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Claims for Patent: 7,091,208

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Claims for Patent: 7,091,208

Title:Pyrrolo[2,3-D]pyrimidine compounds
Abstract: A compound of the formula ##STR00001## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, which are inhibitors of the enzyme protein kinases such as Janus Kinase 3 and as such are useful therapy as immunosuppressive agents for organ transplants, xeno transplation, 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.
Inventor(s): Blumenkopf; Todd A. (Old Lyme, CT), Flanagan; Mark E. (Gales Ferry, CT), Munchhof; Michael J. (Salem, CT)
Assignee: Pfizer Inc. (New York, NY)
Application Number:11/211,217
Patent Claims: 1. A method for treating rheumatoid arthritis comprising administering to a mammal, including a human, a therapeutically effective amount of a compound selected from the group consisting of: Methyl-[4-methyl-1-(propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d- ]pyrimidin-4-yl)-amine; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-- carboxylic acid methyl ester; 3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-a- mino]-piperidin-1-yl}-propan-1-one; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-- carboxylic acid dimethylamide; 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-- 1-yl}-3-oxo-propionitrile; 3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(5-methyl-7H-pyrrolo[2,3-d]pyrimidi- n-4-yl)-amino]-piperidin-1-yl}-propan-1-one; 1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-- 1-yl}-but-3-yn-1-one; 1-{3-[(5-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-p- iperidin-1-yl)-propan-1-one; and 1-{3-[(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-p- iperidin-1-yl}-propan-1-one; or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein said compound is 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-- 1-yl}-3-oxo-propionitrile, or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 further comprising one or more additional agents which modulate a mammalian immune system or with antiinflammatory agents.

4. The method according to claim 3 wherein said one or more additional agents is chosen from the group consisting of cyclosporin A, rapamycin, tacrolimus, leflunomide, deoxyspergualin, mycophenolate, azathioprine, daclizumab, muromonab-CD3, antithymocyte globulin, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, prednisolone and dexamethasone.

5. A method for treating rheumatoid arthritis comprising administering to a mammal, including a human, a therapeutically effective amount of a compound of the Formula I; ##STR00010## or a pharmaceutically acceptable salt thereof; wherein R.sup.1 is a group of the formula ##STR00011## 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.1 C.sub.6)alkylsulfonyl, (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.6alkyl).sub.2amino, 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.2amino, 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 a piperidinyl 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.2amino(C.sub.1 C.sub.6)acyl, R.sup.15R.sup.16N--CO--O--, R.sup.15R.sup.16N--CO--(C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkyl-S(O).sub.m, R.sup.15R.sup.16NS(O).sub.m, R.sup.15R.sup.16NS(O).sub.m(C.sub.1 C.sub.6)alkyl, R.sup.15S(O).sub.mR.sup.16N, R.sup.15S(O).sub.mR.sup.16N(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 a group of the formula ##STR00012## wherein a is 0, 1, 2, 3 or 4; b, c, e, f and g are each independently 0 or 1; d is 0, 1, 2, or 3; X is S(O).sub.n wherein n is 0, 1 or 2; oxygen, carbonyl or --C(.dbd.N-cyano)-; Y is S(O).sub.n wherein n is 0, 1 or 2; or carbonyl; and Z is carbonyl, C(O)O--, C(O)NR-- or S(O).sub.n wherein n is 0, 1 or 2; R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are each independently selected from the group consisting of hydrogen or (C.sub.1 C.sub.6)alkyl 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.2amino, 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.12 is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C.sub.1 C.sub.6)alkyl, trifluoromethyl(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, ((C.sub.1 C.sub.6)alkyl).sub.2amino, 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, 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.2amino(C.sub.1 C.sub.6)acyl, R.sup.15R.sup.16N--CO--O--, R.sup.15R.sup.16N--CO--(C.sub.1 C.sub.6)alkyl, R.sup.15C(O)NH, R.sup.15OC(O)NH, R.sup.15NHC(O)NH, (C.sub.1 C.sub.6)alkyl-S(O).sub.m, (C.sub.1 C.sub.6)alkyl-S(O).sub.m-(C.sub.1 C.sub.6)alkyl, R.sup.15R.sup.16NS(O).sub.m, R.sup.15R.sup.16NS(O).sub.m(C.sub.1 C.sub.6)alkyl, R.sup.15S(O).sub.mR.sup.16N, R.sup.15S(O).sub.mR.sup.16N(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; R.sup.2 and R.sup.3 are each hydrogen.

6. The method according to claim 5 further comprising one or more additional agents which modulate a mammalian immune system or with antiinflamatory agents.

7. The method according to claim 6 wherein said one or more additional agents is chosen from the group consisting of cyclosporin A, rapamycin, tacrolimus, leflunomide, deoxyspergualin, mycophenolate, azathioprine, daclizumab, muromonab-CD3, antithymocyte globulin, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, prednisolone and dexamethasone.

8. A method for treating rheumatoid arthritis comprising administering to a mammal, including a human, a therapeutically effective amount of a compound of the Formula I; ##STR00013## or a pharmaceutically acceptable salt thereof; wherein R.sup.1 is a group of the formula ##STR00014## wherein y is 0; R.sup.4 is (C.sub.1 C.sub.6)alkyl; R.sup.5 is piperidinyl 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.2amino(C.sub.1 C.sub.6)acyl, R.sub.15R.sub.16N--CO--O--, R.sub.15R.sub.16N--CO--(C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkyl-S(O).sub.m, R.sub.15R.sub.16NS(O).sub.m, R.sub.15R.sub.16NS(O).sub.m(C.sub.1 C.sub.6)alkyl, R.sub.15S(O).sub.mR.sub.16N, R.sub.15S(O).sub.mR.sub.16N(C.sub.1 C.sub.6)alkyl, or a group of the formula ##STR00015## wherein: m is 0, 1 or 2; R.sub.15 and R.sub.16 are each independently selected from hydrogen or (C.sub.1 C.sub.6)alkyl; d is 1; R.sup.9 and R.sup.10 are each independently selected from the group consisting of hydrogen or (C.sub.1 C.sub.6)alkyl 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.2amino, 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.12 is cyano, trifluoromethyl, (C.sub.1 C.sub.6)alkyl, trifluoromethyl(C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkylamino, ((C.sub.1 C.sub.6)alkyl).sub.2amino, (C.sub.2 C.sub.6)alkynyl, cyano(C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkyl-S(O).sub.m wherein m is 0, 1 or 2; and R.sup.2 and R.sup.3 are each H.

9. The method according to claim 8 further comprising one or more additional agents which modulate a mammalian immune system or with antiinflamatory agents.

10. The method according to claim 9 wherein said one or more additional agents is chosen from the group consisting of cyclosporin A, rapamycin, tacrolimus, leflunomide, deoxyspergualin, mycophenolate, azathioprine, daclizumab, muromonab-CD3, antithymocyte globulin, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, prednisolone and dexamethasone.

11. A method for treating organ transplant rejection comprising administering to a mammal, including a human, a therapeutically effective amount of a compound selected from the group consisting of: Methyl-[4-methyl-1-(propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d- ]pyrimidin-4-yl)-amine; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-- carboxylic acid methyl ester; 3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-a- mino]-piperidin-1-yl}-propan-1-one; 4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-- carboxylic acid dimethylamide; 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-- 1-yl}-3-oxo-propionitrile; 3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(5-methyl-7H-pyrrolo[2,3-d]pyrimidi- n-4-yl)-amino]-piperidin-1-yl}-propan-1-one; 1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-- 1-yl}-but-3-yn-1-one; 1-{3-[(5-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-p- iperidin-1-yl}-propan-1-one; and 1-{3-[(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-p- iperidin-1-yl}-propan-1-one; or a pharmaceutically acceptable salt thereof.

12. The method according to claim 11, wherein said compound is 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-- 1-yl}-3-oxo-propionitrile, or a pharmaceutically acceptable salt thereof.

13. The method according to claim 11 further comprising one or more additional agents which modulate a mammalian immune system or with antiinflamatory agents.

14. The method according to claim 13 wherein said one or more additional agents is chosen from the group consisting of cycle sperm A, rapamycin, tacrolimus, leflunomide, deoxyspergualin, mycophenolate, azathioprine, daclizumab, muromonab-CD3, antithymocyte globulin , aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, prednisolone and dexamethasone.

15. A method for treating organ transplant rejection comprising administering to a mammal, including a human, a therapeutically effective amount of a compound of the Formula I; ##STR00016## or a pharmaceutically acceptable salt thereof; wherein R.sup.1 is a group of the formula ##STR00017## 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.1 C.sub.6)akylsulfonyl, (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.2amino, 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.2amino, 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 a piperidinyl 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.2amino(C.sub.1 C.sub.6)acyl, R.sup.15R.sup.16N--CO--O--, R.sup.15R.sup.16N--CO--(C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkyl-S(O).sub.m, R.sup.15R.sup.16NS(O).sub.m, R.sup.15R.sup.16NS(O).sub.m(C.sub.1 C.sub.6)alkyl, R.sup.15S(O).sub.mR.sup.16N, R.sup.15S(O).sub.mR.sup.16N(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 a group of the formula ##STR00018## wherein a is 0, 1, 2, 3 or 4; b, c, e, f and g are each independently 0 or 1; d is 0, 1, 2, or 3; X is S(O).sub.n wherein n is 0, 1 or 2; oxygen, carbonyl or -C(.dbd.N-cyano)-; Y is S(O).sub.n wherein n is 0, 1 or 2; or carbonyl; and Z is carbonyl, C(O)O--, C(O)NR-- or S(O).sub.n wherein n is 0, 1 or 2; R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are each independently selected from the group consisting of hydrogen or (C.sub.1 C.sub.6)alkyl 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.2amino, 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.12 is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C.sub.1 C.sub.6)alkyl, trifluoromethyl(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, ((C.sub.1 C.sub.6)alkyl).sub.2amino, 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, 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.2amino(C.sub.1 C.sub.6)acyl, R.sup.15R.sup.16N--CO--O--, R.sup.15R.sup.16N--CO--(C.sub.1 C.sub.6)alkyl, R.sup.15C(O)NH, R.sup.15OC(O)NH, R.sup.15NHC(O)NH, (C.sub.1 C.sub.6)alkyl-S(O).sub.m, (C.sub.1 C.sub.6)alkyl-S(O).sub.m-(C.sub.1 C.sub.6)alkyl, R.sup.15R.sup.16NS(O).sub.m, R.sup.15R.sup.16NS(O).sub.m(C.sub.1 C.sub.6)alkyl, R.sup.15S(O).sub.mR.sup.16N, R.sup.15S(O).sub.mR.sup.16N(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; R.sup.2 and R.sup.3 are each hydrogen.

16. The method according to claim 15 further comprising one or more additional agents which modulate a mammalian immune system or with antiinflamatory agents.

17. The method according to claim 16 wherein said one or more additional agents is chosen from the group consisting of cyclosporin A, rapamycin, tacrolimus, leflunomide, deoxyspergualin, mycophenolate, azathioprine, daclizumab, muromonab-CD3, antithymocyte globulin, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, prednisolone and dexamethasone.

18. A method for treating organ transplant rejection comprising administering to a mammal, including a human, a therapeutically effective amount of a compound of the Formula I; ##STR00019## or a pharmaceutically acceptable salt thereof; wherein R.sup.1 is a group of the formula ##STR00020## wherein y is 0; R.sup.4 is (C.sub.1 C.sub.6)alkyl; R.sup.5 is piperidinyl 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.2amino(C.sub.1 C.sub.6)acyl, R.sub.15R.sub.16N--CO--O--, R.sub.15R.sub.16N--CO--(C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkyl-S(O).sub.m, R.sub.15R.sub.16NS(O).sub.m, R.sub.15R.sub.16NS(O).sub.m(C.sub.1 C.sub.6)alkyl, R.sub.15S(O).sub.mR.sub.16N, R.sub.15S(O).sub.mR.sub.16N(C.sub.1 C.sub.6)alkyl, or a group of the formula ##STR00021## wherein: m is 0, 1 or 2; R.sub.15 and R.sub.16 are each independently selected from hydrogen or (C.sub.1 C.sub.6)alkyl; d is 1; R.sup.9 and R.sup.10 are each independently selected from the group consisting of hydrogen or (C.sub.1 C.sub.6)alkyl 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.2amino, 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.12 is cyano, trifluoromethyl, (C.sub.1 C.sub.6)alkyl, trifluoromethyl(C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkylamino, ((C.sub.1 C.sub.6)alkyl).sub.2amino, (C.sub.2 C.sub.6)alkynyl, cyano(C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkyl-S(O).sub.m wherein m is 0, 1 or 2; and R.sup.2 and R.sup.3 are each H.

19. The method according to claim 18 further comprising one or more additional agents which modulate a mammalian immune system or with antiinflamatory agents.

20. The method according to claim 19 wherein said one or more additional agents is chosen from the group consisting of cyclosporin A, rapamycin, tacrolimus, leflunomide, deoxyspergualin, mycophenolate, azathioprine, daclizumab, muromonab-CD3, antithymocyte globulin, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, prednisolone and dexamethasone.

21. The method according to claim 1, wherein said compound is 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-- 1-yl}-3-oxo-propionitrile, or a pharmaceutically acceptable salt thereof, in combination with one or more additional agents chosen from the group consisting of cyclosporin A, rapamycin, tacrolimus, leflunomide, deoxyspergualin, mycophenolate, azathioprine, daclizumab, muromonab-CD3, antithymocyte globulin, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, prednisolone and dexamethasone.

22. The method according to claim 11, wherein said compound is 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-- 1-yl}-3-oxo-propionitrile, or a pharmaceutically acceptable salt thereof, in combination with one or more additional agents chosen from the group consisting of cyclosporin A, rapamycin, tacrolimus, leflunomide, deoxyspergualin, mycophenolate, azathioprine, daclizumab, muromonab-CD3, antithymocyte globulin, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, prednisolone and dexamethasone.
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