Substituted pyridine spleen tyrosine kinase (syk) inhibitors

A compound of the Formula (I)

• or a pharmaceutically acceptable salt thereof, wherein
• R1 is selected from the group consisting of H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and 4-piperidinyloxy;
• R2 is selected from the group consisting of H, methyl, methoxy, —CHF2, —CF3, halo, and cyano;
• R3 is selected from the group consisting of H, C1-C3 alkyl and halo;
• R4 is selected from the group consisting of H, C1-C3 alkyl, C1-C3 fluoroalkyl, C3-C6 cycloalkyl, halo, —N(R4a)2, —N(R4a)C(O)R4b, —N(R4a)C(O)N(R4a)2, —CO2H,
• each R4ais independently selected from the group consisting of H and C1-C3 alkyl;
• R4bis C1-C3 alkyl;
• Cy is a 6-membered heteroaryl selected from the group consisting of:
• t is 0, 1, 2, or 3;
• each Rcy is independently selected from the group consisting of:
• A. a group of the formula
• wherein
• Y1 is a bond, —CH2—, or —C(O)—;
• D1 is
• (i) a 4- to 9-membered mono- or bicyclic heterocyclic ring optionally containing one to two additional heteroatoms selected from the group consisting of N, O, S, S(O), and S(O)2;
• (ii) a 9- to 11-membered spiroheterocyclic ring containing one to two additional heteroatoms selected from the group consisting of N and O;
• each R10 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halo, hydroxyl, C1-C3 fluoroalkyl, —(CH2)n5CO2Rg, hydroxyl(C1-C3)alkyl, —(CH2)n5OCH3, —C(O)—(C1-C3) alkyl, —(CH2)n5C(O)N(Rh)2, —S(O)2—(C1-C3) alkyl, —C(O)CH2CN, and —C(O)CH2OH,
• or wherein when two R10 moieties are geminally substituted on a common ring carbon atom of D1, the two geminally substituted R10 moieties together with the carbon atom on which they are attached form —C(O)—;
• n5 is 0, 1, 2, or 3;
• each Rg is independently selected from the group consisting of:
• (i) H;
• (ii) C1-C8 alkyl;
• (iii) a group of the formula -M-RCH, wherein
• M is a bond or —(CH2)n6—, wherein n6 is 1 or 2;
• RCH is (a) aryl or C3-C6 cycloalkyl optionally substituted with 1-3 groups independently selected from halo, C1-C4 alkyl, or C1-C4 alkoxy;
• or (b) a 5- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, wherein said heterocycle of RCH is optionally substituted with 1 or 2 groups independently selected from the group consisting of oxo and C1-3 alkyl;
• (iv) a group of the formula —(CH2)n6—Rm or —(CH2)2—O—(CH2)2—Rm wherein
• Rm is —CO2Rm1, —C(O)N(Rm2)2, or —O(CO)Rm1;
• Rml is C1-C4 alkyl;
• and
• Rm2 is H or C1-C4 alkyl;
• n6 is 1 or 2;
• (v) a group of the formula —(CH2)2—Rn,
• Rn is OH, —O—(C1-C4 alkyl), —O—(CH2)2—O—(C1-C4 alkyl), NH2, —N(H)(C1-C4 alkyl) or —N(C1-C4 alkyl)2;
• (vi) a group of the formula NO O, wherein
• Ro is H or C1-C4 alkyl;
• and
• Rp is C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl;
• and,
• (vii) a group of the formula
• wherein Ro and Rp are as set forth above;
• each Rh is independently H, C1-C3 alkyl, C3-C6 cycloalkyl, —CH2CO2H, —CH2C(O)NH2, —S(O)2—C1-C3 alkyl, or —S(O)2—NH2;
• q is 0, 1, 2, 3, 4, or 5;
• the group —YE-E is absent or present, and if present,
• —YE is a bond or —C(O)—;
• E is
• (i) a C3-C6 cycloalkyl ring;
• (ii) a 5- or 6-membered heterocyclic ring containing one N atom;
• or
• (iii) an indolyl,
• wherein E is unsubstituted or substituted by one to three RYE moieties, wherein said RYE moieties are selected from the group consisting of C1-C3 alkyl, —CO2H, or wherein when two RYE moieties are geminally substituted on a common ring carbon atom of E, the two geminally substituted RYE moieties together with the carbon atom on which they are attached form —C(O)—;
• B. a group of the formula
• wherein
• Y2 is a bond, —CH2—, —C(O)—, —N(Rk)—, —O—, —C(O)—N(Rk)—, —S(O)2—N(Rk)—, or —N(Rk)—S(O)2—;
• Rk is H or C1-C3 alkyl;
• D2 is selected from the group consisting of:
• (i) a C3-C6 cycloalkyl,
• (ii) a 5- to 9-membered mono- or bicyclic heterocyclyl containing 1 or 4 heteroatoms selected from the group consisting of N, O, S, S(O), and S(O)2;
• (iii) a 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, wherein said heteroaryl of D2 is other than indolyl;
• and
• (iv) phenyl;
• each Ri is independently H, C1-C3 alkyl, hydroxyl, —CO2H, or —N(H)C(O)NH2;
• each Rj is independently H, C1-C4 alkyl, or cyclopropyl;
• s is 0, 1, 2, or 3;
• and
• R10 and q are as described above;
• C. a group of the formula
• wherein
• Y3 is (i) a bond,
• Re is H, C1-C3 alkyl;
• hydroxyl(C2-C3) alkyl, or —(CH2)n3CN;
• wherein n3 is 2 or 3
• each Ra is independently selected from the group consisting of H, C1-C6 alkyl, C1-C3 fluoroalkyl, hydroxy(C1-C3) alkyl, —(CH2)n4—O—(C1-C3) alkyl, —(CH2)n4C(O)NH2, —(CH2)n4S—(C1-C3) alkyl, and —(CH2)n4S(O)2—(C1-C3) alkyl;
• wherein each n4 is independently 1, 2 or 3;
• each Rb is independently selected from the group consisting of H, hydroxyl, fluoro, C1-C6 alkyl, C1-C3 fluoroalkyl, hydroxy(C1-C3) alkyl, —(CH2)n4—O—(C1-C3) alkyl, —(CH2)n4C(O)NH2, —(CH2)n4S—(C1-C3) alkyl, and —(CH2)n4S(O)2—(C1-C3) alkyl;
• each Rc is independently selected from the group consisting of H and C1-C3 alkyl;
• Rf is H, CHF2, CF3, —CO2Rg, —C(O)N(Rh)2, —CN, hydroxyl, —N(Rh)2, or (C1-C3) alkoxy,
• n1 is 0, 1, 2, or 3;
• n2 is 0 or 1;
• Rg and Rh are as defined above;
• D. amino;
• E. halo;
• F. —C(O)NH2;
• G. —S(O)2NH2;
• H. a group of the formula
• wherein
• Ra′ is H or F;
• and
• Rf1 is hydroxyl, C1-C3 alkoxy, or —NH2;
• I. —C(O)—Rq, wherein Rq is C1-C3 alkyl, or —(CH2)n4CN, wherein n4 is as defined above;
• J. —C(O)N(H)—S(O)2—Rs, wherein Rs is C1-C3 alkyl, —NH2, —N(H)(C1-C3 alkyl), or —N(C1-C3 alkyl)2;
• K. a group of the —N(H)C(O)—CH2—C(O)ORg or —N(H)S(O)2—CH2—C(O)ORg;
• and
• L. —N(H)S(O)2—(C1-C3 alkyl);
• or two Rcy moieties when substituted on adjacent carbon atoms of Cy optionally form a 5- or 6-membered ring selected from the group consisting of pyrroline, imidazolidone, or dihydrooxazine, wherein said 5- or 6-membered ring is unsubstituted or substituted by C1-C3 alkyl.