4, O(CH2)2_4NRι3Rι4 or phenyl;
or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι_3 alkyl, Ci_3alkoxy, OH or -(CH2)nNRι3Rι4;
Ri2 is H or Chalky! optionally substituted with phenyl, OH, Cι.3alkoxy or NRι3Rι4; Rι3 and Rj4 are each independently selected from H and Cι.6 alkyl optionally substituted with Cι.3alkoxy, OH or phenyl; and or Rι3 and R]4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2.
Another embodiment ofthe compounds ofthe formula(III) are those described immediately above, and wherein:
Ari is phenyl, or pyridyl;
X is NH or N-CH3; Y is NH and
Ra is H, hydroxyC].2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo- propyl, vinyl or C3.5alkynyl substituted by Cι_3alkoxy or phenyl;
Ri and R2 are the same or different and selected from: halogen, Cι_3 alkyl, wherein the Cι_3 alkyl are optionally partially or fully halogenated, NO2, NRι3Rj4;
R3 is H, halogen, methoxy or methyl;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι.3alkoxy, Cι.3alkyl branched or unbranched, optionally substituted with OH, C\. 3alkoxy, Cι-3acyloxy, CO2Rι2, NRι3Rι , O(CH2)2. NR]3Rι4 or phenyl; or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι.3 alkyl, Cι.3alkoxy or OH;
Rι is H or Cι.3alkyl optionally substituted with phenyl, OH, C].3alkoxy or NRι3Rj4;
Rι3 and Rj4 are each independently selected from H and C].3alkyl optionally substituted with Cι.3alkoxy or OH; or R[3 and Rj4 together form a chain completing a ring, said chain is (CH2)4.5 or
(CH2)2O(CH2)2.
In yet another embodiment ofthe compounds of formula(III) are those described immediately above, and wherein:
Ari is phenyl;
Ra is H or hydroxy methyl;
Ri and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy;
Rio and Rn may be the same or different and are each independently selected from H, OH, methoxy, Cι.3alkyl branched or unbranched, optionally substituted with OH, NRι3Rι4 or phenyl; or Rio and Rn together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι-2 alkyl; and Rι2 is Cι-3alkyl optionally substituted with morpholino.
In a further embodiment ofthe invention, there are provided the following compounds of the fomulas (I) and (la):
2-(2,6-Dichlorophenylamino)-6,7-dimethyl-l,8-dihydro-imidazo[4,5-Λ]isoquinoline-9- one;
2-(2,6-Dichlorophenylamino)-3,5-dihydro-imidazo[4,5-i]phenanthridin-4-one;
2-(2,6-Dichlorophenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5-A]isoquinoline-9- one;
2-(2,6-Dichlorophenylamino)-7-methyl-l,8-dihydro-imidazo[4,5- 2]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino) -l,7-dimethyl-9-oxo-l,8-dihydro-imidazo[4,5- Ajisoquinolin-6-acetic acid ethyl ester;
3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- z]isoquinolin-7-yι]-acrylic acid methyl ester;
2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl-6-(2-hydroxyethyl)- 1 ,8-dihydro-imidazo[4,5- h] isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl-9-oxo- 1 ,8-dihydro-imidazo[4,5- Λ]isoquinoline-6- carboxylic acid methyl ester; 2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl- 1 ,8-dihydro-imidazo[4,5-/z]isoquinoline-9- one;
3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- A]isoquinolin-7-yl]-acrylic acid methyl ester;
3-[2-(2,6-Dichlorophenylamino) -l,7-dimethyl-9-oxo-l,8-dihydro-imidazo[4,5- Λ]isoquinolin-6-yl]propionic acid ethyl ester
N-Benzyl-N-methyl-2-[(2,6-dichlorophenylamino)- 1 ,7-dimethyl-9-oxo- 1 ,8-dihydro- imidazo[4,5- z]isoquinolin-6-yl] acetamide;
2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl-6-(2-morpholin-4-ylethyl)- 1 ,8-dihydro- imidazo[4,5-Λ]isoquinoline-9-one;
2-(2-Chloro-6-methylphenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5- h] isoquinoline-9-one ;
2-(4-Bromo-2-dichlorophenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5- Λ]isoquinoline-9-one;
3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- Λ]isoquinolin-7-yl]-Ν-methoxy-Ν-methylacrylamide;
2-(2-Chloro-6-nitrophenylamino)-l,6,7-trimethyl-l,8-dihydro-imidazo[4,5- A]isoquinoline-9-one;
N-Benzyl-3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h] isoquinolin-7-yl] -acrylamide ; 3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- Λ]isoquinolin-7-yl] -acrylic acid 4-morpholine amide;
2-(2,6-Dichlorophenylamino)-l,7-dimethyl -6-[3-(4-morpholino)propyl]-l,8-dihydro- imidazo[4,5-Λ]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-4-hydroxymethyl-l,6,7-trimethyl-l,8-dihydro-imidazo[4,5- h] isoquinoline-9-one ;
2-(2,6-Dimethylphenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5-/z]isoquinoline-9- one;
2-(2-Ethyl-6-methylphenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5- Λ]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl-6-(3-phenylaminopropyl)- 1 ,8-dihydro- imidazo[4,5-/ι]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino-6-{3-[4-(2-diethylaminoethoxy)-phenylamino]propyl}-l,7- dimethyl- l,8-dihydro-imidazo[4,5-Λ]isoquinoline-9-one;
2-(2-Bromo-6-chloro-4-fluorophenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro- imidazo[4,5- Λ]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-4-(2-hydroxyethylaminomethyl)- 1 ,6,7-trimethyl- 1 ,8- dihydro-imidazo[4,5-Λ]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-4-(4-methoxybenzylaminomethyl)- 1 ,6,7-trimethyl- 1 ,8- dihydro-imidazo[4,5- 2]isoquinoline-9-one; 2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-vinyl- 1 ,8-dihydro-imidazo[4,5- Λ]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-4-(2,6-difluoropyridin-3yl)- 1 ,6,7-trimethyl- 1 ,8-dihydro- imidazo[4,5-Λ]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-4-(3-methylphenyl)- 1 ,6,7-trimethyl- 1 ,8-dihydro- imidazo[4,5-Λ]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl-9-oxo- 1 ,8-dihydro-imidazo[4,5- Λ]isoquinoline-6- carboxylic acid 2-(4-moropholino)ethyl ester;
2-(2,6-Dichlorophenylamino)-4-(3-hydroxy-2-oxo-propyl)- 1 ,6,7-trimethyl- 1 ,8-dihydro- imidazo[4,5- z]isoquinoline-9-one;
N-4-(2-Diethylaminoethoxy)phenyl-3-[2-(2,6-dichlorophenylamino)-l-methyl-9-oxo-8,9- dihydro-lH-imidazo[4,5-Λ]isoquinolin-7-yl]-acrylamide;
3-[2-(2,6-Dichlorophenylamino)- 1 -methyl-9-oxo-8,9-dihydro- 1 H-imidazo[4,5- Λ]isoquinolin-7-yl]-N-methyl acrylamide;
9- Hydroxy-2-(2,6-dichlorophenylamino)-3,5,6,7,8,9-hexahydro-imidazo[4,5- i]phenanthridin-4-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-hydroxypropen- 1 -yl)- 1 ,8-dihydro- imidazo[4,5-/z]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(2-phenylethenyl)- 1 ,8-dihydro- imidazo[4,5-A]-isoquinolin-9-one; 2-(2-Amino-6-chlorophenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5- /z]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6,7-trimethyl-4-vinyl- 1 ,8-dihydro-imidazo[4,5- Λ]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-4-(3-methoxypropyn- 1 -yl)- 1 ,6,7-trimethyl- 1 ,8-dihydro- imidazo[4,5-Λ]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6,7-trimethyl-4-(5-phenylpent- 1 -ynyl)- 1 ,8-dihydro- imidazo[4,5- 2]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-oxazol-5-yl- 1 ,8-dihydro-imidazo[4,5- Λ]isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-l-methyl-7-vinyl-l,8-dihydro-imidazo[4,5-Λ]isoquinoline- 9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3 -morpholin-4-yl-propen- 1 -yl)- 1,8- dihydro-imidazo[4,5-Λ]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl-6-[2-(2-hydroxyethyl)aminoethyl]- 1 ,8- dihydro-imidazo[4,5-/?]isoquinoline-9-one;
3-[2-(2,6-Dichlorophenylamino)-l,7-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- A]isoquinolin-7-yl]-acrylonitrile;
2-(2-Chloro-6-methylphenylamino)- 1 ,7-dimethyl- 1 ,8-dihydro-imidazo[4,5- Λ]isoquinoline-9-one; 2-(2 , 6-Dichloropheny lamino)- 1 -methy l-7-oxazol-5 -yl- 1 , 8 -dihydro-imidazo [4,5- Λ]isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-l,7-dimethyl-6-(3-hydroxypropyl)-l,8-dihydro- imidazo[4,5-Λ]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-hydroxypropen- 1 -yl)- 1 -methyl- 1 ,8-dihydro- imidazo[4,5-/z]-isoquinolin-9-one;
2-(2-Chloro-6-methylphenylamino)-7-(3-hydroxypropen- 1 -yl)- 1 -methyl- 1 ,8-dihydro- imidazo[4,5-A]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen- 1 -yl)- 1 ,6-dimethyl- 1 ,8-dihydro- imidazo[4,5-/z]-isoquinolin-9-one;
7-(3-Aminopropen- 1 -yl)-2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl- 1 ,8-dihydro- imidazo[4,5-Λ]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-pyrrolidin- 1 -yl-propen- 1 -yl)- 1 ,8- dihydro-imidazo[4,5-Λ]-isoquinolin-9-one;
7-(3-Benzylmethylaminopropen- 1 -yl)2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl- 1 ,8- dihydro-imidazo[4,5-Λ]-isoquinolin-9-one;
2-(2,6-Dichloro-4-methoxyphenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5- Λ]isoquinoline-9-one;
2-(2,6-Dichloro-4-methoxyphenylamino)-l,6-dimethyl-7-oxazol-5-yl-l,8-dihydro- imidazo [4,5 -h] isoquinolin-9-one ; 2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen- 1 -yl)- 1 -methyl- 1 ,8-dihydro- imidazo[4,5-Λ]-isoquinolin-9-one;
2-(2,6-Dimethylphenylamino)- 1 ,7-dimethyl- 1 ,8-dihydro-imidazo[4,5-/z]isoquinoline-9- one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(4-methylpiperazin- 1 -yl-propen- 1 -yl)- 1 ,8- dihydro-imidazo[4,5-/z]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-piperidin- 1 -yl-propen- 1 -yl)- 1 ,8- dihydro-imidazo[4,5-/z]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7- {3-[ethyl(2-hydroxyethyl)amino]propen- 1 - yl} - 1 ,8-dihydro-imidazo[4,5-Λ]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-[3-(3-hydroxypyrrolidin- 1 -yl)-propen- 1 - yl]- l,8-dihydro-imidazo[4,5-Λ]-isoquinolin-9-one;
7-(3-Dibutylaminopropen- 1 -yl)-2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl- 1 ,8-dihydro- imidazo[4,5-Λ]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-{3-[(2-methoxyethyl)methylamino]propen- l-yl}-l,8-dihydro-imidazo[4,5-A]-isoquinolin-9-one;
7-(3-Diethylaminopropen- 1 -yl)- 1 ,6-dimethyl-2-(2,6-dimethylphenylamino)- 1 ,8-dihydro- imidazo[4,5-Λ]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7- { 3 -[(2-diethylaminoethyl)methylamino] -propen- 1 -yl } - 1 ,6-dimethyl- 1 ,8-dihydro-imidazo[4,5-Λ]-isoquinolin-9-one; 7-(3-Diethylaminopropen- 1 -yl)- 1 ,6-dimethyl-2-(2,4,6-trichlorophenylamino)- 1,8- dihydro-imidazo[4,5-h]-isoquinolin-9-one
2-(2,6-Dichlorophenylamino)-6-methyl-7-oxazol-5-yl-l,8-dihydro-imidazo[4,5- h]isoquinolin-9-one
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-[3-(2-pyrrolidin- 1 -ylmethylpyrrolidin- 1 - yl)-propen-l-yl]-l,8-dihydro-imidazo[4,5-/z]-isoquinolin-9-one
7-[3-(2S-Aminomethylpyrrolidin- 1 -yl)-propen- 1 -yl]-2-(2,6-dichlorophenylamino)- 1 ,6- dimethyl- 1 ,8-dihydro-imidazo[4,5-/z]-isoquinolin-9-one
l-{3-[2-(2,6-Ddichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h] isoquinolin-7-yl] -propenyl } - -proline carboxamide
l-{3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h] isoquinolin-7-yl] -propenyl } -piperidine-3 -carboxamide
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(methylhydrazonomethyl)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one
7-[3-(3-Aminopyrrolidin- 1 -yl)-propen- 1 -yl]-2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl- l,8-dihydro-imidazo[4,5-A]-isoquinolin-9-one
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-[3-(3-acetamidopyrrolidin- 1 -yl)-propen- 1 - yl]- l,8-dihydro-imidazo[4,5-Λ]-isoquinolin-9-one
2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-[3-(3-dimethylaminopyrrolidin-l-yl)- propen- 1 -yl]- 1 ,8-dihydro-imidazo[4,5-/ϊ]-isoquinolin-9-one l-{3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h] isoquinolin-7-yl] -propenyl } -piperidine-2-carboxamide
7-[3-(3-Aminomethylpiperidin- 1 -yl)-propen- 1 -yl]-2-(2,6-dichlorophenylamino)- 1 ,6- dimethyl- 1 ,8-dihydro-imidazo[4,5-Λ]-isoquinolin-9-one
l-{3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl} -piperidine-3-carboxylic acid diethylamide
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-ethynyl- 1 ,8-dihydro-imidazo[4,5-h]- isoquinolin-9-one
l-{3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl} -3-methyl urea
Cyclohexane carboxylic acid {3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro-lH-imidazo[4,5-h]isoquinolin-7-yl]-propenyl} amide
2-(2,6-Dichlorophenylamino)-l-methyl-7-phenyl-l,8-dihydro-imidazo[4,5-h]isoquinolin- 9-one
N-{3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl} methanesulfonamide
3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lΗ-imidazo[4,5- h]isoquinolin-7-yl]-propenyl urea
l-Cyclohexyl-3-{3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH- imidazo [4,5 -h] isoquinolin-7-yl] -propenyl } -urea N- {3-[2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9-dihydro- lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl} benzenesulfonamide
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-ethylaminopropen- 1 -yl)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one
N-{3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl}-guanidine
Piperidine-3-carboxylic acid {3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro- lΗ-imidazo[4,5-h]isoquinolin-7-yl]-propenyl} amide
I-Proline {3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH- imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide
E>-Proline {3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH- imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide
3-[2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9-dihydro- 1 H-imidazo[4,5- h]isoquinolin-7-yl]-benzamide
I-Azetidine-2-carboxylic acid {3-[2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9- dihydro- 1 H-imidazo [4, 5 -h] i soquinolin-7-y 1] -propenyl } amide
Piperidine-2-carboxylic acid {3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro- 1 H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl} amide; and
the pharmacueticaliy acceptable derivatives thereof. In yet still a further embodiment ofthe invention, there are provided the following compounds ofthe fomulas (I) and (la):
2-(2,6-Dichlorophenylamino)-3,5-dihydro-imidazo[4,5-i]phenanthridin-4-one;
2-(2,6-Dichlorophenylamino)-l,6,7-trimethyl-l,8-dihydro-imidazo[4,5-h]isoquinoline-9- one;
2-(2,6-Dichlorophenylamino)-l,7-dimethyl-6-(2-hydroxyethyl)-l,8-dihydro-imidazo[4,5- h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl-9-oxo- 1 ,8-dihydro-imidazo[4,5- h]isoquinoline-6- carboxylic acid methyl ester;
3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-acrylic acid methyl ester;
2-(2-Chloro-6-methylphenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5- h]isoquinoline-9-one;
3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-N-methoxy-N-methylacrylamide;
2-(2-Chloro-6-nitrophenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5- h]isoquinoline-9-one;
N-Benzyl-3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-acrylamide; 3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-acrylic acid 4-morpholine amide;
2-(2,6-Dichlorophenylamino)-4-hydroxymethyl-l,6,7-trimethyl-l,8-dihydro-imidazo[4,5- h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-vinyl- 1 ,8-dihydro-imidazo[4,5- h] isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-l,7-dimethyl-9-oxo-l,8-dihydro-imidazo[4,5- h]isoquinoline-6- carboxylic acid 2-(4-moropholino)ethyl ester;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-hydroxypropen- 1 -yl)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-oxazol-5-yl-l,8-dihydro-imidazo[4,5- h] isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-l-methyl-7-vinyl-l,8-dihydro-imidazo[4,5-h]isoquinoline- 9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-morpholin-4-yl-propen- 1 -yl)- 1 ,8- dihydro-imidazo[4,5-h]-isoquinolin-9-one;
3-[2-(2,6-Dichlorophenylamino)-l,7-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h] isoquinolin-7-yl] -acrylonitrile;
2-(2-Chloro-6-methylphenylamino)- 1 ,7-dimethyl- 1 ,8-dihydro-imidazo[4,5- h]isoquinoline-9-one; 2-(2,6-Dichlorophenylamino)- 1 -methyl-7-oxazol-5-yl- 1 ,8-dihydro-imidazo[4,5- h]isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-hydroxypropen- 1 -yl)- 1 -methyl- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2-Chloro-6-methylphenylamino)-7-(3-hydroxypropen- 1 -yl)- 1 -methyl- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen-l-yl)-l,6-dimethyl-l,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-pyrrolidin- 1 -yl-propen- 1 -yl)- 1 ,8- dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen- 1 -yl)- 1 -methyl- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(4-methylpiperazin- 1 -yl-propen- 1 -yl)- 1 ,8- dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-piperidin- 1 -yl-propen- 1 -yl)- 1 ,8- dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7- {3-[ethyl(2-hydroxyethyl)amino]propen- 1 - yl} - 1 ,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-Diethylaminopropen- 1 -yl)- 1 ,6-dimethyl-2-(2,6-dimethylphenylamino)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one; 2-(2,6-Dichlorophenylamino)-7-{3-[(2-diethylaminoethyl)methylamino]-propen-l-yl}- 1 ,6-dimethyl-l ,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-Diethylaminopropen- 1 -yl)- 1 ,6-dimethyl-2-(2,4,6-trichlorophenylamino)- 1 ,8- dihydro-imidazo[4,5-h]-isoquinolin-9-one
2-(2,6-Dichlorophenylamino)-6-methyl-7-oxazol-5-yl-l,8-dihydro-imidazo[4,5- h] isoquinolin-9-one
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-[3-(2-pyrrolidin- 1 -ylmethylpyrrolidin- 1 - yl)-propen- 1 -yl]- 1 ,8-dihydro-imidazo[4,5-/*]-isoquinolin-9-one
7-[3 -(2S- Aminomethylpyrrolidin- 1 -yl)-propen- 1 -yl] -2-(2,6-dichlorophenylamino)- 1 ,6- dimethyl- 1 ,8-dihydro-imidazo[4,5-A]-isoquinolin-9-one
1 - {3-[2-(2,6-Ddichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9-dihydro- 1 H-imidazo[4,5- h]isoquinolin-7-yl]-propenyl} -Z-proline carboxamide
1 - {3-[2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9-dihydro- 1 H-imidazo[4,5- h]isoquinolin-7-yl]-propenyl}-piperidine-3-carboxamide
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(methylhydrazonomethyl)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one
7-[3-(3-Aminopyrrolidin- 1 -yl)-propen- 1 -yl]-2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl- l,8-dihydro-imidazo[4,5-Λ]-isoquinolin-9-one
2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-[3-(3-acetamidopyrrolidin-l-yl)-propen-l- yl]- 1 ,8-dihydro-imidazo[4,5-/z]-isoquinolin-9-one 2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-[3-(3-dimethylaminopyrrolidin- 1 -yl)- propen- 1 -yl]- 1 ,8-dihydro-imidazo[4,5-Λ]-isoquinolin-9-one
l-{3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl}-piperidine-2-carboxamide
7-[3-(3-Aminomethylpiperidin-l -yl)-propen- 1 -yl]-2-(2,6-dichlorophenylamino)- 1 ,6- dimethyl- 1 ,8-dihydro-imidazo[4,5-/ι]-isoquinolin-9-one
l-{3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl} -piperidine-3-carboxylic acid diethylamide
2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-ethynyl-l,8-dihydro-imidazo[4,5-h]- isoquinolin-9-one
l-{3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl} -3-methyl urea
Cyclohexane carboxylic acid {3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro-lH-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide
2-(2,6-Dichlorophenylamino)- 1 -methyl-7-phenyl- 1 ,8-dihydro-imidazo[4,5-h]isoquinolin- 9-one
N- {3-[2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9-dihydro- lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl} methanesulfonamide
3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lΗ-imidazo[4,5- h]isoquinolin-7-yl]-propenyl urea 1 -Cyclohexyl-3- {3-[2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9-dihydro- 1 H- imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-urea
N-{3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl] -propenyl} benzenesulfonamide
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-ethylaminopropen- 1 -yl)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one
N-{3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h] isoquinolin-7-yl] -propenyl } -guanidine
Piperidine-3-carboxylic acid {3-[2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9- dihydro- lΗ-imidazo[4,5-h]isoquinolin-7-yl]-propenyl} amide
-Proline {3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH- imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide
E)-Proline {3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH- imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide
3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-benzamide
E-Azetidine-2-carboxylic acid {3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro-lH-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide
Piperidine-2-carboxylic acid {3-[2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9- dihydro- 1 H-imidazo [4,5 -h] isoquinolin-7-yl] -propenyl } amide ; and
the pharmacuetically acceptable derivatives thereof. Any compounds of this invention containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
Some ofthe compounds of the invention can exist in more than one tautomeric form. The invention includes all such tautomers.
The compounds ofthe invention are only those which are contemplated to be 'chemically stable' as will be appreciated by those skilled in the art. For example, a compound which would have a 'dangling valency', or a 'carbanion' are not compounds contemplated by the invention.
All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, "d.6alkoxy" is a Cι-6alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkylene or alkynyl groups shall be understood as being branched or unbranched unless otherwise specified. Other more specific definitions are as follows:
The term "halogen" as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine.
The term "heteroaryl" refers to a stable 5-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic aromatic heterocycle radical. Each heterocycle consists of carbon atoms and from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle may be attached by any atom ofthe cycle, which results in the creation of a stable structure. Example "heteroaryl" radicals include, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, 2,4-dioxo-quinazolinyl, imidazo[4,5-c]pyridinyl and indazolyl, or a fused heteroaryl such as cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene;
The term "heterocycle" refers to a stable 4-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated, and is non-aromatic. Each heterocycle consists of carbon atoms and from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle may be attached by any atom ofthe cycle, which results in the creation of a stable structure. Example "heterocycle" radicals include azetidinyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl,indolinyl, 2,3-dihydrobenzimidazolyl and 2,3-dihydro- lH-imidazo[4,5-c] pyridinyl. As used herein and throughout this specification, the terms "nitrogen" and "sulfur" and their respective elements symbols include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
The term "aryl" shall be understood to mean a 6-10 membered aromatic carbocycle, "aryl" includes, for example, phenyl and naphthyl; other terms comprising "aryl" will have the same definition for the aryl component, examples of these moieties include: arylalkyl, aryloxy or arylthio.
The term "carbocycle" shall be understood to mean a 3-10 membered aromatic or nonaromatic cyclic carbon chain. Examples of nonaromatic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl and the like. Examples of aromatic carbocycles include the "aryl" compounds as described hereinabove.
The term "acyl" shall be understood to mean an R-(C=O)- moiety wherein R is an alkyl. Examples of R can be a Ci-ioalkyl, saturated or unsaturated, branched or unbranched, or R can be "aryl" as defined hereinabove. "Acyloxy" shall be understood to mean an R- CO2- group wherein R is as defined in this paragraph.
The invention includes pharmaceutically acceptable derivatives of compounds of the invention. A "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt or ester of a compound of this invention, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, a pharmacologically active metabolite or pharmacologically active residue thereof.
Pharmaceutically acceptable salts ofthe compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of this invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C J-C4
alkyl)4+ salts.
In addition, the compounds of this invention include prodrugs of compounds ofthe invention. Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce a compound of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction, enzymatically, metabolically or otherwise. Specifically, when a prodrug of this invention is administered to a patient, the prodrug may be transformed into a compound of the invention, thereby imparting the desired pharmacological effect.
General Synthetic Methods
The compounds ofthe invention may be prepared by the methods described below. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitered by thin layer chromatography (TLC) if desired. If desired, intermediates and products may be purified by chromatography on silica gel and/or recrystallization. Starting materials and reagents are either commercially available or may be prepared by one skilled in the art using methods described in the chemical literature.
A general procedure (Method A) that may be used to synthesize compounds of formula (I) is illustrated in Scheme I.
Scheme I (Method A)
A NCS
Figure imgf000063_0002
Figure imgf000063_0001
Figure imgf000063_0003
I (NRb = X; Rb = H or C^ alkyl; Y = NH) or a precursor to I
An optionally substituted diamine II is reacted with an aryl isothiocyanate in a suitable solvent such as EtOAc, DMF or THF at about ambient to reflux temperature for about 3 to 24 hr to provide thiourea III. Alternately, one can begin with a salt of II and react with an aryl isothiocyanate in pyridine or in a neutral solvent such as THF in the presence of a suitable base such as triethylamine. Reaction ofthe thiourea with a suitable activating agent such as 1,3-dicyclohexylcarbodiimide (DCC) or mercuric oxide in a suitable solvent such as THF or DMF at about ambient to reflux temperature provides I or a precursor to I which may undergo further chemical transformation to obtain the desired compound. If desired, one may perform the two steps without isolating the thiourea, by adding DCC or mercuric oxide to the reaction of II and the aryl isothiocyanate.
One may also prepare benzothiazoles (formula I, X = S) by Method A, starting with the analogous aminothiophenol. Preferably, one may also use Method B illustrated in Scheme II and described below.
Scheme II (Method B)
Figure imgf000064_0001
IV V
Figure imgf000064_0002
I (X = S; Y = NH) or a precursor to I
In this method, an appropriately substituted aniline is reacted with an aryl isothiocyanate as in Method A to provide thiourea V. Reaction of V under cyclizing conditions, such as in the presence of bromine in a suitable solvent such as chloroform at about reflux temperature, provides I (X = S) or a precursor to I.
The starting diamine (II) in Method A may be prepared by reduction of a nitroaniline, for example under hydrogen atmosphere in the presence of a suitable catalyst such as palladium on carbon in a suitable solvent, such as EtOAc or HO Ac.
One procedure (Method C) for preparing starting nitroanilines is illustrated in Scheme III and described below.
Scheme III (Method C)
Figure imgf000065_0001
VI VII (Rb = H or C,^ alkyl) IX
Figure imgf000065_0002
X XI
In Method C, 2,6-dichloro-3-nitrobenzonitrile (VI) is reacted with an amine in a suitable solvent, such as EtOH, THF or EtOAc, optionally in a pressure flask and at about 0 to 80 °C, to provide NIL Reaction of VII with keto-ester VIII in the presence of a suitable base, such as K2CO3, potassium t-butoxide or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a suitable solvent, such as DMF or DMSO at about ambient temperature provides IX. Hydrolysis and cyclization of IX to provide X is accomplished by reaction with aqueous acid, for example a mixture of acetic acid, sulfuric acid and water at about reflux temperature. Reduction of nitroaniline X, in a suitable solvent, preferably acetic acid and/or trifluoroacetic acid, as described above, provides XL
In a variation of Method C, one may reduce intermediate IX as described above, to the corresponding diamine and form the benzimidazole by Method A prior to formation of the isoquinolinone.
A procedure for introducing RA into compounds of formula (I) is illustrated in Scheme IV.
Scheme IV Method A
Figure imgf000066_0001
XII XIII
Figure imgf000066_0002
XIV XV
Intermediate XII (prepared as described in Scheme III for preparation of IX, followed by reduction) is reacted with bromine in a suitable solvent, such as chloroform at ambient temperature to provide XIII. Intermediate XIII is converted to XIV according to Method A. Cross-coupling chemistry can be used to introduce carbon in place of bromine. For example, reaction with vinyl tributyltin in the presence of a suitable catalyst, such as (PPh3)2PdCl , in a suitable solvent, such as l-methyl-2-pyrrolidinone (NMP) at about 100 °C, provides XV. Alternately, reaction with a terminal alkyne in the presence of a suitable catalyst, such as (PPh3) 2PdCl2, and Cul, and a suitable base, such as triethylamine in a solvent such as THF at about ambient temperature provides an alkyne as Ra. Other Ra may be obtained by transformation of these Ra by methods known to those skilled in the art. Several of these transformations are exemplified below.
A method for preparing compounds ofthe invention in which R4 and R5 represent ring B, which is based on the procedure described in J. Heterocyclic Chem., 1970, 7, 615, is shown in Scheme V.
Scheme V
Figure imgf000067_0001
XVI XVII
cone. H2SO4
Figure imgf000067_0002
XVIII Intermediate XVI (prepared according to Method A or Method B) is reacted with a reducing agent such as sodium borohydride, in a suitable solvent, such as THF or dioxane, at about 0°C to ambient temperature, to give intermediate XVII, in which one carbonyl ofthe imide has been reduced selectively. Treatment of XVII with a strong acid, such as sulfuric acid, at ambient temperature, causes rearrangement to the isoquinolone XVIII. It will be appreciated that this method is most suitable for compounds where R^ R7, Rs and R9 are all the same group, preferably methyl. In a variation of this method, the reduction ofthe imide and rearrangement to the isoquinolone can be carried out prior to forming the benzimidazole ring.
Functional groups at Rs or R9 on compounds of formula (I) or intermediates prepared as illustrated in the Schemes above may also be transformed by methods known to those skilled in the art to prepare additional compounds ofthe invention. Several of these transformations are also exemplified below. Methods of Therapeutic Use
The compounds ofthe invention are useful in inhibiting the activity of src-family kinases and PDGFR kinase. In doing so, the compounds are effective in blocking disease processes mediated by these kinases. For example, by inhibiting p56 lck, the compounds block downstream signaling events following T cell activation by antigen. Activation of antigen-specific T cells is necessary for the induction and progression of diseases, including autoimmune diseases, allergic diseases and transplant rejection (J.H. Hanke et al., Inflamm. Res., 1995, 44, 357). Therefore the compounds ofthe invention are useful for treating such diseases. These include but are not limited to rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus erythematosus, insulin-dependent diabetes mellitus and asthma.
In view of their inhibitory effect on src-family kinases and PDGFR kinase, the compounds ofthe invention are useful in treating cancer. For example, the compounds of the invention are useful in treating src-dependent tumors, such as in mammary carcinoma, colon carcinoma, melanoma and sarcoma, and are also useful in treating PDGF-dependent tumors, such as ovarian cancer, prostate cancer and glioblastoma.
By inhibiting p60src, compounds ofthe invention may also be useful in treating osteoporosis, Paget's disease, bone inflammation and joint inflammation . By inhibiting PDGFR kinase, compounds ofthe invention may also be useful in treating fibrotic diseases, restenosis and atherosclerosis. By inhibiting lyn kinase, the compounds ofthe invention may also be useful in enhancing or potentiating the effectiveness of radiation therapy.
For therapeutic use, the compounds ofthe invention may be administered in any conventional dosage form in any conventional manner. Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, rectally, topically or by inhalation. The preferred modes of administration are oral and intravenous. Compositions comprising the compounds ofthe invention for each ofthe aforementioned routes of administration will be apparent to the skilled artisan. For example, one embodiment ofthe invention provides for pharmaceutical compositions including a pharmaceutically effective amount ofthe compounds according to the invention. Such pharmaceutical compositions will include pharmaceutically acceptable carriers and adjuvants as further described below.
The compounds of this invention may be administered alone or in combination with adjuvants that enhance stability ofthe inhibitors, facilitate administration of pharmaceutic compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients. Advantageously, such combination therapies utilize lower dosages ofthe conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. Compounds ofthe invention may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of formula (I) (w/w) or a combination thereof. The optimum percentage (w/w) of a compound of formula(I) may vary and is within the purview of those skilled in the art. Alternatively, the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.
As mentioned above, dosage forms ofthe compounds of this invention include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include, tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific dosage and treatment regimens will depend on factors such as the patient's general health profile, the severity and course ofthe patient's disorder or disposition thereto, and the judgment ofthe treating physician.
SYNTHETIC EXAMPLES
Example 1: Synthesis of 2-(2,6-Dichlorophenylamino)-6,6-dimethyl-lH,6H- imidazo[4,5-/ι]isoquinoline-7,9-dione.
Figure imgf000071_0001
4,4-Dimethyl-7-nitro-2H,4H-isoquinoline-l,3-dione, prepared as described in US 4666923 (1987), (l.Og, 4.5mmol) in methanol (50mL) was hydrogenated over 10% Pd/C (30mg) at 50psi for 1.5h. The catalyst was removed by filtration and the solvent removed to give 8-amino-4,4-dimethyl-2H,4H-isoquinoline-l,3-dione (0.90g, 98%).
The above amine (1.5g, 7.35mmol) was stirred in acetic anhydride (9mL) at room temperature for 3h, then poured on to ice. The precipitate was filtered, washed with water and dried to give 7-acetamido-4,4-dimethyl-2H,4H-isoquinoline-l,3-dione (1.55g, 86%)
The above amide was converted to 7-acetamido-4,4-dimethyl-8-nitro-2H,4H- isoquinoline-l,3-dione as described in US 4176184 (1979).
7-Acetamido-4,4-dimethyl-8-nitro-2H,4H-isoquinoline-l,3-dione (4.0g, 13.7mmol) was added to 90% Η2SO4 and heated at 70°C for 8h. The cooled mixture was poured onto ice. The precipitate was collected, dissolved in ethyl acetate, washed with water, dried and evaporated to give 7-amino-4,4-dimethyl-8-nitro-2H,4H-isoquinoline-l,3-dione (3.38g, 99%), mp 259-263°C; MS (CI) 250 (MΗ+).
A solution ofthe above amine (1.5g, ό.Ommol) in methanol (50mL) was hydrogenated over platinum oxide (30mg) at 50 psi for 1.25h. The mixture was filtered through diatomaceous earth and evaporated to provide 7,8-diamino-4,4-dimethyl-2H,4H- isoquinoline-l,3-dione. (1.31g, 100%). MS (CI) 220 (MΗ+).
As described in Method A, 2,6-dichlorophenylisothiocyanate ( 1.16g, 5.7mmol) was added to a suspension of 7,8-diamino-4,4-dimethyl-2H,4H-isoquinoline-l,3-dione (1.3 lg, ό.Ommol) in ethyl acetate (40mL) and the mixture stirred overnight. The solid was filtered and dried to yield the thiourea (1.55g, 61%). mp >300°C; MS (CI) 423, 425 (MΗ+). A solution of the thiourea (2.23g, 5.28mmol) in THF (50mL) and dicyclohexylcarbodiimide ( 1.11 g, 5.4mmol) was heated under reflux with stirring for 4h. The cooled solution was stirred overnight, filtered, and the crystals washed with CH2C12 to give the title compound (1.20g). The filtrate was evaporated and triturated with CH2C12 to give more product (0.7g, 93% combined yield), mp 290-292°C; MS (El) 388, 390 (M+).
Example 2: Synthesis of 2-(2,6-Dichlorophenylamino)-6,6-dimethyl-7,8-dihydro- lH,6H-imidazo[4,5-Λ]isoquinoline-9-one.
Figure imgf000073_0001
To a solution ofthe product of Example 1 (90mg, .23mmol) in THF (5mL) was added NaBH4 (90mg, 2.3mmol) followed by water (4 drops). The reaction mixture was stirred at ambient temperature for 1 h. Subsequently, IN HCl (5mL) was added dropwise and the reaction mixture was stirred an additional 15 minutes, neutralized with NaHCO3 and extracted with EtOAc. The extract was washed with brine, dried and evaporated yielding the alcohol 2-(2,6-dichlorophenylamino)-6,6-dimethyl-7-hydroxy-7,8-dihydro- 1H,6H- imidazo[4,5-Λ]isoquinoline-9-one (90mg 99%). This intermediate was used immediately due to its instability. It was characterized as the methyl ether, which was prepared by dissolving the product in MeOΗ/ΗCl and stirring for several hours. After evaporation, the residue was partitioned between EtOAc/aq NaΗCO3. The organic phase was washed with brine, dried and evaporated to the methyl ether derivative, mp 278-280°C(dec); MS (ES) 405 (MH+).
The alcohol from above (lOOmg, .26mmol) was dissolved in TFA (2 mL) and this solution was subsequently added to a solution of sodium tristrifluoroacetoxyborohydride (generated in-situ from 160mg, 4.2mmol of sodium borohydride and 3mL TFA) at 0°C. The reaction mixture was stirred at ambient temperature for 4h, the solvent was evaporated, the residue was triturated with water and the resultant mixture was neutralized with NaHCO3 and filtered yielding the title compound (85mg, 92%). This product was purified by flash chromatography on SiO2 using 4% MeOH/CH2Cl as eluant and recrystallization from EtOAc, mp 287-290°C; MS (CI) 375 (MH+).
Example 3a : Synthesis of 2-(2,6-Dichlorophenylamino)-6,7-dimethyl-l,8-dihydro- imidazo [4,5-Λ] isoquinoline-9-one.
Figure imgf000074_0001
2-(2,6-Dichlorophenylamino)-6,6-dimethyl-7-hydroxy-7,8-dihydro-lH,6H-imidazo[4,5- 2]isoquinoline-9-one (from Example 2) (45mg, 0.1 lmmol) was suspended in cone. Η2SO4 (lmL) and the resultant mixture was stirred at ambient temperature for 15 min. The solution was poured over ice, neutralized with NaHCO3 and filtered. The filtrate was triturated with water (lOmL) and centrifuged. The liquid was decanted, and the residual solid was triturated with methanol and centrifuged. The supernatant was decanted and the residue dried to give the title compound (35mg, 84%). Mp >300°C; MS (ES) 373 (MH+).
Example 3b: Synthesis of 2-(2,6-Dichlorophenylamino)-6,7-dimethyl-l,8-dihydro- imidazo [4,5-Λ] isoquinoline-9-one (Method C).
Figure imgf000075_0001
H2, Pd/C ArNCS TFA HOAc pyridine
Figure imgf000075_0002
Figure imgf000075_0003
Figure imgf000075_0004
A 500mL pressure flask was charged with 2,6-dichloro-3-nitrobenzonitrile (30. Og, 138mmol) and a 5.1M solution of ammonia in EtOH (170mL). The flask was sealed and heated in an oil bath at 80°C with stirring for 1.5h. The cooled solution was filtered, the crystals washed with water and dried to yield 2-amino-6-chloro-3-nitrobenzonitrile (18.4g, 68%), mp 181-184°C; MS (ES-) 196, 198 (M-H").
To a solution of 2-amino-6-chloro-3-nitrobenzonitrile (1.97g, lOmmol) and ethyl 2- methylacetoacetate (3.6g, 25mmol) in DMF (lOmL) was added finely powdered K2CO3, and the mixture stirred vigorously for 24h. The deep red mixture was diluted with EtOAc and washed in turn with 2M HCl, water and brine. The residue after evaporation was purified by flash chromatography in hexane/EtOAc 3:1 to yield 2-(3-amino-2-cyano-4- nitrophenyl)-2-methyl-3-oxobutyric acid ethyl ester as an oil (1.39g, 46%), MS (NH3 CI) 323 (M+NH ), 293 (M+NIL-NO+). The ester from above (1.39g, 4.56mmol) was added to a mixture of acetic acid (20mL), H2SO4 (3mL) and water (2mL), and the solution heated at 100°C for 3h. The cooled solution was diluted with water (30mL), the precipitate was collected, washed with water and MeOH and dried to give 8-amino-3,4-dimethyl-7-nitro-2H-isoquinolin-l-one (0.76g, 72%). mp >300°C.
A solution ofthe amino isoquinolin-1-one from above (0.20g, 0.86mmol) in trifluoroacetic acid (1 lmL) and acetic acid (7mL) was hydrogenated over 10% palladium on carbon (21mg) at 50psi for 2h. The solution was filtered through diatomaceous earth, washing with acetic acid, and the filtrate evaporated to give 7,8-diamino-3,4-dimethyl- 2H-isoquinolin-l-one ditrifluoroacetate salt (310mg, 83%).
A suspension ofthe diamino isoquinolin-1-one ditrifluoroacetate salt from above (1.15g, 2.67mmol) and 2,6-dichlorophenylisothiocyanate (0.60g, 2.93mmol) in pyridine (16mL) was stirred for 18h at room temperature (Method A). The solution was diluted with toluene and evaporated, and remaining pyridine removed with a toluene azeotrope. The residue was triturated with EtOAc to give the thiourea (1.17g). A portion of this material (0.50g, 1.23mmol) and dicyclohexylcarbodiimide (0.375g, 1.84mmol) were heated together in DMF under argon at 80°C for 4h. The cooled solution was evaporated and triturated first with cold MeOΗ, then with boiling MeOΗ, to leave the title compound as a light tan solid, (0.309g, 73%), identical with the sample obtained in Example 3a.
Example 4: Synthesis of 2-(2,6-Dichlorophenylamino)-l,6,7-trimethyl-l,8-dihydro- imidazo[4,5-Λ]isoquinoline-9-one.
Figure imgf000077_0001
Figure imgf000077_0002
Figure imgf000077_0003
4
A solution of 2,6-dichloro-3-nitrobenzonitrile (98.7g, 0.455mol) in EtOAc (910mL) was cooled to 5°C. 40% Aqueous methylamine (79.5mL, 1.14mol) was added with vigorous mechanical stirring, keeping the temperature at 10-15°C. After addition was complete, stirring was continued for 3h at the same temperature. More methylamine (16mL, 0.23mol) was added, and the mixture stirred for a further 1.5h at room temperature. Water (300mL) was added, followed by hexane (450mL). The mixture was stirred for 15min, filtered, and the solid washed with water and MeOH, to give 6-chloro-2- methylamino-3-nitrobenzonitrile (80.3g, 83%), mp 167-170°C.
To a stirred solution of potassium t-butoxide (24.3g, 206mmol) in DMSO (500mL) was added ethyl 2-methylacetoacetate (34.3g, 233mmol), dropwise over 5min. The temperature rose to 30°C. 6-Chloro-2-methylamino-3-nitrobenzonitrile (43.6g, 190mmol) was added in portions over 15min. The temperature rose to 40°C. The solution was stirred for lh with no external heating or cooling. The mixture was poured into 10% NH4C1 (500mL), and extracted with EtOAc (2 x 500mL). The combined extracts were washed with water (2 x 250mL) and brine, and evaporated. MeOH (200mL) was added to the residue and stirred for 1.5h. The yellow solid was filtered, washed with cold MeOH (25mL) and dried to give 2-(2-cyano-3-methylamino-4- nitroρhenyl)-2-methyl-3-oxobutyric acid ethyl ester (36.2g, 60%), mp 87-91°C.
A solution of the above ester (10.5g, 32.5mmol) in EtOAc (130mL) was hydrogenated over 10% palladium on carbon (0.5g) at 50psi for 24h. The catalyst was removed by filtration through diatomaceous earth, and the filtrate was evaporated. A mixture of
EtOAc/hexane (1: 1, lOmL) was added to the residue and the resulting mixture was stirred for 0.5h. The crystals were filtered and washed with hexane to give 2-(4-amino-2-cyano- 3-methylaminophenyl)-2-methyl-3-oxobutyric acid ethyl ester (7.74g, 81%), mp 118- 123°C.
A solution ofthe amino ester from above (7.7g, 26.6mmol) and 2,6- dichlorophenylisothiocyanate (5.43g, 26.6mmol) in THF (150mL) was stirred at room temperature for 5h. Mercuric oxide (6.34g, 29.3 mmol) was then added in one portion, and stirring continued overnight. The mixture was filtered through diatomaceous earth, washing well with THF. The filtrate was evaporated, and the residue triturated with ether to give 2-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimiazol-5-yl]-2- methyl-3-oxobutyric acid ethyl ester as an off-white solid (7.7g, 63%).
To a stirred mixture of cone. Η2SO4 (40mL), HO Ac (40mL) and water (40mL) at 60°C was added 2-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimiazol-5-yl]-2- methyl-3-oxobutyric acid ethyl ester (7.4g, 16mmol) in one portion. The solution was heated at 100°C for 2.5h, then stirred overnight at room temperature. The reaction mixture was poured onto ice, and neutralized with cone. NΗ4OΗ, with ice cooling. The precipitate was filtered and washed well with water. The solid was slurried in MeOH, stirred well, filtered, washed with MeOH until washings were colorless, and dried. The title compound was obtained as a grey solid (5.48g, 88%), mp >300°C; MS (NH3 CI) 387, 389 (MH+).
Example 5: Synthesis of 2-(2,6-Dichlorophenylamino)-6,6-dimethyl-6H-thiazolo[4,5- Λ]isoquinoline-7,9-dione (Method B).
ArNCS, EtOAc
Figure imgf000079_0002
Figure imgf000079_0001
Figure imgf000079_0003
To a suspension of 7-amino-4,4-dimethyl-2H,4H-isoquinoline-l,3-dione (204mg, lmmol) in EtOAc (25mL) was added 2,6-dichlorophenylisothiocyanate (223mg, l.lmmol) in three portions, and the mixture was stirred overnight. The solid was filtered and dried to yield the thiourea (380mg, 93%), mp 142-144°C; MS (CI) 408(MΗ+). To a suspension ofthe thiourea (140mg, 0.34mmol) in CHC13 (20mL) was added Br2 (60mg, 0.37mmol) in CHC13 (2mL) dropwise. The solution was heated to reflux for lh. The solvent was evaporated and the residue triturated with saturated NaHCO3 (50mL). The solid was filtered, washed with water, and dried, to yield the title compound (114mg, 82%), mp >300°C; MS (CI) 406(MH+).
Example 6: Synthesis of 2-(2,6-Dichlorophenylamino)-6,7-dimethyl-8H-thiazolo[4,5- Λ]isoquinoline-9-one (Method B).
Figure imgf000080_0001
Figure imgf000080_0002
To a solution of 7-nitro-4,4-dimethyl-2H,4H-isoquinoline-l,3-dione from Example 1 (l.Og, 4.3mmol) in TΗF (50mL) was added NaBFL (330mg, 8.7mmol) followed by water (10 drops). The reaction mixture was stirred at room temperature for 2.5h, cooled in an ice bath and treated with IN ΗC1 until a pale yellow color was maintained. After 10 min. the reaction mixture was neutralized with saturated NaΗCO3 and extracted with EtOAc. The extract was washed with brine, dried and evaporated to the alcohol, which was immediately taken up in cone. H2SO4 (8mL). This mixture was stirred until completely dissolved (10 min.), poured over ice, neutralized with 10% NH4OH, allowed to stand several hours, filtered and dried to yield 3,4-dimethyl-7-nitro-isoquinoline-l-one (780mg, 83%). MS (CI) 219(MH+).
A solution of 3,4-dimethyl-7-nitro-isoquinoline-l-one (750mg, 3.4mmol) in MeOH (250mL) was hydrogenated over Pd/C (25mg) at 60psi for 24h. The reaction mixture was filtered through diatomaceous earth, washing well with MeOH. Evaporation ofthe filtrate provided the amine (554mg, 85%) which was immediately dissolved in EtOAc (60mL) and treated with 2,6-dichlorophenylisothiocyanate (663mg, 3.3mmol). The mixture was stirred at ambient temperature for 48h, refluxed for 4h and stirred at ambient temperature an additional 72h. The thiourea was filtered and washed with EtOAc (850mg, 74%). mp 220°C (dec). A portion ofthe thiourea (490mg, 1.25mmol) was suspended in CHC13 (50mL) and treated with a solution of Br2 (200mg, 1.25mmol) in CHC13 (5mL), and the resulting mixture was refluxed for lh. The solvent was evaporated, the residue was suspended in a saturated solution of NaHSO3, filtered, then treated analogously with a saturated solution of NaHCO3. Purification by silica column chromatography (0 to 5% MeOH in CH2C12 eluant) yielded the title compound (28 lmg, 58%), mp >300°C, MS (CI) 390 (MH+).
Example 7: Synthesis of 2-(2,6-Dichlorophenylamino)-l,7-dimethyl-6-(2-morpholin- 4-yl-2-oxoethyl)-l,8-dihydro-imidazo[4,5-Λ]isoquinoline-9-one.
morpholine TB M T F U ι-rt
Figure imgf000081_0003
Figure imgf000081_0002
Figure imgf000081_0001
7
To a solution of 2-(2,6-dichlorophenylamino)-l,7-dimethyl-9-oxo-l,8-dihydro- imidazo[4,5- z]isoquinolin-6-yl acetic acid (prepared using Methods C and A) (1.0g, 2.3mmol) in DMF (7mL) was added O-benzotriazol-l-yl-N,NN',N'-tetramethyluronium tetrafluoroborate (TBTU) (0.82g, 2.6mmol) and morpholine (0.24mL, 2.8mmol), and the mixture stirred 18h at room temperature. Ice water was added, the precipitate collected, washed with water and dried to give the title compound, 0.97g, 84%, mp >300°C; MS (ES) 500, 502 (MH+).
Example 8: Synthesis of 2-(2,6-Dichlorophenylamino)-l,7-dimethyl-6-(2-morpholin- 4-yl-ethyl)-l,8-dihydro-imidazo[4,5-A]isoquinoline-9-one.
Figure imgf000082_0001
A stirred suspension ofthe product of Example 7 (85mg, 0.17mmol) in THF (9mL) was heated to reflux and borane-methylsulfide (0.09mL, 0.9mmol) added. Stirring was continued for 3.5h at reflux and overnight at room temperature. 6M HCl was added and the solution stirred for 2h. The solution was applied to a Varian SCX column, washed with MeOH/CH2Cl2 50:50, then the product eluted with MeOH/CH2Cl2/NH4OH 50:50:1. The product was further purified on a silica column eluting with CH2Cl2/MeOH 98:2 to give the title compound 32mg, 39%, mp 285-290°C; MS (ES) 486, 488 (MH+).
Example 9: Synthesis of 2-(2,6-Dichlorophenylamino)-l,7-dimethyl-9-oxo-l,8- dihydro-imidazo[4,5-Λ]isoquinolin-6-yl acetic acid ethyl ester.
Figure imgf000082_0002
Prepared from 2-(2,6-dichlorophenylamino)-l,7-dimethyl-9-oxo-l,8-dihydro- imidazo[4,5-Λ]isoquinolin-6-yl acetic acid by refluxing in ethanol and H2SO4. Mp 280- 285°C (dec); MS(CI) 459, 461 (MH+).
Example 10: Synthesis 2-(2,6-Dichlorophenylamino)-l,7-dimethyl-6-(2- hydroxyethyI)-l,8-dihydro-imidazo[4,5-A]isoquinoline-9-one.
Figure imgf000083_0001
To a stirred solution ofthe product of Example 9 (25mg, 0.05mmol), in THF (2mL), under nitrogen, was added a solution of lithium aluminum hydride (1M in THF, 0.25mL, 0.25mmol). The mixture was stirred for 30min at room temperature. Ethyl acetate was added, followed by water, and then acidified with IN HCl. The whole mixture was applied to a Narian SCX cartridge, and washed in turn with IN HCl, water, acetone, MeOH, and MeOH/CH2Cl2 (1:1). The product was then eluted with MeOH/CH2Cl2 /ΝH4OH (49:49:2). Evaporation ofthe eluent gave the title compound (15mg, 72%). Mp >300°C; MS(ES) 417, 419 (MH+).
Example 11: Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro-lH-imidazo[4,5-A]isoquinoline-7-carbaldehyde.
The method described below is useful for preparing intermediate compounds such as 11, which possess an aldehyde moiety at the 7-position.
Figure imgf000083_0002
11
To a suspension of the product from Example 4 (52 lmg, 1.3mmol) in dioxane (30mL) was added selenium dioxide (430mg, 3.9mmol) and the mixture was heated at 100°C for 5h. The reaction was then cooled to room temperature, filtered through diatomaceous earth with 10% MeOH-CH2Cl2 and then concentrated in vacuo. The crude material was triturated with CH2C12 to provide the title compound (476mg, 92%), mp: >300°C; MS (CI) 401, 403 (MH+).
Example 12: Synthesis of 3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro-lH-imidazo[4,5-Λ]isoquinolin-7-yl]-acrylic acid methyl ester.
Figure imgf000084_0001
11 12 To a suspension ofthe product of Example 11 (329mg, 0.82mmol) in THF (5mL) was added sequentially, trimethyl phosphonoacetate (164mg, 0.90mmol), lithium hydroxide monohydrate (76mg, 1.8mmol) and water (0.9mL). The blood red solution was stirred for 2h, quenched with water, and the resulting solid was collected and dried in vacuo. Column chromatography (5% MeOH-CH2Cl2) provided the title compound (300mg, 80%), mp >300°C; MS (ES) 457, 459 (MH+).
Example 13: Synthesis of 3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro-lH-imidazo[4,5-Λ]isoquinolin-7-yl]-propionic acid methyl ester.
Figure imgf000084_0002
To a solution ofthe product of Example 12 (30mg, O.Oόmmol) in EtOH (3mL) and AcOH (4mL) in a Parr reactor was added PtO2 (2mg, 0.007mmol). The Parr reactor was charged with 50psi of H2 and shaken for 12h. The crude reaction was filtered through diatomaceous earth with EtOH and concentrated in vacuo. Column chromatography (2% MeOH-CH2Cl2) provided the title compound (9mg, 30%), mp 268°C(dec); MS(ES) 459, 461(MH+).
Example 14: Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-(3-hydroxy- propen-l-yl)-l,8-dihydro-imidazo[4,5-A]isoquinolin-9-one.
Figure imgf000085_0001
A suspension ofthe product of Example 12 (lOOmg, 0.22mmol) in THF (7mL) was cooled to -78°C. Sodium bis(trimethylsilyl)amide (1M in THF, 0.44mmol) was added dropwise. The bright red solution was warmed to 0°C for 15 minutes, then lithium aluminum hydride (1M in THF, 2.6mmol) was added and the orange solution was warmed to room temperature for 0.5h. The mixture was cooled to 0°C, quenched with saturated ammonium chloride and extracted with ethyl acetate. Column chromatography (3-6% MeOH-CH2Cl2) provided the title compound (32 mg, 34%), mp 298-300°C; MS(ES) 429, 431(MH+).
Example 15: Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-vinyl-l,8- dihydro-imidazo[4,5-A]isoquinoline-9-one.
Figure imgf000086_0001
To a suspension of the product of Example 11 (lOOmg, 0.25mmol) in THF (5mL) was added trimethylsilylmethyl magnesium chloride (2mL, 2mmol) at -78°C. The reaction was warmed to room temperature for lh, then cooled to 0°C and quenched with water and extracted with ethyl acetate to provide the silyl alcohol (85 mg, 70%). The crude silyl alcohol was suspended in CH2C12 and cooled to 0°C. Borontrifluoride etherate (42μL, 0.32mmol) was added and the slurry was warmed to room temperature for 1 h. The reaction was quenched with water, and the CH2C12 was removed in vacuo. Collection ofthe resulting solid followed by CH2C12 trituration provided the title compound (17mg, 61%), mp > 300°C; MS(Es) 399, 401(MH+).
Example 16: Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-(l- hydroxyprop-2-en-l-yl)-l,8-dihydro-imidazo[4,5-Λ]isoquinolin-9-one.
Figure imgf000086_0002
A suspension of 2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9-dihydro- 1H- imidazo[4,5-/z]isoquinoline-7-carbaldehyde (2) (lOOmg, 0.25mmol) in TΗF (3ml) was cooled to -78°C. Ninylmagnesium bromide (IM in TΗF, 2.0mmol) was added dropwise, and the brown suspension was warmed gradually to -10°C over 2h. The solution was quenched with saturated ammonium chloride and extracted with ethyl acetate, and concentrated in vacuo to provide the title compound, which was used in the next step without purification, mp 235-236°C, MS (ES) 429 (MH+).
Example 17: Synthesis of 2-(2,6-Dichlorophenylamino)-7-(l-acetoxyprop-3-en-l-yι)- l,6-dimethyl-l,8-dihydro-imidazo[4,5-Λ]isoquinolin-9-one.
Figure imgf000087_0001
To a solution ofthe product of Example 16 (106mg, 0.25mmol) in THF (1ml) was added acetic anhydride (1ml). Triethylamine (35μL, 0.25mmol) was added, and the reaction was stirred for 14h, then concentrated in vacuo. Column chromatography (2% MeOH- CH2C12) provided the title compound (85mg, 79%), mp 169-171°C; MS (ES) 471 (MH+).
Example 18: Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-(3- morpholin-4-yl-propen-l-yl)- l,8-dihydro-imidazo[4,5-Λ]-isoquinolin-9-one.
Figure imgf000087_0002
Tris(dibenzylideneacetone) dipalladium(O) (1.8mg, 0.002mmol) and triphenylphosphine (1.6mg, 0.006mmol) were stirred in THF (0.5ml) for 20min under inert atmosphere until the red solution turned yellow. To this solution was added sequentially, the product of Example 17 (20mg, 0.04mmol) in THF (0.5 ml), triethylamine (17μL, 0.12mmol) and morpholine (1 lμL, 0.12mmol). The solution was stirred 14h, then concentrated to an oil. Column chromatography (10% MeOH-CH2Cl2) provided the title compound (10 mg, 50%), mp 175-177°C; MS (ES) 498 (MH+).
Example 19: Synthesis of 7-Benzylaminomethyl-2-(2,6-dichlorophenylamino)-l,6- dimethyl-l,8-dihydro-imidazo[4,5-Λ]-isoquinolin-9-one.
Figure imgf000088_0001
To a suspension ofthe product of Example 11 (50mg, 0.12mmol) in THF (4mL) was added benzylamine (54mg, 0.50mmol). The reaction was stirred for 12h, then concentrated in vacuo. The crude imine was suspended in MeOH (2mL), sodium borohydride (21mg, 0.55mmol) was added, and the reaction was stirred for 3h. The reaction was quenched with water, and the resulting solid was collected and dried to provide the title compound (1 lmg, 39%), mp 231-234°C; MS (ES) 492(MH+).
Example 20: Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-oxazol-5-yl- 1 ,8-dihydro-imidazo [4,5-A] isoquinolin-9-one.
Figure imgf000088_0002
A suspension ofthe product of Example 11 (40mg, O.lOmmol), tosylmethyl isocyanide (21mg, 0.1 lmmol) and K2CO3 in methanol (2mL) was heated to 40°C for 90min. The mixture was diluted with water (3mL) and the solid collected by filtration to obtain the title compound (26mg, 60 %), mp >300°C; MS (ES) 440, 442(MH+).
Example 21: Synthesis of 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-(3-methyl- 3H-imidazol-4-yl)-l,8- dihydro-imidazo[4,5-A]isoquinolin-9-one.
Figure imgf000089_0001
11 21
A suspension ofthe product of Example 11 (50mg, 0.13mmol) and methylamine (2M in THF, 2mL, 4mmol) in dry THF (2mL) was stirred at room temperature for 12h. The THF was evaporated and the resulting imine was mixed with tosylmethyl isocyanide (27mg, 0.14mmol), K2CO3 (31mg, 0.23mmol) and dry DMSO (2mL). This suspension was stirred for five days at room temperature. Water (5mL) was added and the precipitate collected by filtration. Flash chromatography in CH2Cl2/MeOH (98:2) gave the title compound (8mg, 14%), mp >300°C; MS(ES) 453, 455 (MH+).
Example 22: Synthesis of 2-(2,6-Dichlorophenylamino)-l,6,7-trimethyl-4-vinyl-l,8- dihydro-imidazo [4,5-Λ] isoquinoline-9-one.
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000090_0003
To a solution of 2-(4-amino-2-cyano-3-methylaminophenyl)-2-methyl-3-oxobutyric acid ethyl ester from Example 4 (9.02g, 31.2mmol) in CHC1 (90mL) was added bromine (4.98g, 31.2mmol) dropwise at ambient temperature. After the addition of bromine, the reaction mixture was diluted with ethyl acetate (800mL). This solution was washed successively with sat. NaHCO3 solution and brine and dried. The residue after evaporation was purified by flash chromatography in hexanes/EtOAc 2:1 to yield 2-(4- amino-5-bromo-2-cyano-3-methylaminophenyl)-2-methyl-3-oxobutyric acid ethyl ester as an oil (6.06g, 53%).
To a solution ofthe above ester (3.32g, 9.02mmol) in 1,4-dioxane (45mL) was added 2,6- dichlorophenylisothiocyanate (2.02g, 9.92mmol) and mercuric oxide (2.54g, 11.7mmol) under nitrogen atmosphere. The resulting mixture was stirred and heated at 95°C overnight. The reaction mixture was cooled to room temperature and filtered though a short pad of diatomaceous earth and SiO2. The filtrate was concentrated and the residue was purified by flash chromatography in hexanes/EtOAc 2:1 to yield 2-[8-bromo-4- cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimiazol-5-yl]-2-methyl-3- oxobutyric acid ethyl ester as a brown solid (3.44g, 71%).
A mixture ofthe above bromo ester (600mg, 1.1 lmmol), (PPh )2PdCl2 (78mg, 0.1 lmmmol) and tributyl(vinyl)tin (0.49mL, 1.67mmol) in NMP (4mL) was degassed and heated at 100°C for 3 days under argon. The mixture was concentrated and the residue was purified by flash chromatography in hexanes/EtOAc 3:1 to yield 2-[4-cyano- 2-(2,6-dichlorophenylamino)-3-methyl-8-vinyl-3H-benzimiazol-5-yl]-2-methyl-3- oxobutyric acid ethyl ester as an oil (530mg, 98%).
A solution ofthe above keto ester (66mg, 0.14mmol) in a mixture of Η2SO4 (0.6mL), acetic acid (0.6mL) and water (0.6mL) was heated at 100°C for 2h. The resulting mixture was cooled to room temperature and diluted with water (lOmL). The solution was adjusted to pH 8 with 10% NaOH solution. The precipitated brown solid was filtered and purified by flash chromatography in CH2Cl2/MeOH 30:1 to yield the title compound (15mg, 27%), mp decomp. above 250°C; MS (CI) 413(MH+).
Example 23: Synthesis of 2-(2,6-Dichlorophenylamino)-l,6,7-trimethyl-9-oxo-l,8- dihydro-imidazo [4,5-Λ] isoquinoline-4-carbaldehyde.
Figure imgf000092_0001
Figure imgf000092_0002
A solution of 2-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-8-vinyl-3H- benzimiazol-5-yl]-2-methyl-3-oxobutyric acid ethyl ester (see Example 22) (538mg, 1.1 lmmol) in TΗF (30mL) was treated with 2.5% OsO4 solution in tBuOΗ (3.0mL), NaIO4 (712mg, 3.33mmol) and water (3mL). After stirring for 1.5h at room temperature, the mixture was diluted with EtOAc. The organic solution was washed with brine, dried and concentrated. The residue was purified by flash chromatography in hexanes/EtOAc 4: 1 to yield 2-[4-cyano-2-(2,6-dichlorophenylamino)-8-formyl-3-methyl-3H- benzimiazol-5-yl]-2-methyl-3-oxobutyric acid ethyl ester as an oil 345mg, 64%).
A solution ofthe above aldehyde (35mg, 0.07mmol) in a mixture of Η2SO4 (0.6mL), acetic acid (0.6mL) and water (0.6mL) was heated at 100°C for 1.5h and cooled to room temperature. The resulting mixture was diluted water (lOmL) and the pH adjusted to 7 with ammonium hydroxide solution. The precipitated orange powder was filtered to give the title compound as an orange solid (18mg, 60%).
Example 24: Synthesis of 2-(2,6-Dichlorophenylamino)-4-(2- hydroxyethylaminomethyl)-l,6,7-trimethyl-l,8-dihydro-imidazo[4,5-Λ]isoquinoline- 9-one.
Figure imgf000093_0001
23 24
A suspension ofthe product of Example 23 (30mg, 0.07mmol) in MeOH (5mL) was treated with ethanolamine (44μL, 0.72mmol) and NaBH3CN (14 mg, 0.22mmol), and stirred at room temperature for 16h. The resulting mixture was concentrated and the residue was diluted with water. The precipitated solid was filtered to give the title compound (12mg, 36%). mp decomp. above 250°C; MS (CI) 460 (MH+).
Example 25: Synthesis of 2-(2,6-DichIorophenylamino)-4-(3-methoxypropyn-l-yl)- l,6,7-trimethyl-l,8-dihydro-imidazo[4,5-A]isoquinoline-9-one.
Figure imgf000093_0002
A mixture of 2-[8-bromo-4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H- benzimidazol-5-yl]-2-methyl-3-oxobutyric acid ethyl ester (see Example 22) (50mg, 0.09mmol), methyl propargyl ether (16μL, 0.19mmol), (PPh3)2PdCl2 (6.5mg, 0.009mmol) and Cul (3.5mg, 0.02mmol) in Et3N (lmL) and THF(lmL) was stirred at room temperature for 5 days under argon. The resulting mixture was concentrated and the residue was purified by flash chromatography in hexanes/EtOAc 3:1 to give 2-[4- cyano-2-(2,6-dichlorophenylamino)-8-(4-methoxypropyn- 1 -yl)-3-methyl-3H- benzimidazol-5-yl]-2-methyl-3-oxobutyric acid ethyl ester as an oil (30mg, 61%).
A solution ofthe above ketoester (29mg, 0.006mmoι) in a mixture of Η2SO4 (0.4mL), acetic acid (0.4mL) and water (0.4mL) was heated at 100°C for 2h. The resulting mixture was cooled to room temperature and diluted with water (lOmL). The pH of this solution was adjusted to 8 with 10% NaOH solution. The precipitated solid was filtered to give the title compound (17mg, 68%), mp decomp. above 250°C; MS(CI) 455 (MH+).
Example 26: Synthesis of 2-(2,6-Dichlorophenylamino)-3,5-dihydro-imidazo[4,5- /] phenanthridin-4-one.
Figure imgf000095_0001
Figure imgf000095_0002
Figure imgf000095_0003
To a solution of N-(t-butoxycarbonyl)aniline (2.0g, 10.35mmol) in dry THF (50mL) at 78°C, a solution of t-BuLi (2.7M in pentane, 26mL, 25.88mmol) was added dropwise over 30min. The resulting yellow solution was warmed to -20°C and stirred at this temperature for 2.5h. «-Bu3SnCl (4.2mL, 15.52mmol) in dry THF (lOmL) was added over 20min, and the solution stirred at -20°C for 2h, then at room temperature for 12h. The reaction mixture was poured into NaHCO3 solution and extracted with ether. The extract was washed with water, brine, and dried over MgSO4. The solvent was evaporated and the resulting oil purified by flash chromatography in hexanes/ether (20:1) to give 2-tributylstannylphenylcarbamic acid t-butyl ester (2.42g, 54%).
Tin(II) chloride (46.67g, 206.84mmol) was added portionwise to a solution of 2-bromo- 5-nitro benzoic acid (12.71g, 49.9mmol) in dry ethanol (200mL). The mixture was heated at 70°C for 45min, then ethanol was evaporated. The residue was cooled to 0°C, and acetic anhydride (43mL) and pyridine (26mL) were added. The solution was stirred at room temperature for 14h and evaporated. The residue was partitioned between aq. 2M HCl and ethyl acetate (400mL). The organic phase was washed with brine and dried over MgSO4. The residue from evaporation was crystallized from water to give 5- acetylamino-2-bromobenzoic acid (12.4 g, 96 %).
5-Acetylamino-2-bromobenzoic acid (6.81 g, 26.39 mmol) was added portionwise to fuming nitric acid (90%, 1 lmL) at 0°C (as described by H. Goldstin, G. Preitner. Helv. Chim. Acta 1944, 27, 888). The ice bath was removed and the solution stirred at room temperature for 1.5h, then poured into ice water. 3-Acetylamino-6-bromo-2-nitro-benzoic acid was collected by filtration (5.07g, 63 %).
To a solution of 3-acetylamino-6-bromo-2-nitro-benzoic acid (3.86g, 14.96mmoι) in dry THF (42mL) and dry methanol (18mL) was added a solution of (trimethylsilyl)diazomethane in hexane (2M, 24mL, 48mmol). The solution was stirred at room temperature for 3h and evaporated. The residue was purified by flash chromatography in hexanes/ethyl acetate (6:1) to give 3-acetylamino-6-bromo-2- nitrobenzoic acid methyl ester (2.45g, 52%).
A solution of 3-acetylamino-6-bromo-2-nitrobenzoic acid methyl ester (1.3g, 4. 1 lmmol) and Pd(PPh3)4 (0.31 g, 0.27 mmol) in dry toluene (15 mL) was stirred at room temperature for 10 min. To this orange solution was added a solution of 2- tributylstannylphenylcarbamic acid t-butyl ester (2.10 g, 4.94 mmol) in dry toluene (10 mL) and the mixture was heated to reflux for 14 h, during which time a precipitate formed. 8-Acetamido-7-nitro-6-oxo-5,6-dihydro-phenanthridin-6-one was collected by filtration as an off-white solid (1.07g, 88%).
A suspension of 8-acetamido-7-nitro-6-oxo-5,6-dihydro-phenanthridin-6-one (770mg, 2.66mmol) and NaOMe (25% w/w solution in MeOH, 3.5mL, 6.64mmoι) in dry methanol (15mL) was heated to reflux for 3h. The methanol was evaporated and the residue triturated with water and filtered to yield 8-amino-7-nitro-5H-phenanthridin-6- one (500mg, 74%).
A mixture of 8-amino-7-nitro-5H-phenanthridin-6-one (412mg, 1.62mmol), Pd/C (10 wt %, 234 mg) in TFA was hydrogenated at 50 psi for 50min. The catalyst was filtered through a plug of diatomaceous earth and rinsed with ethanol. The solvent was evaporated to obtain 7,8-diamino-5H-phenanthridin-6-one trifluoroacetate salt (520 mg, 71 %).
To a solution of 7,8-diamino-5H-phenanthridin-6-one trifluoroacetate salt (200mg, 0.44mmoι) in pyridine (3mL) was added 2,6-dichlorophenylisothiocyanate (93mg, 0.46mmol). The suspension was stirred at room temperature for 14h. The pyridine was evaporated using a toluene azeotrope. The residue was triturated with ethanol to obtain the thiourea (150mg, 79%). A mixture of thiourea (146mg, 0.34mmol) and dicyclohexylcarbodiimide (83mg, 40.80mmol) in dry TΗF (2mL) and dry DMF (0.9mL) was heated to 80°C for 8h. The solvent was removed under high vacuum and the residue triturated with hot ethanol to give the title compound (82mg, 61%), mp >300°C; MS(CI) 395, 397(MΗ+).
Example 27: Synthesis of 2-(2,6-Dichlorophenylamino)-3-methyl-5,6,7,8-tetrahydro- 3//-l,3,5-triaza-dicyclopenta[aj/]naphthalen-4-one.
Figure imgf000098_0001
Figure imgf000098_0002
A mixture of 6-chloro-2-methylamino-3-nitrobenzonitrile (200mg, 0.95mmol) (Example 4), ethyl 2-oxocyclopentanecarboxylate (177mg, 1.13mmol) and K CO3 (287mg, 2.07mmol) in DMF (5mL) was stirred at room temperature for 60h. The mixture was diluted with sat. NH4C1 solution and extracted with ether. The ethereal layer was washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography on silica (hexanes: EtOAc = 3:1) to give ethyl l-(2-cyano-3- methylamino-4-nitrophenyl)-2-oxo-cyclopentanecarboxylate (127mg, 40%) as a yellow solid.
To a solution ofthe above compound (lOOmg, 0.30mmol) in acetic acid (lmL) was added a solution of tin (II) chloride dihydrate (681mg, 3.0mmol) in c. HCl (0.5mL) at room temperature. The resulting mixture was stirred at room temperature for 2h and quenched with sat. NaHCO3 solution. The pH of the mixture was adjusted to 8 with NaHCO3. The product was extracted into EtOAc and the organic layer was washed with water and brine, dried (Na2SO4), and concentrated to give ethyl l-(4-amino-2-cyano-3- methylaminophenyl)-2-oxo-cyclopentanecarboxylate (76mg, 84%) as a yellow oil.
A mixture ofthe above diamine (140mg, 0.46mmol), 2,6-dichlorophenyl isothiocyanate (104mg, 0.51mmol) and HgO (1 lOmg, 0.51mmol) in THF (5mL) was refluxed for 8h. The cooled mixture was filtered through diatomaceous earth and concentrated. The residue was diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica in hexanes/EtOAc, (1:1) to give ethyl l-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazol- 5-yl]-2-oxo-cyclopentanecarboxylate (200mg, 92%) as a light yellow solid.
A solution ofthe above benzimidazole (195mg, 0.41mmol) in a 1:1: 1 mixture of water, acetic acid and Η2SO4 (1.5mL) was heated at 100 °C for 3h. The reaction mixture was cooled and diluted with water. The precipitate was collected and washed with water. The collected yellow solid was purified by chromatography on SiO2 in CH2C12 /MeOH (20:1) to give the title compound (70mg, 43%) as a light yellow solid. Mp >300°C (dec), MS (CI) m/z 399 (M++H).
Example 28: Synthesis of 7-(3-Aminopropen-l-yl)-2-(2,6-dichlorophenylamino)-l,6- dimethyl-l,8-dihydro-imidazo[4,5-Λ]-isoquinolin-9-one.
Figure imgf000099_0001
A suspension of tris(dibenzylideneacetone) dipalladium(O) (185mg, 0.25mmol) and triphenylphosphine (320mg, 1.2mmol) in THF (40mL) was stirred for 20 min under N2. A solution ofthe product from Example 17 (1.88g, 4.0mmol) in THF (5 mL) was added and the mixture stirred for 20 min. Sodium azide (280mg, 4.4mmol) and water (4.0mL) were added and the reaction was heated at 60°C for 3h. The solution was cooled to rt and triphenylphosphine (l.Og, 3.8mmol) was added. After stirring for 45 min., ammonium hydroxide (4 mL) was added and stirring continued overnight. The resulting solution was dried over MgSO4, then concentrated to an oil. Column chromatography on silica eluting with CH2Cl2/MeOH (90: 10 increasing to 50:50) provided the title compound (1.2 g, 70%), mp >300°C; MS (ES) 428 (MH+). Example 29: Synthesis of l-{3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro-lH-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-3-phenyl urea.
Figure imgf000100_0001
28 29
A solution ofthe product of Example 28 (50mg, 0.12mmoι) and phenyl isocyanate (17mg, 0.13mmol) in DMF (2mL) was heated at 60°C for lOh. The resulting precipitate was filtered, triturated with MeOH/CH2Cl2 (90:10), and dried to provide the title compound (57 mg, 89%) mp >290°C; MS (ES) 547 (MH+).
Other Examples
Using methods analogous to those described above, the following compounds of this invention (Tables 1-3) were prepared:
Table 1: Compounds of Formula I with R4, R5 = C
Figure imgf000101_0001
Figure imgf000101_0002
Table 2: Compounds of Formula I with Rj, R5 = A
Figure imgf000102_0001
Figure imgf000102_0002
Table 3: Compounds of Formula I with t, R5 = B
Figure imgf000103_0001
o t
Figure imgf000103_0002
Figure imgf000104_0001
o
4^
Figure imgf000105_0001
Figure imgf000106_0001
o as
Figure imgf000107_0001
Figure imgf000108_0001
o oo
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Table 4: Compounds of Formula I with t, R5 = B
Figure imgf000115_0001
Figure imgf000115_0002
Figure imgf000116_0001
Table 5: Compounds of Formula I wherein R4, R5 = B and Rg and R9 together form a ring
ON
Figure imgf000117_0001
Figure imgf000117_0002
Figure imgf000118_0001
Assessment of Biological Properties
Tyrosine Kinase Inhibition Assay
The inhibition of tyrosine kinases by the compounds ofthe invention was measured with the following assay.
Kinase Reaction Buffer 50mM Hepes, pH 7.5, 50mM KC1, 25mM MgCl2, 5mM MnCl2, 100 μM, Na3NO4, .01% CHAPS, ImM DTT, and 50mg/mL BSA, Adenosine 5'-
Triphosphate (ATP) solution at lOOmM, pH 7.5 -γ33P-ATP, 2000 Ci/mmol at lOμCi/μl, - Poly(L-glutamic acid-L-tyrosine, 4: 1) or (E4Y)n at lOmg/mL in water.
Assay: Test compounds, obtained routinely at 5mg/mL in 100% DMSO were diluted appropriately into complete Kinase assay buffer with 10% DMSO, lOμl ofthe 6Xcompound solution was distributed into each assay well, the final compound concentration for IC50 determinations ranged from 200 to lμg/mL. [γ33P]-ATP label was prepared as a 10 Ci/mmol working solution in complete Kinase assay buffer. Protein kinase was initiated by adding 10 to 50ηg of diluted enzyme stock.
Plates were incubated at 30 °C for 30 min. During the incubation period, the MultiScreen harvest plates were pre-wetted with 10% TCA/5% Ppi. 150μl of TCA/PPi was added to all MultiScreen plate wells after pre-wetting. The kinase reaction was stopped via replica transfer ofthe polypropylene reaction wells into the MultiScreen plates. The plates were incubated at room temperature for 5 min then vacuum harvested and washed with 200 μl TCA/PPi 3-4 times per well, then 100 μl of cocktail per well was added.
Experimental data consisted of eight (8) compound doses in duplicate with ten (10) enzyme control reaction wells (so-called totals) and six (6) background wells. The results were obtained as percent inhibition (mean with S.D.) over the full compound dose range. IC50 potency estimates are determined using a floating inhibition maximum (Imax).
All compounds in the synthetic examples and Tables above were evaluated in the tyrosine kinase assay above using a kinase such as p56 lck and were found to have IC50's less than 10 μM.
Representative compounds from the examples above were evaluated in the tyrosine kinase assay above using p60 src and were found to have IC5o's less than 10 μM.
Representative compounds from the examples above were evaluated in the tyrosine kinase assay above using PDGFR kinase and were found to have IC50's less than 10 μM.
Inhibition of IL-2 Production
Inactivation of T cells resulting from inhibition ofthe tyrosine kinase p56 lck can be measured by inhibition of IL-2 production in Jurkat cells. 96-well flat bottom plates were coated with anti-CD3, clone UCHT1, (Immunotech cat. # 1304) at 4 μg/ml in Phosphate Buffered Saline (PBS), 100 μl/well. The solution was prepared by taking 200 μl of 200 μg/ml anti-CD3 stock/ 10ml PBS. The plate was then incubated at 37°C for 2h. Jurkat cells were pelleted and counted. The cells were resuspended at 2.5 x 10 6 cells/ml in RPMI, 10 % FBS (complete media). Test compounds were diluted from a 5mg/ml DMSO stock directly into complete media.
10 μl of 20 X compound/ well was added to a separate plate, followed by lOOμl of cell suspension in triplicate and this plate was preincubated at 37°C for 30min. The 96-well plate containing anti-CD3 was aspirated, and the cells and compound transferred to this plate. 100 μl of PMA (Phorbol 12-Myristate 13-Acetate, Sigma cat.# P-8139) at 20 ng/ml was added, and the plate was incubated overnight at 37° C. (PMA stock at 1 mg/ml in ethanol, dilute 10 μl/ml in complete media, then 20 μl/10 mis. in complete media. 100 μl/well = 10 ng/ml. final concentration). The next day, the plate was centrifuged at 1500 φm for 5 min. at room temperature and the supematants were removed. The supematants were tested using R&D Systems Quantikine Human IL-2 Kit (cat.#2050). Samples were diluted 1:5 in RPMI 1640, and 100 μl/well used in the ELISA. The optical density of each well was determined using a microplate reader set to 450 nm. EC50 values were determined using Origin (non-linear regression) or SAS by plotting absorbance vs. concentration of compound.
Representatives from the synthetic examples and the Tables above were screened in this assay and had IC50-s below 10 μM.

Claims

We claim:
A Compound of the formula(I):
Figure imgf000122_0001
wherein:
Ari is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more Ri, R2 and R3;
X is NH, N-Cι.3alkyl, N-cyclopropyl, S or O;
Figure imgf000122_0002
Ra is H, Ci-ioalkyl, C2.ι0alkenyl or C2.ι0alkynyl, each of which may be branched or cyclic; or Rg is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more Ci-βalkyl, Cι-6 alkoxy, halogen, OH, oxo, NRι0Rn, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, Cι.3alkyl, Cι_3alkoxy, hydroxyCι.3alkyl and (CH2)mNRιoRn; and wherein Ra is attached at the 4- or 5- position; Ri and R2 are the same or different and selected from H, halogen, CN, NO2, CMO branched or unbranched saturated or unsaturated alkyl, CMO branched or unbranched alkoxy, CMO branched or unbranched acyl, CMO branched or unbranched acyloxy, CM0 branched or unbranched alkylthio, aminosulfonyl, di-(Cι-3)alkylaminosulfonyl, NRioRn, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned Ri and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, Cι.6 branched or unbranched alkyl, C3.7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(Cι- 3)alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2)nNRι0Rn, CONRι0Rn, (CH2)nCO2Rι2; C,.3alkyl optionally substituted with OH, Cj.3 alkoxy optionally halogenated or Cι-3 alkylthio;
> and R5 together with the atoms to which they are attached complete a fused ring system ofthe formulas A or B:
Figure imgf000123_0001
A B
Rό is Cι-3alkyl or H;
R7 is Cι-6alkyl branched or unbranched or H; Rs is H, Cι-6alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or C,.3alkoxy; or R8 is (CH2)mNR10Rn, (CH2)mNRι0CORι2, (CH2)nCO2Rι , (CH2)nCONRioRn; or R8 is phenyl or heteroaryl, each being optionally substituted with Cι- alkyl, Cι.3alkoxy, OH, -SO3H or halogen;
R is H, CN or CONRioRn; or R9 is Ci-ioalkyl branched or unbranched, C3.ι0cycloalkyl, C5.7cycloalkenyl, C2.6 alkenyl, C2.6 alkynyl each being optionally substituted with one or more C3.ι0cycloalkyl, C3.ι0cycloalkylidene, C5.7cycloalkenyl, halogen, OH, oxo, CN, Ci. 3alkoxy, C,.3acyloxy, NRioRn, NRioCONRioRn, NRι0C(=NRιo)NRιoRn, NR10COR,2, NRιoS(O)pRι2, SR12, CONR10Rn, CO2R,2, C(Rio)=NNRi0Rn, C(Rι0)=NNR,0CONRιoRιι, aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with Cι.3alkyl, Cι.3alkoxy, halogen, (CH2)nNRι0Rn or O(CH2)2.
or R9 is aryl, heteroaryl, or heterocycle, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three groups selected from Cι-3alkyl optionally substituted with phenyl or NRι0C(=NRιo)NRιoRπ, Cι. alkoxy, halogen, CN, oxo, (CH2)nNR,0Rιι, (CH2)nCO2R,2; (CH2)nCONR,oRπ and O(CH2)2.4NR,0Rπ;
or R8 and R9 together form a saturated or unsaturated 5 or 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two Cι_3alkyl, OH, oxo or (CH2)nNRιoRn, or optionally spiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3 dioxolane group or 1,3 dithiolane group optionally substituted by Cι.6alkyl,
C,.6alkoxy, OH or (CH2)nNRι0Rn;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι.3alkoxy, Cι-6alkyl branched or unbranched, C3.8cycloalkyl, aryl, arylCι.3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylCι-3alkyl or heteroaryl are optionally substituted with OH, Cι-3alkoxy, CN, NO2, Cι_3acyloxy, CO2R]2, NRι3Rι4, O(CH2)2_ 4NRι3Rι4, aryl or heteroaryl; or Rio and Rn together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p, and NRι3; and wherein said ring is optionally substituted by Cι_3 alkyl, Ci. 3alkoxy, OH, -(CH2)nNRι3Rι4, CONRι3RH or NRι3CORM;
Rι is H, Cι.6alkyl or C3.8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, Cι.3alkoxy or NR]3R]4; or Rι2 is phenyl or heterocycle, optionally substituted with one to three groups selected from Cι.3alkyl, Cι-3alkoxy, halogen, (CH2)mNR10Rn, (CH2)„CONRιoRn and O(CH2)MNRι0Rn;
Rι3 and Rj4 are each independently selected from H and Cι.6 alkyl optionally substituted with Cι-3alkoxy, OH or phenyl; or Rι3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or
(CH2)2O(CH2)2;
Rι5 is H or Cι_3 alkyl;
m is 1-4; n is 0-3 and p is 0-2; and
the pharmaceutically acceptable acid or salt derivatives thereof.
2. The compound according to claim 1 wherein
a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl; b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, cycloheptenyl; c) phenyl, naphthyl; indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl; d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl,or a fused heteroaryl selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or e) a heterocycle selected from pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, moφholinyl, thiomoφholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl;
wherein each ofthe above Ari are optionally substituted by one or more Rj, R2 and R3;
Ra is H, Ci-βalkyl, C2.5alkenyl, C2.5alkynyl, phenyl or heteroaryl selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; each Ra being optionally substituted with one or more phenyl, halogen, Cι.3alkyl, Cι.3 alkoxy, OH, oxo, or NRioRn; wherein Ra is at the 4- position;
Ri and R2 are as hereinabove defined; R3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
R8 is H, Cι.3alkyl branched or unbranched, saturated or unsaturated, optionally substituted with OH; or Rg is (CH2)2.3NRι0Rn, (CH2)nCO2Rι2 or (CH2)nCONRι0Rn;
R9 is CN or CONRioRn; or R is Cι.3alkyl branched or unbranched, C2_4 alkenyl, C2.
4alkynyl each being optionally substituted with one or more C5.7cycloalkyl, C5.7 cycloalkylidene, C5.7cycloalkenyl,OH, CN, Cι. acyloxy, NRioRn, NRioCONRioRn, NRιoC(=NR,o)NRιoRn, NR,0CORι2, NR10S(O)PR,2, CONRioRn, CO2R,2, C(Rιo)=NNRιoRπ, C(Rιo)=NNRι0CONRιoRn, aryl or heteroaryl; wherein each aryl or heteroaryl is optionally substituted with Cι.3alkyl, Cι.3alkoxy, halogen, (CH2)nNRιoRn or O(CH2)2.4NR10Rn;
or R is aryl,heteroaryl or heterocycle, each optionally substituted with one to three groups selected from Cι.3alkyl optionally substituted with phenyl or NRιoC(=NRιo)NRιoRn, . 3alkoxy, halogen, CN, oxo, (CH2)nNRι0Rn, (CH2)nCO2Rι2; (CH2)nCONR,oRn and O(CH2)2.4NR,0Rn;
or R8 and R9 together form a saturated or unsaturated 5 or 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by Cι.3alkyl or OH, or optionally spiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3 dioxolane group or 1,3 dithiolane group optionally substituted by C].3alkyl, Cι_3alkoxy, OH or (CH2)nNRιoRn;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι.3alkoxy, Cι.6alkyl branched or unbranched, C3.8cycloalkyl, benzyl and phenyl; wherein said alkyl, cycloalkyl, benzyl or phenyl are optionally substituted with OH, Cι-3alkoxy, Ci. 3acyloxy, CN, NO2, CO2Rι2, NRι3Rι4, O(CH2)2^NRι3R]4 or phenyl;
or Rio and Rn together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι_3 alkyl, Cι.3alkoxy, OH, -(CH2)nNRι3RM, CONRι3Rι4 or NROCORH;;
Rι2 is H, Cι.6alkyl or C . cycloalkyl, each optionally substituted with phenyl, OH, Ci. 3alkoxy or NRι3Rι4; or Rι2 is phenyl or heterocycle, each optionally substituted with one to three groups selected from Cι.3alkyl, Cι.3alkoxy, halogen, (CH2)mNRιoRn, (CH2)nCONRi0Rii and O(CH2)2.4NRι0Rn; Rι3 and Rι4 are each independently selected from H and Cι.6 alkyl optionally substituted with Cι-3alkoxy, OH or phenyl;
or Rι3 and R]4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2; and
3. The compound according to claim 2 wherein:
Ari is phenyl, or pyridyl, wherein each is optionally substituted by one or more
Ri, R2 and R3 as defined below;
X is NH or N-CH3;
Y is NH and
Ra is H, hydroxyCι.2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C3.5alkynyl substituted by Cι.3alkoxy or phenyl;
Ri and R2 are the same or different and selected from: H, halogen, Cι.3 alkyl, wherein the Cι-3 alkyl are optionally partially or fully halogenated, NO2, NR]3Rι4;
R3 is H, halogen, methoxy or methyl;
R and R5 together complete a fused ring of formula B;
Rs is H, Cι.3alkyl optionally substituted with OH; or R8 is (CH2)2.3NRι0Rn or CO2Rι2; R is CN; or R9 is methyl, C2.3 alkenyl or C2.3 alkynyl, each being optionally substituted with one or more C5.7 cycloalkylidene, C5.7cycloalkenyl, OH, CN, NRioRn, NRioCONRioRn, NR10COR,2, NRι0S(O)pR,2, CONR10Rn, CO2Rι2, C(R10)=NNRι0Rn or heteroaryl;
or R9 is aryl or heteroaryl optionally substituted with one to three groups selected from C\. 3alkyl optionally substituted with phenyl, Cι_3alkoxy, halogen, amino or CONH2;
or Rs and R9 together form a cyclopentene ring spiro-fused to a 1,3 dioxolane group, said 1,3 dioxolane group being optionally substituted by Cι_3alkyl, Cι.3alkoxy, OH or (CH2)nNR,oRn;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι_3alkoxy, Cι_3alkyl branched or unbranched, C5.7cycloalkyl or phenyl, wherein said alkyl, cycloalkyl or phenyl are optionally substituted with OH, Cι-3alkoxy, Cι.3acyloxy, NO2, CO2Rι2, NR,3Ri4, O(CH2)2.4NRι3Rι4 or phenyl;
or Rio and Rn together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C].3 alkyl, Cι-3alkoxy,OH, (CH2)nNRι3Rι4, CONRι3R] or NRι3CORM;
Rι2 is H, Cι.3alkyl or C5. cycloalkyl, each optionally substituted with phenyl, OH, C\. 3alkoxy or NRι3R]4; or Rι2 is phenyl or is a saturated, 4- to 6-membered nitrogen- containing heterocycle, each optionally substituted with one to three groups selected from Cι.3alkyl, Cι_3alkoxy, halogen, (CH2)mNRι0Rn, (CH2)nCONRι0Rn and O(CH2)MNR10Rn;
Rn and Rι4 are each independently selected from H and Cι_3alkyl optionally substituted with Cι-3alkoxy or OH; or Rj3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2.
4. The compound according to claim 3 wherein:
Ari is phenyl;
Ra is H or hydroxy methyl;
Ri and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy;
Rio and Rn may be the same or different and are each independently selected from H, OH, methoxy, Cι.3alkyl branched or unbranched or C5.7cycloalkyl, wherein said alkyl or cycloalkyl are optionally substituted with OH, NRι3Rt4 or phenyl;
or Rio and Rn together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι-2 alkyl, NRι3Rι4, CONRι3Rι4 or NRι3CORι4; and
Rι2 is Cι-3alkyl optionally substituted with moφholino; or Rι2 is phenyl or is azetidinyl, pyrrolidinyl or piperidinyl, each optionally substituted with one to three groups selected from Cι-3alkyl, Cι-3alkoxy and halogen.
5. A compound according to claim 1, wherein: Ari is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more Ri, R2 and R3;
X is NH, N-Cι.3alkyl, N-cyclopropyl, S or O;
Y is NRis, S or O;
Ra is H, Ci-ioalkyl, C2.ιoalkenyl or C2_ιoalkynyl, each of which may be branched or cyclic; or Ra is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more Cι_3alkyl, C].6 alkoxy, halogen, OH, oxo, NRioRn, aryl or heteroaryl, each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, Cι-3alkyl, Cι.3alkoxy, hydroxyCι.3alkyl and (CH2)mNRιoRn; and wherein Rg is attached at the 4- or 5- position;
Ri and R2 are the same or different and selected from H, halogen, CN, NO2, C O branched or unbranched saturated or unsaturated alkyl, C O branched or unbranched alkoxy, C O branched or unbranched acyl, CMO branched or unbranched acyloxy, CMO branched or unbranched alkylthio, aminosulfonyl, di-(Cι_ )alkylaminosulfonyl, NRio n , aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned Ri and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioR , Cι.6 branched or unbranched alkyl, C .7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(Cι_ 3)alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2)nNRι0Rn, (CH2)nCO2Rι2; Cι.3alkyl optionally substituted with OH, Cι-3 alkoxy optionally halogenated or Cι_3 alkylthio;
R4 and R5 together with the atoms to which they are attached complete a fused ring system ofthe formulas A or B:
Figure imgf000132_0001
B
Re is Cι-3alkyl or H;
R7 is Cι_6alkyl branched or unbranched or H;
Rs is H, Cι.6alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or Cι.3alkoxy; or Rs is (CH2)mNR10Rn, (CH2)mNRι0CORι2,
(CH2)nCO2Ri2, (CH2)nCONRιoRn; or R8 is phenyl or heteroaryl, each being optionally substituted with Cι-3alkyl, Cι-3alkoxy, OH, -SO3H or halogen;
R is H; or R is Ci-ioalkyl branched or unbranched, C3.ιocycloalkyl, C2.6 alkenyl, C2.6 alkynyl each being optionally substituted with one or more halogen, OH, oxo, CN, C . 3alkoxy, NRioRn, NR10CORι2, SRι2, CONRioRn, CO2Rι2, aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with Cι_3alkyl, Cι.3alkoxy, halogen, (CH2)nNRι0Ru or O(CH2)2^NRι0Rn;
or R9 is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to three groups selected from Cι.3alkyl optionally substituted with phenyl, Ci.
3alkoxy, halogen, (CH2)πNR,0Rn, (CH2)nCO2Rι2; (CH2)nCONRι0Rn and O(CH2)2.
4NRιoRιι; or R8 and R together form a saturated or unsaturated 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two OH, oxo or (CH2)nNRιoRn;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι. alkoxy, Cι.6alkyl branched or unbranched, C .8cycloalkyl, aryl, arylCι.3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylCι.3alkyl or heteroaryl are optionally substituted with OH, Cι_3alkoxy, Cι.3acyloxy, CO2Rι2, NR]3R]4, O(CH2)2.4NRπRι4, aryl or heteroaryl;
or Rio and Rn together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p, and NRι3; and wherein said ring is optionally substituted by Cι. alkyl, . 3alkoxy, OH or -(CH2)„NRι3Rι4;
Rι is H, Cι-6alkyl or C3.8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, Cι.3alkoxy or NRι3Rj4; or Rι2 is phenyl, optionally substituted with one to three groups selected from Cι_3alkyl, Cι.3alkoxy, halogen, (CH2)mNRι0Rn, (CH2)nCONRι0Rn and O(CH2)2.4NRι0Rn;
Rn and Rι4 are each independently selected from H and Cι.6 alkyl optionally substituted with Cι_3alkoxy, OH or phenyl; or Rj3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2;
Rι5 is H or Cι_3 alkyl;
m is 1-4; n is 0-3 and p is 0-2; and
the pharmaceutically acceptable acid or salt derivatives thereof.
6. A compound according to claim 5, wherein: Ari is a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl; b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, cycloheptenyl; c) phenyl, naphthyl; indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl; d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl,or a fused heteroaryl selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or e) a heterocycle selected from: pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, moφholinyl, thiomoφholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl;
wherein each ofthe above Ari are optionally substituted by one or more Ri, R2 and R3 as hereinabove defined;
Ra is H, Cι.6alkyl, C2_5alkenyl, C2.5alkynyl, phenyl or heteroaryl selected from: pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; each Ra being optionally substituted with one or more phenyl, halogen, Cι.3alkyl, C1.3 alkoxy, OH, oxo, or NRioRn; wherein Ra is at the 4- position; R3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
R8 is H, Cι.3alkyl branched or unbranched, saturated or unsaturated, optionally substituted with OH; or R8 is (CH2)2.3NR,0Rι t , (CH2)nCO2Rι2 or (CH2)nCONR,0Rι i ;
R9 is Cι.3alkyl branched or unbranched, C2.4 alkenyl, C2.4alkynyl each being optionally substituted with one or more OH, CN, NRioRn, CONRioRn, CO2Rι2, aryl or heteroaryl; wherein each aryl or heteroaryl is optionally substituted with Cι. alkyl, Cι.3alkoxy, halogen, (CH2)nNRι0Rn or O(CH2)2.4NRι0Rn; or R9 is aryl or heteroaryl optionally substituted with one to three groups selected from C\. 3alkyl optionally substituted with phenyl, Cι. alkoxy, halogen, (CH2)nNRι0Rn, (CH2)nCO2R12; (CH2)nCONR,oR.ι and O(CH2)2_4NRι0Rn;
or Rs and R together form a saturated or unsaturated 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by OH;
Rio and Rn may be the same or different and are each independently selected from H, OH, C].3alkoxy, Cι_6alkyl branched or unbranched, C3.8cycloalkyl, benzyl and phenyl; wherein said alkyl, cycloalkyl, benzyl or phenyl are optionally substituted with OH, Cι_3alkoxy, Cj. 3acyloxy, CO2Rι2, NR)3R,4, O(CH2)2.4NRι3Rι4 or phenyl;
or Rio and Rn together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι.3 alkyl, Cι_3alkoxy, OH or -(CH2)nNRι3Rι4;
Rι2 is H or Cι.6alkyl optionally substituted with phenyl, OH, Cι-3alkoxy or NRj3Rι4;
Rι3 and Rι4 are each independently selected from H and Cι.6 alkyl optionally substituted with Cι_3alkoxy, OH or phenyl; or Rι3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2; and
7. The compound according to claim 6 wherein:
Ari is phenyl, or pyridyl;
X is NH or N-CH3;
Y is NH and
Ra is H, hydroxyCι.2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo- propyl, vinyl or C3.5alkynyl substituted by Cι_3alkoxy or phenyl;
Ri and R2 are the same or different and selected from: halogen, Cι_3 alkyl, wherein the Cι-3 alkyl are optionally partially or fully halogenated, NO2, NRι3Rι4;
R is H, halogen, methoxy or methyl;
R4 and R5 together complete a fused ring of formula B;
Rs is H, Ci.3alkyl optionally substituted with OH; or R8 is (CH2)2-3NRι0Rn or CO2Rι2;
R9 is methyl or C2.3 alkenyl each being optionally substituted with one or more OH, CN,
NRioRn, CONRioRn or CO2Rι2; or R9 is heteroaryl optionally substituted with one to three groups selected from Cι_3alkyl optionally substituted with phenyl, Cj.3alkoxy, halogen or amino; Rio and Rn may be the same or different and are each independently selected from H, OH, Cι_3alkoxy, Cι.3alkyl branched or unbranched, optionally substituted with OH, Cι-3alkoxy, Cι.3acyloxy, CO2Rι2, NRι3R,4, O(CH2)2.4NRι3R,4 or phenyl;
or Rio and Ri i together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι. alkyl, Cι.3alkoxy or OH;
Rι2 is H or Cι.3alkyl optionally substituted with phenyl, OH, C].3alkoxy or NRι Rι4;
Rι3 and R]4 are each independently selected from H and Cι.3alkyl optionally substituted with Cι-3alkoxy or OH; or Rι3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2.
8. The compound according to claim 7 wherein:
Ari is phenyl;
Ra is H or hydroxymethyl;
Ri and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R is H, chloro, fluoro, bromo or methoxy;
Rio and Rn may be the same or different and are each independently selected from H, OH, methoxy, Cι-3alkyl branched or unbranched, optionally substituted with OH, NRι3R]4 or phenyl; or Rio and R together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι.2 alkyl; and Rι is Ci.3alkyl optionally substituted with moφholino.
A compound ofthe formula (la):
Figure imgf000138_0001
wherein:
X is NH, N-Cι.3alkyl, N-cyclopropyl, S or O;
Ra is H, Ci-ioalkyl, C2-ιoalkenyl or C2_ιoalkynyl, each of which may be branched or cyclic; or Ra is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more Cι_6alkyl, Cι.6 alkoxy, halogen, OH, oxo, NRioRn, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, Cι.3alkyl, C\.
3alkoxy, hydroxyCι.3alkyl and (CH2)mNRιoRn; and wherein Ra is attached at the 4- or 5- position;
Ri and R2 are the same or different and selected from H, halogen, CN, NO2, CM O branched or unbranched saturated or unsaturated alkyl, CMO branched or unbranched alkoxy, C O branched or unbranched acyl, CMO branched or unbranched acyloxy, C O branched or unbranched alkylthio, aminosulfonyl, di-(C].3)alkylaminosulfonyl, NRι0Rn, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned Ri and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, Cι_6 branched or unbranched alkyl, C .7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(Cι_ 3)alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2)nNRι0Rn, CONRioRn, (CH2)nCO2Rι2; Cι_3alkyl optionally substituted with OH, C1.3 alkoxy optionally halogenated or Cι_3 alkylthio;
R4 and R5 together with the atoms to which they are attached complete a fused ring system ofthe formulas A or B:
Figure imgf000139_0001
B
Rό is Cι. alkyl or H;
R7 is Cι-6alkyl branched or unbranched or H;
Rs is H, Ci-όalkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or Cι.3alkoxy; or Rs is (CH2)mNRι0Rn, (CH2)mNRι0CORι2, (CH2)nCO2Rι2, (CH2)nCONRιoRn or Rs is phenyl or heteroaryl, each being optionally substituted with Cι-3alkyl, Cι.3alkoxy, OH, -SO H or halogen;
R9 is H, CN or CONRioRn! or R is Ci-ioalkyl branched or unbranched, C3.ιocycloalkyl, C5.7cycloalkenyl, C .6 alkenyl, C2.6 alkynyl each being optionally substituted with one or more C3-ιocycloalkyl, .iocycloalkylidene, C5. cycloalkenyl, halogen, OH, oxo, CN, C\. 3alkoxy, C,.3acyloxy, NR,0Rn, NRιoCONR,0Rn, NRι0C(=NR,o)NR10Rn, NRι0CORι2, NR,oS(O)pR,2, SRi2, CONRioRn, CO2R12, C(Rιo)=NNR,0Rn, C(R,o)=NNR,0CONRιoRn, aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with Cι.3alkyl, Cι.3alkoxy, halogen, (CH )nNRιoRn or O(CH2)2. 4NR,oRn;
or R9 is aryl, heteroaryl, or heterocycle, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three groups selected from Cι_3alkyl optionally substituted with phenyl or NRιoC(=NRι0)NRιoRn, Cι.3alkoxy, halogen, CN, oxo, (CH2)nNRιoRn, (CH2)nCO2R12; (CH2)nCONRI0Rn and O(CH2)2^NR10Rn;
or Rs and R together form a saturated or unsaturated 5 or 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two Cι-3alkyl, OH, oxo or (CH2)nNRιoRn, or optionally spiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3 dioxolane group or 1,3 dithiolane group optionally substituted by Cι_6alkyl,
Cι.6alkoxy, OH or (CH2)„NRι0Rn;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι. alkoxy, Cι_6alkyl branched or unbranched, C3.8cycloalkyl, aryl, arylCι-3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylCι„3 alkyl or heteroaryl are optionally substituted with OH, Cι.3alkoxy, CN, NO2, Cι_3acyloxy, CO2Rj2, NRι3R , O(CH2)2. 4NRι3Rι4, aryl or heteroaryl;
or Rio and R\ ι together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p, and NRι3; and wherein said ring is optionally substituted by Cι.3 alkyl, Cι_ 3alkoxy, OH, -(CH2)nNRι3Rι4, CONRι3Rι4 or NRι3CORι4;
Rι2 is H, Ci_6alkyl or C3.8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, Cι.3alkoxy or NRι3Rj4; or Rι2 is phenyl or heterocycle, optionally substituted with one to three groups selected from Cι.3alkyl, Cι. alkoxy, halogen, (CH2)mNR,0Rn, (CH2)nCONR,0Rn and O(CH2)2.4NRι0Rn;
Rι3 and Rι4 are each independently selected from H and Cι-6 alkyl optionally substituted with Cι.3alkoxy, OH or phenyl; or Rι3 and Rj4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2;
m is 1-4, n is 0-3 and p is 0-2; and
the pharmaceutically acceptable acid or salt derivatives thereof.
10. The compound according to claim 9 wherein:
X is NH or N-CH3;
Ra is H, hydroxyCι-2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo- propyl, vinyl or C3.5alkynyl substituted by Cι.3alkoxy or phenyl; and wherein Ra is attached at the 4- position; Ri and R2 are the same or different and selected from: H, halogen, Cι- alkyl, wherein the Cu alkyl is optionally partially or fully halogenated, NO2, NR]3Rι ;
R3 is H, halogen, methoxy or methyl;
i and R5 together complete a fused ring of formula B;
R8 is H, Cι.3alkyl optionally substituted with OH; or Rs is (CH2)2.3NRι0Rn or CO2Rι2;
R is CN; or R9 is methyl, C2.3 alkenyl or C2.3 alkynyl, each being optionally substituted with one or more C5.7 cycloalkylidene, C5.7cycloalkenyl, OH, CN, NRι0Rn, NRioCONRioRn, , NR,0COR12, NRι0S(O)pR,2, CONRioRn, CO2Rι2, C(Rι0)=NNR,0Rn or heteroaryl;
or R9 is aryl or heteroaryl optionally substituted with one to three groups selected from Ci. 3alkyl optionally substituted with phenyl, Cι_3alkoxy, halogen, amino or CONH2;
or R8 and R9 together form a cyclopentene ring spiro-fused to a 1 ,3 dioxolane group, said 1,3 dioxolane group being optionally substituted by Cι.3alkyl, Cι_3alkoxy, OH or (CH2)nNRιoRn;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι_3alkoxy, Cι.3alkyl branched or unbranched, C5.7cycloalkyl or phenyl, wherein said alkyl, cycloalkyl or phenyl are optionally substituted with OH, C^alkoxy, Cι_3acyloxy, NO2, CO2Rι2, NRΠRH, O(CH2)MNRI3RI4 or phenyl;
or Rio and Rn together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι-3 alkyl, Cι.3alkoxy,OH, (CH2)nNRι3Rι , CONRι3Rj4 or NRι3COR)4; Rι2 is H, Cι.3alkyl or C5.7cycloalkyl, each optionally substituted with phenyl, OH, C\. 3alkoxy or NRι3Rι4; or Rι2 is phenyl or is a saturated, 4- to 6-membered nitrogen- containing heterocycle, each optionally substituted with one to three groups selected from Cι_3alkyl, C,.3alkoxy, halogen, (CH2)mNR,0Rn, (CH2)nCONRι0Rn and O(CH2)2.4NRι0Rn;
Rι3 and R]4 are each independently selected from H and Cι.3alkyl optionally substituted with Cι. alkoxy or OH; or Rn and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or
(CH2)2O(CH2)2.
11. The compound according to claim 10 wherein:
Ra is H or hydroxymethyl;
Ri and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy;
Rio and Rn may be the same or different and are each independently selected from
H, OH, methoxy, Cι.3alkyl branched or unbranched or C5.7cycloalkyl, wherein said alkyl or cycloalkyl are optionally substituted with OH, NRι3R]4 or phenyl;
or Rio and Rn together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι.2 alkyl, NRι3Rι4, CONRι3R)4 or NRι3CORι4; and Rι2 is Cι.3alkyl optionally substituted with moφholino; or Rι2 is phenyl or is azetidinyl, pyrrolidinyl or piperidinyl, each optionally substituted with one to three groups selected from Cι.3alkyl, Cι.3alkoxy and halogen.
12. The compound according to claim 9, wherein:
X is NH, N-Cι.3alkyl, N-cyclopropyl, S or O;
Ra is H, Ci-ioalkyl, C2.ιoalkenyl or C2.ιoalkynyl, each of which may be branched or cyclic; or Ra is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more Cι_6 alkoxy, halogen, OH, oxo, NRι0Rn, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, Cι_3alkyl, Cι-3alkoxy, hydroxyCι_3alkyl and (CH2)mNRι0Rn; and wherein Ra is attached at the 4- or 5- position;
Ri and R2 are the same or different and selected from H, halogen, CN, NO2, CMO branched or unbranched saturated or unsaturated alkyl, CMO branched or unbranched alkoxy, CMO branched or unbranched acyl, CMO branched or unbranched acyloxy, CMO branched or unbranched alkylthio, aminosulfonyl, di-(Cι.3)alkylaminosulfonyl, NRioRn, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned Ri and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, Cj.6 branched or unbranched alkyl, C3.7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(Cι. 3)alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2)nNRιoRn, (CH2)nCO2Rι2; Cι.3alkyl optionally substituted with OH, Cι-3 alkoxy optionally halogenated or d-3 alkylthio;
t and R5 together with the atoms to which they are attached complete a fused ring system ofthe formulas A or B:
Figure imgf000145_0001
B
Rό is Cι.3alkyl or H;
R7 is Cι.6alkyl branched or unbranched or H;
R8 is H, Cι.6alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or Cι.3alkoxy; or R8 is (CH2)mNR]0Rn, (CH2)mNR10CORι2,
(CH2)nCO2Ri2, (CH2)nCONRιoRn or Rs is phenyl or heteroaryl, each being optionally substituted with Cι_3alkyl, Cι_3alkoxy, OH, -SO3H or halogen;
R9 is H; or R9 is Ci-ioalkyl branched or unbranched, C3.ιocycloalkyl, C2.6 alkenyl, C2. 6alkynyl each being optionally substituted with one or more halogen, OH, oxo, CN, C\. 3alkoxy, NRioRn, NRι0CORι2, SRj2, CONRioRn, CO2Rι2, aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with Cι.3alkyl, Cι.3alkoxy, halogen, (CH2)nNRι0Rn or O(CH2)2.4NRι0Rn; or R is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to three groups selected from Cι-3alkyl optionally substituted with phenyl, Cι- alkoxy, halogen, (CH2)nNR10Rn, (CH2)nCO2Rι2; (CH2)nCONRι0Rn and O(CH2)2^NRι0Rn;
or Rs and R together form a saturated or unsaturated 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two OH, oxo or (CH2)nNRιoRn; Rio and Rn may be the same or different and are each independently selected from H, OH, Cι_ alkoxy, Cι_6alkyl branched or unbranched, C3.8cycloalkyl, aryl, arylCι.3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylC].3alkyl or heteroaryl are optionally substituted with OH, Cι.3alkoxy, Cι.3acyloxy, CO2Rι2, NRι3Rι4, O(CH2)2-4NRι3Rι4, aryl or heteroaryl;
or Rio and Rn together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p, and NRι3; and wherein said ring is optionally substituted by Cι.3 alkyl, Ci. 3alkoxy, OH or -(CH2)nNRι3Rι4;
Rι2 is H, Cι.6alkyl or C3.8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, Cι_3alkoxy or NRι3Rι4; or Rι2 is phenyl, optionally substituted with one to three groups selected from Cι.3alkyl, Cι.3alkoxy, halogen, (CH2)mNRιoRn, (CH2)nCONR,oRn and O(CH2)2.4NRι0Rn;
Rι3 and Rι4 are each independently selected from H and Cι.6 alkyl optionally substituted with Cι- alkoxy, OH or phenyl; or R13 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2;
m is 1-4, n is 0-3 and p is 0-2; and
the pharmaceutically acceptable acid or salt derivatives thereof.
13. The compound according to claim 12 wherein: X is NH orN-CH3;
Ra is H, hydroxyCι-2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo- propyl, vinyl or C3.5alkynyl substituted by Cι.3alkoxy or phenyl; and wherein Ra is attached at the 4- position;
Ri and R2 are the same or different and selected from: halogen, Cι.3 alkyl, wherein the Cι-3 alkyl is optionally partially or fully halogenated, NO2, NRι3Rι4;
R3 is H, halogen, methoxy or methyl;
i and R5 together complete a fused ring of formula B;
Rs is H, Cι.3alkyl optionally substituted with OH; or Rs is (CH2)2.3NRιoRn or CO2R]2;
R9 is methyl or C2.3 alkenyl each being optionally substituted with one or more OH, CN, NRioRn, CONRioRn or CO2Rj2; or R9 is heteroaryl optionally substituted with one to three groups selected from Cι.3alkyl optionally substituted with phenyl, Cι.3alkoxy, halogen or (CH2)nNRιoRn;
Rio and Ri ι may be the same or different and are each independently selected from H, OH, Cι_3alkoxy, Cι.3alkyl branched or unbranched, optionally substituted with OH, Cι.3alkoxy, Cι_3acyloxy, CO2R)2, NRι3R,4, O(CH2)2.4NR13R14 or phenyl;
or Rio and Rn together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι-3 alkyl, Cι-3alkoxy or OH;
Rι2 is H or Cι.3alkyl optionally substituted with phenyl, OH, C].3alkoxy or NRι3Rι4; Rι3 and Rι4 are each independently selected from H and Cι.3alkyl optionally substituted with Cι_ alkoxy or OH; or R[3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or
(CH2)2O(CH2)2.
14. The compound according to claim 13 wherein:
Ra is H or hydroxymethyl;
Ri and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy;
Rio and Rn may be the same or different and are each independently selected from H, OH, methoxy, Cι.3alkyl branched or unbranched, optionally substituted with OH, NRι3Rι4 or phenyl; or Rio and Ri ι together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι-2 alkyl; and
Rι2 is Cι-3alkyl optionally substituted with moφholino.
15. An intermediate compound ofthe formula(III):
Figure imgf000149_0001
wherein:
Ari is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more Ri, R2 and
R3;
X is NH, N-Cι.3alkyl, N-cyclopropyl, S or O;
Figure imgf000149_0002
Ra is H, Ci-ioalkyl, C2.ιoalkenyl or C2.ιoalkynyl, each of which may be branched or cyclic; or Ra is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more Cι.3alkyl, Cι_6 alkoxy, halogen, OH, oxo, NRioRn, aryl or heteroaryl, each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, Cι.3alkyl, Cj. 3alkoxy, hydroxyCι.3alkyl and (CH2)mNRι0Rn; and wherein Ra is attached at the 4- or 5- position;
Ri and R2 are the same or different and selected from H, halogen, CN, NO , CMO branched or unbranched saturated or unsaturated alkyl, CMO branched or unbranched alkoxy, CMO branched or unbranched acyl, CMO branched or unbranched acyloxy, CMO branched or unbranched alkylthio, aminosulfonyl, di-(Cι_3)alkylaminosulfonyl, NRioRn, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned Ri and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NRioRn, Cι.6 branched or unbranched alkyl, C3.7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(Cι. 3)alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2)nNRι0Rn, (CH2)nCO2Rι2; d.3alkyl optionally substituted with OH, Cι-3 alkoxy optionally halogenated or Cι. alkylthio;
t and R5 together with the atoms to which they are attached complete a fused ring system ofthe formula C:
Figure imgf000150_0001
Re is Cι_3alkyl or H;
R is Cι.6alkyl branched or unbranched or H;
Rio and Rn may be the same or different and are each independently selected from H, OH, Cι-3alkoxy, Cι.6alkyl branched or unbranched, C3.8cycloalkyl, aryl, arylCι.3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylCι.3alkyl or heteroaryl are optionally substituted with OH, Cι.3alkoxy, Cι_3acyloxy, CO2Rι2, NRι3Rι4, O(CH2)2^NRι3R]4, aryl or heteroaryl;
or Rio and Ri i together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p and NRι ; and wherein said ring is optionally substituted by Cι.3 alkyl, C\. 3alkoxy, OH or -(CH2)nNRt3Rι4;
Rι2 is H, Cι.6alkyl or C3.8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, Cι.3alkoxy or NRι3Rι4; or Rι2 is phenyl, optionally substituted with one to three groups selected from Cι_ alkyl, Cι_3alkoxy, halogen, (CH2)mNRιoRn, (CH2)„CONR10Rιι and O(CH2)2.4NRι0Rn;
Rι3 and Rι4 are each independently selected from H and Cι-6 alkyl optionally substituted with alkoxy, OH or phenyl; or Rj3 and Rj4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2; and
m is 1-4, n is 0-3 and p is 0-2.
16. The compound according to claim 15 wherein
Figure imgf000151_0001
a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl; b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, cycloheptenyl; c) phenyl, naphthyl; indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl; d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl and indazolyl, or a fused heteroaryl selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or e) a heterocycle selected from: pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, moφholinyl, thiomoφholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl;
wherein each ofthe above Ari are optionally substituted by one or more Ri, R2 and R3 as hereinabove defined;
Ra is H, Ci-βalkyl, C2.5alkenyl, C2.salkynyl, phenyl or heteroaryl selected from: pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; each Ra being optionally substituted with one or more phenyl, halogen, Cι.3alkyl, Cι-3 alkoxy, OH, oxo, or NRioRn ; wherein Ra is at the 4- position;
R3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
Re is Cι-3alkyl or H;
R is Cι_6alkyl branched or unbranched or H; Rio and Rn may be the same or different and are each independently selected from H, OH, Cι-3alkoxy, Cι_6alkyl branched or unbranched, C3.8cycloalkyl, benzyl and phenyl; wherein said alkyl, cycloalkyl or phenyl are optionally substituted with OH, Cι.3alkoxy, Ci- 3acyloxy, CO2Rι2, NR]3Rι4, O(CH2)2.4NRι3Rι4 or phenyl;
or Rio and Rn together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι_3 alkyl, Cμ3alkoxy, OH or -(CH2)nNRι3Rι4;
Rι2 is H or Cι.6alkyl optionally substituted with phenyl, OH, Cι.3alkoxy or NRι3Rj4;
Rι3 and Rι4 are each independently selected from H and Cι_6 alkyl optionally substituted with Cι.3alkoxy, OH or phenyl; and or Rι3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2.
17. The compound according to claim 16 wherein:
Ari is phenyl, or pyridyl;
X is NH or N-CH3; Y is NH and
Ra is H, hydroxyd-2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo- propyl, vinyl or C .5alkynyl substituted by Cι-3alkoxy or phenyl;
Ri and R2 are the same or different and selected from: halogen, Cι.3 alkyl, wherein the Ci.3 alkyl are optionally partially or fully halogenated, NO2, NRι Rι4; R3 is H, halogen, methoxy or methyl;
Rio and Ri i may be the same or different and are each independently selected from H, OH, Cι.3alkoxy, Cι.3alkyl branched or unbranched, optionally substituted with OH, Cι.3alkoxy, Cijacyloxy, CO2Rι2, NRι3Rι4, O(CH2)2.4NRι3R,4 or phenyl;
or Rio and Rn together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by Cι.3 alkyl, Cι.3alkoxy or OH;
Rι2 is H or Cι.3alkyl optionally substituted with phenyl, OH, Cι_3alkoxy or NRι3Rι4;
Rι and Rj4 are each independently selected from H and Cι.3alkyl optionally substituted with Cι.3alkoxy or OH; or Rι3 and Rι4 together form a chain completing a ring, said chain is (CH2)4.5 or (CH2)2O(CH2)2.
18. The compound according to claim 17 wherein:
Ari is phenyl;
Ra is H or hydroxymethyl;
Ri and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy; Rio and Rn may be the same or different and are each independently selected from H, OH, methoxy, Cι.3alkyl branched or unbranched, optionally substituted with OH, NRι3Rι4 or phenyl; or Rio and Rn together form moφholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by d-2 alkyl; and
Rι2 is Ci.3alkyl optionally substituted with moφholino.
19. A compound selected from the group consisting of:
2-(2,6-Dichlorophenylamino)-3,5-dihydro-imidazo[4,5-i]phenanthridin-4-one;
2-(2,6-Dichlorophenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5-h]isoquinoline-9- one;
2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl-6-(2-hydroxyethyl)- 1 ,8-dihydro-imidazo[4,5- h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl-9-oxo- 1 ,8-dihydro-imidazo[4,5-h]isoquinoline- 6-carboxylic acid methyl ester;
3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-acrylic acid methyl ester;
2-(2-Chloro-6-methylphenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5- h]isoquinoline-9-one;
3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h] isoquinolin-7-yl] -N-methoxy-N-methylacry lamide ; 2-(2-Chloro-6-nitrophenylamino)- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5-h]isoquinoline- 9-one;
N-Benzyl-3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-acrylamide;
3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-acrylic acid 4-moφholine amide;
2-(2,6-Dichlorophenylamino)-4-hydroxymethyl-l,6,7-trimethyl-l,8-dihydro-imidazo[4,5- h] isoquinoline-9-one ;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-vinyl- 1 ,8-dihydro-imidazo[4,5- h] isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl-9-oxo- 1 ,8-dihydro-imidazo[4,5-h]isoquinoline- 6- carboxylic acid 2-(4-moropholino)ethyl ester;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-hydroxypropen- 1 -yl)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-oxazol-5-yl- 1 ,8-dihydro-imidazo[4,5- h]isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 -methyl-7-vinyl- 1 ,8-dihydro-imidazo[4,5-h]isoquinoline-9- one;
2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-(3-moφholin-4-yl-propen-l-yl)- 1,8- dihydro-imidazo[4,5-h]-isoquinolin-9-one; 3-[2-(2,6-Dichlorophenylamino)-l,7-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-acrylonitrile;
2-(2-Chloro-6-methylphenylamino)-l,7-dimethyl-l,8-dihydro-imidazo[4,5-h]isoquinoline- 9-one;
2-(2,6-Dichlorophenylamino)-l-methyl-7-oxazol-5-yl-l,8-dihydro-imidazo[4,5- h] isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-hydroxypropen- 1 -yl)- 1 -methyl- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2-Chloro-6-methylphenylamino)-7-(3-hydroxypropen- 1 -yl)- 1 -methyl- 1 ,8-dihydro- imidazo [4,5 -h] -isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen- 1 -yl)- 1 ,6-dimethyl- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-pyrrolidin- 1 -yl-propen- 1 -yl)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen- 1 -yl)- 1 -methyl- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(4-methylpiperazin- 1 -yl-propen- 1 -yl)- 1 ,8- dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3 -piperidin- 1 -yl-propen- 1 -yl)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one; 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-{3-[ethyl(2-hydroxyethyl)amino]propen-l- yl } - 1 ,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-Diethylaminopropen- 1 -yl)- 1 ,6-dimethyl-2-(2,6-dimethylphenylamino)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7- {3-[(2-diethylaminoethyl)methylamino]-propen- 1 -yl} - 1 ,6- dimethyl- 1 ,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-Diethylaminopropen- 1 -yl)- 1 ,6-dimethyl-2-(2,4,6-trichlorophenylamino)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-6-methyl-7-oxazol-5-yl-l,8-dihydro-imidazo[4,5- h] isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-[3-(2-pyrrolidin- 1 -ylmethylpyrrolidin- 1 -yl)- propen-l-yl]-l,8-dihydro-imidazo[4,5-A]-isoquinolin-9-one;
7-[3-(2S-Aminomethylpyrrolidin- 1 -yl)-propen- 1 -yl]-2-(2,6-dichlorophenylamino)- 1 ,6- dimethyl- 1 , 8 -dihydro-imidazo [4,5 - h] -isoquinolin-9-one ;
1 - {3-[2-(2,6-Ddichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9-dihydro- 1 H-imidazo[4,5- h]isoquinolin-7-yl]-propenyl}-Z-proline carboxamide;
l-{3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl}-piperidine-3-carboxamide;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(methylhydrazonomethyl)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one; 7-[3-(3-Aminopyrrolidin-l-yl)-propen-l-yl]-2-(2,6-dichlorophenylamino)-l,6-dimethyl- 1 , 8 -dihydro-imidazo [4,5 -h] -isoquinolin-9-one ;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-[3-(3-acetamidopyrrolidin- 1 -yl)-propen- 1- yl]- l,8-dihydro-imidazo[4,5-/z]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-[3-(3-dimethylaminopyrrolidin- 1 -yl)-propen- 1 -yl]- 1 ,8-dihydro-imidazo[4,5-Λ]-isoquinolin-9-one;
l-{3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl}-piperidine-2-carboxamide;
7-[3-(3-Aminomethylpiperidin- 1 -yl)-propen- 1 -yl]-2-(2,6-dichlorophenylamino)- 1 ,6- dimethyl- 1 ,8-dihydro-imidazo[4,5-Λ]-isoquinolin-9-one;
1 - {3-[2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9-dihydro- 1 H-imidazo[4,5- h]isoquinolin-7-yl]-propenyl} -piperidine-3-carboxylic acid diethylamide;
2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-ethynyl-l,8-dihydro-imidazo[4,5-h]- isoquinolin-9-one;
l-{3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl} -3-methyl urea;
Cyclohexane carboxylic acid {3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro- 1 H-imidazo [4, 5 -h] isoquinolin-7-yl] -propenyl } amide ;
2-(2,6-Dichlorophenylamino)- 1 -methyl-7-phenyl- 1 ,8-dihydro-imidazo[4,5-h]isoquinolin- 9-one; N-{3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-propenyl} methanesulfonamide;
3-[2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9-dihydro- lΗ-imidazo[4,5- h]isoquinolin-7-yl]-propenyl urea;
l-Cyclohexyl-3-{3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH- imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-urea;
N- {3-[2-(2,6-Dichlorophenylamino)-l ,6-dimethyl-9-oxo-8,9-dihydro- lH-imidazo[4,5- h] isoquinolin-7-yl] -propenyl } benzenesulfonamide;
2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-(3-ethylaminopropen-l-yl)-l,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
N-{3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h] isoquinolin-7-yl] -propenyl } -guanidine;
Piperidine-3 -carboxylic acid {3-[2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9- dihydro-lΗ-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide;
E-Proline {3-[2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9-dihydro-lH- imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide;
E)-Proline {3-[2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9-dihydro-lH- imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide;
3-[2-(2,6-Dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-benzamide; -Azetidine-2-carboxylic acid {3-[2-(2,6-dichlorophenylamino)- 1 ,6-dimethyl-9-oxo-8,9- dihydro-lH-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide;
Piperidine-2-carboxylic acid {3-[2-(2,6-dichlorophenylamino)-l,6-dimethyl-9-oxo-8,9- dihydro-lH-imidazo[4,5-h]isoquinolin-7-yl]-propenyl} amide; and
the pharmacuetically acceptable derivatives thereof.
20. A compound according to claim 19 selected from the group consisting of:
2-(2,6-Dichlorophenylamino)-3,5-dihydro-imidazo[4,5-i]phenanthridin-4-one;
2-(2,6-Dichlorophenylamino)-l,6,7-trimethyl-l,8-dihydro-imidazo[4,5-h]isoquinoline-9- one;
2-(2,6-Dichlorophenylamino)-l,7-dimethyl-6-(2-hydroxyethyl)-l,8-dihydro-imidazo[4,5- h] i soquinoline-9-one ;
2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl-9-oxo- 1 ,8-dihydro-imidazo[4,5-h]isoquinoline- 6- carboxylic acid methyl ester;
3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-acrylic acid methyl ester;
2-(2-Chloro-6-methylphenylamino)-l,6,7-trimethyl-l,8-dihydro-imidazo[4,5- h] isoquinoline-9-one ;
3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-N-methoxy-N-methylacrylamide; 2-(2-Chloro-6-nitrophenylamino)-l,6,7-trimethyl-l,8-dihydro-imidazo[4,5-h]isoquinoline- 9-one;
N-Benzyl-3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-acrylamide;
3-[2-(2,6-Dichlorophenylamino)-l-methyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-acrylic acid 4-moφholine amide;
2-(2,6-Dichlorophenylamino)-4-hydroxymethyl- 1 ,6,7-trimethyl- 1 ,8-dihydro-imidazo[4,5- h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-vinyl- 1 ,8-dihydro-imidazo[4,5- h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,7-dimethyl-9-oxo- 1 ,8-dihydro-imidazo[4,5-h]isoquinoline- 6- carboxylic acid 2-(4-moropholino)ethyl ester;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-hydroxypropen- 1 -yl)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-oxazol-5-yl- 1 ,8-dihydro-imidazo[4,5- h] isoquinolin-9-one ;
2-(2,6-Dichlorophenylamino)- 1 -methyl-7-vinyl- 1 ,8-dihydro-imidazo[4,5-h]isoquinoline-9- one;
2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-(3-moφholin-4-yl-propen-l-yl)- 1,8- dihydro-imidazo[4,5-h]-isoquinolin-9-one; 3-[2-(2,6-Dichlorophenylamino)-l,7-dimethyl-9-oxo-8,9-dihydro-lH-imidazo[4,5- h]isoquinolin-7-yl]-acrylonitrile;
2-(2-Chloro-6-methylphenylamino)-l,7-dimethyl-l,8-dihydro-imidazo[4,5-h]isoquinoline- 9-one;
2-(2,6-Dichlorophenylamino)-l-methyl-7-oxazol-5-yl-l,8-dihydro-imidazo[4,5- h]isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3 -hydroxypropen- 1 -yl)- 1 -methyl- 1 ,8-dihydro- imidazo[4,5 -h] -isoquinolin-9-one;
2-(2-Chloro-6-methylphenylamino)-7-(3-hydroxypropen- 1 -yl)- 1 -methyl- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen- 1 -yl)- 1 ,6-dimethyl- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-pyrrolidin- 1 -yl-propen- 1 -yl)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen- 1 -yl)- 1 -methyl- 1 ,8-dihydro- imidazo[4,5 -h] -isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(4-methylpiperazin- 1 -yl-propen- 1 -yl)- 1 ,8- dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)- 1 ,6-dimethyl-7-(3-piperidin- 1 -yl-propen- 1 -yl)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one; 2-(2,6-Dichlorophenylamino)-l,6-dimethyl-7-{3-[ethyl(2-hydroxyethyl)amino]propen-l- yl}-l,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-Diethylaminopropen- 1 -yl)- 1 ,6-dimethyl-2-(2,6-dimethylphenylamino)- 1 ,8-dihydro- imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7- {3-[(2-diethylaminoethyl)methylamino]-propen- 1 -yl} - 1 ,6- dimethyl- 1 ,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one; and
the pharmaceutically acceptable derivatives thereof.
21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 1, 9, 15 or 19.
22. A method of treating an autoimmune disease or cancer, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claims 1, 9, 15 or 19.
23. A method according to claim 22, wherein the autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus erythematosus, insulin-dependent diabetes mellitus and asthma.
24. A method according to claim 22, wherein the cancer is selected from a src-dependent tumor or a PDGF-dependent tumor.
25. A method according to claim 24, wherein the src-dependent tumor is selected from mammary carcinoma, colon carcinoma, melanoma and sarcoma.
26. A method according to claim 24, wherein the PDGF-dependent tumor is selected from ovarian cancer, prostate cancer and glioblastoma.
27. A method of treating a disease selected from osteoporosis, Paget's disease, bone inflammation, and joint inflammation , said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claims 1, 9, 15 or 19.
28. A method of treating a disease selected from fibrotic diseases, restenosis and atherosclerosis, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claims 1, 9, 15 or 19.
29. A method of enhancing or potentiating the effectiveness of radiation therapy by administering to a patient undergoing such therapy a therapeutically effective amount of compound according to claims 1, 9, 15 or 19.
30. A method of making a compound of the formula(I)
Figure imgf000165_0001
wherein X is N-Rj5 and Ari, R», R5, R15 and Ra are as defined in claim 1, said process comprising:
a) reacting a compound ofthe formula(II) with ArjNCS in a suitable solvent at about ambient to reflux temperature for about 3 to 24 hr to provide a compound ofthe formula(III);
Figure imgf000166_0001
b) reacting the product (II) of step a) with a suitable activating agent chosen from 1,3- dicyclohexylcarbodiimide (DCC) and mercuric oxide in a suitable solvent at about ambient to reflux temperature to form a compound ofthe formula(I) as shown above or precursors thereof.
31. A method of making a compound ofthe formula(I)
Figure imgf000166_0002
wherein X is S, Y is NH and Ari, R4, R5 and Ra are as defined in claim 1, said process comprising: a) reacting a compound of the formula(IV) with ArjNCS in a suitable solvent at about ambient to reflux temperature for about 3 to 24 hr to form a compound ofthe formula(V);
Figure imgf000167_0001
IV V
b) reacting the product(V) of step a) under cyclizing conditions in a suitable solvent at about reflux temperature to form a compound ofthe formula(I) or a precursor thereof.
32. A method of making a compound ofthe formula(XI) wherein Rι5, R8 and R are as described in claim 1 :
Figure imgf000167_0002
said method comprising:
a) reacting a compound of the formula(VI) with NHRι5 in a suitable solvent optionally in a pressure flask and at about 0 to 80 °C, to provide VII, and subsequently reacting compound VII with keto-ester VIII in the presence of a suitable base in a suitable solvent, at about ambient temperature to form a compound ofthe formula(IX.):
Figure imgf000168_0001
VI VII IX
b) hydrolyzing the product of step a) by reacting with aqueous acid, and cyclizing at about reflux temperature; followed subsequently reducing the cyclized product in a suitable solvent to form a compound ofthe formula(XI).
33. A method of making a compound of the formula:
Figure imgf000168_0002
wherein Ra, Rs, R and Ari are as described in claim 1;
said method comprising:
a) reacting a compound ofthe formula(XII) with bromine in a suitable solvent at ambient temperature to provide XIII.
Figure imgf000169_0001
XII XIII
b) reacting a compound ofthe formula(XIII) with AriNCS in a suitable solvent at about ambient to reflux temperature for about 3 to 24 hr and subsequently reacting the product with a suitable activating agent chosen from 1,3-dicyclohexylcarbodiimide (DCC) and mercuric oxide in a suitable solvent at about ambient to reflux temperature to form a compound ofthe formula(XIV);
c) cross-coupling to introduce Ra in place of bromine in the presence of a suitable catalyst in a suitable solvent at about 100 °C, to form the product compound shown below:
Figure imgf000169_0002
XIV
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