Disclosed are novel compounds of formula (I):

This invention relates to substituted compounds of formula (I):
wherein Ar1, X, Y, P, Q and Het 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, as well as conditions resulting from cerebral ischemia, such as stroke. This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases, processes for preparing these compounds and intermediate useful in these processes.
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 interlukin-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 of the 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 of the src family can be ascertained by linking functional defects seen in gene disruption studies in mice. Src(xe2x88x92/xe2x88x92) mice had severe abnormalities in bone remodeling. Inhibition of src may therefore be useful in treating osteoporosis. Lck(xe2x88x92/xe2x88x92) mice display a complete lack of CD4+ cells are unable to mount antigen-dependent immune responses.
A kinase of particular interest is p56lck, which is only expressed in T-cells. Within the TCR signal transduction cascade the tyrosine kinase p56lck 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 p56lck protein are unable to signal through the T cell receptor (D. B. Straus and A. Weiss, Cell, 1992, 70, 585). Transfection of p56lck back into these cell lines restores TCR responsiveness. Also, it has been shown in mice that inactivation of the p56lck 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 p56lck plays a crucial role in T cell maturation and antigen-induced T-cell activation. Therefore, an agent blocking p56lck 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 of the 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 of the 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. Karni et al., Oncogene, 1999, 18, 4654) suggesting that src kinase inhibitors may be useful anti-cancer agents.
Src inhibitors have also been reported to be effective in an animal model of cerebral ischemia (R. Paul et al. Nature Medicine 2001, 7, 222), suggesting that src kinase inhibitors may thus be useful in treating conditions involving cerebral ischemia. For example, src kinase inhibitors may be useful in reducing brain damage following stroke.
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. Bomfeldt, 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 p56lck 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 p56lck and PDGFR kinase. Fused polycyclic 2-aminopyrimidine derivatives that inhibit p56lck 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.
EP 322 746 A1 discloses heterocyclic lactam derivatives described as being useful as cardiotonic agents, antihypertensive agents and vasodilators.
Examples of tricyclic systems similar to formula (I) above are known, but not having the 2-amino substituents on the benzimidazole ring. See S. W. Schneller et al., J. Med. Chem., 1989, 32, 2247. Examples of tricyclic systems similar to formula (I) with a carbamate at the 2-position have been reported in S. Kumar et al., Indian J. Chem. 1981, 20B, 1068 and S. Agarwal et al., Z. Naturforsch. C, 1993, 48, 829.
The compounds of the present invention represent a novel structural class, which is distinct from previously reported tyrosine kinase inhibitors.
The work cited above supports the principle that inhibition of the kinases mentioned above will be beneficial in the treatment of various disease states.
It is therefore an object of the 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 of the 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, cerebral ischemic conditions, atherosclerosis, restenosis and allergic diseases, using the novel compounds of the invention.
It is yet a further object of the invention to provide processes of preparation of the above-mentioned novel compounds and pharmaceutical compositions comprising the same.
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 of the invention may have different inhibitory potencies against individual tyrosine kinases. Thus some of compounds of the 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 p56lck kinase, p60src kinase and PDGFR kinase. See the section entitled xe2x80x9cAssessment of Biological Propertiesxe2x80x9d disclosed herein.
In its broadest generic aspect, the invention provides novel compounds of the formula (I) below:
wherein:
Ar1 is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more R1, R2 and R3;
X is NH, Nxe2x80x94C1-3alkyl, N-cyclopropyl, S or O;
Y is NR13;
R1 and R2 are the same or different and are selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-10 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR8R9, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from the group consisting of oxo, OH, NR8R9, C1-6 branched or unbranched alkyl, C3-7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
R3 is selected from the group consisting of H, halogen, OH, (CH2)nNR8R9, (CH2)nCO2R10, C1-3alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated and C1-3 alkylthio;
Het represents a fused heterocylic ring having a formula A, B or C:
R4 is selected from H, C1-6 alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with phenyl, OH or C1-3alkoxy, C3-10-cycloalkyl, or C5-8cycloalkenyl; or R4 is selected from (CH2)mNR8R9, (CH2)mNR8COR10, (CH2)nCO2R10, (CH2)nCONR8R9, phenyl, heteroaryl or heterocycle, each phenyl , heteroaryl or heterocycle being optionally substituted with C1-3alkyl, C1-3alkoxy, (CH2)mNR8R9, OH, SO3H or halogen;
R5 is selected from H, C1-10alkyl branched or unbranched, C3-10 cycloalkyl, C5-7cycloalkenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6acyl, each being optionally substituted with one or more halogen, OH, oxo, CN, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3alkoxy, NR8R9, ureido, guanidino, NR8COR10, SR10, CONR8R9, CO2R10, C3-10 cycloalkyl C3-10cycloalkylidene, C5-7cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle; wherein each of C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, C3-10cycloalkylidene, C5-7cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle is optionally substituted with one or more C1-3alkyl, C1-3alkoxy, halogen, CN, NO2, amidino, guanidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the ureido, amidino or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl, C1-3alkoxy or CO2R10;
or R5 is selected from CO2R10, NR8R9, CONR8R9, aryl, heteroaryl, heterocycle, aryl-COxe2x80x94, heteroaryl-COxe2x80x94 or heterocycle-COxe2x80x94, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three:
C1-3alkoxy, halogen, NO2, CN, S(O)pNR8R9, C0-3alkylS(O)p, NR8R9, (CH2)nCO2R10, (CH2)nCONR8R9, CO(CH2)nNR8R9, O(CH2)2-4NR8R9, ureido, guanidino, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkyl-Zxe2x80x94, aryl-Zxe2x80x94, heteroaryl-Zxe2x80x94, heterocycle-Zxe2x80x94, or C1-3alkyl optionally substituted with phenyl or NR8R9, wherein Z is a bridging group selected from C1-10 alkylene branched or unbranched, CO, S(O)p, O, S, NH, CONH, NHCO, COO or OOC, and wherein each cycloalkyl, aryl, heteroaryl or heterocycle is optionally substituted with NO2, C1-3alkyl, C1-3alkoxy, halogen, CO2R10, (CH2)nNR8R9, O(CH2)2-4NR8R9, ureido or guanidino, wherein one or more of the amino nitrogens in the ureido or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy; and wherein each alkyl, alkoxy and phenyl in this paragraph is optionally partially or fully halogenated;
or R5 is a C6-12 bridged- or spiro-bicyclic ring system, optionally having one or two double bonds in the ring system, and wherein up to 3 carbon atoms in the ring system may be replaced by heteroatoms selected from N, O and S; and wherein said ring system may be optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, CO2R10, ureido, guanidino, amidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the ureido, guanidino or amidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy;
R6 is selected from H, C1-6alkyl branched or unbranched, C2-6 alkenyl branched or unbranched, CO2R10, C3-8cycloalkyl, C3-8cycloalkenyl, aryl, arylC1-3alkyl, heteroaryl and heterocyclyl; wherein said C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, C3-8cycloalkenyl, aryl, arylC1-3alkyl, heteroaryl or heterocyclyl are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl, heteroaryl or heterocyclyl;
R7 is H or C1-6alkyl;
R8 and R9 are the same or different and are each independently selected from H, OH, CO2R10, C1-10 acyl branched or unbranched, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-6alkenyl,C3-8cycloalkyl, aryl, arylC1-3alkyl, aroyl, heteroaryl or heterocycle; wherein said alkyl, cycloalkyl, aryl, arylC1-3alkyl, aroyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl, or heteroaryl;
or R8 and R9 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, NCOR10, NCO2R10, NR11 or NC(xe2x95x90NR11)NR11R12; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR11R12;
R10 is selected from H, C1-6alkyl, C3-8cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3alkoxy, C1-3alkanoyloxy or NR11R12, or R10 is phenyl optionally substituted with one to three C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR8R9, (CH2)nCONR8R9 or O(CH2)2-4NR8R9;
R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
R13 is H or C1-3alkyl;
P and Q are each independently CH or N;
m is 1-4;
n is 0-3;
and p is 0-2;
wherein one or more of the primary amine or secondary amine nitrogen atoms in any of the R4, R5, R6 and R7 substituent groups may optionally be protected by a protecting group;
and the pharmaceutically acceptable derivatives thereof.
In one embodiment of the invention, there are provided compounds of the formula (I) as described above, and wherein:
Ar1 is
a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl;
b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, and cycloheptenyl;
c) an aromatic carbocycle selected from phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl,
d) a heteroaryl selected from pyridyl, 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 Ar1 are optionally substituted by one or more R1, R2 and R3;
R1 and R2 are as defined in claim 1, and R3 is hydrogen, halogen, methyl, methoxy, hydroxymethyl or OH;
wherein each of the above Ar1 are optionally substituted by one or more R1, R2 and R3;
R1 and R2 are as defined in claim 1, and R3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
R4 is H, C1-3alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with OH; or R4 is (CH2)2-3NR8R9, (CH2)nCO2R10 or (CH2)nCONR8R9;
R5 is selected from H, C1-10alkyl branched or unbranched, C3-10 cycloalkyl, C5-7cycloalkenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6acyl, each being optionally substituted with one or more halogen, OH, oxo, CN, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3alkoxy, NR8R9, ureido, guanidino, NR8COR10, SR10, CONR8R9, CO2R10, C3-10 cycloalkyl, C3-10cycloalkylidene, C5-7cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle; wherein each of C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, C3-10cycloalkylidene, C5-7cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle is optionally substituted with one or more C1-3alkyl, C1-3alkoxy, halogen, CN, NO2, amidino, guanidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the ureido, amidino or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl, C1-3alkoxy or CO2R10;
or R5 is selected from CO2R10, NR8R9, CONR8R9, aryl, heteroaryl, heterocycle, aryl-COxe2x80x94, heteroaryl-COxe2x80x94 or heterocycle-COxe2x80x94, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three:
C1-3alkoxy, halogen, NO2, CN, S(O)pN8R9, C0-3alkylS(O)p, NR8R9, (CH2)nCO2R10, (CH2)nCONR8R9,CO(CH2)nNR8R9, O(CH2)2-4NR8R9, ureido, guanidino, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkyl-Zxe2x80x94, aryl-Zxe2x80x94, heteroaryl-Zxe2x80x94, heterocycle-Zxe2x80x94, or C1-3alkyl optionally substituted with phenyl or NR8R9, wherein Z is a bridging group selected from C1-10 alkylene branched or unbranched, CO, S(O)p, O, S, NH, CONH, NHCO, COO or OOC, and wherein each cycloalkyl, aryl, heteroaryl or heterocycle is optionally substituted with NO2, C1-3alkyl, C1-3alkoxy, halogen, CO2R10, (CH2)nNR8R9, O(CH2)2-4NR8R9, ureido or guanidino, wherein one or more of the amino nitrogens in the ureido or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy; and wherein each alkyl, alkoxy and phenyl in this paragraph is optionally partially or fully halogenated;
or R5 is a C6-12 bridged- or spiro-bicyclic ring system, optionally having one or two double bonds in the ring system, and wherein up to 3 carbon atoms in the ring system may be replaced by heteroatoms selected from N, O and S; and wherein said ring system may be optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, CO2R10, ureido, guanidino, amidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the ureido, guanidino or amidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy;
R6 is selected from H, C1-6alkyl branched or unbranched, C2-6 alkenyl branched or unbranched, or CO2R10; wherein said C1-6alkyl or C1-6 alkenyl are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl, heteroaryl or heterocyclyl;
R7 is H or C1-6alkyl;
R8 and R9 are the same or different and are each independently selected from H, OH, C1-3alkyl branched or unbranched, CO2R10, C3-8cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl or heterocycle; wherein said alkyl, cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl or heteroaryl;
or R8 and R9 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, NCOR10, NCO2R10, NR11 or NC(xe2x95x90NR11)NR11R12; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR11R12;
R10 is H or C1-6alkyl optionally substituted with phenyl, OH, C1-3alkoxy, C1-3alkanoyloxy or NR11R12;
R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
R13 is H; and
P and Q are each CH.
In another embodiment of the invention, there are provided compounds of the formula (I) as described immediately above, and wherein:
Ar1 is phenyl or pyridyl, each optionally subsituted by one or more R1, R2 and R3;
X is NH or Nxe2x80x94C1-3alkyl;
Y is NH;
R1 and R2 are the same or different and selected from: halogen, C1-3 alkyl, wherein the C1-3 alkyl is optionally partially or fully halogenated, NO2 or NR8R9;
R3 is H, halogen, methyl or methoxy;
R4 is H, C1-3alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with OH; or R4 is (CH2)2-3NR8R9 or CO2R10;
R5 is selected from H, C1-3alkyl branched or unbranched, C3-8 cycloalkyl, C5-7cycloalkenyl or C2-4 alkenyl, each being optionally substituted with one or more OH, CN, NR8R9, CONR8R9, C3-8 cycloalkyl, C5-7cycloalkenyl, phenyl, heteroaryl or heterocycle; wherein each phenyl, heteroaryl or heterocycle is optionally substituted with one or more C1-3alkyl, C1-3alkoxy, halogen, CN, NO2, amidino, guanidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the amidino or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl, C1-3alkoxy or CO2R10;
or R5 is selected from CO2R10, NR8R9, CONR8R9, phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, benzofuranyl, benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl, pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl, or indolyl-COxe2x80x94, wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, benzofuranyl, benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl, pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl or indolyl-COxe2x80x94 is optionally substituted with one to three:
halogen, NO2, S(O)pNR8R9, C0-3alkylS(O)p, NR8R9, (CH2)nCO2R10, ureido, guanidino, cycloalkyl, phenyl, heteroaryl, heterocycle, cycloalkyl-Zxe2x80x94, phenyl-Zxe2x80x94, heteroaryl-Zxe2x80x94, heterocycle-Zxe2x80x94, or C1-3alkyl optionally substituted with phenyl or NR8R9, wherein Z is a bridging group selected from C1-3 alkylene branched or unbranched, O, S(O)p or NH, and wherein each cycloalkyl, phenyl, heteroaryl or heterocycle is optionally substituted with NO2, C1-3alkyl, C1-3alkoxy, CO2R10, (CH2)nNR8R9, O(CH2)2-4NR8R9 or guanidino, wherein one or more of the amino nitrogens in the guanidino group in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy; and wherein each alkyl, alkoxy and phenyl in this paragraph is optionally partially or fully halogenated;
or R5 is a C6-7 bridged-bicyclic ring system, optionally having one or two double bonds in the ring system, and wherein up to 1 carbon atom in the ring system may be replaced by a nitrogen atom; and wherein said ring system may be optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR8R9, or O(CH2)2-4N8NR9;
R6 is selected from H, C1-6alkyl branched or unbranched or CO2R10;
R7 is H or C1-6alkyl;
R8 and R9 are the same or different and are each independently selected from H, C1-3alkyl branched or unbranched, CO2R10, phenyl, or benzoyl; wherein said alkyl, phenyl or benzoyl are optionally substituted with OH or C1-3alkoxy;
or R8 and R9 together form a xe2x80x94(CH2)2xe2x80x94N(CO2R10)xe2x80x94(CH2)2xe2x80x94 group, a xe2x80x94(CH2)2xe2x80x94N(COR10)xe2x80x94(CH2)2xe2x80x94 group, a xe2x80x94(CH2)2xe2x80x94N(R11)xe2x80x94(CH2)2xe2x80x94 group or a xe2x80x94(CH2)2xe2x80x94N(C(xe2x95x90NR11)NR11R12)xe2x80x94(CH2)2xe2x80x94 group; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, or OH;
R10 is H or C1-6alkyl optionally substituted with phenyl, OH, C1-3alkoxy, C1-3alkanoyloxy or NR11R12;
R11 and R12 are each independently selected from H and C1-3 alkyl optionally substituted with C1-3alkoxy or OH;
or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2.
In yet another embodiment of the invention there are provided compounds of the formula (I) as described immediately above, and wherein:
Ar1 is phenyl;
R1 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;
R5 is selected from C2-4 alkenyl, C3-8 cycloalkyl or C5-7cycloalkenyl, each being optionally substituted with one or more OH, CN, NR8R9, CONR8R9 or phenyl; wherein phenyl is optionally substituted with one or more C1-3alkyl, C1-3alkoxy, halogen, amidino, guanidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the amidino or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy;
or R5 is selected from phenyl, furyl, thienyl, oxazolyl, thiazolyl , pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl or indolyl-COxe2x80x94, wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl, pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, or indolyl-COxe2x80x94 is optionally substituted with one to two:
halogen, NO2, SO2NR8R9, NR8R9, (CH2)nCO2R10, ureido, cycloalkyl, phenyl, heteroaryl, heterocycle, cycloalkyl-Zxe2x80x94, heteroaryl-Zxe2x80x94 or heterocycle-Zxe2x80x94, or C1-3alkyl optionally substituted with NR8R9, wherein Z is a bridging group selected from C1-3 alkylene branched or unbranched, wherein each cycloalkyl, phenyl, heteroaryl or heterocycle is optionally substituted with NO2, C1-3alkyl, CO2R10, NR8R9 or guanidino, wherein one or more of the amino nitrogens in the guanidino group in this paragraph may be optionally substituted with C1-3alkyl; and wherein each alkyl and phenyl in this paragraph is optionally partially or fully halogenated;
or R5 is a 7-azabicyclo[2.2.1]heptane ring system, optionally having one or two double bonds in the ring system, wherein said ring system may be optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR8R9, or O(CH2)2-4NR8R9;
R6 is selected from H or C1-3alkyl branched or unbranched;
R7 is H or C1-3alkyl;
R8 and R9 are the same or different and are each independently selected from H or C1-3alkyl branched or unbranched; wherein said alkyl is optionally substituted with OH or C1-3alkoxy;
or R8 and R9 together form a xe2x80x94(CH2)2xe2x80x94N(CO2R10)xe2x80x94(CH2)2xe2x80x94, a xe2x80x94(CH2)2xe2x80x94N(COR10)xe2x80x94(CH2)2xe2x80x94 group, a xe2x80x94(CH2)2xe2x80x94N(R11)xe2x80x94(CH2)2xe2x80x94 group or a xe2x80x94(CH2)2xe2x80x94N(C(xe2x95x90NR11)NR11R12)xe2x80x94(CH2)2xe2x80x94 group; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, or OH;
R10 is H or C1-3alkyl optionally substituted with phenyl, OH or C1-3alkanoyloxy; and
R11 is selected from H and C1-3 alkyl.
In yet another embodiment of the invention, there are provided any of the compounds of formula (I) described above wherein Het represents a fused ring having formula B:
In still another embodiment of the invention, there are provided compounds of the formula (Ixe2x80x2) below:
wherein:
X is NH, Nxe2x80x94C1-3alkyl, N-cyclopropyl, S or O;
R1 and R2 are the same or different and are selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-10 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR8R9, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from the group consisting of oxo, OH, NR8R9, C1-6 branched or unbranched alkyl, C3-7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
R3 is selected from the group consisting of H, halogen, OH, (CH2)nNR8R9, (CH2)nCO2R10, C1-3alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated and C1-3 alkylthio;
Het represents a fused heterocyclic ring having a formula A, B or C:
R4 is selected from H, C1-6 alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with phenyl, OH or C1-3alkoxy, C3-10-cycloalkyl, or C5-8cycloalkenyl; or R4 is selected from (CH2)mNR8R9, (CH2)mNR8COR10, (CH2)nCO2R10, (CH2),CONR8R9, phenyl, heteroaryl or heterocycle, each phenyl , heteroaryl or heterocycle being optionally substituted with C1-3alkyl, C1-3alkoxy, (CH2)mNR8R9, OH, SO3H or halogen;
R5 is selected from H, C1-10alkyl branched or unbranched, C3-10 cycloalkyl, C5-7cycloalkenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6acyl, each being optionally substituted with one or more halogen, OH, oxo, CN, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3alkoxy, NR8R9, ureido, guanidino, NR8COR10, SR10, CONR8R9, CO2R10, C3-10 cycloalkyl, C3-10cycloalkylidene, C5-7cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle; wherein each of C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, C3-10cycloalkylidene, C5-7cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle is optionally substituted with one or more C1-3alkyl, C1-3alkoxy, halogen, CN, NO2, amidino, guanidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the ureido, amidino or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl, C1-3alkoxy or CO2R10;
or R5 is selected from CO2R10, NR8R9, CONR8R9, aryl, heteroaryl, heterocycle, aryl-COxe2x80x94, heteroaryl-COxe2x80x94 or heterocycle-COxe2x80x94, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three:
C1-3alkoxy, halogen, NO2, CN, S(O)pNR8R9, C0-3alkylS(O)p, NR8R9, (CH2)nCO2R10, (CH2)nCONR8R9, CO(CH2)nNR8R9, O(CH2)2-4NR8R9, ureido, guanidino, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkyl-Zxe2x80x94, aryl-Zxe2x80x94, heteroaryl-Zxe2x80x94, heterocycle-Zxe2x80x94, or C1-3alkyl optionally substituted with phenyl or NR8R9, wherein Z is a bridging group selected from C1-10 alkylene branched or unbranched, CO, S(O)p, O, S, NH, CONH, NHCO, COO or OOC, and wherein each cycloalkyl, aryl, heteroaryl or heterocycle is optionally substituted with NO2, C1-3alkyl, C1-3alkoxy, halogen, CO2R10, (CH2)nNR8R9, O(CH2)2-4NR8R9, ureido or guanidino, wherein one or more of the amino nitrogens in the ureido or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy; and wherein each alkyl, alkoxy and phenyl in this paragraph is optionally partially or fully halogenated;
or R5 is a C6-12 bridged- or spiro-bicyclic ring system, optionally having one or two double bonds in the ring system, and wherein up to 3 carbon atoms in the ring system may be replaced by heteroatoms selected from N, O and S; and wherein said ring system may be optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, CO2R10, ureido, guanidino, amidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the ureido, guanidino or amidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy;
R6 is selected from H, C1-6alkyl branched or unbranched, C2-6 alkenyl branched or unbranched, CO2R10, C3-8cycloalkyl, C3-8cycloalkenyl, aryl, arylC1-3alkyl, heteroaryl and heterocyclyl; wherein said C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, C3-8cycloalkenyl, aryl, arylC1-3alkyl, heteroaryl or heterocyclyl are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl, heteroaryl or heterocyclyl;
R7 is H or C1-6alkyl;
R8 and R9 are the same or different and are each independently selected from H, OH, CO2R10, C1-10 acyl branched or unbranched, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-6alkenyl,C3-8cycloalkyl, aryl, arylC1-3alkyl, aroyl, heteroaryl or heterocycle; wherein said alkyl, cycloalkyl, aryl, arylC1-3alkyl, aroyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl or heteroaryl;
or R8 and R9 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, NCOR10, NCO2R10, NR11 or NC(xe2x95x90NR11)NR11R12; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR11R12;
R10 is selected from H, C1-6alkyl, C3-8cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3alkoxy, C1-3alkanoyloxy or NR11R12, or R10 is phenyl optionally substituted with one to three C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR8R9, (CH2)nCONR8R9 or O(CH2)2-4NR8R9;
R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
R13 is H or C1-3alkyl;
P and Q are each independently CH or N;
m is 1-4;
n is 0-3;
and p is 0-2;
wherein one or more of the primary amine or secondary amine nitrogen atoms in any of the R4, R5, R6 and R7 substituent groups may optionally be protected by a protecting group;
and the pharmaceutically acceptable derivatives thereof.
In another embodiment of the invention there are provided compounds of the formula(Ixe2x80x2) as described above, and wherein:
X is NH or Nxe2x80x94C1-3alkyl;
R1 and R2 are the same or different and selected from: halogen, C1-3 alkyl, wherein the C13 alkyl is optionally partially or fully halogenated, NO2 or NR8R9;
R3 is H, halogen, methyl or methoxy;
R4 is H, C1-3alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with OH; or R4 is (CH2)2-3NR8R9 or CO2R10;
R5 is selected from H, C1-3alkyl branched or unbranched, C3-8 cycloalkyl, C5-7cycloalkenyl or C2-4 alkenyl, each being optionally substituted with one or more OH, CN, NR8R9, CONR8R9, C3-8 cycloalkyl, C5-7cycloalkenyl, phenyl, heteroaryl or heterocycle; wherein each phenyl, heteroaryl or heterocycle is optionally substituted with one or more C1-3alkyl, C1-3alkoxy, halogen, CN, NO2, amidino, guanidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the amidino or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl, C1-3alkoxy or CO2R10;
or R5 is selected from CO2R10, NR8R9, CONR8R9, phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, benzofuranyl, benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl, pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl, or indolyl-COxe2x80x94, wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, benzofuranyl, benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl, pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl or indolyl-COxe2x80x94 is optionally substituted with one to three:
halogen, NO2, S(O)pNR8R9, CO0-3alkylS(O)p, NR8R9, (CH2)nCO2R10, ureido, guanidino, cycloalkyl, phenyl, heteroaryl, heterocycle, cycloalkyl-Zxe2x80x94, phenyl-Zxe2x80x94, heteroaryl-Zxe2x80x94, heterocycle-Zxe2x80x94, or C1-3alkyl optionally substituted with phenyl or NR8R9, wherein Z is a bridging group selected from C1-3 alkylene branched or unbranched, O, S(O)p or NH, and wherein each cycloalkyl, phenyl, heteroaryl or heterocycle is optionally substituted with NO2, C1-3alkyl, C1-3alkoxy, CO2R10, (CH2)nNR8R9, O(CH2)2-4NR8R9 or guanidino, wherein one or more of the amino nitrogens in the guanidino group in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy; and wherein each alkyl, alkoxy and phenyl in this paragraph is optionally partially or fully halogenated;
or R5 is a C6-7 bridged-bicyclic ring system, optionally having one or two double bonds in the ring system, and wherein up to 1 carbon atom in the ring system may be replaced by a nitrogen atom; and wherein said ring system may be optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR8R9, or O(CH2)2-4NR8R9;
R6 is selected from H, C1-6alkyl branched or unbranched or CO2R10;
R7 is H or C1-6alkyl;
R8 and R9 are the same or different and are each independently selected from H, C1-3alkyl branched or unbranched, CO2R10, phenyl, or benzoyl; wherein said alkyl, phenyl or benzoyl are optionally substituted with OH or C1-3alkoxy;
or R8 and R9 together form a xe2x80x94(CH2)2xe2x80x94N(CO2R10)xe2x80x94(CH2)2xe2x80x94 group, a xe2x80x94(CH2)2xe2x80x94N(COR10)xe2x80x94(CH2)2xe2x80x94 group, a xe2x80x94(CH2)2xe2x80x94N(R11)xe2x80x94(CH2)2xe2x80x94 group or a xe2x80x94(CH2)2xe2x80x94N(C(xe2x95x90NR11)NR11R12)xe2x80x94(CH2)2xe2x80x94 group; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, or OH;
R10 is H or C1-6alkyl optionally substituted with phenyl, OH, C1-3alkoxy, C1-3alkanoyloxy or NR11R12;
R11 and R12 are each independently selected from H and C1-3 alkyl optionally substituted with C1-3alkoxy or OH;
or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2; and
P and Q are each CH.
In still a further embodiment of the invention there are provided compounds of the formula (Ixe2x80x2) as described immediately above, and wherein:
R1 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;
R5 is selected from C2-4 alkenyl, C3-8 cycloalkyl or C5-7cycloalkenyl, each being optionally substituted with one or more OH, CN, NR8R9, CONR8R9 or phenyl; wherein phenyl is optionally substituted with one or more C1-3alkyl, C1-3alkoxy, halogen, amidino, guanidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the amidino or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy;
or R5 is selected from phenyl, furyl, thienyl, oxazolyl, thiazolyl , pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl or indolyl-COxe2x80x94, wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl, pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl or indolyl-COxe2x80x94 is optionally substituted with one to two:
halogen, NO2, SO2NR8R9, NR8R9, (CH2)nCO2R10, ureido, cycloalkyl, phenyl, heteroaryl, heterocycle, cycloalkyl-Zxe2x80x94, heteroaryl-Zxe2x80x94 or heterocycle-Zxe2x80x94, or C1-3alkyl optionally substituted with NR8R9, wherein Z is a bridging group selected from C1-3 alkylene branched or unbranched or S(O)p, wherein each cycloalkyl, phenyl, heteroaryl or heterocycle is optionally substituted with NO2, C1-3alkyl, CO2R10, NR8R9 or guanidino, wherein one or more of the amino nitrogens in the guanidino group in this paragraph may be optionally substituted with C1-3alkyl; and wherein each alkyl and phenyl in this paragraph is optionally partially or fully halogenated;
or R5 is a 7-azabicyclo[2.2.1]heptane ring system, optionally having one or two double bonds in the ring system, wherein said ring system may be optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR8R9, or O(CH2)2-4NR8R9;
R6 is selected from H or C1-3alkyl branched or unbranched;
R7 is H or C1-3alkyl;
R8 and R9 are the same or different and are each independently selected from H or C1-3alkyl branched or unbranched; wherein said alkyl is optionally substituted with OH or C1-3alkoxy;
or R8 and R9 together form a xe2x80x94(CH2)2xe2x80x94N(CO2R10)xe2x80x94(CH2)2xe2x80x94, a xe2x80x94(CH2)2xe2x80x94N(COR10)xe2x80x94(CH2)2xe2x80x94 group, a xe2x80x94(CH2)2xe2x80x94N(R11)xe2x80x94(CH2)2xe2x80x94 group or a xe2x80x94(CH2)2xe2x80x94N(C(xe2x95x90NR11)NR11R12)xe2x80x94(CH2)2xe2x80x94 group; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, or OH;
R10 is H or C1-3alkyl optionally substituted with phenyl, OH or C1-3alkanoyloxy; and
R11 is selected from H and C1-3 alkyl.
In yet another embodiment of the invention, there are provided any of the compounds of formula (Ixe2x80x2) described above wherein Het represents a fused ring having formula B:
In yet another aspect of the invention, there are provided compounds of the following formula Ib:
wherein R is H, C1-3alkyl or cyclopropyl, and Ar1 and R5 are as defined in formula (I) above.
The present invention is also directed to the intermediate compounds of the following formulae (VI), (XII), (XVIII) and (XIX) useful in the synthetic schemes and examples set forth below.
In their broadest generic aspect, intermediate compounds of the formula (VI) are represented by the following formula:
wherein:
R is H, C1-3alkyl or cyclopropyl;
R4 is selected from H, C1-6 alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with phenyl, OH or C1-3alkoxy; or R4 is selected from (CH2)mNR8R9, (CH2)mNR8COR10, (CH2)nCO2R10 or (CH2)nCONR8R9;
R8 and R9 are the same or different and are each independently selected from H, OH, CO2R10, C1-10acyl branched or unbranched, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-6alkenyl,C3-8cycloalkyl, aryl, arylC1-3alkyl, aroyl, heteroaryl or heterocycle; wherein said alkyl, cycloalkyl, aryl, arylC1-3alkyl, aroyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl or heteroaryl;
or R9 and R9 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, NCOR10, NCO2R10, NR11 or NC(xe2x95x90NR11)NR11R12; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR11R12;
R10 is selected from H, C1-6alkyl, C3-8cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3alkoxy, C1-3alkanoyloxy or NR11R12, or R10 is phenyl optionally substituted with one to three C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR8R9, (CH2)nCONR8R9 or O(CH2)2-4NR8R9;
R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
m is 1-4;
n is 1-3;
and p is 0-2;
wherein one or more of the primary amine or secondary amine nitrogen atoms in the R4 substituent group may optionally be protected by a protecting group.
One embodiment of the compounds of formula(VI) are those wherein:
R is H or C1-3alkyl; and
R4 is H, C1-3alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with OH; or R4 is (CH2)2-3NR8R9, (CH2)nCO2R10 or (CH2)nCONR8R9.
In their broadest generic aspect, intermediate compounds of formula (XII) are represented by the following formula:
wherein:
R is H, C1-3alkyl or cyclopropyl; and
R5 is selected from H, C1-10alkyl branched or unbranched, C3-10 cycloalkyl, C5-7cycloalkenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6acyl, each being optionally substituted with one or more halogen, OH, oxo, CN, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3alkoxy, NR8R9, ureido, guanidino, NR8COR10, SR10, CONR8R9, CO2R10, C3-10 cycloalkyl, C3-10cycloalkylidene, C5-7cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle; wherein each of C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, C3-10cycloalkylidene, C5-7cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle is optionally substituted with one or more C1-3alkyl, C1-3alkoxy, halogen, CN, NO2, amidino, guanidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the ureido, amidino or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl, C1-3alkoxy or CO2R10;
or R5 is selected from CO2R10, NR8R9, CONR8R9, aryl, heteroaryl, heterocycle, aryl-COxe2x80x94, heteroaryl-COxe2x80x94 or heterocycle-COxe2x80x94, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three:
C1-3alkoxy, halogen, NO2, CN, S(O)pNR8R9, C0-3alkylS(O)p, NR8R9, (CH2)nCO2R10, (CH2)nCONR8R9, CO(CH2)nNR8R9, O(CH2)2-4NR8R9, ureido, guanidino, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkyl-Zxe2x80x94, aryl-Zxe2x80x94, heteroaryl-Zxe2x80x94, heterocycle-Zxe2x80x94, or C1-3alkyl optionally substituted with phenyl or NR8R9, wherein Z is a bridging group selected from C1-10 alkylene branched or unbranched, CO, S(O)p, O, S, NH, CONH, NHCO, COO or OOC, and wherein each cycloalkyl, aryl, heteroaryl or heterocycle is optionally substituted with NO2, C1-3alkyl, C1-3alkoxy, halogen, CO2R10, (CH2)nNR8R9, O(CH2)2-4NR8R9, ureido or guanidino, wherein one or more of the amino nitrogens in the ureido or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy; and wherein each alkyl, alkoxy and phenyl in this paragraph is optionally partially or fully halogenated;
or R5 is a C6-12 bridged- or spiro-bicyclic ring system, optionally having one or two double bonds in the ring system, and wherein up to 3 carbon atoms in the ring system may be replaced by heteroatoms selected from N, O and S; and wherein said ring system may be optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, CO2R10, ureido, guanidino, amidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the ureido, guanidino or amidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy;
R6 is selected from H, C1-6alkyl branched or unbranched, C2-6 alkenyl branched or unbranched, CO2R10, C3-8cycloalkyl, C3-8cycloalkenyl, aryl, arylC1-3alkyl, heteroaryl and heterocyclyl; wherein said C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, C3-8cycloalkenyl, aryl, arylC1-3alkyl, heteroaryl or heterocyclyl are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl, heteroaryl or heterocyclyl;
R7is H or C1-6alkyl;
R8and R9 are the same or different and are each independently selected from H, OH, CO2R10, C1-10 acyl branched or unbranched, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-6alkenyl,C3-8cycloalkyl, aryl, arylC1-3alkyl, aroyl, heteroaryl or heterocycle; wherein said alkyl, cycloalkyl, aryl, arylC1-3alkyl, aroyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl or heteroaryl;
or R8 and R9 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, NCOR10, NCO2R10, NR11 or NC(xe2x95x90NR11)NR11R12; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR11R12;
R10 is selected from H, C1-6alkyl, C3-8cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3alkoxy, C1-3alkanoyloxy or NR1 R12, or R10 is phenyl optionally substituted with one to three C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR8R9, (CH2)nCONR8R9 or O(CH2)2-4NR8R9;
R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R11 and R12 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;
wherein one or more of the primary amine or secondary amine nitrogen atoms in any of the R4, R5, R6 and R7 substituent groups may optionally be protected by a protecting group.
One embodiment of the compounds of formula (XII) are those wherein:
R is H or C1-3alkyl; and
R5 is selected from H, C1-3alkyl branched or unbranched, C3-8 cycloalkyl, C5-7cycloalkenyl or C2-4 alkenyl, each being optionally substituted with one or more OH, CN, NR8R9, CONR8R9, C3-8 cycloalkyl, C5-7cycloalkenyl, phenyl, heteroaryl or heterocycle; wherein each phenyl, heteroaryl or heterocycle is optionally substituted with one or more C1-3alkyl, C1-3alkoxy, halogen, CN, NO2, amidino, guanidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the amidino or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl, C1-3alkoxy or CO2R10;
or R5 is selected from CO2R10, NR8R9, CONR8R9, phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, benzofuranyl, benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl, pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl, or indolyl-COxe2x80x94, wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, benzofuranyl, benzimidazolyl, 1,2,5,6-tetrahydro-pyridinyl, pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl, benzoyl or indolyl-COxe2x80x94 is optionally substituted with one to three:
halogen, NO2, S(O)pNR8R9, CO0-3alkylS(O)p, NR8R9, (CH2)nCO2R10, ureido, guanidino, cycloalkyl, phenyl, heteroaryl, heterocycle, cycloalkyl-Zxe2x80x94, phenyl-Zxe2x80x94, heteroaryl-Zxe2x80x94, heterocycle-Zxe2x80x94, or C1-3alkyl optionally substituted with phenyl or NR8R9, wherein Z is a bridging group selected from C1-3 alkylene branched or unbranched, O, S(O)p or NH, and wherein each cycloalkyl, phenyl, heteroaryl or heterocycle is optionally substituted with NO2, C1-3alkyl, C1-3alkoxy, CO2R10, (CH2)nNR8R9, O(CH2)2-4NR8R9 or guanidino, wherein one or more of the amino nitrogens in the guanidino group in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy; and wherein each alkyl, alkoxy and phenyl in this paragraph is optionally partially or fully halogenated;
or R5 is a C6-7 bridged-bicyclic ring system, optionally having one or two double bonds in the ring system, and wherein up to 1 carbon atom in the ring system may be replaced by a nitrogen atom; and wherein said ring system may be optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR8R9, or O(CH2)2-4NR8R9;
Yet another embodiment of the compounds of formula (XII) are those described immediately above, wherein:
R5 is selected from C2-4 alkenyl, C3-8 cycloalkyl or C5-7cycloalkenyl, each being optionally substituted with one or more OH, CN, NR8R9, CONR8R9 or phenyl; wherein phenyl is optionally substituted with one or more C1-3alkyl, C1-3alkoxy, halogen, amidino, guanidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9; wherein one or more of the amino nitrogens in the amidino or guanidino groups in this paragraph may be optionally substituted with C1-3alkyl, phenylC0-3alkyl or C1-3alkoxy;
or R5 is selected from phenyl, furyl, thienyl, oxazolyl, thiazolyl , pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl or indolyl-COxe2x80x94, wherein each phenyl, furyl, thienyl, oxazolyl, thiazolyl, pyridinyl, benzofuranyl, 1,2,5,6-tetrahydropyridinyl, pyrrolinyl, 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl or indolyl-COxe2x80x94 is optionally substituted with one to two:
halogen, NO2, SO2NR8R9, NR8R9, (CH2)nCO2R10, ureido, cycloalkyl, phenyl, heteroaryl, heterocycle, cycloalkyl-Zxe2x80x94, heteroaryl-Zxe2x80x94 or heterocycle-Zxe2x80x94, or C1-3alkyl optionally substituted with NR8R9, wherein Z is a bridging group selected from C1-3 alkylene branched or unbranched or S(O)p, wherein each cycloalkyl, phenyl, heteroaryl or heterocycle is optionally substituted with NO2, C1-3alkyl, CO2R10, NR8R9 or guanidino, wherein one or more of the amino nitrogens in the guanidino group in this paragraph may be optionally substituted with C1-3alkyl; and wherein each alkyl and phenyl in this paragraph is optionally partially or fully halogenated;
or R5 is a 7-azabicyclo[2.2.1]heptane ring system, optionally having one or two double bonds in the ring system, wherein said ring system may be optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR8R9, or O(CH2)2-4NR8R9;
In their broadest generic aspect, intermediate compounds of the formula (XVIII) are represented by the following formula:
wherein:
Ar1 is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more R1, R2 and R3;
R is H, C1-3alkyl or cyclopropyl;
R1 and R2 are the same or different and are selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-10 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR8R9, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from the group consisting of oxo, OH, NR8R9, C1-6 branched or unbranched alkyl, C3-7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
R3 is selected from the group consisting of H, halogen, OH, (CH2)nNR8R9, (CH2)nCO2R10, C1-3alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated and C1-3 alkylthio;
R4 is selected from H, C1-6 alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with phenyl, OH or C1-3alkoxy, C3-10-cycloalkyl, or C5-8cycloalkenyl;
or R4 is selected from (CH2)mNR8R9, (CH2)mNR8COR10, (CH2)nCO2R10, (CH2)nCONR8R9, phenyl, heteroaryl or heterocycle, each phenyl , heteroaryl or heterocycle being optionally substituted with C1-3alkyl, C1-3alkoxy, (CH2)mNR8R9, OH, SO3H or halogen;
R8 and R9 are the same or different and are each independently selected from H, OH, CO2R10, C1-10 acyl branched or unbranched, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-6alkenyl, C3-8cycloalkyl, aryl, arylC1-3alkyl, aroyl, heteroaryl or heterocycle; wherein said alkyl, cycloalkyl, aryl, arylC1-3alkyl, aroyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl or heteroaryl;
or R8 and R9 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, NCOR10, NCO2R10, NR11 or NC(xe2x95x90NR11)NR11R12; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR11R12;
R10 is selected from H, C1-6alkyl, C3-8cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3alkoxy, C1-3alkanoyloxy or NR11R12, or R10 is phenyl optionally substituted with one to three C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR8R9, (CH2)nCONR8R9 or O(CH2)2-4NR8R9;
R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R11 and R12 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;
wherein one or more of the primary amine or secondary amine nitrogen atoms in any of the R4, R5, R6 and R7 substituent groups may optionally be protected by a protecting group.
One embodiment of the compounds of formula (XVIII) are those wherein:
Ar1 is
a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl;
b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, and cycloheptenyl;
c) an aromatic carbocycle selected from phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl,
d) a heteroaryl selected from pyridyl, 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 Ar1 are optionally substituted by one or more R1, R2 and R3;
R1 and R2 are as defined in claim 1, and R3 is hydrogen, halogen, methyl, methoxy, hydroxymethyl or OH; and
R4 is H, C1-3alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with OH; or R4 is (CH2)2-3NR8R9, (CH2)nCO2R10or (CH2)nCONR8R9;
R8 and R9 are the same or different and are each independently selected from H, OH, C1-3alkyl branched or unbranched, CO2R10, C3-8cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl or heterocycle; wherein said alkyl, cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl or heteroaryl; or R8 and R9 together form a 4-6 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by NCO2R10 or NR11; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR11R12;
R10 is H or C1-6alkyl optionally substituted with phenyl, OH, C1-3alkoxy or NR11R12;
R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2; and
n is 0-3.
Yet another embodiment of the compounds of formula (XVIII) are those described immediately above, wherein:
Ar1 is phenyl or pyridyl, each optionally substituted by one or more R1, R2 and R3;
R is H or C1-3alkyl;
R1 and R2 are the same or different and selected from: halogen, C1-3 alkyl, wherein the C1-3 alkyl is optionally partially or fully halogenated, NO2 or NR8R9;
R3 is H, halogen, methyl or methoxy;
R4 is H, C1-3alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with OH; or R4 is (CH2)2-3NR8R9 or CO2R10;
R8 and R9 are the same or different and are each independently selected from H, C1-3alkyl branched or unbranched, CO2R10, phenyl, or benzoyl; wherein said alkyl, phenyl or benzoyl are optionally substituted with OH or C1-3alkoxy;
or R8 and R9 together form a xe2x80x94(CH2)2xe2x80x94N(CO2R10)xe2x80x94(CH2)2xe2x80x94 group or a xe2x80x94(CH2)2xe2x80x94N(R11)xe2x80x94(CH2)2xe2x80x94 group; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, or OH;
R10 is H or C1-3alkyl optionally substituted with phenyl, OH, C1-3alkoxy or NR11R12;
R11 and R12 are each independently selected from H and C1-3 alkyl optionally substituted with C1-3alkoxy or OH;
or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2.
In their broadest generic aspect, intermediate compounds of formula (XIX) are represented by the following formula:
wherein: Ar1 is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more R1, R2 and R3;
R is H, C1-3alkyl or cyclopropyl
R1 and R2 are the same or different and are selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-10 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR8R9, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from the group consisting of oxo, OH, NR8R9, C1-6branched or unbranched alkyl, C3-7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
R3 is selected from the group consisting of H, halogen, OH, (CH2)nNR8R9, (CH2)nCO2R10, C1-3alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated and C1-3 alkylthio;
R4 is selected from H, C1-6 alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with phenyl, OH or C1-3alkoxy, C3-10-cycloalkyl, or C5-8cycloalkenyl;
or R4 is selected from (CH2)mNR8R9, (CH2)mNR8COR10, (CH2)nCO2R0, (CH2)nCONR8R9 phenyl, heteroaryl or heterocycle, each phenyl, heteroaryl or heterocycle being optionally substituted with C1-3alkyl, C1-3alkoxy, (CH2)mNR8R9, OH, SO3H or halogen;
R8 and R9 are the same or different and are each independently selected from H, OH, CO2R10, C1-10 acyl branched or unbranched, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-6alkenyl, C3-8cycloalkyl, aryl, arylC1-3alkyl, aroyl, heteroaryl or heterocycle; wherein said alkyl, cycloalkyl, aryl, arylC1-3alkyl, aroyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl or heteroaryl;
or R8 and R9 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, NCOR10, NCO2R10, NR11 or NC(xe2x95x90NR11)NR11R12; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR11R12;
R10 is selected from H, C1-6alkyl, C3-8cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3alkoxy, C1-3alkanoyloxy or NR11R12, or R10 is phenyl optionally substituted with one to three C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR8R9, (CH2)nCON8R9 or O(CH2)2-4NR8R9;
R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R11 and R12 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;
wherein one or more of the primary amine or secondary amine nitrogen atoms in any of the R4, R5, R6 and R7 substituent groups may optionally be protected by a protecting group.
One embodiment of the compounds of formula (XIX) above is wherein:
Ar1 is
a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl;
b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, and cycloheptenyl;
c) an aromatic carbocycle selected from phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl,
d) a heteroaryl selected from pyridyl, 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 Ar1 are optionally substituted by one or more R1, R2 and R3;
R1 and R2 are as defined in claim 1, and R3 is hydrogen, halogen, methyl, methoxy, hydroxymethyl or OH; and
R4 is H, C1-3alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with OH; or R4 is (CH2)2-3NR8R9, (CH2)nCO2R10 or (CH2)nCONR8R9;
R8 and R9 are the same or different and are each independently selected from H, OH, C1-3alkyl branched or unbranched, CO2R10, C3-8cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl or heterocycle; wherein said alkyl, cycloalkyl, phenyl, benzyl, benzoyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl or heteroaryl;
or R8 and R9 together form a 4-6 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by NCO2R10 or NR11; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR11R12;
R10 is H or C1-6alkyl optionally substituted with phenyl, OH, C1-3alkoxy or NR11R12;
R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2; and
n is 0-3.
Yet another embodiment of the compounds of formula (XIX) are those described immediately above, wherein:
Ar1 is phenyl or pyridyl, each optionally substituted by one or more R1, R2 and R3;
R is H or C1-3alkyl;
R1 and R2 are the same or different and selected from: halogen, C1-3 alkyl, wherein the C1-3 alkyl is optionally partially or fully halogenated, NO2 or NR8R9;
R3 is H, halogen, methyl or methoxy;
R4 is H, C1-3alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with OH; or R4 is (CH2)2-3NR8R9 or CO2R10;
R8 and R9 are the same or different and are each independently selected from H, C1-3alkyl branched or unbranched, CO2R10, phenyl, or benzoyl; wherein said alkyl, phenyl or benzoyl are optionally substituted with OH or C1-3alkoxy;
or R8 and R9 together form a xe2x80x94(CH2)2xe2x80x94N(CO2R10)xe2x80x94(CH2)2xe2x80x94 group or a xe2x80x94(CH2)2xe2x80x94N(R11)xe2x80x94(CH2)2xe2x80x94 group; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, or OH;
R10 is H or C1-3alkyl optionally substituted with phenyl, OH, C1-3alkoxy or NR11R12;
R11 and R12 are each independently selected from H and C1-3 alkyl optionally substituted with C1-3alkoxy or OH;
or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2.
In a further embodiment of the invention, there are provided the following compounds of the formula (I):
2-(2,6-Dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-7-furan-2-yl-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-phenyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-(3-nitrophenyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
7-(3-Aminophenyl)-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
1- {3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-phenyl}-3-ethylurea;
2-(2,6-Dichlorophenylamino)-1-methyl-7-vinyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-thiophen-2-yl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-[2-(3-nitrophenyl)-thiazol-4-yl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-7-imidazol-2-yl-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-phenyloxazol-5-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazoline-7-carboxamide;
2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-methylpropen-1-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-pyridin-2-yl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-pyridin-3-yl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-1H-imidazo[4,5-f]quinazoline-7,9-6H,8H-dione;
4,5-f]quinazoline-9-one;
7-Cyclopent-1-enyl-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
7-[2-(3-Aminophenyl)-thiazol-4-yl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
Ethyl 2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazoline-7-carboxylate;
7-Benzofuran-2yl-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-(1-methylprop-1-enyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-methyloxazol-5-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-7-(1H-indole-3-carbonyl)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-(3-piperazin-1-yl-cyclopent-1-enyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
7-Cyclohex-1-enyl-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-[5-(2-nitrophenyl)-furan-2-yl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-7-furan-3-yl-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
7-(5-Bromofuran-2-yl)-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-(3-methylfuran-2-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
7-Cyclopropyl-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-[3-(4-methylpiperazine-1-sulfonyl)-phenyl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
4-{3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-cyclopent-2-enyl}-piperazine-1-carboxylic acid tert-butyl ester;
2-(2,6-Dichlorophenylamino)-7-(3-hydroxycyclopent-1-enyl)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-[3-(piperazine-1-sulfonyl)-phenyl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-cyclopent-3-enecarbonitrile;
7-Amino-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
3-{2-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-propenyl}-benzonitrile;
3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-cyclopent-3-enecarboxamide;
2-{4-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H -imidazo[4,5-f]quinazolin-7-yl]-thiazol-2-yl}-pyrrolidine-1-carboxylic acid benzyl ester;
2-(2,6-Dichlorophenylamino)-1-methyl-7-[1-methyl-2-(3-nitrophenyl)-vinyl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
3-{4-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H -imidazo[4,5-f]quinazolin-7-yl]-thiazol-2-ylmethyl}-piperidine-1-carboxylic acid benzyl ester;
7-[2-(2-Aminocyclohexyl)-thiazol-4-yl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-piperidin-3-ylmethyl-thiazol-4-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-methylthiazol-4-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-(3-oxocyclopent-1-enyl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester;
7-[2-(3-Aminophenyl)-1-methylvinyl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
Acetic acid 2-(4-{3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-benzenesulfonyl}-piperazin-1-yl)-2-oxoethyl ester;
2-(2,6-Dichlorophenylamino)-7-(2,5-dihydro-1H-pyrrol-3-yl)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
7-[2-(3-Aminomethylphenyl)-1-methylvinyl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
4-{3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-benzenesulfonyl}-piperazine-1-carboxamidine;
2-(2,6-Dichlorophenylamino)-7-{3-[4-(2-hydroxyacetyl)-piperazine-1-sulfonyl]-phenyl}1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
3-{2-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-propenyl}-benzamidine;
7-(7-Azabicyclo[2.2.1]hepta-2,5-dien-2-yl)-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
5-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-1,8,-dihydro-9H-imidazo[4,5-f]quinazolin-7-yl]-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester;
2-(2,6-Dichlorophenylamino)-7-(1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrol-5-yl)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-(2-pyrrolidin-2yl-thiazol-4-yl)-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one;
7-[2-(3,5-Diaminophenyl)-1-methylvinyl]-2-(2,6-dichlorophenylamino)-1-methyl-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one; and
2-(2,6-Dichlorophenylamino)-1-methyl-7-[4-(piperazine-1-sulfonyl)-phenyl]-1,8-dihydro-9H-imidazo[4,5-f]quinazoline-9-one; 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 of the compounds of the invention can exist in more than one tautomeric form. The invention includes all such tautomers.
The compounds of the invention are only those which are contemplated to be xe2x80x98chemically stablexe2x80x99 as will be appreciated by those skilled in the art. For example, a compound which would have a xe2x80x98dangling valencyxe2x80x99, or a xe2x80x98carbanionxe2x80x99 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, xe2x80x9cC1-6alkoxyxe2x80x9d is a C1-6alkyl 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 xe2x80x9chalogenxe2x80x9d as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine.
The term xe2x80x9cheteroarylxe2x80x9d 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 of the cycle, which results in the creation of a stable structure. Example xe2x80x9cheteroarylxe2x80x9d radicals include, pyridyl, 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 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 xe2x80x9cheterocyclexe2x80x9d refers to a stable 5-8 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 to the main structure by any atom of the cycle, which results in the creation of a stable structure. Example xe2x80x9cheterocyclexe2x80x9d radicals include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, 1,2,5,6-tetrahydropyridinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl, indolinyl, and 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrolyl.
As used herein and throughout this specification, the terms xe2x80x9cnitrogenxe2x80x9d and xe2x80x9csulfurxe2x80x9d and their respective elements symbols include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
The term xe2x80x9carylxe2x80x9d shall be understood to mean a 6-10 membered aromatic carbocycle, xe2x80x9carylxe2x80x9d includes, for example, phenyl and naphthyl; other terms comprising xe2x80x9carylxe2x80x9d will have the same definition for the aryl component, examples of these moieties include: arylalkyl, aryloxy or arylthio.
The term xe2x80x9ccarbocyclexe2x80x9d shall be understood to mean a 3-10 membered aromatic or nonaromatic cyclic carbon chain. Examples of nonaromatic carbocycles include cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl; cycloalkylidene groups such as cyclopentylidene, cyclohexylidene; and cycloalkenyl groups such as cyclopentenyl, cyclohexenyl and cycloheptenyl. Examples of aromatic carbocycles include the xe2x80x9carylxe2x80x9d compounds as described hereinabove.
The xe2x80x9cC6-12 bridged- or spiro-bicyclic ring system, optionally having one or two double bonds in the ring system, and wherein up to 3 carbon atoms in the ring system may be replaced by heteroatoms selected from N, O and Sxe2x80x9d in the R5 definition shall be understood to mean any ring system containing 6 to 12 carbon atoms and having at least one bridged-type or spiro-type fusion within the ring system, wherein up to 3 of the aforementioned carbon atoms may optionally be replaced by a heteroatom independently selected from N, O and S. An example is a C6-10-, preferably, C6-7- bridged-bicyclic ring system, optionally having one or two double bonds in the system, wherein up to 2, preferably up to 1, carbon atoms in the ring system are replaced by a nitrogen atom. An example of such a ring system is 7-azabicyclo[2.2.1]hept-2,5-diene. Other examples within the broad definition include norbornenyl, tropanyl, 1-azabicyclo[2.2.2]oct-2-enyl, 7-azabicyclo[3.2.1]oct-6-enyl, spiro[4.5]dec-1-enyl, and spiro[4.4]non-1-enyl.
The term xe2x80x9cacylxe2x80x9d shall be understood to mean an Rxe2x80x94(Cxe2x95x90O)xe2x80x94 moiety wherein R is an alkyl. Examples of R can be a C1-10alkyl, saturated or unsaturated, branched or unbranched, or R can be xe2x80x9carylxe2x80x9d as defined hereinabove. An example when R is an aryl is the benzoyl group or C6H5xe2x80x94CO. xe2x80x9cAcyloxyxe2x80x9d shall be understood to mean an Rxe2x80x94CO2xe2x80x94 group wherein R is as defined in this paragraph.
As indicated above, one or more of the primary amine or secondary amine nitrogen atoms in any of the R4, R5, R6 and R7 substituent groups may optionally be protected by a protecting group. Suitable protecting groups for this purpose, for example, are those disclosed in T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Wiley, New York, 1990. Examples of suitable protecting groups for this purpose include benzyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, acetyl and trifluoroacetyl. The invention includes pharmaceutically acceptable derivatives of compounds of the invention. A xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d 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 of the 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 them selves 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 Nxe2x80x94(C1-C4 alkyl)4+ salts.
In addition, the compounds of this invention include prodrugs of compounds of the invention. Prodrugs include t hose 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 of the invention may be prepared by the methods described below. In each of the schemes below, the groups R4, R5, R6, R7, R9 and Ar1 are as defined above for general formula I except as noted. 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 monitored by thin layer chromatography (TLC) 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.
Compounds of formula (I) in which Het is the dione shown in formula (Ia) (Scheme 1) may be prepared as illustrated in Scheme 1 and described below (Method A).
6-Chloroanthranilic acid (II) is reacted with sodium cyanate in the presence of a suitable acid, such as acetic acid, followed by a suitable base such as sodium hydroxide. Following an acidic work-up, the quinazolinedione III is isolated. In cases where R4 is not H, one may react II (R4=H) with an appropriate aldehyde (RCHO) in the presence of a suitable reducing agent, such as sodium borohydride to provide IIa (R4=RCH2).
Intermediate III is then subjected to nitration conditions, for example treatment with nitric acid in the presence of sulfuric acid to provide IV. Intermediate IV is then treated with excess amine RNH2 (R=H, C1-3 alkyl or cyclopropyl) in a suitable solvent, such as n-butanol, preferably in a sealed vessel with heating at about 50 to 150xc2x0 C., to provide V.
Reduction of V, for example by treatment with hydrogen preferably at 10-60 psi in the presence of a suitable catalyst such as 10% Pd/c, provides VI. Treatment of VI with the desired isothiocyanate (Ar1NCS), in a suitable solvent such as DMF provides thiourea (VII). Cyclization of VII may be accomplished by treatment with a suitable coupling reagent, such as dicyclohexylcarbodiimide or mercury oxide in a suitable solvent such as THF or DMF to provide the desired compound Ia.
Compounds of formula (I) in which Het is substituted with R5 as shown in formula (Ib) (Scheme 2) may be prepared as illustrated in Scheme 2 and described below (Method B).
In cases where R5 is H, one may treat 6-chloroanthranilic acid (II) with triazine in a suitable solvent, such as EtOH, in the presence of a suitable base such as piperidine, preferably while heating at about the reflux temperature of the solvent to provide the quinazolinone VIII (R5=H). to obtain compounds where R5 is not H, one may react the amide IX with an acid chloride R5 COCl, in a suitable solvent, such as THF, in the presence of a suitable base, such as triethylamine to provide an intermediate amide which is cyclized to VIII by treatment with a suitable base, for example sodium methoxide in methanol, preferably at reflux temperature. Intermediate VIII may then be converted to Ib by the same general procedure described in Method A for a converting III to Ia.
The preparation of benzimidazole intermediates, which may be used in alternate procedures to prepare compounds of formula (I) is illustrated in Scheme 3 and described below (Method C):
2,6-Dichloro-3-nitrobenzonitrile (XIII) is treated with the desired amine RNH2 (R=H, C1-3 alkyl or cyclopropyl) in a suitable solvent such as THF or EtOAc to provide XIV. This intermediate is then treated with R4NH2 in a suitable solvent such as EtOH, preferably in a sealed vessel while heating at about 50-110xc2x0 C. to provide XV. Reduction to XVI, formation of thiourea XVII and cyclization to benzimidazole XVIII may be carried out as described for the conversion of V to Ia in Method A. Hydrolysis of the nitrile, for example, by treatment with concentrated H2SO4 at about 100xc2x0 C., provides XIX.
Method D (Scheme 4) illustrates how one may prepare compounds of formula (Ib) from intermediate XVIII (R4=H).
Treatment of XVIII (R4=H) with an acid halide R5COX (where X is a halogen) or acid anhydride (R5CO)2O or with an acid R5CO2H and a coupling reagent such as dicyclohexylcarbodiimide or 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, in a suitable solvent, such as THF or DMF, in the presence of a suitable base such as triethylamine or 4-(dimethylamino)pyridine provides amide XX.
Hydrolysis of the nitrile, followed by cyclization to Ib may be achieved, for example, by treatment of XX with a suitable base, such as aqueous sodium hydroxide, and an oxidant such as hydrogen peroxide or sodium perborate in a suitable solvent such as dioxane.
Intermediate XIX (R4=H) may be used to prepare compounds of formula (Ib) as outlined in Scheme 5 (Method E):
Formation of XXI may be accomplished as described above for conversion of XVIII to XX. Intermediate XXI may then by cyclized by treatment with a suitable base such as sodium methoxide or potassium t-butoxide in a suitable solvent such as MeOH or THF, respectively, at about reflux temperature to provide Ib.
Intermediate XIX may also be used to prepare compounds of formula (Ia) as illustrated in Scheme 6 (Method F).
Treatment of XIX with carbonyldiimidazole (CDI) or a phosgene equivalent in a suitable solvent such as THF provides Ia.
Compounds of formula (I) in which Het is partially saturated may be prepared from intermediate XIX, as illustrated in Scheme 7 (Method G).
Treatment of XIX with a ketone (R6C(O)R7, where R6 and R7 are not H) in the presence of a catalytic amount of an acid such as p-TsOH, in a suitable solvent such as THF provides Ic (R6 and R7 are not H). When R4=H, the use of an aldehyde (R5CHO) instead of a ketone provides Id. This compound may be oxidized to Ib by treatment with a suitable oxidizing agent such as MnO2 or dichlorodicyanobenzoquinone.
Compounds of formula (Ib) where R5=NHR9, represented by formula (Ibxe2x80x2) below, may be prepared from intermediate XIX (where R4=H) by Method H as illustrated in Scheme 8.
Reaction of XIX with an isothiocyanate in a suitable solvent such as DMF or THF provides thiourea XXII. Cyclization or XXII may be accomplished by the addition of a suitable condensing agent such as mercury oxide to produce the desired product of formula (Ibxe2x80x2).
Scheme 9 (Method I) illustrates a procedure by which compounds of formula (I) with X=S may be prepared. Intermediate XXV may be prepared from XXIII by reaction with an acid chloride (R5C(O)Cl) to form an intermediate amide, followed by cyclization by treating with a suitable base such as sodium methoxide. Alternatively, if R5=H one may react XXIV with triazine in a suitable solvent such as EtOH, in the presence of a suitable base such as piperidine to produce XXV (R5=H). Reduction of the nitro group to give XXVI and formation of thiourea XXVII may be accomplished by procedures described in the above Methods. Cyclization of XXVII to give I (X=S) may be achieved by treatment with bromine in a suitable solvent such as CHCl3.
Several of these transformations are also exemplified below.
The compounds of the 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 of the 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 compound of the 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. In view of their inhibitory effect on src kinase, the compounds of the invention are also useful in treating conditions involving cerebral ischemia, for example, in reducing brain damage following a stroke.
By inhibiting p60src, compounds of the invention may also be useful in treating osteoporosis, Paget""s disease, bone inflammation and joint inflammation. By inhibiting PDGFR kinase, compounds of the invention may also be useful in treating fibrotic diseases, restenosis and atherosclerosis. By inhibiting lyn kinase, the compounds of the invention may also be useful in enhancing or potentiating the effectiveness of radiation therapy.
For therapeutic use, the compounds of the 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 of the invention for each of the aforementioned routes of administration will be apparent to the skilled artisan. For example, one embodiment of the invention provides for pharmaceutical compositions including a therapeutically effective amount of the 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 of the 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 of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. Compounds of the 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 of the 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 of the patient""s disorder or disposition thereto, and the judgment of the treating physician.

Heterocyclic compounds useful as inhibitors of tyrosine kinases

Abstract: wherein Ar1, X, Y, P, Q and Het are defined herein, 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, as well as conditions resulting from cerebral ischemia, such as stroke. Also disclosed are pharmaceutical compositions comprising these compounds, processes for preparing these compounds and novel intermediate compounds useful in these processes.

Boehringer Ingelheim Pharmaceuticals, Inc.