IP Library › Granted Patent US 7,687,507

Granted Patent B2

US 7,687,507 · App. 11/064,873 · Granted Mar 30, 2010

Pyrrolo[2,3-d]pyrimidine compounds

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Quick Facts

Patent No.: US 7,687,507
App. No.: 11/064,873
Granted: Mar 30, 2010
Kind: B2

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Abstract

A compound of the formula wherein R 1 , R 2 and R 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.

Claims (184)

1. A pharmaceutical composition comprising a compound of the formula

or the pharmaceutically acceptable salt thereof; wherein

R 1 is OR 9 , S(O) q R 9 , or a group of the formula

R 2 and R 3 are each independently hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy wherein the alkyl or alkoxy groups are optionally substituted by one to three groups selected from halo, hydroxy, carboxy, amino(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 5 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl, (C 3 -C 9 )cycloalkyl or (C 6 -C 10 )aryl;

or R 2 and R 3 are each independently (C 7 -C 10 )cycloalkyl, (C 7 -C 10 )cycloalkoxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 6 -C 10 )arylamino, (C 1 -C 6 )alkylthio, (C 6 -C 10 )arylthio, (C 1 -C 6 )alkylsulfinyl, (C 6 -C 10 )arylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 6 -C 10 )arylsulfonyl, (C 1 -C 6 )acyl, (C 1 -C 6 )alkoxy-CO—NH—, (C 1 -C 6 )alkylamino-CO—, (C 5 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or (C 6 -C 10 )aryl wherein the heteroaryl, heterocycloalkyl and aryl groups are optionally substituted by one to three halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-CO—NH—, (C 1 -C 6 )alkoxy-CO—NH—, (C 1 -C 6 )alkyl-CO—NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH—(C 1 -C 6 )alkoxy, carboxy, carboxy(C 1 -C 6 )alkyl, carboxy(C 1 -C 6 )alkoxy, benzyloxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 6 -C 10 )aryl, amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonylamino, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxycarbonylamino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, cyano, amino-CO—NH—, (C 1 -C 6 )alkylamino-CO—NH—, ((C 1 -C 6 )alkyl) 2 amino-CO—NH—, (C 6 -C 10 )arylamino-CO—NH—, (C 5 -C 9 )heteroarylamino-CO—NH—, (C 1 -C 6 )alkylamino-CO—NH—(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino-CO—NH—(C 1 -C 6 )alkyl, (C 6 -C 10 )arylamino-CO—NH—(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroarylamino-CO—NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl, (C 6 -C 10 )arylsulfonylamino, (C 6 -C 10 )arylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl or (C 2 -C 9 )heterocycloalkyl;

R 4 is hydrogen, (C 1 -C 6 )alkyl,(C 2 -C 6 )alkenyl,or (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 4 )alkoxy, (C 1 -C 6 )acyloxy, (C 1 -C 6 ) alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, nitro, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 1 -C 6 )acylamino;

or R 4 is (C 7 -C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 6 )acyloxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, cyano(C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, nitro, nitro(C 1 -C 6 )alkyl or (C 1 -C 6 )acylamino;

R 5 is trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, or (C 3 -C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, nitro(C 1 -C 6 )alkyl, trifluoromethyl(C 1-C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, amino(C 1 -C 6 )acyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S(O) m , R 15 R 16 NS(O) m , R 15 R 16 NS(O) m (C 1 -C 6 )alkyl, R 15 S(O) m R 16 N, or R 15 S(O) m R 16 N(C 1 -C 6 )alkyl;

or R 5 is (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, (C 2 -C 6 )alkoxy(C 1 -C 6 )alkyl, piperazinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by one to five cyano, nitro, halo, deuterium, hydroxy, carboxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl or ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl;

or R 5 is R 13 CO(C 1 -C 6 )alkyl, R 13 CO(C 7 -C 10 )cycloalkyl, R 14 , R 14 (C 1 -C 6 )alkyl or R 14 (C 7 -C 10 )cycloalkyl;

or R 5 is a group of the formula

R 6 is hydrogen, (C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(difluoromethylene), (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, (C 6 -C 10 )aryl, C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, hydroxy(C 2 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 2 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkyl, piperazinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, R 13 CO(C 1 -C 6 )alkyl or R 14 (C 2 -C 6 )alkyl;

R 7 and R 8 are each independently hydrogen, (C 1 -C 6 )alkyl, amino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl)amino, (C 1 -C 6 )acylamino, (C 1 -C 6 )acyl(C 1 -C 6 )alkylamino, carboxy, (C 1 -C 6 )alkoxyacyl, (C 1 -C 6 )alkylaminoacyl, ((C 1 -C 6 )alkyl) 2 aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(difluoromethylene), (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1-6 )alkyl, piperazinyl(C 3 -C 6 )alkyl, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, R 13 CO(C 1 -C 6 )alkyl, R 13 CO(C 7 -C 10 )cycloalkyl, R 14 , R 14 (C 1 -C 6 )alkyl or R 14 (C 7 -C 10 )cycloalkyl; or a group of the formula

R 9 is trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, or (C 3 -C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by one to five carboxy, cyano, amino, hydroxy, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )alkyl S(O) m , R 15 R 16 NS(O) m , (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 3 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, nitro(C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, or ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl;

or R 9 is (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, (C 2 -C 6 )alkoxy(C 1 -C 6 )alkyl, piperazinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino, or (C 1 -C 6 )alkyl wherein the alkyl group is optionally substituted by one to five cyano, nitro, hydroxy, carboxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl or ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl;

or R 9 is R 13 CO(C 1 -C 6 )alkyl, R 13 CO(C 7 -C 10 )cycloalkyl, R 14 , R 14 (C 1 -C 6 )alkyl or R 14 (C 7 -C 10 )cycloalkyl;

or R 9 is a group of the formula

R 13 is R 20 O or R 20 R 21 N;

R 14 is (C 2 -C 9 )heterocycloalkyl, (C 3 -C 6 )acylpiperazino, (C 6 -C 10 )arylpiperazino, (C 5 -C 9 )heteroarylpiperazino, (C 1 -C 6 )alkylpiperazino, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperazino, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -C 6 )alkylpiperidinyl, (C 6 -C 10 )arylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperidyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperidyl or (C 1 -C 6 )acylpiperidyl;

R 15 and R 16 are each independently hydrogen or (C 1 -C 6 )alkyl;

R 17 and R 18 are each independently hydrogen, (C 1 -C 6 )alkyl, piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperidyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperidyl, (C 1 -C 6 )acylpiperidyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, R 22 (C 1 -C 6 )alkyl, (C 1 -C 5 )alkyl(CHR 22 )(C 1 -C 6 )alkyl, R 23 (C 1 -C 6 )alkyl, or (C 1 -C 5 )alkyl(CHR 23 )(C 1 -C 6 )alkyl;

R 20 and R 21 are each independently hydrogen, deuterium, (C 1 -C 6 alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 5 -C 9 )heteroaryl(C 1 -C 6 alkyl;

R 22 is hydroxy, (C 1 -C 6 )acyloxy, (C 1 -C 6 )alkoxy, piperazino, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkylthio, (C 6 -C 10 )arylthio, (C 1 -C 6 )alkylsulfinyl, (C 6 -C 10 )arylsulfinyl, (C 1 -C 6 )alkylsulfoxyl, (C 6 -C 10 )arylsulfoxyl, amino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 1 -C 6 )acylpiperazino, (C 1 -C 6 )alkylpiperazino, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperazino, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino,

R 23 is piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl or (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperidyl;

F, K and P are each independently oxygen, S(O) d , NR 6 or CR 7 R 8 ;

Z is hydroxy(C 1 -C 6 )alkoxy or NR 17 R 18 ;

d, m, q, w and y are each independently is 0, 1 or 2;

g, h and j are each independently 0 to 6;

p and x are each independently is 0, 1, 2 or 3:

with the proviso that when R 4 is hydrogen, unsubstituted (C 1 -C 6 )alkyl or unsubstituted (C 3 -C 10 )cycloalkyl, R 5 cannot be (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl or (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl; and R 14 cannot be (C 2 -C 9 )heterocycloalkyl, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidinyl or (C 1 -C 6 )alkylpiperidinyl;

with the proviso that the sp 2 and sp carbons of alkenyl or alkynyl cannot be substituted by hydroxy or amino;

with the proviso that when R 4 is hydrogen, R 5 cannot be amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl;

with the proviso that both R 4 and R 5 cannot both be hydroxy(C 1 -C 6 )alkyl; and

with the proviso that the (C 3 -C 10 )cycloalkyl group of R 5 contains zero levels of unsaturation,

and a pharmaceutically acceptable carrier.

2. A pharmaceutical composition comprising a compound of the formula

or the pharmaceutically acceptable salt thereof; wherein

R 1 is OR 9 , S(O) q R 9 , or a group of the formula

R 4 is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 4 )alkoxy, (C 1 -C 6 )acyloxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, nitro, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 1 -C 6 )acylamino;

R 5 is trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, or (C 3 -C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, nitro(C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, amino(C 1 -C 6 )acyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S(O) m , R 15 R 16 NS(O) m , R 15 R 16 NS(O) m (C 1 -C 6 )alkyl, R 15 S(O) m R 16 N, or R 15 S(O) m R 16 N(C 1 -C 6 )alkyl;

or R 5 is (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, (C 2 -C 6 )alkoxy(C 1 -C 6 )alkyl, piperazinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl(C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by one to five cyano, nitro, halo, deuterium, hydroxy, carboxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl or ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl;

or R 5 is R 13 CO(C 1 -C 6 )alkyl, R 13 CO(C 7 -C 10 )cycloalkyl, R 14 , R 14 (C 1 -C 6 )alkyl or R 14 (C 7 -C 10 )cycloalkyl,

or R 5 is a group of the formula

R 6 is hydrogen, (C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(difluoromethylene), (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, hydroxy(C 2 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 2 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkyl, piperazinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arlsulfonyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 3 -C 6 )alkyl, R 13 CO(C 1 -C 6 )alkyl or R 14 (C 2 -C 6 )alkyl,

R 7 and R 8 are each independently hydrogen, (C 1 -C 6 )alkyl, amino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl)amino, (C 1 -C 6 )acylamino, (C 1 -C 6 )acyl(C 1 -C 6 )alkylamino, carboxy, (C 1 -C 6 )alkoxyacyl, (C 1 -C 6 )alkylaminoacyl, ((C 1 -C 6 )alkyl) 2 aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(difluoromethylene), (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, piperazinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arlsulfonyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, R 13 CO(C 1 -C 6 )alkyl, R 13 CO(C 7 -C 10 )cycloalkyl, R 14 , R 14 (C 1 -C 6 )alkyl or R 14 (C 7 -C 10 )cycloalkyl; or a group of the formula

R 9 is trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, or (C 3 -C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by one to five carboxy, cyano, amino, hydroxy, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )alkyl S(O) m , R 15 R 16 NS(O) m , (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, nitro(C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, or ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl;

or R 9 is (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, (C 2 -C 6 )alkoxy(C 1 -C 6 )alkyl, piperazinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl(C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino, or (C 1 -C 6 )alkyl wherein the alkyl group is optionally substituted by one to five cyano, nitro, hydroxy, carboxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl or ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl;

or R 9 is R 13 CO(C 1 -C 6 )alkyl, R 13 CO(C 7 -C 10 )cycloalkyl, R 14 , R 14 (C 1 -C 6 )alkyl or R 14 (C 7 -C 10 )cycloalkyl;

or R 9 is a group of the formula

R 13 is R 20 O or R 20 R 21 N;

R 14 is (C 2 -C 9 )heterocycloalkyl, (C 1 -C 6 )acylpiperazino, (C 6 -C 10 )arylpiperazino, (C 5 -C 9 )heteroarylpiperazino, (C 1 -C 6 )alkylpiperazino, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperazino, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -C 6 )alkylpiperidinyl, (C 6 -C 10 )arylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl, (C 6 -C 10 )aryl, (C 1 -C 6 )alkylpiperidyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperidyl or (C 1 -C 6 )acylpiperidyl;

R 15 and R 16 are each independently hydrogen or (C 1 -C 6 )alkyl;

R 20 and R 21 are each independently hydrogen, deuterium, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl;

R 1 is OR 9 , S(O) q R 9 , or a group of the formula

or R 2 and R 3 are each independently (C 7 -C 10 )cycloalkyl, (C 7 -C 10 )cycloalkoxy(C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 6 -C 10 )arylamino, (C 1 -C 6 )alkylthio, (C 6 -C 10 )arylthio, (C 1 -C 6 )alkylsulfinyl, (C 6 -C 10 )arylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 6 -C 10 )arylsulfonyl, (C 1 -C 6 )acyl, (C 1 -C 6 )alkoxy-CO—NH—, (C 1 -C 6 )alkylamino-CO—, (C 5 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or (C 6 -C 10 )aryl wherein the heteroaryl, heterocycloalkyl and aryl groups are optionally substituted by one to three halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-CO—NH—, (C 1 -C 6 )alkoxy-CO—NH—, (C 1 -C 6 )alkyl-CO—NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH—(C 1 -C 6 )alkoxy, carboxy, carboxy(C 1 -C 6 )alkyl, carboxy(C 1 -C 6 )alkoxy, benzyloxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 6 -C 10 )aryl, amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonylamino, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxycarbonylamino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, cyano, amino-CO—NH—, (C 1 -C 6 )alkylamino-CO—NH—, ((C 1 -C 6 )alkyl) 2 amino-CO—NH—, (C 6 -C 10 )arylamino-CO—NH—, (C 5 -C 9 )heteroarylamino-CO—NH—, (C 1 -C 6 )alkylamino-CO—NH—(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino-CO—NH—(C 1 -C 6 )alkyl, (C 6 -C 10 )arylamino-CO—NH—(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroarylamino-CO—NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl, (C 6 -C 10 )arylsulfonylamino, (C 6 -C 10 )arylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl or (C 2 -C 9 )heterocycloalkyl;

R 4 is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, C 6 )alkypiperazino, (C 6 -C 10 )aryl(C 1 -C 6 )alkypiperazino, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino, or pyrrolidino;

R 23 is piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl or (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperidyl;

F, K and P are each independently oxygen, S(O) d , NR 6 or CR 7 R 8 ;

Z is hydroxy, (C 1 -C 6 )alkoxy or NR 17 R 18 ;

d, m, q, w, and y are each independently is 0, 1 or 2;

g, h and j are each independently 0 to 6;

p and x are each independently is 0, 1, 2 or 3;

with the proviso that the sp 2 and sp carbons of alkenyl or alkynyl cannot be substituted by hydroxy or amino;

with the proviso that when R 4 is hydrogen, R 5 cannot be amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl;

with the proviso that both R 4 and R 5 cannot both be hydroxy(C 1 -C 6 )alkyl; and

with the proviso that the (C 3 -C 10 )cycloalkyl group of R 5 contains zero levels of unsaturation. alone or in combination with one or more additional agents which modulate a mammalian immune system or with antiinflammatory agents, and a pharmaceutically acceptable carrier.

3. A method for treating organ transplant rejection, rheumatoid arthritis, or psoriasis, in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of the formula

or the pharmaceutically acceptable salt thereof; wherein

R 1 is OR 9 , S(O) q R 9 , or a group of the formula

or R 2 and R 3 are each independently (C 7 -C 10 )cycloalkyl, (C 7 -C 10 )cycloalkoxy(C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 6 -C 10 )arylamino, (C 1 -C 6 )alkylthio, (C 6 -C 10 )arylthio, (C 1 -C 6 )alkylsulfinyl, (C 6 -C 10 )arylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 6 -C 10 )arylsulfonyl, (C 1 -C 6 )acyl, (C 1 -C 6 )alkoxy-CO—NH—, (C 1 -C 6 )alkylamino-CO—, (C 5 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or (C 6 -C 10 )aryl wherein the heteroaryl, heterocycloalkyl and aryl groups are optionally substituted by one to three halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-CO—NH—, (C 1 -C 6 )alkoxy-CO—NH—, (C 1 -C 6 )alkyl-CO—NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH—(C 1 -C 6 )alkoxy, carboxy, carboxy(C 1 -C 6 )alkyl, carboxy(C 1 -C 6 )alkoxy, benzyloxycarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 6 -C 10 )aryl, amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonylamino, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxycarbonylamino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, cyano, amino-CO—NH—, (C 1 -C 6 )alkylamino-CO—NH—, ((C 1 -C 6 )alkyl) 2 amino-CO—NH—, (C 6 -C 10 )arylamino-CO—NH—, (C 5 -C 9 )heteroarylamino-CO—NH—, (C 1 -C 6 )alkylamino-CO—NH—(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino-CO—NH—(C 1 -C 6 )alkyl, (C 6 -C 10 )arylamino-CO—NH—(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroarylamino-CO—NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl, (C 6 -C 10 )arylsulfonylamino(C 6 -C 10 )arylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl or (C 2 -C 9 )heterocycloalkyl;

R 4 is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 4 )alkoxy, (C 1 -C 6 )acyloxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, nitro, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 1 -C 6 )acylamino;

R 5 is trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, or (C 3 -C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, nitro(C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, amino(C 1 -C 6 )acyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S(O) m , R 15 R 16 NS(O) m , R 15 R 16 NS(O) m (C 1 -C 6 )alkyl, R 15 S(O) m , R 16 N, or R 15 S(O) m R 16 N(C 1 -C 6 )alkyl;

or R 5 is R 13 CO(C 1 -C 6 )alkyl, R 13 CO(C 7 -C 10 )cycloalkyl, R 14 , R 14 (C 1 -C 6 )alkyl or R 14 (C 7 -C 10 )cycloalkyl;

or R 5 is a group of the formula

R 6 is hydrogen, (C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(difluoromethylene), (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, hydroxy(C 2 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 2 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkyl, piperazinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, R 13 CO(C 1 -C 6 )alkyl or R 14 (C 2 -C 6 )alkyl;

R 7 and R 8 are each independently hydrogen, (C 1 -C 6 )alkyl, amino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl)amino, (C 1 -C 6 )acylamino, (C 1 -C 6 )acyl(C 1 -C 6 )alkylamino, carboxy, (C 1 -C 6 )alkoxyacyl, (C 1 -C 6 )alkylaminoacyl, ((C 1 -C 6 )alkyl) 2 aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(difluoromethylene), (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, piperazinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, R 13 CO(C 1 -C 6 )alkyl, R 13 CO(C 7 -C 10 )cycloalkyl, R 14 , R 14 (C 1 -C 6 )alkyl or R 14 (C 7 -C 10 )cycloalkyl, or a group of the formula

R 9 is trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, or (C 3 -C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by one to five carboxy, cyano, amino, hydroxy, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )alkyl S(O) m , R 15 R 16 NS(O) m , (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, nitro(C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, or ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl,

or R 9 is R 13 CO(C 1 -C 6 )alkyl, R 13 CO(C 7 -C 10 )cycloalkyl, R 14 , R 14 (C 1 -C 6 )alkyl or R 14 (C 7 -C 10 )cycloalkyl;

or R 9 is a group of the formula

R 13 is R 20 O or R 20 R 21 N;

R 14 is (C 2 -C 9 )heterocycloalkyl, (C 1 -C 6 )acylpiperazino, (C 6 -C 10 )arylpiperazino, (C 5 -C 9 )heteroarylpiperazino, (C 1 -C 6 )alkylpiperazino, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperazino, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -C 6 )alkylpiperidinyl, (C 6 -C 10 )arylpiperidyl(C 5 -C 9 )heteroarylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperidyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperidyl or (C 1 -C 6 )acylpiperidyl;

R 15 and R 16 are each independently hydrogen or (C 1 -C 6 )alkyl;

R 20 and R 21 are each independently hydrogen, deuterium, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl;

R 23 is piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl or (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperidyl;

F, K and P are each independently oxygen, S(O) d , NR 6 or CR 7 R 8 ;

Z is hydroxy, (C 1 -C 6 )alkoxy or NR 17 R 18 ;

d, m, q, w, and v are each independently is 0, 1 or 2;

g, h and j are each independently 0 to 6;

p and x are each independently is 0, 1, 2 or 3;

with the proviso that the sp 2 and sp carbons of alkenyl or alkynyl cannot be substituted by hydroxy or amino;

with the proviso that when R 4 is hydrogen, R 5 cannot be amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl;

with the proviso that both R 4 and R 5 cannot both be hydroxy(C 1 -C 6 )alkyl; and

with the proviso that the (C 3 -C 10 )cycloalkyl group of R 5 contains zero levels of unsaturation.

4. A method for treating organ transplant rejection, rheumatoid arthritis, or psoriasis in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of the formula

or the pharmaceutically acceptable salt thereof; wherein

R 1 is OR 9 , S(O) q R 9 , or a group of the formula

R 2 and R 3 are each independently hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy wherein the alkyl or alkoxy groups are optionally substituted by one to three groups selected from halo, hydroxy, carboxy, amino(C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 5 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl, (C 3 -C 9 )cycloalkyl or (C 6 -C 10 )aryl;

R 4 is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 4 )alkoxy, (C 1 -C 6 )acyloxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, nitro, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 1 -C 6 )acylamino;

R 5 is trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, or (C 3 -C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, nitro(C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, amino(C 1 -C 6 )acyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S(O) m , R 15 R 16 NS(O) m , R 15 R 16 NS(O) m (C 1 -C 6 )alkyl, R 15 S(O) m R 16 N, or R 15 S(O) m R 16 N(C 1 -C 6 )alkyl;

or R 5 is R 13 CO(C 1 -C 6 )alkyl, R 13 CO(C 7 -C 10 )cycloalkyl, R 14 , R 14 (C 1 -C 6 )alkyl or R 14 (C 7 -C 10 )cycloalkyl;

or R 5 is a group of the formula

R 6 is hydrogen, (C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(difluoromethylene), (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10)aryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, hydroxy(C 2 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 2 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkyl, piperazinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, R 13 CO(C 1 -C 6 )alkyl or R 14 (C 2 -C 6 )alkyl;

R 7 and R 8 are each independently hydrogen, (C 1 -C 6 )alkyl, amino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl)amino, (C 1 -C 6 )acylamino, (C 1 -C 6 )acyl(C 1 -C 6 )alkylamino, carboxy, (C 1 -C 6 )alkoxyacyl, (C 1 -C 6 )alkylaminoacyl, ((C 1 -C 6 )alkyl) 2 aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(difluoromethylene), (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10)aryl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, piperazinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 alkyl, (C 6 -C 10 )arylsulfonyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, R 13 CO(C 1 -C 6 )alkyl, R 13 CO(C 7 -C 10 )cycloalkyl, R 14 , R 14 (C 1 -C 6 )alkyl or R 14 (C 7 -C 10 )cycloalkyl; or a group of the formula

R 9 is trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, or (C 3 -C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by one to five carboxy, cyano, amino, hydroxy, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )alkyl S(O) m , R 15 R 16 NS(O) m , (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, nitro(C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, or ((C 1 -C 6 alkyl) 2 amino(C 1 -C 6 )acyl;

or R 9 is R 13 CO(C 1 -C 6 )alkyl, R 13 CO(C 7 -C 10 )cycloalkyl, R 14 , R 14 (C 1 -C 6 )alkyl or R 14 (C 7 -C 10 )cycloalkyl;

or R 9 is a group of the formula

R 13 is R 20 O or R 20 R 21 N;

R 14 is (C 2 -C 9 )heterocycloalkyl, (C 1 -C 6 )acylpiperazino, (C 6 -C 10 )arylpiperazino, (C 5 -C 9 )heteroarylpiperazino, (C 1 -C 6 )alkylpiperazino, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperazino, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -C 6 )alkylpiperidinyl, (C 6 -C 10 )arylpiperidyl(C 5 -C 9 )heteroarylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperidyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperidyl or (C 1 -C 6 )acylpiperidyl;

R 15 and R 16 are each independently hydrogen or (C 1 -C 6 )alkyl;

R 17 and R 18 are each independently hydrogen, (C 1 -C 6 )alkyl, piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl(C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperidyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperidyl, (C 1 -C 6 )acylpiperidyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, R 22 (C 1 -C 6 )alkyl, (C 1 -C 5 )alkyl(CHR 22 )(C 1 -C 6 )alkyl, R 23 (C 1 -C 6 )alkyl, or (C 1 -C 5 )alkyl(CHR 23 )(C 1 -C 6 )alkyl;

R 20 and R 21 are each independently hydrogen, deuterium, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl;

R 23 is piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl or (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkylpiperidyl;

F, K and P are each independently oxygen, S(O) d , NR 6 or CR 7 R 8 ;

Z is hydroxy, (C 1 -C 6 )alkoxy or NR 17 R 18 ;

d, m, q, w, and y are each independently is 0, 1 or 2;

g, h and j are each independently 0 to 6;

p and x are each independently is 0, 1, 2 or 3;

with the proviso that the sp 2 and sp carbons of alkenyl or alkynyl cannot be substituted by hydroxy or amino;

with the proviso that when R 4 is hydrogen, R 5 cannot be amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl;

with the proviso that both R 4 and R 5 cannot both be hydroxy(C 1 -C 6 )alkyl; and

with the proviso that the (C 3 -C 10 )cycloalkyl group of R 5 contains zero levels of unsaturation, alone or in combination with one or more additional agents which modulate a mammalian immune system or with antiinflammatory agents.

5. The pharmaceutical composition of claim 2 , wherein the compound is 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)-amino]-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)-amino]-cyclohexyl}-propan-2-ol;

2-{4-Methyl-5-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclohex-3-enyl}-propan-2-ol;

(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(5-isopropenyl-2-methyl-cyclohexyl)-methyl-amine;

2-{3-[(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]4-methyl-cyclohexyl}-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]cyclopentyl}-propan-2-ol;

2-[(2-Ethyl-4-isopropenyl-cyclopentyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-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;

Bicyclo[2.2.1]hept-2-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine; and

or a pharmaceutically acceptable salt thereof.

6. The method of claim 4 , wherein the compound is selected from the group consisting of: