C-linked heterocycloaklyl substituted pyrimidines and their uses

A pharmaceutical composition comprising a compound of formula I-I and a pharmaceutically acceptable carrier, diluent or excipient, wherein in said compound of formula I-I

• wherein
• R1 is selected from the group consisting of C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, —OR1a, —SR1a, —N(H)(R1a), and —N(R1a)(R1b) wherein R1a and R1b are each independently selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl, and wherein the aliphatic and aromatic portions of R1 are independently further substituted with 0 to 5 RA1 substituents selected from the group consisting of —F, —Cl, —Br, —I, —CN, —NO2, —SF5, —OH, —NH2, —CF3, ═O, C1-4 alkyl, C1-4 haloalkyl, C1-4 heteroalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C1-4 dialkylamino, R1c—C(═O)—, R1c—C(═O)N(H)—, R1c—C(═O)N(R1d)—, R1c—C(═O)O—, R1c—S(O)1-2—, R1c—S(O)1-2N(R1d)—, R1c—S(O)1-2N(H)—, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl, wherein R1c is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C5-6 heteroaryl, 3-7 membered heterocycloalkyl, phenyl and 3-6 membered cycloalkyl, R1d is selected from the group consisting of hydrogen, C1-3 alkyl and C1-3 haloalkyl, and wherein said 5-6 membered heteroaryl, phenyl, 3-6 membered cycloalkyl and 3-7 membered heterocycloalkyl of a RA1 substituent are substituted with from 0-4 substituents selected from —F, —Cl, —Br, I, —CN, —NO2, —SF5, —OH, —NH2, —CF3, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino and C1-4 dialkylamino;
• R2 is selected from the group consisting of hydrogen, C1-6 alkyl and C1-6 haloalkyl;
• R3 is selected from the group consisting of —F, —Cl, —Br, —I, —(X3)0-1—CN, —(X3)0-1—NO2, —(X3)0-1—SF5, —(X3)0-1-OH, —(X3)0-1—NH2, —(X3)0-1—N(H)(R3a), —(X3)0-1—N(R3b)(R3a), —(X3)0-1—CF3, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, —(X3)0-1-3-7 membered cycloalkyl, —(X3)0-1-3-7 membered heterocycloalkyl, —(X3)0-1-5-6 membered heteroaryl, —(X3)0-1—C6 aryl, —(X3)0-1—C(═Y3)N(H)(R3a), —(X3)0-1—C(═Y3)NH2, —(X3)0-1—C(═Y3)N(R3a)(R3b), —(X3)0-1—C(═Y3)OR3a, —(X3)0-1—C(═Y3)OH, —(X3)0-1—N(H)C(═Y3)(R3a), —(X3)0-1—N(R3b)C(═Y3)(R3a), —(X3)0-1—N(H)C(═Y3)OR3a, —(X3)0-1—N(R3b)C(═Y3)OR3a, (X3)0-1—S(O)1-2R3a, —(X3)0-1—N(H)S(O)1-2R3a, —(X3)0-1—N(R3b)S(O)1-2R3a, —(X3)0-1—S(O)0-1N(H)(R3a), —(X3)0-1—S(O)0-1N(R3b)(R3a), —(X3)0-1—S(O)0-1NH2, —(X4)0-1—S(═O)(═NR3b)R3a, —(X3)0-1—C(═Y3)R3a, —(X3)0-1—C(═Y3)H, —(X3)0-1—C(═NOH)R3a, —(X3)0-1—C(═NOR3b)R3a, —(X3)0-1—NHC(═Y3)N(H)(R3a), —(X3)0-1—NHC(═Y3)NH2, —(X3)0-1—NHC(═Y3)N(R3b)(R3a), —(X3)0-1—N(R3a)C(═Y3)N(H)(R3a), —(X3)0-1—N(R3a)C(═Y3)NH2, —(X3)0-1—OC(═Y3)R3a, —(X3)0-1—OC(═Y3)H, —(X3)0-1—OC(═Y3)OR3a, —(X3)0-1-OP(═Y3)(OR3a)(OR3b), —(X3)_SC(═Y3)OR3a and —(X3)—SC(═Y3)N(R3a)(R3b) wherein X3 is selected from the group consisting of C1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene, and C2-4 alkynylene, R3a and R3b are each independently selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkyl-C1-4 alkyl, 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl-C1-4 alkyl, C6 aryl, C6 aryl-C1-4 alkyl and benzyl;
• Y3 is O, NR3d or S wherein R3d is hydrogen or C1-6 alkyl;
• wherein aliphatic or aromatic portion of R3 is independently further substituted with from 0 to 4 RA3 substituents selected from the group consisting of —F, —Cl, —Br, —I, —CN, —NO2, —SF5, —OH, —NH2, —CF3, ═O, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, —C(═O)N(H)(C1-6 alkyl), —C(═O)N(C1-6 alkyl)2, —C(═O)NH2, —C(═O)OC1-6 alkyl, —C(═O)OH, —N(H)C(═O)(C1-6 alkyl), —N(C1-6 alkyl)C(═O)(C1-6 alkyl), —N(H)C(═O)OC1-6 alkyl, —N(C1-6 alkyl)C(═O)OC1-6 alkyl, —S(O)1-2C1-6 alkyl, —N(H)S(O)1-2C1-6 alkyl, —N(C1-6 alkyl)S(O)1-2C1-6 alkyl, —S(O)0-1N(H)(C1-6 alkyl), —S(O)0-1N(C1-6 alkyl)2, —S(O)0-1NH2, —C(═O)C1-6 alkyl, —C(═NOH)C1-6 alkyl, —C(═NOC1-6 alkyl)C1-6 alkyl, —NHC(═O)N(H)(C1-6 alkyl), —NHC(═O)N(C1-6 alkyl)2, —NHC(═O)NH2, —N(C1-6 alkyl)C(═O)N(H)(C1-6 alkyl), —N(C1-6 alkyl)C(═O)NH2, —OC(═O)C1-6 alkyl, —OC(═O)OC1-6 alkyl, —OP(═O)(OC1-6 alkyl)2, —SC(═O)OC1-6 alkyl and —SC(═O)N(C1-6 alkyl)2;
• alternatively any two R3 substituents located on adjacent atoms are optionally combined to form a 5-6 membered heteroaryl ring comprising 1-2 heteroatoms selected from N, O and S and further comprising 0 to 4 R3a substituents;
• m is an integer from 0 to 4;
• the ring represented by the structure
• is a 4 to 10 membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S, wherein said 4 to 7 membered heterocyclic ring is optionally substituted with 1 to 3 R4 groups;
• R4 is selected from the group consisting of —F, —Cl, —Br, —I, —(X4)0-1—CN, —(X4)0-1—NO2, —(X4)0-1—SF5, —(X4)0-1-OH, —(X4)0-1—NH2, —(X4)0-1—N(H)(R4a), —(X4)0-1—N(R4b)(R4a), —(X4)0-1—CF3, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, —(X4)0-1-(3-10 membered heterocycloalkyl), —(X4)0-1-(5-10 membered heteroaryl), —(X4)0-1-(3-7 membered cycloalkyl), —(X4)0-1—C(═Y4)N(H)(R4a), —(X4)0-1—C(═Y4)NH2, —(X4)0-1—C(═Y4)N(R4a)(R4b), —(X4)0-1—C(═Y4)OR4a, —(X4)0-1—C(═Y4)OH, —(X4)0-1—N(H)C(═Y4)(R4a), —(X4)0-1—N(R4b)C(═Y4)(R4a), —(X4)0-1—N(H)C(═Y4)OR4a, —(X4)0-1—N(R4b)(═Y4)OR4, —(X4)0-1—S(O)1-2R4a, —(X4)0-1—N(H)S(O)1-2R4a, —(X4)0-1—N(R4b)S(O)1-2R4a, —(X4)0-1—S(O)0-1N(H)(R4a), —(X4)0-1—S(O)0-1N(R4b)(R4a), —(X4)0-1—S(O)0-1NH2, —(X4)0-1—S(═O)(═NR4b)R4a, —(X4)0-1—C(═Y4)R4a, —(X4)0-1—C(═Y4)H, —(X4)0-1—C(═NOH)R4a, —(X4)0-1—C(═NOR4b)R4a, —(X4)0-1—NHC(═Y4)N(H)(R4a), —(X4)0-1—NHC(═Y3)NH2, —(X4)0-1—NHC(═Y4)N(R4b)(R4a), —(X4)0-1—NR4aC(═Y4)N(H)(R4a), —(X4)0-1—N(R4a)C(═Y4)NH2, —(X4)0-1—OC(═Y4)R4a, —(X4)0-1—OC(═Y4)H, —(X4)0-1—OC(═Y4)OR4a, —(X4)0-1—P(═Y4)(OR)(OR4a)(OR4b), —SC(═Y4)OR4a and —SC(═Y4)N(R4a)(R4b) wherein R4a and R4b at each occurrence are each independently selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 6-10 membered aryl, 3-7 membered cycloalkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, 6-10 membered aryl-C1-4 alkyl, 3-7 membered cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl and 3-7 membered heterocycloalkyl-C1-4 alkyl, and X4 is selected from the group consisting of C1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene and C2-4 alkynylene;
• Y4 is O, NR4c or S wherein R4c is hydrogen or C1-6 alkyl;
• wherein the aromatic and aliphatic portions of R4 is independently further substituted with 0 to 4 RA4 substituents selected from the group consisting of —F, —Cl, —Br, I, —CN, —NO2, —SF5, —OH, —NH2, —CF3, ═O, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, —C(═O)N(H)(C1-6 alkyl), —C(═O)N(C1-6 alkyl)2, —C(═O)NH2, —C(═O)OC1-6 alkyl, —C(═O)OH, —N(H)C(═O)(C1-6 alkyl), —N(C1-6 alkyl)C(═O)(C1-6 alkyl), —N(H)C(═O)OC1-6 alkyl, —N(C1-6 alkyl)C(═O)OC1-6 alkyl, —S(O)1-2C1-6 alkyl, —N(H)S(O)1-2C1-6 alkyl, —N(C1-6 alkyl)S(O)1-2C1-6 alkyl, —S(O)0-1N(H)(C1-6 alkyl), —S(O)0-1N(C1-6 alkyl)2, —S(O)0-1NH2, —C(═O)C1-6 alkyl, —C(═NOH)C1-6 alkyl, —C(═NOC1-6 alkyl)C1-6 alkyl, —NHC(═O)N(H)(C1-6 alkyl), —NHC(═O)N(C1-6 alkyl)2, —NHC(═O)NH2, —N(C1-6 alkyl)C(═O)N(H)(C1-6 alkyl), —N(C1-6 alkyl)C(═O)NH2, —OC(═O)C1-6 alkyl, —OC(═O)OC1-6 alkyl, —OP(═O)(OC1-6 alkyl)2, —SC(═O)OC1-6 alkyl and —SC(═O)N(C1-6 alkyl)2;
• n is an integer from 0 to 5;
• R5 is absent or is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, —OH, OR5a, —CN and halogen, wherein R5a is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and C1-6 heteroalkyl;
• or optionally R4 and R5 are optionally combined to form a 5-7 membered cycloalkyl or heterocycloalkyl and is independently further substituted with 0-4 RA4 substituents;
• and
• R6 is hydrogen, —F, —Cl, —Br, —I, C1-3 alkyl or C1-3 haloalkyl.