| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | August 26, 2003 |
| PATENT TITLE |
Pyrrolo[2,3-d]pyrimidine compounds |
| PATENT ABSTRACT |
A compound of the formula ##STR1## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, which are inhibitors of the enzyme protein tyrosine kinases such as Janus Kinase 3 and as such are useful therapy as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia and other autoimmune diseases. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | September 19, 2001 |
| PATENT REFERENCES CITED |
J. J. O'Shea, et al., Phosphorylation and activation of the Jak-3 Janus Kinase in response to Interleukin-2, Nature, 370, 151 (1994. S. M. Russell, et al., Interaction of IL-2R.beta. and .gamma.c Chains with Jak1 and Jak3: Implications for XSCID and XCID, Science, 266, 10 (1994). J. N. Ihle, The Janus Protein Tyrosine Kinase Family and Its Role in Cytokine Signaling, Adv. Immunology, 60, 1, (1995). J. N. Ihle, The Janus Protein Tyrosine Kinases in hematopoietic cytokine signaling, Semin. Immunology, 7, 247, (1995). T. Musso, et al., Regulation of JAK3 Expression in Human Monocytes: Phosphorylation in Response to Interleukings 2, 4, and 7 _Exp. Med., 181, 1425 (1995). R. A. Kirken, et al., Activation of JAK3, but not JAK1, is critical for IL-2-induced proliferation and STAT5 Recruitment by a COOH-terminal region of the IL-2 receptor .beta.-chain, Cytokine, 7 689, (1995). M. G. Malabarba, et al., Activation of JAK3, but not JAK1, is Critical to Interleukin-4 (IL4) Stimulated Proliferation and Requires a Membrane-proximal Region of Il4 Receptor .alpha.*, J. Biol. Chem., 270, 9630, (1995). J. H. Hanke, B. A. Pollok, and P. S. Changelian, Role of tyrosine kinases in lymphocyte activation: Targets for drug intervention, Inflamm. Res., 44, 357, (1995). E.E. Eynon, et al., Disruption of Cytokine Signaling in Lymphoid Development: Unique Contributions of the Common Cytokine Gamma Chain and the JAK3 Kinase, J. Interferon Res., 16, 677 (1996). S. A. Oakes, et al., Signaling via IL-2 and IL-4 in JAK#-Deficient Severe Combined Immunodeficiency Lyumphocytes: JAK3-Dependent and Independent Pathways, Immunity, 5, 605 (1996). L. D. Norangelo, et al, Severe Combined Immune Deficiency due to Defects of the JAK3 Tyrosine Kinase, Prog. Immunodeficienc 6, 61, (1996). D. C. Thomis, et al., Peripheral Expression of JAK3 is Required to Maintain T Lymphocyte Function, J. Exp. Med., 185, 197, (199. B. H. Nelson, et al., Requirement for an initial signal from the membrane-proximal region of the interleukin 2 receptor .gamma.c chain for Janus kinase activation leading to T cell proliferation, Proc. Natl. Acad. Sci. USA, 94, 1878, (1997). A. M. Baird, et al., T Cell development and activation in Jak3-deficient mice, J. Leukocyte Biol., 63, 669, (1998). K. D. Liu, et al., JAK/STAT signaling by cytokine receptors, Curr. Opin. Immunol. W. J. Leonard and J. J. O'Shea, JAKS and STATS: Biological Implications, Annu. Rev. Immunol., 16, 293, (1998). F. Candotti, et al., Severe combined immune deficiencies due to defects in the common .gamma. chain-JAK3 signaling pathway, Springe Semin. Immuopathol., 19, 401, (1998). R. Malaviya, et al., Targeting Janus Kinase 3 in Mast Cells Prevents Immediate Hypersensitivity Reactions and Anaphylaxis, J. B Chem., 274, 27028 (1999). D. C. Thomis, et al., The Jak Family Tyrosine Kinase Jak3 is Required for IL-2 Synthesis by Naive/Resting CD4+ T Cells, J. Immunol., 163, 5411 (1999). E. Chen, et al., Advances in Cytokine Signaling: The Role of Jaks and STATs, Transplantation Proc., 31, 1482 (1999). R. Moriggi, et al., Stat5 Activation is Uniquely Associated with Cytokine Signaling in Peripheral T Cells, Immunity, 11, 225 (1995). L. H. Wang, et al., JAK3, STAT, and MAPK Signaling Pathways as Novel Molecular Targets for the Tyrphostin AG-490 Regulatio IL-2-Mediated T Cell Response, J. Immunol., 162, 3897, (1999). E. A. Sudbeck, et al., Structure-based Design of Specific Inhibitors of Janus Kinase 3 as Apoptosis-inducing Antileukemic Agents, Clin. Cancer Res., 5, 1569, (1999). F. M. Uckun, et al., In Vivo Toxicity and Pharmacokinetic features of the Janus Kinase 3 Inhibitor WHI-P131 [40(4'-Hydroxyphen Amino-6,7-Dimethosyquinazoline], Clin. Cancer Research, 5, 2954, (1999). E. A. Sudbeck and F. M. Uckun, Recent Advances in JAK3 kinase inhibitors, IDrugs, 2, 1026, (1999). R. Malaviya, et al., Genetic and Biochemical Evidence for a Critical Role of Janus Kinase (JAK)-3 in Mast Cell-Mediated Type I Hypersensitivity Reactions, Biochem. Biophys., Res. Commun., 257, 807, (1999). V. N. Trieu, et al., A Specific Inhibitor of Janus Kinase-3 Increases Survival in a Transgenic Mouse Model of Amyotropic Lateral Sclerosis, Biochem. Biophys. Res. Commun., 267, 22, (2000). X. C. Li, et al., Blocking the Common .gamma.-Chain of Cytokine Receptors Induces T Cell Apoptosis and Long-Term Islet Allog Survival, J. Immunol., 164, 1193 (2000)/. R. Malaviya, et al., Treatment of allergic asthma by targeting Janus kinase 3-dependent leukotriene synthesis in mast cells wit (3'-5'-Dibromo-4'hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97), J. Pharmacol. Exp. Ther., 295, 912 (2000). S. Ghosh, et al., 4-[93-Bromo-4-hydroxypheynl)amino]6,7-dimethoxyquinazolin-1-ium chloride methanol solvate and 4 hydroxyphenyl)amino0-6,7-dimethoxy-1-quinazolinium chloride. Acta Crystallogr., C: Cryst. Struct. Commun., C57, 76 (2001). E. A. Skudbeck, et al. An inhibitor of janus kinase 3: 4-(4-hydroxyphenylamino)-6,7-dimethoxyquinazolin-1-ium chloride, A Crystallogr., SectC: Cryst. Struct. Commun., C56, 1282 (2000). Traxler, P. M., et al., Protein tyrosine kinase inhibitors in cancer treatment, Exp. Opin. Ther. Patents, (1997), 7 (6): 571-588. Traxler, P. M., et al., 4-(phenylamino)pyrrolopyrimidine: Potent and Selective, ATP Site Directed Inhibitors of the EGF-Recpetor Protein Tyrosine Kinase, J. Med. Chem., (1996), 39, 2285-2292. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
-------------------------------------------------------------------------------- What is claimed is: 1. A compound selected from the group consisting of: 2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclohexyl}- propan-2-ol; 2-{3-[(2-Hydroxy-ethyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-4-methyl -cyclohexyl}-propan-2-ol; 2-[(5-Isopropenyl-2-methyl-cyclohexyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-am ino]-ethanol; (5-Isopropenyl-2-methyl-cyclohexyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(2,2, 2-trifluoro -ethyl)-amine; 2-{4-Methyl-3-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(2,2,2-trifluoro-ethyl)-am ino]-cyclohexyl}-propan-2-ol; 2-{4-Methyl-5-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclohex-3-e nyl}-propan-2-ol; (5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(5-isopropenyl-2-methyl-cyclohex yl)-methyl-amine; 2-{3-[(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-cyc lohexyl}-propan-2-ol; (2-Ethyl-4-isopropenyl-cyclopentyl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl )-amine; 2-{3-Ethyl-4-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclopentyl}- propan-2-ol; 2-{3-Ethyl-4-[(2-hydroxy-ethyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cy clopentyl}-propan-2-ol; 2-[(2-Ethyl-4-isopropenyl-cyclopentyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-am ino]-ethanol; (5-(S)-Isopropenyl-2-methyl-cyclohexyl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-amine; 2-[Cycloheptyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-ethanol; 2-[Cyclooctyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-ethanol; and Bicyclo[2.2.1]hept-2-yl-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION The present invention relates to pyrrolo[2,3-d]pyrimidine compounds which are inhibitors of protein tyrosine kinases, such as the enzyme Janus Kinase 3 (hereinafter also referred to as JAK3) and as such are useful therapy as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia and other indications where immunosuppression would be desirable. This invention also relates to a method of using such compounds in the treatment of the above indications in mammals, especially humans, and the pharmaceutical compositions useful therefor. JAK3 is a member of the Janus family of protein tyrosine kinases. Although the other members of this family are expressed by essentially all tissues, JAK3 expression is limited to hematopoetic cells. This is consistent with its essential role in signaling through the receptors for IL-2, IL4, IL-7, IL-9 and IL-15 by non-covalent association of JAK3 with the gamma chain common to these multichain receptors. XSCID patient populations have been identified with severely reduced levels of JAK3 protein or with genetic defects to the common gamma chain, suggesting that immunosuppression should result from blocking signaling through the JAK3 pathway. Animal studies have suggested that JAK3 not only plays a critical role in B and T lymphocyte maturation, but that JAK3 is constitutively required to maintain T cell function Modulation of immune activity through this novel mechanism can prove useful in the treatment of T cell proliferative disorders such as transplant rejection and autoimmune diseases. SUMMARY OF THE INVENTION The present invention relates to a compound of the formula ##STR2## or the pharmaceutically acceptable salt thereof; wherein R.sup.1 is a group of the formula ##STR3## wherein y is 0, 1 or 2; R.sup.4 is selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.6)acyloxy, (C.sub.1 -C.sub.6)alkylamino, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino, cyano, nitro, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl or (C.sub.1 -C.sub.6)acylamino; or R.sup.4 is (C.sub.3 -C.sub.10)cycloalkyl wherein the cycloalkyl group is optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C.sub.1 -C.sub.6)acyloxy, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)alkylamino, ((C.sub.1 -C.sub.6)alkyl.sub.2 amino, cyano, cyano(C.sub.1 -C.sub.6)alkyl, trifluoromethyl(C.sub.1 -C.sub.6)alkyl, nitro, nitro(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)acylamino; R.sup.5 is selected from the group consisting of trifluoromethyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.3)alkyl(difluoromethylene)(C.sub.1 -C.sub.3)alkyl,(C.sub.3 -C.sub.10)cycloalkyl wherein the cycloalkyl group is optionally substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, halo, (C.sub.1 -C.sub.6)acyl, (C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy-CO--NH, (C.sub.1 -C.sub.6)alkylamino-CO--, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6) alkynyl, C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, C.sub.1 -C.sub.6)acyloxy(C.sub.1 -C.sub.6)alkyl, nitro, cyano(C.sub.1 -C.sub.6)alkyl, halo(C.sub.1 -C.sub.6)alkyl, nitro(C.sub.1 -C.sub.6)alkyl, trifluoromethyl, trifluoromethyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)acylamino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)acylamino, amino(C.sub.1 -C.sub.6)acyl, amino(C.sub.1 -C.sub.6)acyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)acyl, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)acyl, R.sup.15 R.sup.16 N--CO--O--, R.sup.15 R.sup.16 N--CO--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-S(O).sub.m, R.sup.15 R.sup.16 NS(O).sub.m, R.sup.15 R.sup.16 NS(O).sub.m (C.sub.1 -C.sub.6)alkyl, R.sup.15 S(O).sub.m R.sup.16 N, R.sup.15 S(O).sub.m R.sup.16 N(C.sub.1 -C.sub.6)alkyl wherein m is 0, 1 or 2 and R.sup.15 and R.sup.16 are each independently selected from hydrogen or (C.sub.1 -C.sub.6)alkyl; or R.sup.5 is (C.sub.3 -C.sub.10)cycloalkyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acyloxy(C.sub.1 C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, piperazinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acylamino(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, C.sub.1 -C.sub.6)alkylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfonyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfonyl(C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl).sub.2 amino, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by one to five cyano, nitro, halo, deuterium, hydroxy, carboxy, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)acylamino, amino(C.sub.1 -C.sub.6)acyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)acyl or ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)acyl; or R.sup.5 is R.sup.13 CO(C.sub.1 -C.sub.6)alkyl or R.sup.13 CO(C.sub.3 -C.sub.10)cycloalkyl wherein R.sup.13 is R.sup.20 O or R.sup.20 R.sup.21 N wherein R.sup.20 and R.sup.21 are each independently selected from the group consisting of hydrogen, deuterium, (C.sup.1 -C.sup.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl or (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl; or R.sup.5 is R.sup.14, R.sup.14 (C.sub.1 -C.sub.6)alkyl or R.sup.14 (C.sub.3 -C.sub.10)cycloalkyl wherein R.sup.14 is (C.sub.2 -C.sub.9)heterocycloalkyl, (C.sub.1 -C.sub.6)acylpiperazino, (C.sub.6 -C.sub.10)arylpiperazino, (C.sub.5 -C.sub.9)heteroarylpiperazino, (C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C.sub.1 -C.sub.6)alkylpiperidinyl, (C.sub.6 -C.sub.10)arylpiperidyl, (C.sub.5 -C.sub.9)heteroarylpiperidyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperidyl or (C.sub.1 -C.sub.6)acylpiperidyl; or R.sup.5 is a group of the formula ##STR4## wherein w is 0, 1 or2; x is 0, 1, 2 or 3; or R.sup.5 is a group of the formula ##STR5## wherein g, h and j are each independently 0 to 3; F, K and P are each independently oxygen, S(O).sub.d wherein d is 0, 1 or 2, NR.sup.6 or CR .sup.7 R.sup.8 ; R.sup.6 is selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, trifluoromethyl, trifluoromethyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl (difluoromethylene), (C.sub.1 -C.sub.3)alkyl(difluoromethylene)(C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)acyl, ((C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)acyl, (C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)acyl, (C.sub.6 -C.sub.10)aryl, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.3 -C.sub.6)cycloalkyl(C.sub.1 -C.sub.5)alkyl, hydroxy(C.sub.2 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acyloxy(C.sub.2 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.2 -C.sub.5)alkyl, piperazinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acylamino(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfonyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfonyl(C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)alkyl, R.sup.13 CO(C.sub.1 -C.sub.6)alkyl wherein R.sup.13 is R.sup.20 O or R.sup.20 R.sup.21 N wherein R.sup.20 and R.sup.21 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl or (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl; or R.sup.14 (C.sub.2 -C.sub.6)alkyl wherein R.sup.14 is (C.sub.1 -C.sub.6)acylpiperazino, (C.sub.6 -C.sub.10)arylpiperazino, (C.sub.5 -C.sub.9)heteroarylpiperazino, (C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.6 -C.sub.10)arylpiperidyl, (C.sub.5 -C.sub.9)heteroarylpiperidyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.1 -C.sub.6)alkoxyacyl, (C.sub.1 -C.sub.6)alkylaminoaryl, ((C.sub.1 -C.sub.6)alkyl.sub.2 aminoacyl or (C.sub.1 -C.sub.6)acylpiperidyl; R.sup.7 and R.sup.8 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, amino, hydroxy, ((C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl)amino, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)acyl(C.sub.1 -C.sub.6)alkylamino, carboxy, (C.sub.1 -C.sub.6)alkoxyacyl, (C.sub.1 -C.sub.6)alkylaminoacyl, ((C.sub.1 -C.sub.6)alkyl).sub.2 aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl (difluoromethylene), (C.sub.1 -C.sub.3)alkyl(difluoromethylene)(C.sub.1 -C.sub.3)alkyl, (C.sub.6 -C.sub.10)aryl, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.3 -C.sub.6)cycloalkyl(C.sub.1 -C.sub.6)alkyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, piperazinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acylamino(C.sub.1 -C.sub.6)alkyl, piperidyl, (C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylthio(C.sub.1 -C.sub.6)alkyl, C.sub.1 -C.sub.6)alkylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfonyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfonyl(C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkyl, C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)alkyl, R.sup.13 CO(C.sub.1 -C.sub.6)alkyl or R.sup.13 CO(C.sub.3 -C.sub.10)cycloalkyl wherein R.sup.13 is R.sup.20 O or R.sup.20 R.sup.21 N wherein R.sup.20 and R.sup.21 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl or (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl; R.sup.14, R.sup.14 (C.sub.1 -C.sub.6)alkyl or R.sup.14 (C.sub.3 -C.sub.10)cycloalkyl wherein R.sup.14 is (C.sub.1 -C.sub.6)acylpiperazino, (C.sub.6 -C.sub.10)arylpiperazino, (C.sub.5 -C.sub.9)heteroarylpiperazino, (C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.6 -C.sub.10)arylpiperidyl, (C.sub.5 -C.sub.9)heteroarylpiperidyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperidyl or C.sub.1 -C.sub.6)acylpiperidyl; or a group of the formula ##STR6## wherein p is 0, 1, 2 or 3; and Z is hydroxy, (C.sub.1 -C.sub.6)alkoxy or NR.sup.1 R.sup.2 wherein R.sup.1 and R.sup.2 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, piperidyl, (C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.6 -C.sub.10)arylpiperidyl, (C.sub.5 -C.sub.9)heteroarylpiperidyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.1 -C.sub.6)acylpiperidyl, (C.sub.6 -C.sub.10)aryl, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.3 -C.sub.6)cycloalkyl(C.sub.1 -C.sub.6)alkyl, R.sup.5 (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.5)alkyl(CHR.sup.5)(C.sub.1 -C.sub.6)alkyl wherein R.sup.5 is hydroxy, (C.sub.1 -C.sub.6)acyloxy, (C.sub.1 -C.sub.6)alkoxy, piperazino, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)alkylthio, (C.sub.6 -C.sub.10)arylthio, (C.sub.1 -C.sub.6)alkylsulfinyl, (C.sub.6 -C.sub.10)arylsulfinyl, (C.sub.1 -C.sub.6)alkylsulfoxyl, (C.sub.6 -C.sub.10)arylsulfoxyl, amino, (C.sub.1 -C.sub.6)alkylamino, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino, (C.sub.1 -C.sub.6)acylpiperazino, (C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R.sup.6 (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.5)alkyl(CHR.sup.6)(C.sub.1 -C.sub.6)alkyl wherein R.sup.6 is piperidyl, (C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.6 -C.sub.10)arylpiperidyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.5 -C.sub.9)heteroarylpiperidyl or (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperidyl; or R.sup.1 is defined as OR.sup.9 or S(O).sub.q R.sup.9 wherein q is 0, 1 or 2; and R.sup.9 is selected from the group consisting of trifluoromethyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.3)alkyl(difluoromethylene)(C.sub.1 -C.sub.3)alkyl, (C.sub.3 -C.sub.10)cycloalkyl wherein the cycloalkyl group is optionally substituted by one to five carboxy, cyano, amino, hydroxy, (C.sub.1 -C.sub.6) alkoxy, halo, (C.sub.1 -C.sub.6)alkyl S(O).sub.m wherein m is 0, 1 or 2; R.sup.15 R.sup.16 NS(O).sub.m wherein m is 0, 1 or 2 and R.sup.15 and R.sup.16 are each independently selected from hydrogen or (C.sub.1 -C.sub.6)alkyl; (C.sub.1 -C.sub.5)acyl, (C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy-CO--NH, C.sub.1 -C.sub.6)alkylamino-CO--, R.sup.15 R.sup.16 N--CO--O--, R.sup.15 R.sup.16 N--CO--(C.sub.1 -C.sub.6)alkyl wherein R.sup.15 and R.sup.16 are as defined above; (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6) alkynyl, (C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acyloxy(C.sub.1 -C.sub.6)alkyl, nitro, cyano(C.sub.1 -C.sub.6)alkyl, nitro(C.sub.1 -C.sub.6)alkyl, trifluoromethyl, trifluoromethyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)acylamino, amino(C.sub.1 -C.sub.6)acyl, C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)acyl or ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)acyl; (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.3 -C.sub.10)cycloalkyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, piperazinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acylamino(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfonyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfonyl(C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino, C.sub.1 -C.sub.6)alkyl wherein the alkyl group is optionally substituted by one to five cyano, nitro, hydroxy, carboxy, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)acylamino, amino(C.sub.1 -C.sub.6)acyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)acyl or ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)acyl; R.sup.13 CO(C.sub.1 -C.sub.6)alkyl or R.sup.13 CO(C.sub.3 -C.sub.10)cycloalkyl wherein R.sup.13 is R.sup.20 O or R.sup.20 R.sup.21 N wherein R.sup.20 and R.sup.21 are each independently selected from the group consisting of hydrogen,(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl or (C.sub.5 -C.sub.9)heteroaryl (C.sub.1 -C.sub.6)alkyl; R.sup.14, R.sup.14 (C.sub.1 -C.sub.6)alkyl or R.sup.14 (C.sub.3 -C.sub.10)cycloalkyl wherein R.sup.14 is (C.sub.2 -C.sub.9)heterocycloalkyl, (C.sub.1 -C.sub.6)acylpiperazino, (C.sub.6 -C.sub.10)arylpiperazino, (C.sub.5 -C.sub.9)heteroarylpiperazino, (C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C.sub.1 -C.sub.6)alkylpiperidinyl, (C.sub.6 -C.sub.10)arylpiperidyl, (C.sub.5 -C.sub.9)heteroarylpiperidyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperidyl or (C.sub.1 -C.sub.6)acylpiperidyl; or R9 is a group of the formula ##STR7## wherein g, h and j are each independently 0 to 6; F, K and P are each independently oxygen, S(O).sub.d wherein d is 0, 1 or 2, NR.sup.6 or CR.sup.7 R.sup.8 wherein R.sup.6, R.sup.7 and R.sup.8 are as defined above; R.sup.2 and R.sup.3 are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, trifluoromethyl, trifluoromethoxy, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy wherein the alkyl or alkoxy groups are optionally substituted by one to three groups selected from halo, hydroxy, carboxy, amino (C.sub.1 -C.sub.6)alkylthio, (C.sub.1 -C.sub.6)alkylamino, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.2 -C.sub.9)heterocycloalkyl, (C.sub.3 -C.sub.9)cycloalkyl or (C.sub.6 -C.sub.10)aryl; or R.sup.2 and R.sup.3 are each independently (C.sub.3 -C.sub.10)cycloalkyl, (C.sub.3 -C.sub.10)cycloalkoxy, (C.sub.1 -C.sub.6)alkylamino, ((C.sub.1 -C.sub.6) alkyl).sub.2 amino, (C.sub.6 -C.sub.10)arylamino, (C.sub.1 -C.sub.6)alkylthio, (C.sub.6 -C.sub.10)arylthio, (C.sub.1 -C.sub.6)alkylsulfinyl, (C.sub.6 -C.sub.10)arylsulfinyl, (C.sub.1 -C.sub.6)alkylsulfonyl, (C.sub.6 -C.sub.10)arylsulfonyl, (C.sub.1 -C.sub.6)acyl, (C.sub.1 -C.sub.6)alkoxy-CO--NH--, (C.sub.1 -C.sub.6) alkyamino-CO--, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.2 -C.sub.9)heterocycloalkyl or (C.sub.6 -C.sub.10)aryl wherein the heteroaryl, heterocycloalkyl and aryl groups are optionally substituted by one to three halo, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-CO--NH--, ((C.sub.1 -C.sub.6)alkoxy-CO--NH--, C.sub.1 -C.sub.6)alkyl-CO--NH--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy-CO--NH--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy-CO--NH--(C.sub.1 -C.sub.6)alkoxy, carboxy, carboxy(C.sub.1 -C.sub.6)alkyl, carboxy(C.sub.1 -C.sub.6)alkoxy, benzyloxycarbonyl(C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkoxycarbonyl(C.sub.1 -C.sub.6)alkoxy, (C.sub.6 -C.sub.10)aryl, amino, amino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxycarbonylamino, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxycarbonylamino, (C.sub.1 -C.sub.6)alkylamino, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)alkyl, hydroxy, (C.sub.1 -C.sub.6)alkoxy, carboxy, carboxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxycarbonyl, (C.sub.1 -C.sub.6)alkoxycarbonyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy-CO--NH--, (C.sub.1 -C.sub.6)alkyl-CO--NH--, cyano, (C.sub.5 -C.sub.9)heterocycloalkyl, amino-CO--NH--, (C.sub.1 -C.sub.6)alkylamino-CO--NH--, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino-CO--NH--, (C.sub.6 -C.sub.10)arylamino-CO--NH--, (C.sub.5 -C.sub.9)heteroarylamino-CO--NH--, (C.sub.1 -C.sub.6)alkylamino-CO--NH--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl).sub.2 amino-CO--NH--(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylamino-CO--NH--(C.sub.1 -C.sub.6)alkyl, (C.sub.5 -C.sub.9)heteroarylamino-CO--NH--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfonyl, (C.sub.1 -C.sub.6)alkylsulfonylamino, (C.sub.1 -C.sub.6)alkylsulfonylamino(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfonyl, (C.sub.6 -C.sub.10)arylsulfonylamino, (C.sub.6 -C.sub.10)arylsulfonylamino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfonylamino, (C.sub.1 -C.sub.6)alkylsulfonylamino(C.sub.1 -C.sub.6)alkyl, (C.sub.5 -C.sub.9)heteroaryl or (C.sub.2 -C.sub.9)heterocycloalkyl; with the proviso that when either R.sup.4 and R.sup.5 is hydrogen, the other of R.sup.4 or R.sup.5 cannot be (C.sub.6 -C.sub.10)aryl or (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl; with the proviso that when R.sup.4 is hydrogen, unsubstituted (C.sub.1 -C.sub.6)alkyl or unsubstituted (C.sub.3 -C.sub.10)cycloalkyl, R.sup.5 cannot be (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl; R.sup.20 and R.sup.21 cannot be (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl; and R.sup.14 cannot be (C.sub.2 -C.sub.9)heterocycloalkyl, morpholino, thiomorphlino, piperidino, pyrrolidino, piperidinyl or (C.sub.1 -C.sub.6)alkylpiperidinyl; with the proviso that the sp.sup.2 and sp carbons of alkenyl or alkynyl cannot be substituted by hydroxy or amino; with the proviso that when R.sup.4 is hydrogen, R.sup.5 cannot be amino (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)alkyl, furanyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl or carboxy(C.sub.1 -C.sub.6)alkyl; with the proviso that both R.sup.4 and R.sup.5 cannot both be hydroxy (C.sub.1 -C.sub.6)alkyl; with the proviso that when R.sup.4 is (C.sub.1 -C.sub.6)alkyl, R.sup.5 cannot be (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl or carboxy(C.sub.1 -C.sub.6)alkyl; and with the proviso that R.sup.1 cannot be carboxy(C.sub.1 -C.sub.6)alkylthio or (C.sub.1 -C.sub.6)alkoxycarbonyl(C.sub.1 -C.sub.6)alkylthio. The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts. The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is defined above. The term "halo", as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. The compounds of this invention may contain double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. Unless otherwise indicated, the alkyl and alkenyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine. (C.sub.3 -C.sub.10)Cycloalkyl when used herein refers to cycloalkyl groups containing zero to two levels of unsaturation such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane, norbornanyl etc. (C.sub.2 -C.sub.9)Heterocycloalkyl when used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, azindinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl. tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl. tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skill in the art will understand that the connection of said (C.sub.2 -C.sub.9)heterocycloalkyl rings is through a carbon or a sp.sup.3 hybridized nitrogen heteroatom. (C.sub.2 -C.sub.9)Heteroaryl when used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7, 8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill in the art will understand that the connection of said (C.sub.2 -C.sub.9)heterocycloalkyl rings is through a carbon atom or a sp.sup.3 hybridized nitrogen heteroatom. (C.sub.6 -C.sub.10)aryl when used herein refers to phenyl or naphthyl. Compounds of formula (I) may be administered in a pharmaceutically acceptable form either alone or in combination with one or more additional agents which modulate a mammalian immune system or with antiinflammatory agents. These agents may include but are not limited to cyclosporin A (e.g. Sandimmune or Neoral.TM., rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g. Cellcept.TM.), azathioprine (e.g. Imuran.TM.), daclizumab (e.g. Zenapax.TM. OKT3 (e.g. Orthoclone.TM.), AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and antiinflammatory steroids (e.g. prednisolone or dexamethasone). These agents may be administered as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice. The compounds of this invention include all conformational isomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., enantiomers and diastereomers), as well as racemic, diastereomeric and other mixtures of such isomers. Preferred compounds of formula I include those wherein R.sup.1 is NR.sup.4 R.sup.5. Other preferred compounds of formula I include those wherein R.sup.4 is hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by hydroxy, amino, trifluoromethyl, (C.sub.1 -C.sub.6)acyloxy, (C.sub.1 -C.sub.6)alkylamino, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino or (C.sub.1 -C.sub.6)acylamino; or R.sup.4 is (C.sub.3 -C.sub.10)cycloalkyl wherein the cycloalkyl group is optionally substituted by hydroxy, trifluoromethyl or (C.sub.1 -C.sub.6)acyloxy. Other preferred compounds of formula I include those wherein R.sup.5 is (C.sub.3 -C.sub.10)cycloalkyl wherein the cycloalkyl group is optionally substituted by one to five deuterium, hydroxy, trifluoromethyl, halo, (C.sub.1 -C.sub.6)alkyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)acyl, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)acyl, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)alkoxy-CO--NH, (C.sub.1 -C.sub.6)alkylamino-CO--, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, halo(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acylamino(C.sub.1 -C.sub.6)alkyl, R.sup.15 S(O).sub.m R.sup.16 N, R.sup.15 S(O).sub.m R.sup.16 N(C.sub.1 -C.sub.6)alkyl wherein m is 0, 1 or 2 and R.sup.15 and R.sup.16 are each independently selected from hydrogen or (C.sub.1 -C.sub.6)alkyl. Other preferred compounds of formula I include those wherein R.sup.2 and R.sup.3 are each independently selected from the group consisting of hydrogen, halo, (C.sub.1 -C.sub.5)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkoxy, (C.sub.3 -C.sub.10)cycloalkyl, (C.sub.3 -C.sub.10)cycloalkoxy, (C.sub.2 -C.sub.9)heterocycloalkyl, (C.sub.5 -C.sub.9)heteroaryl or (C.sub.6 -C.sub.10)aryl. Specific preferred compounds of formula I include the following: 2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclohexyl}- propan-2-ol; 2-{3-[(2-Hydroxy-ethyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-4-methyl-c yclohexyl}-propan-2-ol; 2-[(5-Isopropenyl-2-methyl-cyclohexyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-am ino]-ethanol; (5-Isopropenyl-2-methyl-cyclohexyl)-(7H-pyrrolo[2,3-d]pyrimidin4-yl)-(2,2,2 -trifluoro-ethyl)-amine; 2-{4-Methyl-3-[(7H-pyrrolo[2,3-d]pyrimidin4-yl)-(2,2,2-trifluoro-ethyl)-ami no]-cyclohexyl}-propan-2-ol; 2-{4-Methyl-5-[methyl-(7H-pyrrolo[2,3-d]pyrimidin4-yl)-amino]-cyclohex-3-en yl}-propan-2-ol; 2-[1-(7H-Pyrrolo[2,3-d]pyrimidin4-yl)-azetidin-3-yl]-propan-2-ol; 2-[1-(7H-Pyrrolo[2,3-d]pyrimidin4-yl)-azetidin-2-yl]-propan-2-ol; (5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin4-yl)-(5-isopropenyl-2-methyl-cyclohexy l)-methyl-amine; 2-{3-[(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin4-yl)-methyl-amino]-4-methyly-clo hexyl}-propan-2-ol; (2-Ethyl4-isopropenyl-cyclopentyl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -amine; 2-{3-Ethyl-4-[methyl-(7H-pyrrolo[2,3-d]pyrimidin4-yl)-amino]-cyclopentyl}-p ropan-2-ol; 2-(3-Ethyl-4[-(2-hydroxy-ethyl)-(7H-pyrrolo[2,3-d]pyrimidin4-yl)-amino]-cyc lopentyl) -propan-2-ol; 2-[(2-Ethyl-4-isopropenyl-cyclopentyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-am ino]-ethanol; (5-(S)-Isopropenyl-2-methyl-cyclohexyl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-amine; 3-Methyl-8-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-8-aza-bicyclo[3.2.1 ]octan-3-ol; 2-[Cycloheptyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-ethanol; 2-[Cyclooctyl-(7H-pyrrolo[2,3-d]pyrimidin4-yl)-amino]-ethanol; Bicyclo[2.2.1]hept-2-yl-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine; and 4-Piperidin-1-yl-5-m-tolyl-7H-pyrrolo[2,3-d]pyrimidine. The present invention also relates to a pharmaceutical composition for (a) treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia, and other autoimmune diseases or (b) the inhibition of protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective in such disorders or conditions and a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition for (a) treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia, and other autoimmune diseases or (b) the inhibition of protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with T-cell immunosuppressant or antiinflammatory agents, effective in such disorders or conditions and a pharmaceutically acceptable carrier. The present invention also relates to a method for the inhibition of protein typrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia, and other autoimmune diseases in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective in treating such a condition. The present invention also relates to a method for the inhibition of protein typrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with T-cell immunosuppressant or antiinflammatory agents. The present invention also relates to a method for treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia, and other autoimmune diseases in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with T-cell immunosuppressant or antiinflammatory agents, effective in treating such a condition. |
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