2-(Amino-substituted)-4-aryl pyrimidines and related compounds useful for treating inflammatory diseases

A compound of formula I-A-i:

• wherein
• a. Cy2 is phenyl optionally substituted by one to three independent occurrences of R9 and one occurrence of R10, wherein each occurrence of R9 is independently selected from —ORB, —N(RB)C(O)RA, —N(RB)2, halo, C1-4aliphatic optionally substituted by halo, NO2, —OS(O)2RC, —S(O)RC, —N(RB)SO2RA, or —S(O)2N(RB)2;
• b. ring A is optionally substituted with 1 or 2 independent occurrences of R5, wherein R5 on ring A, when present, is selected from F, Cl, Br, or methyl;
• c. W is selected from:
• wherein m is 1, 2, or 3, RF is H or C1-3alkyl, and RE is H, C1-3alkyl, or SO2CH3, and wherein each of the foregoing pyridyl, pyrrolidinyl, piperidinyl, and piperazinyl groups is optionally substituted at one or more carbon atoms with 1, 2, or 3 independent occurrences of R11, and at one or more substitutable nitrogen atoms with R12;
• ii) —V—R8, wherein V is —CH2— and R8 is a group selected from:
• wherein the pyrrolidinyl, piperidinyl, and pyridyl groups are unsubstituted, or are substituted on one or two carbon atoms with one or two occurrences of C1-4alkyl, phenyl, heteroaryl, halo, —COOH, —COO(C1-4alkyl), —CONH2, —CONH(C1-4alkyl), —CON(C1-4alkyl)2, —CONH(heteroaryl), —CN, —NH2, —OH, —O(C1-4alkyl), —NH(C1-4alkyl), —N(C1-4alkyl)2, ═O, or C1-4alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, —COOH, —COO(C1-4alkyl), —CONH2, —CONH(C1-4alkyl), —CON(C1-4alkyl)2, —CONH(heteroaryl), —CN, —NH2, —OH, —O(C1-4alkyl), —NH(C1-4alkyl), or —N(C1-4alkyl)2, and are optionally substituted on one nitrogen atom with —C1-4alkyl, or —COO(C1-4alkyl), —SO2(C1-4alkyl), benzyl, or CH2(heteroaryl);
• and
• d) Cy1 is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is -OMe, methyl, ethyl, F, or Cl.

A method for treating an inflammatory or immune-related physiological disorder, symptom or disease in a patient in need of such treatment, comprising administering to the patient a compound of formula I:

• or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein:
• R1 and R2 are each independently H, C1-3 alkyl or C3-5 cycloalkyl;
• R3 is H or F;
• R4 is H, F, —ORA, —C(O)RA, —C(O)ORA or —N(RA)2;
• or R3 and R4 together with the carbon atom to which they are attached form a carbonyl group;
• wherein each occurrence of RA is independently H, C1-3alkyl or C3-5cycloalkyl;
• Ring A is optionally substituted with 1 or 2 independent occurrences of R5, wherein each R5 is independently selected from halo, C1-4 aliphatic, —CN, —ORB, —SRC, —N(RB)2, —NRBC(O)RB, —NRBC(O)N(RB)2, —NRBCO2RC, —CO2RB, —C(O)RB, —C(O)N(RB)2, —OC(O)N(RB)2, —S(O)2RC, —SO2N(RB)2, —S(O)RC, —NRBSO2N(RB)2, —NRBSO2RC, or C1-4aliphatic optionally substituted with halo, —CN, —ORB, —SRC, —N(RB)2, —NRBC(O)RB, NRBC(O)N(RB)2, NRBCO2RC, CO2RB, C(O)RB, C(O)N(RB)2, —OC(O)N(RB)2, —S(O)2RC, —SO2N(RB)2, —S(O)RC, —NRBSO2N(RB)2, or —NRBSO2RC, wherein each occurrence of RB is is independently H or C1-4 aliphatic;
• or two RB on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, O or S;
• and each occurrence of RC is independently C1-4 aliphatic;
• Cy1 is selected from:
• a) a 6-membered aryl or heteroaryl ring substituted by one occurrence of W at the meta or para position of the ring;
• or
• b) a 5-membered heteroaryl ring substituted by one occurrence of W;
• wherein Cy1 is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is independently selected from -halo, C1-8 aliphatic, —CN, —ORB, —SRD, —N(RE)2, —NREC(O)RB, —NREC(O)N(RE)2, —NRECO2RD, —CO2RB, —C(O)RB, —C(O)N(RE)2, —OC(O)N(RE)2, —S(O)2RD, —SO2N(RE)2, —S(O)RD, —NRESO2N(RE)2, —NRESO2RD, —C(═NH)—N(RE)2, or C1-8 aliphatic optionally substituted with halo, —CN, —ORB, —SRD, —N(RE)2, —NREC(O)RB, —NREC(O)N(RE)2, —NRECO2RD, —CO2RB, —C(O)RB, —C(O)N(RE)2, —OC(O)N(RE)2, —S(O)2RD, —SO2N(RE)2, —S(O)RD, NRESO2N(RE)2, —NRESO2RD, or —C(═NH)—N(RE)2, wherein each occurrence of RD is C1-6 aliphatic and each occurrence of RE is independently H, C1-6 aliphatic, —C(═O)RB, —C(O)ORB or —SO2R B;
• or two RE on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, O or S;
• W is -R8, V—R8, L1-R7, V-L1-R7, L1-V—R8, or L1-V-L2-R7;
• wherein:
• L1 and L2 are each independently an optionally substituted C1-6 alkylene chain;
• V is —CH2—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —NRE—, —NREC(O)—, —NRECO2—, —NRESO2—, —C(O)N(RB), —SO2N(RB)—, —NREC(O)N(RB)— or —OC(O)—;
• R7 is H, halo, —OH, —N(RF)2, —CN, —ORG, —C(O)RG, —CO2H, —CO2RG, —SRG, —S(O)RG, —S(O)2RG, —N(RE)C(O)RG, —N(RE)CO2RG, —N(RE)SO2RG, —C(O)N(RF)2, —SO2N(RF)2, —N(RE)C(O)N(RF)2, —OC(O)RF or an optionally substituted group selected from C1-10aliphatic, C6-10aryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl, wherein each occurrence of RF is independently H, C1-6 aliphatic, C6-10aryl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, —C(═O)RB, —C(O)ORB or —SO2RB;
• or two RF on the same nitrogen atom taken together with the nitrogen atom form an optionally substituted 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, O or S;
• and each occurrence of RG is C1-6 aliphatic, C6-10aryl, 3-14 membered heterocyclyl, or 5-14 membered heteroaryl;
• R8 is an optionally substituted group selected from C1-10 aliphatic, C6-10 aryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl;
• Q is a bond, CH2 or C(═O);
• Cy2 is a C6-10 aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl ring, wherein each ring is optionally substituted by one to three independent occurrences of R9 and one occurrence of
• wherein each occurrence of R9 is independently selected from C1-4aliphatic, —N(RB)2, halo, NO2, —CN, —ORB, —C(O)RA, —CO2RA, —SRC, —S(O)RC, —S(O)2RC, —OS(O)2RC—, N(RB)C(O)RA, —N(RB)CO2RA, —N(RB)SO2RA, —C(O)N(RB)2, —SO2N(RB)2, —N(RB)C(O)N(RB)2, —OC(O)RA, or C1-4 aliphatic optionally substituted by —N(RB)2, halo, NO2, —CN, —ORB, C(O)RA, —CO2RA, —SRC, —S(O)RC, —OS(O)2RC, —S(O)2RC, —N(RB)C(O)RA, —N(RB)CO2RA, —N(RB)SO2RA, —C(O)N(RB)2, —SO2N(RB)2, —N(RB)C(O)N(RB)2, or —OC(O)RA, and
• R10 is selected from phenyl, or a 5-6 membered heterocyclyl or heteroaryl ring.

A method of inhibiting PKC-theta activity in a biological sample or a patient, which method comprises administering to the patient or contacting said biological sample with a compound of formula I:

• or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein:
• R1 and R2 are each independently H, C1-3 alkyl or C3-5 cycloalkyl;
• R3 is H or F;
• R4 is H, F, —ORA, —C(O)RA, C(O)ORA or N(RA)2;
• or R3 and R4 together with the carbon atom to which they are attached form a carbonyl group;
• wherein each occurrence of RA is independently H, C1-3alkyl or C3-5cycloalkyl;
• Ring A is optionally substituted with 1 or 2 independent occurrences of R5, wherein each R5 is independently selected from halo, C1-4 aliphatic, —CN, —ORB, —SRC, —N(RB)2, NRBC(O)RB, —NRBC(O)N(RB)2, —NRBCO2RC, —CO2RB, —C(O)RB, —C(O)N(RB)2, —OC(O)N(RB)2, —S(O)2RC, —SO2N(RB)2, —S(O)RC, NRBSO2N(RB)2, —NRBSO2RC, or C1-4aliphatic optionally substituted with halo, —CN, —ORB, —SRC, —N(RB)2, —NRBC(O)RB, —NRBC(O)N(RB)2, —NRBCO2RC, —CO2RB, —C(O)RB, —C(O)N(RB)2, —OC(O)N(RB)2, —S(O)2RC, —SO2N(RB)2, —S(O)RC, —NRBSO2N(RB)2, or —NRBSO2RC, wherein each occurrence of RB is is independently H or C1-4 aliphatic;
• or two RB on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, O or S;
• and each occurrence of RC is independently C1-4 aliphatic;
• Cy1 is selected from:
• a) a 6-membered aryl or heteroaryl ring substituted by one occurrence of W at the meta or para position of the ring;
• or
• b) a 5-membered heteroaryl ring substituted by one occurrence of W;
• wherein Cy1 is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is independently selected from -halo, C1-8 aliphatic, —CN, —ORB, —SRD, —N(RE)2, —NREC(O)RB, —NREC(O)N(RE)2, —NRECO2R-D, —CO2RB, —C(O)RB, —C(O)N(RE)2, —OC(O)N(RE)2, —S(O)2RD, —SO2N(RE)2, —S(O)RD, —NRESO2N(RE)2, —NRESO2RD, —C(═NH)—N(RE)2, or C1-8 aliphatic optionally substituted with halo, —CN, —ORB, —SRD, —N(RE)2, —NREC(O)RB, —NREC(O)N(RE)2, —NRECO2RD, —CO2RB, —C(O)RB, —C(O)N(RE)2, —OC(O)N(RE)2, —S(O)2RD, —SO2N(RE)2, —S(O)RD, —NRESO2N(RE)2, —NRESO2RD, or —C(═NH)—N(RE)2, wherein each occurrence of RD is C1-6 aliphatic and each occurrence of RE is independently H, C1-6 aliphatic, —C(═O)RB, —C(O)ORB or —SO2RB;
• or two RE on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, O or S;
• W is -R8, V—R8, L1-R7, V-L1-R7, L1-V—R8, or L1-V-L2-R7;
• wherein:
• L1 and L2 are each independently an optionally substituted C1-6 alkylene chain;
• V is —CH2—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —NRE—, NREC(O)—, —NRECO2—, —NRESO2—, —C(O)N(RB)—, —SO2N(RB)—, —NREC(O)N(RB)— or —OC(O)—;
• R7 is H, halo, —OH, —N(RF)2, —CN, —ORG, —C(O)RG, —CO2H, —CO2RG, SRG, —S(O)RG, —S(O)2RG, —N(RE)C(O)RG, —N(RE)CO2RG, —N(RE)SO2RG, —C(O)N(RF)2, —SO2N(RF)2, —N(RE)C(O)N(RF)2, —OC(O)RF or an optionally substituted group selected from C1-10 aliphatic, C6-10aryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl, wherein each occurrence of RF is independently H, C1-6 aliphatic, C6-10aryl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, —C(═O)RB, —C(O)ORB or —SO2RB;
• or two RF on the same nitrogen atom taken together with the nitrogen atom form an optionally substituted 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, O or S;
• and each occurrence of RG is C1-6 aliphatic, C6-10aryl, 3-14 membered heterocyclyl, or 5-14 membered heteroaryl;
• R8 is an optionally substituted group selected from C1-10 aliphatic, C6-10 aryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl;
• Q is a bond, CH2 or C(═O);
• Cy2 is a C6-10 aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl ring, wherein each ring is optionally substituted by one to three independent occurrences of R9 and one occurrence of R10,
• wherein each occurrence of R9 is independently selected from C1-4aliphatic, —N(RB)2, halo, NO2, —CN, —ORB, —C(O)RA, —CO2RA, —SRC, —S(O)RC, —S(O)2RC, —OS(O)2RC—, N(RB)C(O)RA, —N(RB)CO2RA, —N(RB)SO2RA, —C(O)N(RB)2, —SO2N(RB)2, —N(RB)C(O)N(RB)2, —OC(O)RA, or C1-4 aliphatic optionally substituted by —N(RB)2, halo, NO2, —CN, —ORB, C(O)RA, —CO2RA, —SRC, —S(O)RC, —OS(O)2RC, —S(O)2RC, —N(RB)C(O)RA, —N(RB)CO2RA, —N(RB)SO2RA, —C(O)N(RB)2, —SO2N(RB)2, —N(RB)C(O)N(RB)2, or —OC(O)RA, and
• R10 is selected from phenyl, or a 5-6 membered heterocyclyl or heteroaryl ring.