US 2018/0127368 A1 · TRICYCLIC SULFONES AS ROR GAMMA MODULATORS

Abstract

There are described RORγ modulators of the formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

The compound of the Formula (I)

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
X is —CR4R5—, —(CR4R5)2, —OCR6R7—, —S(O)pCR6R7—, —S(O)(NRg)CR6R7— or —NR6CR6R7—;
A is a monocyclic 5- or 6-membered aromatic or heteroaromatic ring;
B is a monocyclic 3-, 4-, 5-, 6- or 7-membered carbocyclic ring;
Y is a 5 or 6-membered aromatic or heteroaromatic ring;
R1 is, independently at each occurrence, selected from hydrogen, CD3, halo, OCF3, CN, S(O)p(C1-C6)alkyl, S(O)(NRg)(C1-C6)alkyl, —S(O)p(C1-C6)alkyl-OH, S(O)(NRg)(C1-C6)alkyl-OH, -thioalkoxyalkoxy, NR11R11, C1-6 alkyl substituted with 0-3 R1a, O—C1-6 alkyl substituted with 0-3 R1a, —(CR1bR1c)r-3-14 membered carbocycle substituted with 0-3 R1a and —(CR1bR1c)r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-3 R1a;
R1a is, independently at each occurrence, hydrogen, ═O, halo, CF3, OCF3, CN, NO2, —(CR1bR1c)r—ORb, —(CR1bR1c)r—S(O)pRb, —(CR1bR1c)r—S(O)(NRg)Rb, —(CR1bR1c)r—C(O)Rb, —(CR1bR1c)r—C(O)ORb, —(CR1bR1c)r—OC(O)Rb, —(CR1bR1c)r—NR11R11, —(CR1bR1c)r—C(O)NR11R11, —(CR1bR1c)r—NRbC(O)Rc, —(CR1bR1c)r—NRbC(O)ORc, —NRbC(O)NR11R11, —S(O)pNR11R11, —NRbS(O)pRc, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, —(CR1bR1c)r-3-14 membered carbocycle substituted with 0-3 Ra, or —(CR1bR1c)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-3 Ra;
R1b and R1c are, independently at each occurrence, hydrogen, halogen or C1-6 alkyl;
R2 is, independently at each occurrence, hydrogen, C1-6 alkyl substituted with 0-3 R2a, ═CR2aR2a, C2-6 alkenyl substituted with 0-3 R2a, —(CR2eR2f)rOR2b, —(CR2eR2f)rC(O)R2b, —(CR2eR2f)rC(O)OR2b, —(CR2eR2f)rOC(O)OR2b, —(CR2eR2f)rOC(O)NR11R11, —(CR2eR2f)rNR2bC(O)NR11R11, —(CR2eR2f)rC(O)NR11R11, —(CR2eR2f)rS(O)pRc, —(CR2eR2f)rS(O)(NRg)Rc, —(CR2eR2f)rS(O)pNR11R11, —(CR2eR2f)rNR2bC(O)R2c, —(CR2eR2f)rNR2bC(O)OR2c, —(CR2eR2f)r NR11R11, —(CR2eR2f)rNR2bS(O)pRc, —(CR2eR2f)rNR2bS(O)pNR11R11, —(CR2eR2f)r-3-10 membered carbocycle substituted with 0-3 R2a or —(CR2eR2f)r-4-10 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg) substituted with 0-3 R2a;
or one R2 together with an R2 on an adjacent carbon combine to form a fused ring substituted with 0-3 R2a, wherein the fused ring is selected from 3-10 membered carbocycle substituted with 0-3 R2a, or 3-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(O), S(O)p and S(O)(NRg), substituted with 0-3 R2a;
R2a is, independently at each occurrence, hydrogen, ═O, halo, OCF3, CN, NO2, —(CR2eR2f)r—ORb, —(CR2eR2f)r—S(O)pRb, —(CR2eR2f)r—S(O)(NRg)Rb, —(CR2eR2f)r—C(O)Rb, —(CR2eR2f)r—C(O)ORb, —(CR2eR2f)r—OC(O)Rb, —(CR2eR2f)r—OC(O)NR11R11, —(CR2eR2f)r—OC(O)ORc, —(CR2eR2f)r—NR11R11, —(CR2eR2f)r—C(O)NR11R11, (CR2eR2f)r—NRbC(O)Rc, —(CR2eR2f)r—NRbC(O)ORC, —NRbC(O)NR11R11, —S(O)pNR11R11, —NRbS(O)pRc, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, —(CR2eR2f)r-3-14 membered carbocycle substituted with 0-3 Ra, or —(CR2eR2f)r-4-7 membered heterocycle comprising carbon atoms, and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-4 Ra;
R2b is, independently at each occurrence, hydrogen, CF3, —(CR2eR2f)qORb, —(CR2eR2f)qS(O)pRb, —(CR2eR2f)qS(O)(NRg)Rb, —(CR2eR2f)r—C(O)Rc, —(CR2eR2f)r—C(O)ORb, —(CR2eR2f)qOC(O)Rb, —(CR2eR2f)qNR11R11, —(CR2eR2f)r—C(O)NR11R11, —(CR2eR2f)qNRbC(O)Rc, —(CR2eR2f)qNRbC(O)ORc, —(CR2eR2f)qNRbC(O)NR11R11, —(CR2eR2f)qS(O)2NR11R11, —(CR2eR2f)qNRbS(O)2Rc, C1-6 alkyl substituted with 0-2 Ra, C1-6 haloalkyl, —(CR2eR2f)r-3-14 membered carbocycle substituted with 0-3 Ra, or —(CR2eR2f)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-4 Ra;
R2c is, independently at each occurrence, hydrogen, C1-6 alkyl substituted with 0-3 Ra, C2-6 alkenyl substituted with 0-3 Ra, C3-10 cycloalkyl substituted with 0-3 Ra, C6-10 aryl substituted with 0-3 Ra, or —(CR2eR2f)r-5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-4 Ra;
R2e and R2f are, independently at each occurrence, hydrogen, halogen or C1-6 alkyl;
R3 is, independently at each occurrence, selected from hydrogen, halo, N3, CN, —(CR1bR1c)r—OR3b, —(CR1bR1c)r—NR11R11, C1-6 alkyl substituted with 0-3 R3a, C3-10 cycloalkyl substituted with 0-3 R3a;
and phenyl substituted with 0-3 R3a, or 4-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-3 R3a, or two R3 located on adjacent carbon atoms link to form a 5-7 membered carbocycle or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatom selected from N, O, S(O)p and S(O)(NRg), both optionally substituted with 0-3 R3a;
R3a is, independently at each occurrence, hydrogen, ═O, halo, OCF3, OCHF2, CF3, CHF2, CN, NO2, —(CR1bR1c)r—ORb, —(CR1bR1c)r—S(O)pRb, —(CR1bR1c)r—S(O)(NRg)Rb, —(CR1bR1c)r—C(O)Rb, —(CR1bR1c)r—C(O)ORb, —(CR1bR1c)r—OC(O)Rb, —(CR1bR1c)r—NR11R11, —(CR1bR1c)r—C(O)NR11R11, —(CR1bR1c)r—NRbC(O)Rc, —(CR1bR1c)r—NRbC(O)ORc, —NRbC(O)NR11R11, —S(O)pNR11R11, —NRbS(O)pRc, C1-6 alkyl substituted with 0-3 Ra, C2-6 alkenyl substituted with 0-3 Ra, C2-6 alkynyl substituted with 0-3 Ra, C1-6 haloalkyl, —(CR1bR1c)r-3-14 membered carbocycle substituted with 0-3 Ra, or —(CR1bR1c)r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-3 Ra;
R3b is, independently at each occurrence, hydrogen, CF3, —(CR1bR1c)qORb, —(CR1bR1c)qS(O)pRb, —(CR1bR1c)qS(O)(NRg)Rb, —(CR1bR1c)r—C(O)R3d, —(CR1bR1c)r—C(O)ORb, (CR1bR1c)qOC(O)Rb, —(CR1bR1c)qNR11R11, —(CR1bR1c)r—C(O)NR11R11, —(CR1bR1c)qNRbC(O)R3c, —(CR1bR1c)qNRbC(O)ORc, —(CR1bR1c)qNRbC(O)NR11R11, —(CR1bR1c)qS(O)2NR11R11, —(CR1bR1c)qNRbS(O)2Rc, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, —(CR1bR1c)r-3-14 membered carbocycle substituted with 0-3 Ra, or —(CR1bR1c)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-3 Ra;
R3c and R3d are, independently at each occurrence, hydrogen or C1-6 alkyl;
R4 and R5 are independently hydrogen, halo, C(═O)C1-4 alkyl, C(═O)OC1-4 alkyl, C1-6 alkyl or C1-6 haloalkyl, or
R4 and R5 taken together are ═O, or together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring;
R6 and R7 are independently hydrogen, C(═O)C1-4 alkyl, C(═O)OC1-4 alkyl, C1-6 alkyl or C1-6 haloalkyl;
or
R6 and R7 taken together are ═O, or together with the carbon atom to which they are attached form a 3- to 6-membered spirocarbocyclyl ring or a spiroheterocyclyl ring;
R11 is, independently at each occurrence, hydrogen, C1-6 alkyl substituted with 0-3 Rf, CF3, —(CR1bR1c)r—C3-10 cycloalkyl substituted with 0-3 Rf, —(CR1bR1c)r-phenyl substituted with 0-3 Rd, or —(CR1bR1c)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-4 Rd;
or one R11 and a second R11, both attached to the same nitrogen atom, combine to form a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-4 Rd;
Ra is, independently at each occurrence, hydrogen, ═O, halo, OCF3, CF3, CHF2, CN, NO2, —(CR1bR1c)r—ORb, —(CR1bR1c)r—S(O)pRb, —(CR1bR1c)r—S(O)(NRg)Rb, —(CR1bR1c)r—C(O)Rb, (CR1bR1c)r—C(O)ORb, —(CR1bR1c)r—OC(O)Rb, —(CR1bR1c)r—NR11R11, —(CR1bR1c)r—C(O)NR11R11, —(CR1bR1c)r—NRbC(O)Rc, —(CR1bR1c)r—NRbC(O)ORc, —NRbC(O)NR11R11, —S(O)pNR11R11, NRbS(O)pRc, —(CR1bR1c)r—O(CR1bR1cO)tP(O)(ORb)2, —(CR1bR1c)r—O(CR1bR1cO)tS(O)2ORb, C1-6 alkyl substituted with 0-3 Rf, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Re, C2-6 alkynyl substituted with 0-3 Re, —(CR1bR1c)r-3-14 membered carbocycle, or —(CR1bR1c)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-4 Rf;
Rb is, independently at each occurrence, hydrogen, C1-6 alkyl substituted with 0-3 Rd, C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-3 Rd, —(CR1bR1c)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-4 Rf, or —(CR1bR1c)r-6-10 membered carbocycle substituted with 0-3 Rd;
Rc is, independently at each occurrence, C1-6 alkyl substituted with 0-3 Rf, —(CR1bR1c)r—C3-6 cycloalkyl substituted with 0-3 Rf, or —(CR1bR1c)r-phenyl substituted with 0-3 Rf;
Rd is, independently at each occurrence, hydrogen, ═O, halo, OCF3, CF3, CN, NO2, —ORe, —(CR1bR1c)r—C(O)Rc, —NReRe, —NReC(O)ORc, C(O)NReRe, —NReC(O)Rc, CO2H, CO2Rc, —NReSO2Rc, SO2Rc, SO(NRg)Rc, C1-6 alkyl substituted with 0-3 Rf, C3-6 cycloalkyl substituted with 0-3 Rf, —(CR1bR1c)r-phenyl substituted with 0-3 Rf or —(CR1bR1c)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), substituted with 0-4 Rf;
Re is, independently at each occurrence, selected from hydrogen, C(O)NRfRf, C1-6 alkyl, C3-6 cycloalkyl, -5-7 membered heterocycle or —(CR1bR1c)r-phenyl substituted with 0-3 Rf;
Rf is, independently at each occurrence, hydrogen, ═O, halo, CN, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, SO2(C1-6 alkyl), SO(NRg)(C1-6 alkyl), CO2H, CO2(C1-6 alkyl), OH, C3-6 cycloalkyl, CF3, O(C1-6 alkyl);
or an optionally substituted —(CR1bR1c)r-5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, S(O)p and S(O)(NRg), phenyl or C3-6 cycloalkyl, each group optionally substituted with halo, CN, CF3, C1-6 alkyl or O(C1-6 alkyl);
Rg is, independently at each occurrence, hydrogen, C1-6 alkyl substituted with 0-3 Rf, C1-6 haloalkyl, —(CR1bR1c)r—C(O)Rb, —(CR1bR1c)r—C(O)ORb, —(CR1bR1c)r—C(O)NR11R11, —(CR1bR1c)r-3-14 membered carbocycle, or —(CR1bR1c)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(O) and S(O)p substituted with 0-4 Rf;
m is 0, 1, 2 or 3;
p is, independently at each occurrence, 0, 1, or 2;
q is, independently at each occurrence, 2 or 3;
r is 0, 1, 2, 3, or 4;
and
t is 0 or 1.

37 more elements

Tricyclic sulfones as ror gamma modulators

Life of this patent

Tricyclic sulfones as ror gamma modulators

Life of this patent

Abstract

Claims20