EA041942B1 - SPIROCYCLIC MODULATORS ROR-GAMMA - Google Patents

Description

cross reference

The present application claims priority under U.S. Provisional Application No.

62/641949, filed March 12, 2018, the contents of which are hereby incorporated by reference in their entirety.

State of the art

Retinoic acid-related orphan nuclear receptors (RORs) consist of three members: RQRa, RORe, and RORy. ROR3 expression is mainly restricted to the brain and retina, while RORa and RORy expression is widespread. RORy also has a shorter isoform than RQRyt, which is primarily expressed in the immune system.

RORyt is required for the development of secondary lymphoid tissues, in particular lymph nodes and Peyer's patches. Recent studies have identified a critical role for RORyt in the specification of the uncommitted CD4+ T helper cell line into Th17 cells, as well as in the development of Tc17 (cytotoxic) T cells. The Th17 response is implicated in a variety of autoimmune diseases such as psoriasis, inflammatory bowel disease, arthritis, and multiple sclerosis. Inhibition of the Th17 and Tc17 response has also been shown in several experimental tumor models through the mechanism of cancer cell evasion from antitumor immunity. These data indicate that both RORy agonists and inverse agonists are potential therapeutic agents for various diseases.

The essence of the invention

In one aspect, provided herein are compounds of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

(R ³ ) _k

Formula (I);

where © represents phenyl or a 5-membered or 6-membered heteroaryl ring;

® represents phenyl or a 5-membered or 6-membered heteroaryl ring;

Z is -(C(R ⁶ )(R ⁷ )) _t -;

R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 to 4 R ^3a groups; and each R ³ is independently selected from halogen and C 1 -C ₆ alkyl;

each R ^3a is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C9 heteroaryl, (C2C9 heteroaryl)-C1-C6 alkylene-, oxo, -S(Q)2R ¹⁰ , -C(O)R ¹⁰ , -C(O) QR ¹¹ , and -C(O)N(R ¹¹ )2, wherein C ₂ -C ₉ heteroaryl and (C ₂ -C ₉ heteroaryl)-C1-C ₆ alkylene- are optionally substituted with 1 to 3 groups independently selected from halogen, C1-C ₆ alkyl, C1-C ₆ haloalkyl and hydroxyl;

each _R ⁴ and each R ⁵ is independently selected from halo, cyano, -OH, _C1-6 alkyl, _C2-6 alkenyl, C1-C6 haloalkyl, C _{g C6} alkoxy, C3- _C8 cycloalkyl, -N(R ⁹ )2, -C(O)R ⁸ , -C(Q)OR ⁹ , -C(Q)N(R ⁹ )2, -N(R ⁹ )C(O)R ⁸ , -N(R ⁹ )SO2R ⁸ , -SO2R ⁸ and -SO2N(R ⁸ )2;

each R ⁶ and each R ⁷ independently represent hydrogen, halogen or C1-C ₆ alkyl;

each R ⁸ is independently C1-C ₆ alkyl or C1-C ₆ haloalkyl;

each R ⁹ is independently hydrogen, C1-C ₆ alkyl or C1-C ₆ haloalkyl;

each R ¹⁰ is independently C 1 -C ₆ alkyl, C 1 -C ₆ haloalkyl, C ₁ -C ₆ alkyl-O-C ₁ -C ₆ alkyl-, C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl, phenyl , (phenyl)-C1-C ₆ alkylene-, C ₂ -C ₉ heteroaryl, or (C ₂ C ₉ heteroaryl) -C1-C ₆ alkylene-, where indicated C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl , phenyl, (phenyl)-C1C ₆ alkylene-, C ₂ -C ₉ heteroaryl or (C ₂ -C ₉ heteroaryl)-C 1 -C ₆ alkylene- are optionally substituted with 1 to 3 groups selected from halogen, C 1 -C ₆ alkyl, _C1-6 haloalkyl and hydroxyl;

each R ¹¹ independently represents hydrogen, C1-C ₆ alkyl or C1-C ₆ haloalkyl;

m is 1, 2, or 3;

n is 1, 2, or 3;

k is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4; and t is 0, 1, 2, or 3;

- 1 041942 where heteroaryl or heterocyclyl contains from one to five heteroatoms, each of which is independently selected from O, S or N, while the remaining ring atoms are carbon atoms. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is provided, wherein O is phenyl.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is provided, wherein is phenyl.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said The 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 to 2 R ^3a groups. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof having formula (II) is provided.

_CF3

OH (R ³ ) _k

Formula (II);

where X represents -O-, -NH-, -N(R ^3a )-, -S-, -S(O)-, or -S(O) ₂ -;

a has a value of 1 or 2; and b has a value of 1 or 2.

In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt or stereoisomer thereof having formula (IIa) is provided.

In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt or stereoisomer thereof, is provided, wherein R ^3a is -S(O)2R ¹⁰ , -C(O)R ¹⁰ , or -C (O)OR ⁿ . In some embodiments, a compound of formula (I), (II) or (IIa), or a pharmaceutically acceptable salt or stereoisomer thereof, is provided, wherein R ^3a is -S(O)2R ¹⁰ . In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt or stereoisomer thereof, is provided, wherein R ¹⁰ is C1-C6 alkyl. In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt or stereoisomer thereof, is provided, wherein each R6 and each ^R7 is hydrogen. In some embodiments, a compound of formula (I), (II), or (IIa) is provided, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein t is 1. In some embodiments, a compound of formula (I), (II) or (IIa) is provided. ), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein p is 0, 1, 2, or 3. In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt or stereoisomer thereof, is provided, wherein each R ⁴ is independently halogen, C1-C6 alkyl, C ₂ -C6 alkenyl, C ₁ -C6 haloalkyl, C ₁ C6 alkoxy, or C ₃ -C ₈ cycloalkyl. In some embodiments, a compound of formula (I), (II), or (IIa) is provided, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein q is 0, 1, or 2. In some embodiments, a compound of formula (I), (II ) or (IIa), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R ⁵ is independently halogen, cyano, C ₁ -C 6 alkyl, C _{1 -C} 6 haloalkyl, or C ₁ -C 6 alkoxy. In some embodiments, a compound of formula (I), (II), or (IIa) is provided, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein k is 0. In another aspect, provided herein is a compound selected from the following:

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2-(2'-ethyl-4'-((4-((methylsulfonyl)methyl)piperidin-1-yl)methyl)-[1,G-biphenyl]-4-yl)1,1,1,3, 3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((4-(methylsulfonyl)piperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1,1,1,3,3 ,3hexafluoropropan-2-ol;

N-((l -((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4yl) methyl)azetidin-3-yl)methyl)-N-methylmethanesulfonamide;

N-((l -((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4yl) methyl)azetidin-3-yl)methyl)methanesulfonamide;

2-(3',6'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)- [1,1'-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(3',5'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)- [1,1'-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

6-((4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2'-methyl-[1,1'-biphenyl]4- yl)methyl)-2-thia-6-azaspiro[3,4]octane 2,2-dioxide;

6-((4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2'-methyl-[1,1'-biphenyl]4- yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide;

2-(2'-(sec-butyl)-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoro propan-2-ol;

2-(2',3'-difluoro-6'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)- [1,1'-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(2'-fluoro-6'-isopropyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2-yl) methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol;

6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2'-methyl-[1,1'-biphenyl]-4yl )methyl)-2-thia-6-azaspiro[3,4]octane 2,2-dioxide;

6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -2thia-6-azaspiro[3,4]octane 2,2-dioxide;

6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2'-methyl-[1,1'-biphenyl]-4yl )methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide;

2-(2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-2-yl)methyl)-[1,G-biphenyl]4-yl)-1, 1,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)methyl)-[1,1'-biphenyl]4-yl)- 1,1,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((6-(isobutylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl)-1,1 ,1,3,3,3-hexafluoro propan-2-ol;

- 3 041942

2-(2'-ethyl-4'-((6-(propylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl)-1,1 ,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((6-(ethylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,G-biphenyl]-4yl)-1,1 ,1,3,3,3-hexafluoropropan-2-ol;

2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- [1,1'-biphenyl]-4-yl)methyl) -7thia-2-azaspiro[3.5]nonane 7,7-dioxide;

2-(2'-(tert-butyl)-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoro propan-2-ol;

2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -6thia-2-azaspiro[3,4]octane 6,6-dioxide;

2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -6thia-2-azaspiro[3,4]octane 6-oxide;

6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -2thia-6-azaspiro[3.3]heptane 2,2-dioxide;

6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -2thia-6-azaspiro[3.3]heptane 2-oxide;

2-(4'-((2-thia-6-azaspiro[3.3]heptan-6-yl)methyl)-2'-ethyl-[1,1'-biphenyl]-4-yl)-1.1, 1,3,3,3hexafluoropropan-2-ol;

2-(2'-ethyl-4'-((2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)-[1,G-biphenyl]-4yl)-1, 1,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-ethyl-4'-((7-(methylsulfonyl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-[1,G-biphenyl]4-yl)-1, 1,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-[1,G-biphenyl]4-yl)-1 ,1,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((2-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-[1,G-biphenyl]4-yl)-1 ,1,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-2-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-2-yl)methyl)-[1,G-biphenyl]-4yl)-1,1 ,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-ethyl-6'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl )-1,1,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-5'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl )-1,1,1,3,3,3-hexafluoro propan-2-ol;

- 4 041942

2-(2'-ethyl-3'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl )-1,1,1,3,3,3-hexafluoro propan-2-ol;

tert-butyl 2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4yl)methyl )-2,6-diazaspiro[3.4]octane-6-carboxylate;

2-(2'-ethyl-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoro propan-2-ol;

methyl 6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4yl)methyl)- 2,6-d iazaspiro[3.3] heptane-2-carboxylate;

2-(4'-((6-(cyclopropylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2'-ethyl-[1,Hbiphenyl]-4-yl)-1,1 ,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-cyclopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl)-1,1 ,1,3,3,3-hexafluoro propan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan2-yl)methyl)-[ 1 ,1'-biphenyl]-4-yl)propan-2-ol;

tert-butyl 6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4yl)methyl )-2,6-d iazaspiro[3.3] heptane-2-carboxylate;

1,1,1,3,3,3-hexafluoro-2-(4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)2'-(prop- 1-en-2-yl)-[1,1'-biphenyl]-4-yl)propan-2-ol;

2-(2'-bromo-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,G-biphenyl]4-yl)-1, 1,1,3,3,3-hexafluoro propan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)2'-(trifluoromethyl) -[ 1,1'-biphenyl]-4-yl)propan-2-ol;

2-(2'-chloro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,G-biphenyl]4-yl)-1, 1,1,3,3,3-hexafluoro propan-2-ol;

-(6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl) methyl)2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one;

2-(2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,G-biphenyl]4-yl)-1, 1,1,3,3,3-hexafluoro propan-2-ol;

-(6-((4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1'-biphenyl]-4yl)methyl) -2,6-d iazaspiro[3.3]heptan-2-yl)ethan-1-one;

1,1,1,3,3,3-hexafluoro-2-(2'-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1 ,1'-biphenyl]-4-yl)propan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(2'-methyl-4'-((6-(pyridin-4-ylmethyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl )-[1,1'-biphenyl]-4-yl)propan-2-ol;

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2-(4-(3-ethyl-5-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2yl)phenyl)-1,1,1,3 ,3,3-hexafluoro propan-2-ol;

7-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- [1,1'-biphenyl]-4-yl)methyl) 2,7-diazaspiro[4.4]nonan-1-one;

7-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- [1,1'-biphenyl]-4-yl)methyl) 2,7-diazaspiro[4.4]nonan-3-one;

4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-HM-dimethyl-4-((6-(methylsulfonyl)2,6-diazaspiro[3.3]heptan- 2-yl)methyl)-[1,G-biphenyl]-2-carboxamide;

2-(2'-ethyl-2-methoxy-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoro propan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(2'-methoxy-2-methyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2-yl)methyl )-[1,1'-biphenyl]-4-yl)propan-2-ol;

7-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- [1,1'-biphenyl]-4-yl)methyl) -2thia-7-azaspiro[4.4]nonane 2,2-dioxide;

2-(5-(2-ethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)phenyl)pyridin-2-yl)-1,1,1,3 ,3,3-hexafluoro propan-2-ol;

2-(4-(4-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3yl)phenyl)-1,1,1,3 ,3,3-hexafluoro propan-2-ol;

4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4-((6-(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2-yl)methyl )-[1,1'-biphenyl]-3-ol;

2-(2'-cyclopropyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-cyclopropyl-2,3',6'-trifluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1'- biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-chloro-2'-cyclopropyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan2-yl)methyl)- [1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(2,3',6'-trifluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3 ]heptane -2-yl)methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol;

2-(2'-cyclopropyl-2-ethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan2-yl)methyl)- [1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-cyclopropyl-3',6'-difluoro-2-methyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2-yl)methyl)- [1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-chloro-5'-fluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl ]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

- 6 041942

1,1,1,3,3,3-hexafluoro-2-(5'-fluoro-2'-isopropyl-2-methyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3] heptane- 2-yl)methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol;

2-(2,5'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl] - 4-yl)-1,1,1,3,3,3 - hexafluoropropan-2-ol;

2-(2-chloro-3', b'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-ethyl-3',6'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(3',6'-difluoro-2'-isopropyl-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan2-yl)methyl)-[ 1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-ethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[1,1-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2,2'-diethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1'- biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-chloro-2'-ethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-chloro-2'-ethyl-5'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[1,1-biphenyl ]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-ethyl-2,5'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[1,1-biphenyl]- 4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(5'-fluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2-yl) methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol;

2-(2,2'-diethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl)-1 ,1,1,3,3,3 - hexafluoro propan-2-ol;

2-(2'-ethyl-2,3',6'-trifluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[1,1 - biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-ethyl-2'-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-chloro-2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(3',6'-difluoro-2'-isopropyl-4'-((2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6yl)methyl)-[1,1'-biphenyl] -4-yl)-1,1,1,3,3,3 - hexafluoropropan-2-ol;

2-(4-(2-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3yl)-3-methylphenyl)-1,1, 1,3,3,3-hexafluoropropan-2-ol;

2-(2'-ethyl-3',6'-difluoro-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2'-ethyl-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3]heptane -2-yl)methyl)-[1, T-biphenyl]-2-carbonitrile;

2-(4-(4-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3yl)-3-methylphenyl)-1,1, 1,3,3,3-hexafluoropropan-2-ol;

2-(6-(2-ethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)phenyl)pyridin-3-yl)-1,1,1, 3,3,3-hexafluoro propan-2-ol;

2-(4-(3-ethyl-5-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2yl)-3-methylphenyl)-1,1, 1,3,3,3-hexafluoropropan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridine-2 -yl)phenyl)propan-2-ol; And

2-(2,2'-dimethyl-3'-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-[1,G-biphenyl]-4yl)-1,1, 1,3,3,3-hexafluoropropan-2-ol or a pharmaceutically acceptable salt thereof.

In another aspect, a pharmaceutical composition is provided for the treatment of psoriasis, psoriatic arthritis, uveitis, ulcerative colitis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, vitiligo, vesiculobullous dermatosis, rheumatoid

- 7 041942 arthritis, ankylosing spondylitis, reactive arthritis, arthritis associated with inflammatory bowel disease, juvenile rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, lupus, lupus nephritis, multiple sclerosis, axial spodiloarthritis, suppurative hydradenitis, Sjögren's syndrome, regional enteritis, Tholos-Hunt syndrome, undifferentiated connective tissue disease, obesity, insulin resistance caused by obesity, atherosclerosis or type II diabetes mellitus, containing a compound of formula (I), (II) or (IIa) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another aspect, the use of a compound of formula (I), (II) or (IIa), or a pharmaceutically acceptable salt or stereoisomer thereof, is provided in the treatment of a disorder or condition selected from psoriasis, psoriatic arthritis, uveitis, ulcerative colitis, asthma, allergic rhinitis, chronic obstructive pulmonary disease. diseases of the lungs (COPD), atopic dermatitis, vitiligo, vesiculobullous dermatosis, rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, arthritis associated with inflammatory bowel disease, juvenile rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, lupus, lupus nephritis, disseminated sclerosis, axial spodiloarthritis, suppurative hidradenitis, Sjögren's syndrome, regional enteritis, Tholos-Hunt syndrome, undifferentiated connective tissue disease, obesity, obesity-induced insulin resistance, atherosclerosis, and type II diabetes mellitus.

Include information by reference

All publications, patents and patent applications referred to in this specification are incorporated herein by reference to the same extent as if each individual publication, patent or patent application were specifically and separately indicated as being incorporated by reference.

Detailed description of the invention

In one aspect, provided herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

(R ³ ) _k

Formula (I);

where represents phenyl or 5-membered or 6-membered heteroaryl ring;

% Y is phenyl or a 5-membered or 6-membered heteroaryl ring;

Z is -(C(R ⁶ )(R ⁷ )) _t -;

R ¹ and R ² are selected from (i) and (ii):

(i) R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted from 1 to 4 R ^3a groups; and (ii) R ¹ is hydrogen and R ² is -S(O)2R ¹⁰ , -C1-C ₆ alkyl-S(O) ₂ R ¹⁰ , -N(R ¹¹ )S(O)2R ¹⁰ or -C1-C ₆ alkyl-N(R ¹¹ )S(O) ₂ R ¹⁰ ;

each R ³ is independently selected from halogen and C ₁ -C ₆ alkyl;

each R ^3a is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C9 heteroaryl, (C2C9 heteroaryl)-C1-C6 alkylene-, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ , -C(O) OR ⁿ , and -C(O)N(R ¹¹ )2, wherein C ₂ -C ₉ heteroaryl and (C ₂ -C ₉ heteroaryl)-C ₁ -C ₆ alkylene- are optionally substituted with 1 to 3 groups independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and hydroxyl;

each R ⁴ and each R ⁵ is independently selected from halo, cyano, -OH, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, -N(R ⁹ )2, -C(O) R ⁸ , -C(O)OR ⁹ , -C(O)N(R ⁹ ) ₂ , -N(R ⁹ )C(O)R ⁸ , -N(R ⁹ )SO2R ⁸ , -SO2R ⁸ and - SO2N( ^R8 )2;

each R ⁶ and each R ⁷ independently represent hydrogen, halogen or C ₁ -C ₆ alkyl;

each R ⁸ is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

each R ⁹ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

each R ¹⁰ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-O-C ₁ -C ₆ alkyl-, C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl , phenyl, (phenyl)-C ₁ -C ₆ alkylene-, C ₂ -C ₉ heteroaryl, or (C ₂ C ₉ heteroaryl) -C ₁ -C ₆ alkylene-, where the specified C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl, phenyl, (phenyl)-C ₁ C ₆ alkylene-, C ₂ -C ₉ heteroaryl or (C ₂ -C ₉ heteroaryl) -C ₁ -C ₆ alkylene- are optionally substituted with 1 to 3 groups, selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and hydroxyl;

- 8 041942 each R ¹¹ independently represents hydrogen, C ₁ -C6 alkyl or C ₁ -C6 haloalkyl; m is 1, 2, or 3;

n is 1, 2, or 3;

k is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1, 2, 3, or 4; and t is 0, 1, 2, or 3.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein O is phenyl or a 6-membered heteroaryl ring. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein CD is phenyl. In some embodiments, a compound of formula (I) or a pharmaceutical thereof is provided.

a legally acceptable salt, solvate, or stereoisomer, wherein is a 6-membered heteroaryl ring. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein ® is pyridyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein O is phenyl or a 6-membered heteroaryl ring.

In some embodiments, a compound of formula (I) or a pharmaceutical thereof is provided. ______ .. . _________ A .... . „.... .

a legally acceptable salt, solvate, or stereoisomer, wherein is phenyl. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable ( ^A ) salt, solvate, or stereoisomer thereof, is provided, wherein is a 6-membered heteroaryl ring. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein is pyridyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted from 1 to 4 R ^3a groups. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted from 1 to 2 R ^3a groups. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof having formula (II) is provided.

F ₃ C^ ^F 3 Y-on )^(R ⁵ ) _q bm y, ' a / η (R ³ )k

Formula (II);

where X represents -O-, -NH-, -N(R ^3a )-, -S-, -S(O)-, or -S(O) ₂ -;

a has a value of 1 or 2; and b has a value of 1 or 2.

In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein a is 1, b is 1, m is 2, and n is 2. In some embodiments, a compound of formula (II) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein a is 1, b is 2, m is 1, and n is 2. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein a is 1 , b is 1, m is 1, and n is 2. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein a is 2, b is 2, m is 1, and n is 1. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or

- 9 041942 stereoisomer, where a is 2, b is 1, m is 1, and n is 1. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, where a is 1, b is 1, m is 1, and n is 1. In some embodiments, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having formula (IIa) is provided.

(R ³ ) _k

Formula (Pa).

In some embodiments, a compound of formula (I), (II) or (IIa) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R ^3a is -S(O)2R ¹⁰ , -C(O)R ¹⁰ , or -C(O)OR ¹¹ . In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is -S(O)2R ¹⁰ . In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ¹⁰ is C1-C6 alkyl or C3-C8 cycloalkyl. In some embodiments, a compound of formula (I), (II), or (Ha), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ¹⁰ is C 1 -C ₆ alkyl. In some embodiments, a compound of formula (I), (II) or (Ha) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R ^3a is -S(O)2CH3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ is hydrogen and R ² is -S(O)2R ¹⁰ , -C1-C6alkyl-S(O)2R ¹⁰ , -N(R11)S(O)2R ¹⁰ , or -C1-C6alkylN(R11)S(O)2R ¹⁰ . In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ² is -S(O)2R ¹⁰ , -CH2S(O)2R ¹⁰ , -N(R11)S(O) 2R ¹⁰ or -CH2N(R ¹¹ )S(O)2R ¹⁰ . In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ¹⁰ is C1-C6 alkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ² is -S(O)2CH3, -CH2S(O)2CH3, -CH2N(H)S(O)2CH3, or -CH2N(CH3)S(O)2CH3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 1 and n is 1. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 2 and n is 1. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein m is 2 and n is 2. In some embodiments, a compound of formula (I), (II ) or (IIa) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is hydrogen. In some embodiments, a compound of formula (I), (II), or (IIa) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 1, 2, or 3. In some embodiments, a compound of formula (I) is provided, (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 1. In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer, where p is 0, 1, 2, or 3. In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein each R ⁴ is independently halogen, C1 -C ₆ alkyl, C ₁ -C ₆ alkenyl, C1C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₃ -C ₈ cycloalkyl. In some embodiments, a compound of formula (I), (II), or (IIa) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁴ is independently halo, C1-C6 alkyl, or C3-C8 cycloalkyl. In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein p is 1. In some embodiments, a compound of formula (I), (II), or ( IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 2. In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 3. In some embodiments, a compound of formula (I), (II), or (IIa) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0. In some embodiments, a compound of formula (I), (II) is provided. or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0, 1, or 2. In some embodiments, a compound of formula (I), (II), or (IIa) is provided, or a pharmaceutically acceptable salt thereof b, solvate or stereoisomer, where each R ⁵ is independently halogen, cyano, C1-C ₆ alkyl, C1-10 041942

C ₆ haloalkyl or C1-Cbalkoxy. In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein each R ⁵ is independently halo or C ₁ -C ₆ alkyl. In some embodiments, a compound of formula (I), (II), or (IIa) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 1. In some embodiments, a compound of formula (I), (II) or ( IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 2. In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0. In some embodiments, a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein k is 0.

In another aspect, a pharmaceutical composition is provided comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition is provided comprising a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition is provided comprising a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

In another aspect, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein disease, disorder or condition selected from psoriasis, psoriatic arthritis, uveitis, ulcerative colitis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, vitiligo, vesiculobullous dermatosis, rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, arthritis associated with inflammatory bowel disease, juvenile rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, lupus, lupus nephritis, multiple sclerosis, axial spondiloarthritis, hidradenitis suppurativa, Sjögren's syndrome, regional enteritis, Tholos-Hunt syndrome, undifferentiated connective tissue disease tissue, obesity, insulin resistance caused by obesity, atherosclerosis and type II diabetes mellitus.

Definitions

In the context of this disclosure, a number of terms are to be used.

Unless otherwise indicated, all technical and scientific terms used in this document have the same meaning as is commonly understood to which the claimed subject matter relates. In the event that there are multiple definitions of terms in this document, the definitions in this section will prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences (eg, those available from GenBank or other databases) mentioned herein are incorporated by reference. If reference is made to a URL or other such identifier or address, it is understood that such identifiers may change and specific information on the Internet may come and go, but equivalent information can be found by searching the Internet. The link to it indicates the existence and public dissemination of such information.

It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and do not limit any claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of or means and/or, unless otherwise indicated. In addition, the use of the term including, as well as other forms such as include, includes, and included, is not limiting.

The section headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter described.

Definitions of standard chemical terms can be found in reference books including, but not limited to, Carey and Sundberg Advanced Organic Chemistry 4 ^th Ed. Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA methods and pharmacology apply.

Unless specific definitions are provided, the applied nomenclature and laboratory tests and procedures for analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the art. Standard techniques can be applied to chemical synthesis, chemical analysis, pharmaceutical formulation, formulation and delivery, and patient management. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, tissue culture, and transformation (eg, electroporation, lipofection). Reactions and purification procedures can be performed, for example, using kits according to the manufacturer's specifications, or as is commonly done in the art, or as described herein. The above techniques and methods are usually

- 11 041942 can be performed in conventional ways and as described in various general and more specific references that are cited and discussed in the present description.

It should be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein, and as such may vary. It should also be understood that the terminology used herein is only intended to describe specific embodiments and is not intended to limit the scope of the methods, compounds, compositions described herein.

In the context of this document, the term C ₁ -C _x includes € ₁ -€ ₂ , C ₁ -C ₃ ...C ₁ -C _x . C ₁ -C _x refers to the number of carbon atoms that make up the moiety it denotes (excluding optional substituents).

An alkyl group refers to an aliphatic hydrocarbon group. Alkyl groups may or may not include units of unsaturation. The alkyl moiety may be a saturated alkyl group, which means that it does not contain any units of unsaturation (ie, carbon-carbon double bond or carbon-carbon triple bond). The alkyl group may also be an unsaturated alkyl moiety, which means that it contains at least one unit of unsaturation. The alkyl moiety, whether saturated or unsaturated, may be branched, linear or cyclic.

An alkyl group can contain from 1 to 6 carbon atoms (wherever it appears here, a numerical range such as 1 to 6 refers to each integer in that range; for example, 1 to 6 carbon atoms means that an alkyl group may consist of 1 carbon, 2 carbons, 3 carbons, etc. up to and including 6 carbons, although this definition also covers the presence of the term alkyl where no numerical range is specified). The alkyl group of the compounds described herein may be referred to as C1- _C6 alkyl or similar designations. By way of example only, C ₁ -C ₆ alkyl means that the alkyl chain contains from one to six carbon atoms, that is, the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, npentyl, isopentyl, neopentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl. Alkyl groups may be substituted or unsubstituted. Depending on the structure, the alkyl group may be a mono-radical or a di-radical (ie, an alkylene group).

Alkylene and alkylene chain, as used herein and unless otherwise indicated, refer to a straight or branched divalent hydrocarbon chain, consisting of only carbon and hydrogen, containing no unsaturation, and having one to eight or one to six carbon atoms, examples of which include methylene, ethylene, propylene, n-butylene and the like. The alkylene chain can be attached to the rest of the molecule by replacing any two hydrogen atoms in the chain. Alkoxy refers to the group -O-alkyl, where alkyl is as defined herein.

The term alkenyl refers to a type of alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, the alkenyl group begins with atoms -C(R)=CR2, where R refers to the remaining parts of the alkenyl group, which may be the same or different. Non-limiting examples of the alkenyl group include -CH=CH ₂ , -C(CH ₃ )=CH ₂ , -CH=CHCH ₃ , -CH=C(CH ₃ ) ₂ and -C(CH ₃ )=CHCH ₃ . The alkenyl moiety may be branched, linear, or cyclic (in which case it may also be known as a cycloalkenyl group). Alkenyl groups may contain from 2 to 6 carbon atoms. Alkenyl groups may be substituted or unsubstituted. Depending on the structure, the alkenyl group may be a monoradical or a diradical (i.e., an alkenylene group).

Alkenylene or alkenylene chain as used herein, and unless otherwise indicated, refers to an unsaturated divalent straight or branched chain group consisting of only carbon and hydrogen atoms, containing two to eight carbon atoms, where the unsaturation is present only in the form of double bonds and where a double bond may exist between any two carbon atoms in the chain, examples of which include ethenylene, prop-1-enylene, but-2-enylene, and the like. The alkenylene chain can be attached to the rest of the molecule by substituting any two hydrogens in the chain.

The term alkynyl refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, the alkynyl group starts with -C^CR atoms, where R refers to the rest of the alkynyl group. Non-limiting examples of the alkynyl group include -C^CH, -C=CCH ₃ , -C=CCH ₂ CH ₃ and -C=CCH ₂ CH ₂ CH ₃ . The R portion of the alkynyl moiety may be branched, straight or cyclic. The alkynyl group may contain from 2 to 6 carbon atoms. Alkynyl groups may be substituted or unsubstituted. Depending on the structure, the alkynyl group may be a monoradical or a diradical (ie, an alkynylene group).

- 12 041942

Alkynylene or alkynylene chain in the context of the present description and unless otherwise indicated, refers to an unsaturated straight or branched divalent group, consisting only of carbon and hydrogen atoms, containing from two to eight carbon atoms, where unsaturation is present only in the form of triple bonds, and where a triple bond may exist between any two carbon atoms in the chain, examples of which include ethynylene, prop-1-ynylene, but-2-ynylene, pent-1-ynylene, pent-3-ynylene, and the like. The alkynylene chain may be attached to the rest of the molecule by substitution of any two hydrogen atoms in the chain. Amino belongs to the -NH2 group.

The term alkylamine or alkylamino refers to the group -N(alkyl) _x H _y where alkyl is as defined herein and x and y are selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen atom to which they are attached, may optionally form a cyclic ring system.

Dialkylamino refers to the group -N(alkyl) ₂ where alkyl is as defined herein.

Aralkyl, as used herein and unless otherwise indicated, refers to a monovalent alkyl group substituted with aryl. In some embodiments, both alkyl and aryl may be optionally substituted with one or more substituents.

The term aromatic refers to a two-dimensional ring having a delocalized π electron system containing 4n+2 π electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine or more than nine atoms. Aromatic hydrocarbons may optionally be substituted. The term aromatic includes both aryl groups (eg phenyl, naphthalene) and heteroaryl groups (eg pyridinyl, quinolinyl). Aryl, as used herein and unless otherwise indicated, refers to the group of carbocyclic ring systems, including monocyclic, bicyclic, tricyclic, tetracyclic C ₆ -C ₁₈ ring systems, wherein at least one of the rings is aromatic. Aryl may be fully aromatic, examples of which are phenyl, naphthyl, anthracenyl, acenaphthylene, azulenyl, fluorenyl, indenyl and pyrenyl. Aryl may also contain an aromatic ring in combination with a non-aromatic ring, examples of which are acenaphthene, indene and fluorene. Carboxy refers to -CO2H. In some embodiments, the carboxyl moieties may be replaced with a carboxylic acid bioisostere, which refers to a functional group or moiety that exhibits the same physical and/or chemical properties as the carboxylic acid moiety. The carboxylic acid bioisostere has biological properties similar to those of the carboxylic acid group. The carboxylic acid moiety compound may have the carboxylic acid moiety replaced by a carboxylic acid bioisostere and have similar physical and/or biological properties as compared to the carboxylic acid containing compound. For example, in one embodiment, a carboxylic acid bioisostere will ionize at physiological pH to about the same extent as the carboxylic acid group. Examples of carboxylic acid bioisosteres include, but are not limited to, the like.

The term cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, where each of the ring-forming atoms (ie, backbone atoms) is a carbon atom. Cycloalkyls may be saturated or partially unsaturated. Cycloalkyls can be fused to an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups containing 3 to 10 ring atoms.

Cycloalkylalkyl as used herein, and unless otherwise indicated, refers to a monovalent alkyl group substituted with cycloalkyl. In some embodiments, both alkyl and cycloalkyl may be optionally substituted with one or more substituents.

Deuterium as used herein, and unless otherwise indicated, refers to the heavy isotope of hydrogen represented by the symbol D or ² H. As used herein, when a particular position in a compound is designated as containing deuterium, that compound is meant to be a compound enriched in isotopes, and the content of deuterium in this position in the compound significantly exceeds its abundance in nature of 0.0156%.

Deuterated in relation to a chemical group and, unless otherwise indicated, refers to a chemical group that is isotopically enriched in deuterium in an amount substantially exceeding its abundance in nature.

Heteroaralkyl as used herein, and unless otherwise indicated, refers to a monovalent alkyl group substituted with heteroaryl. In some embodiments, both alkyl and heteroaryl may be optionally substituted with one or more substituents.

Heteroaryl, as used herein and unless otherwise indicated, refers to a 5- to 15-membered monocyclic aromatic ring or a polycyclic aromatic ring system, where the ring or at least one ring of the polycyclic system contains from one to five heteroatoms, each independently selected from O, S or N, with the remaining ring atoms being carbon atoms. Each ring of a heteroaryl group may contain up to two O atoms, up to two S atoms, and/or up to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. Examples of such heteroaryl groups include, but are not limited to, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyridinyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzisoxazolyl, benzopyranyl , benzothiadiazolyl, benzothiazolyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, thieno[3,2b]pyridinyl, thieno[2,3-b]pyridinyl, 1H-pyrazolo [4,3-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 1H-imidazo[4,5-b]pyrazinyl, 1H-pyrazolo[3,4 -b]pyridinyl, thiadiazolopyrimidyl and thienopyridyl. Heterocyclyl in the context of the present description and, unless otherwise indicated, refers to a 3- to 15-membered monocyclic non-aromatic ring or a polycyclic ring system that contains at least one non-aromatic ring, where the ring or at least one ring contains from one to five heteroatoms, each independently selected from O, S or N; and the rest of the ring atoms are carbon atoms. In some embodiments, heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which nitrogen or sulfur atoms may be optionally substituted with an oxo group, or additionally with a second oxo group, or an imino group, atoms nitrogen may be optionally quaternized or substituted, and some rings may be partially or fully saturated or aromatic. In some embodiments, heterocyclyl is monocyclic, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally substituted with an oxo group or additionally with a second oxo group or an imino group, the nitrogen atoms may be optionally quaternized or substituted, and some rings may be partially or fully saturated or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom, resulting in the formation of a stable compound. Heterocyclyl, when substituted, may be substituted on a carbon atom or a heteroatom. Representative heterocylic radicals include, but are not limited to, homopiperazinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, ethylene oxide, oxetanyl, azetidinyl, quinuclidinyl, octahydroquinolizinyl, decahydroquinolizinyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2. 2]octanyl, 6,7,8,9tetrahydro-5H-pyrazino[2,3-b]indolyl.

Heterocyclylalkyl as used herein, and unless otherwise indicated, refers to a monovalent alkyl group substituted with heterocyclyl. In some embodiments, both alkyl and heterocyclyl may be optionally substituted with one or more substituents.

The term halo or alternatively halogen refers to fluorine, chlorine, bromine and iodine.

The term haloalkyl refers to an alkyl group that is substituted with one or more halogens. Halogens can be the same or different. Non-limiting examples of haloalkyls include CH ₂ Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3 and the like.

The terms fluoroalkyl and fluoroalkoxy include alkyl and alkoxy groups, respectively, which are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyls include -CF ₃ , -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH ₃ ) ₃ and the like. Non-limiting examples of fluoroalkoxy groups include -OCF ₃ , -OCHF2, -OcH ₂ F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH ₃ ) ₂ and the like.

Imino in the context of the present description and, unless otherwise indicated, refers to a ═NH or ═NR group attached to a carbon or sulfur atom.

The term bond or single bond refers to a chemical bond between two atoms or two fragments, when the atoms connected by this bond are considered to be part of a larger substructure.

The term fragment refers to a particular segment or functional group of a molecule. Chemical moieties are often chemical building blocks built into or attached to a molecule.

In the context of this document, the substituent R, occurring by itself and without the designation

- 14 041942 numbers, refers to a substituent selected from alkyl, haloalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (linked through a ring carbon atom) and heterocyclyl.

The term optionally substituted or substituted means that said group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkyl sulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C ₁ -C ₆ alkylalkyne, halogen, acyl, acyloxy, -CO2H, -CO ₂ -alkyl, nitro, haloalkyl, fluoroalkyl and amino, including mono- and disubstituted groups (for example, -NH ₂ , -NHR, -N(R) ₂ ) and their protected derivatives. As an example, optional substituents may be L ^s R ^s , where each L ^s is independently selected from a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O )2-, -NH-, -NHC(O)-, -C(O)NH-, S(=O)2NH-, -NHS(=O)2, -OC(O)NH-, -NHC( O)O-, -(C1-C6 alkyl)- or -(C2-C6 alkenyl)-; and each R ^s is independently selected from H, (C1-C ₆ alkyl), (C ₃ C ₈ cycloalkyl), aryl, heteroaryl, and heterocyclyl. Protective groups that can form protective derivatives of the above substituents can be found in sources such as Greene and Wuts, supra.

Oxo, as used herein, refers to a ═O group attached to a carbon or sulfur atom.

As used herein, the term about or approximately means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

The term "therapeutically effective amount" as used herein refers to an amount of a RORy modulator that, when administered to a mammal in need, is effective to at least partially improve or at least partially prevent conditions associated with skin aging.

In the context of the present description, the term expression includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides or proteins.

The term modulate encompasses either a decrease or increase in activity or expression, depending on the target molecule.

The term activator in the context of the present description is used to refer to any molecular compounds that lead to the activation of the specified receptor, regardless of whether the compound itself binds to the receptor or a metabolite of this compound binds to the receptor when the compound is administered topically. Thus, the activator may be a receptor ligand, or it may be an activator that is metabolized to a receptor ligand, ie, a metabolite that is formed in the tissue and is the actual ligand.

The term mammal refers to a human, non-human primate, dog, cat, cow, sheep, pig, mouse, or other laboratory or veterinary mammal. Those skilled in the art will recognize that a therapy that reduces the severity of pathology in one mammalian species is predictive of the effect of the therapy in another mammalian species.

The term skin aging includes conditions resulting from intrinsic chronological aging (e.g., deepening of expression lines, thinning of the skin, inelasticity and/or a flawless smooth surface), conditions resulting from photoaging (e.g., deep wrinkles, yellow and leathery surface, thickening of the skin, elastosis, roughness, dyspigmentations (pigmentation) and/or blotchy skin) and conditions resulting from thinning of the skin caused by steroids.

In the description herein, if there is any inconsistency between the chemical name and the chemical structure, the structure preferably takes precedence.

RORy modulators

RORy modulators contemplated for use in the compositions and methods described herein are compounds with RORy modulator activities. The term RORy modulator includes RORy and/or RORyt agonists and inverse agonists.

In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

- 15 041942 where yy represents phenyl or a 5-membered or 6-membered heteroaryl ring;

CD is phenyl or a 5-membered or 6-membered heteroaryl ring;

Z is -(C(R ⁶ )(R ⁷ ))t-;

R ¹ and R ² are selected from (i) and (ii):

(i) R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted from 1 to 4 R ^3a groups; and (ii) R ¹ is hydrogen and R ² is -S(O)2R ¹⁰ , -C1-C ₆ alkyl-S(O) ₂ R ¹⁰ , -N(R ¹¹ )S(O)2R ¹⁰ or -C1-C6alkyl-N(R ¹¹ )S(O)2R ¹⁰ ;

each R ³ is independently selected from halogen and C ₁ -C ₆ αkyl;

each R ^3a is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C9 heteroaryl, (C2C9 heteroaryl)-C1-C6 alkylene-, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ , -C(O) OR ⁿ , and -C(O)N(R ⁿ )2, wherein C ₂ -C ₉ heteroaryl and (C ₂ -C ₉ heteroaryl)-C ₁ -C ₆ alkylene- are optionally substituted with 1 to 3 groups independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and hydroxyl;

each R ⁴ and each R ⁵ is independently selected from halogen, cyano, -OH, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl, C1-C6α alkoxy, C3-C8 cycloalkyl, -N(R ⁹ )2, -C(O) R ⁸ , -C(O)OR ⁹ , -C(O)N(R ⁹ ) ₂ , -N(R ⁹ )C(O)R ⁸ , -N(R ⁹ )SO2R ⁸ , -SO2R ⁸ , and -SO2N(R ⁸ )2;

each R ⁶ and each R ⁷ independently represent hydrogen, halogen or C ₁ -C ₆ alkyl;

each R ⁸ is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

each R ⁹ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

each R ¹⁰ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-O-C ₁ -C ₆ alkyl-, C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl , phenyl, (phenyl)-C ₁ -C ₆ alkylene-, C ₂ -C ₉ heteroaryl, or (C ₂ C ₉ heteroaryl) -C ₁ -C ₆ alkylene-, where C ₃ -C ₈ cycloalkyl, C ₂ - C ₉ heterocyclyl, phenyl, (phenyl)-C ₁ -C ₆ alkylene-, C ₂ -C ₉ heteroaryl or (C ₂ -C ₉ heteroaryl) -C ₁ -C ₆ alkylene- are optionally substituted with 1 to 3 groups, selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and hydroxyl;

each R ¹¹ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

m is 1, 2, or 3;

n is 1, 2, or 3;

k is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3, or 4; and t is 0,1,2, or 3.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein ^and are each independently phenyl or 6-membered heteroaryl.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein the moiety is phenyl or 5-membered heteroaryl.

each independently represents co In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer ^thereof is provided, wherein and each is independently selected from phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, triazole, oxadiazole, thiophene and furan.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein and each is independently selected from phenyl, pyridine, pyrimidine, pyrazine, and pyridazine.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein © and © are both pyridine.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein CD is selected from phenyl, pyridine, pyrimidine, pyrazine, and pyridazine and CD is phenyl or pyridine.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein CD is selected from phenyl, pyridine, pyrimidine, pyrazine, and pyridazine, and © is phenyl.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein CD is phenyl or pyridine and ©

- 16 041942 is phenyl.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein ^both are phenyl.

In some embodiments, a compound of formula (I) or a pharmaceutical thereof is provided ____ ^ · _ (c) ____ _{x x} is pyridine and O is phenyl.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein is phenyl and CE) is pyridine.

In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently hydrogen or Cl-C6 alkyl. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is hydrogen. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently Cl-C6 alkyl. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is -CH3. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently halogen. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 0. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. where t is 1, 2, or 3. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where t is 1. In some embodiments, provided herein is a compound of formula ( I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 2. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 3. In some embodiments, in this document provides a compound of formula (I) or its a pharmaceutically acceptable salt, solvate or stereoisomer wherein Z is -CH ₂ -. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -CH2CH2-. In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -CH2CH2CH2-.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 1 and n is 1. In some embodiments, a compound of formula (I) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where m is 2 and n is 1. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 2 and n is 2. In some embodiments, a compound of formula (I) is provided. or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein m is 3 and n is 1. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided wherein m is 3 and n is 2. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 3 and n is 3 In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring where said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 to 4 R ^3a groups. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ring is optionally substituted with 1 to 4 R ^3a groups. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ring is optionally substituted with 1 to 4 R ^3a groups. In some embodiments, the implementation is

- 17 041942 a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 6-membered heterocyclyl ring, where a 6-membered heterocyclyl ring is optional substituted with 1 to 4 R ^3a groups. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted 1 R ^3a group. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups, and each R ^3a is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C9 heteroaryl, (C2-C9 heteroaryl)-C1-C6 alkylene-, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ , -C(O)OR ⁿ , and -C(O)N(R ¹¹ )2, where C ₂ -C ₉ heteroaryl and (C ₂ -C ₉ heteroaryl)-C ₁ -C ₆ alkylene is optionally substituted with 1 to 3 groups independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ C ₆ haloalkyl and hydroxyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups and each R ^3a is selected from C1-C6 alkyl, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ⁿ . In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups, and each R ^3a is selected from C1-C ₆ alkyl, oxo, -S(O) ₂ R ¹⁰ , -C(O )R ¹⁰ and -C(O)OR ⁿ . In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups, and each R ^3a is selected from C1-C6 alkyl, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ⁿ . In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups and each R ^3a is selected from C1-C ₆ alkyl, oxo, -S(O) ₂ R ¹⁰ , -C(O)R ¹⁰ , and -C(O)OR ⁿ . In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups, and each R ^3a is selected from C ₁ C6 alkyl, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ¹¹ .

- 18 041942

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted 1 R ^3a group, and R ^3a represents-S(O)2R ¹⁰ . In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group, R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is C1-C6αkyl, C1-C6haloalkyl, C1-C6alkyl-O -C1C6 alkyl-, C3-C8 cycloalkyl, C2-C9 heterocyclyl, C6-C10 aryl, or (C6-C10 aryl)-C1-C6αkylene-. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is C1-C6 alkyl or C3-C8 cycloalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said The 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is C1-C6 alkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH2CH3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH2CH2CH3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is —S(O)2R ¹⁰ , and R ¹⁰ is C3C8 cycloalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is cyclopropyl.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a and R ^3a is -C(O)R ¹⁰ In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, where R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group , R ^3a is -C(O)R ¹⁰ and R ¹⁰ is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-O-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C9 heterocyclyl, C6-C10 aryl, or (C6 -C10aryl)-C1-C6alkylene-. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a group, R ^3a represents -C(O)R ¹⁰ and R ¹⁰ represents C 1 -C ₆ alkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted 1 R ^3a group, R ^3a represents -C(O)R ¹⁰ and R ¹⁰ represents -CH ₃ . In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a salt

- 19 041942 wat or a stereoisomer, where R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, where the specified 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)R ¹⁰ and R ¹⁰ is -CH2CH3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)R ¹⁰ and R ¹⁰ is -CH2CH ₂ CH ₃ .

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted 1 R ^3a group and R ^3a represents -C(O)OR ⁿ . In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is —C(O)OR ⁿ , and R ¹¹ is C1-C6 alkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said The 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)OR ⁿ and R ¹¹ is -CH3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)ORn, and R ¹¹ is -CH2CH3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted 1 R ^3a group, R ^3a represents -C(O)OR ^H and R ¹¹ represents -CH2CH ₂ CH ₃ .

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 0, 1, 2, or 3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer, where p is 0. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, where p is 1. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer, where p is 2. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, where p is 3. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer where p is 1, 2, or 3. In some embodiments, p represents a compound of formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein p is 1, 2, or 3 and each R ⁴ is independently halo, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 1, 2, or 3 and each R ⁴ is independently halo, C1- _C6 alkyl, or _C3 - _C8 cycloalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 1 and R ⁴ is halo, C1-C6 alkyl, or C3-C8 cycloalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 2 and each R ⁴ is independently halogen, C1-C ₆ αkyl, or C ₃ -C ₈ cycloalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 3 and each R ⁴ is independently halogen, C ₁ -C ₆ αkyl, or C ₃ -C ₈ cycloalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 0, 1, 2, or 3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein q is 0. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein q is 2. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or

- 20 041942 stereoisomer, where q is 1, 2, or 3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, where q is 1, 2, or 3 and each R ⁵ independently represents is halogen, cyano, C1-C6 alkyl, C1C6 haloalkyl, C1-C6 alkoxy or C3-C8 cycloalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1, 2, or 3 and each R ⁵ is independently halogen, cyano, C1-C ₆ alkyl, C ₁ C ₆ haloalkyl or C ₁ -C ₆ alkoxy. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1, 2, or 3 and each R ⁵ is independently halo or C1-C6 alkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1 and R ⁵ is halo or C1-C ₆ alkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 2 and each R ⁵ is independently halo or C1-C6 alkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 3 and each R ⁵ is independently halo or C1-C ₆ alkyl.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 0, 1, 2, 3, or 4. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, a solvate or stereoisomer wherein k is 0, 1, 2, or 3. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 0, 1, or 2. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided wherein k is 0 or 1. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided wherein k is 0. B in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided wherein k is 1 In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein k is 1 and R ³ is halo, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 2. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 2 and each R ³ is independently halogen, C 1 -C ₆ alkyl, or C ₁ -C ₆ haloalkyl.

In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Formula (1a);

ABOUT .

where o represents phenyl;

O is a pyridyl ring;

Z is -(C(R ⁶ )(R ⁷ ))t-;

R ¹ and R ² are selected from (i) and (ii):

(i) R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted from 1 to 4 R ^3a groups; and (ii) R ¹ is hydrogen and R ² is -S(O)2R ¹⁰ , -C1-C ₆ alkyl-S(O) ₂ R ¹⁰ , -N(R11)S(O)2R ¹⁰ or -C1-C6alkyl-N(R ¹¹ )S(O)2R ¹⁰ ;

each R ³ is independently selected from halo and C ₁ -C ₆ alkyl;

each R ^3a is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C9 heteroaryl, (C2C9 heteroaryl)-C1-C6 alkylene-, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ , -C(O) OR ¹¹ , and -C(O)N(R ¹¹ )2, wherein C ₂ -C ₉ heteroaryl and (C ₂ -C ₉ heteroaryl)-C ₁ -C ₆ alkylene- are optionally substituted with 1 to 3 groups independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and hydroxyl;

each R ⁴ and each R ⁵ is independently selected from halogen, cyano, -OH, C ₁ -C ₆ alkyl, C ₁ -C 6 alkenyl, C 1 -C ₆ haloalkyl, ^^ alkoxy, C3-C 8 cycloalkyl, -N(R ⁹ )2 , -C(O)R ⁸ , -C(O)OR ⁹ , -C(O)N(R ⁹ )2, -N(R9)C(O)R ⁸ , -N(R ⁹ )SO2R ⁸ , -SO2R ⁸ and -SO2N(R ⁸ ^;

- 21 041942 each R ⁶ and each R ⁷ independently represent hydrogen, halogen or C1-C ₆ alkyl;

each R ⁸ is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

each R ⁹ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

each R ¹⁰ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ αkyl-O-C ₁ -C ₆ αkyl-, C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl , phenyl, (phenyl)-C ₁ -C ₆ alkylene-, C ₂ -C ₉ heteroaryl, or (C ₂ C ₉ heteroaryl) -C ₁ -C ₆ alkylene-, where C ₃ -C ₈ cycloalkyl, C ₂ - C ₉ heterocyclyl, phenyl, (phenyl)-C ₁ -C ₆ alkylene-, C ₂ -C ₉ heteroaryl, or (C ₂ -C ₉ heteroaryl) -C ₁ -C ₆ alkylene- are optionally substituted with 1 to 3 groups selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and hydroxyl;

each R ¹¹ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

m is 1, 2, or 3;

n is 1, 2, or 3;

k is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3 or 4;

q is 0,1,2, or 3; and t is 0, 1, 2, or 3.

In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently hydrogen or C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is hydrogen. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently C 1 -C ₆ alkyl. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is -CH3. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently halogen. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 0. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. where t is 1, 2, or 3. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 1. In some embodiments, provided herein is a compound of formula ( Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 2. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 3. In some embodiments, in This document provides a compound of formula (Ia) or and a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is -CH2-. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -CH ₂ CH ₂ -. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -CH2CH2CH2-.

In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 1 and n is 1. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 2 and n is 1. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 2 and n is 2. In some embodiments, a compound of formula (Ia) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein m is 3 and n is 1. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 3 and n is 2. In some embodiments, represents a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein m is 3 and n is 3. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl a ring wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 to 4 R ^3a groups. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ring is optionally substituted with 1 to 4 R ^3a groups. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt thereof is provided,

- 22 041942 solvate or stereoisomer, where R ¹ and R ² together with the carbon atom to which they are attached, form a 5-membered heterocyclyl ring, where the 5-membered heterocyclyl ring is optionally substituted with 1 to 4 R ^3a groups. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with 1 to 4 R ^3a groups. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5or 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted 1 R ^3a group. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group.

In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups and each R ^3a is selected from C1-C6αalkyl, C1-C6haloalkyl, C2-C9heteroaryl, (C2-C9heteroaryl)-C1-C6αkylene-, oxo , -S(O)2R ¹⁰ , -C(O)R ¹⁰ , -C(O)OR ¹¹ and -C(O)N(R ¹¹ )2, where C ₂ -C ₉ heteroaryl and (C ₂ -C ₉ heteroaryl)-C ₁ -C ₆ alkylene is optionally substituted with 1 to 3 groups independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ C ₆ haloalkyl and hydroxyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups and each R ^3a is selected from C1-C6αalkyl, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ¹¹ . In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups and each R ^3a is selected from C1-C ₆ alkyl, oxo, -S(O) ₂ R ¹⁰ , -C(O) R ¹⁰ and -C(O)OR ¹¹ . In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups, and each R ^3a is selected from C1-C6 alkyl, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ¹¹ . In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups and each R ^3a is selected from C1-C ₆ alkyl, oxo, -S(O) ₂ R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ¹¹ . In some embodiments, a compound of formula (Ia) or a compound thereof is provided.

- 23 041942 a pharmaceutically acceptable salt, solvate or stereoisomer, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups and each R ^3a is selected from C1C6 alkyl, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ¹¹ .

In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group and R ^3a is -S(O)2R ¹⁰ . In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group, R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is C1-C6 alkyl, C1-C6 haloalkyl, CiC6 alkyl-O-C1 -C6 alkyl-, C3-C8 cycloalkyl, C2-C9 heterocyclyl, C6-C10 aryl, or (C6-C10 aryl)-C1C6 alkylene-. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is C1-C6 alkyl or C3-C8 cycloalkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a group, R ^3a represents -S(O) 2 R ¹⁰ and R ¹⁰ represents C 1 -C 6 alkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH3. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH2CH3. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH2CH2CH3. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is C3-C8 cycloalkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is —S(O)2R ¹⁰ and R ¹⁰ is cyclopropyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group and R ^3a is -C(O)R ¹⁰ In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate or a stereoisomer where R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group , R ^3a is -C(O)R ¹⁰ and R ¹⁰ is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-O-C1-C6 alkyl-, C3C8 cycloalkyl, C2-C9 heterocyclyl, C6-C10 aryl, or (C6- C10aryl)-C1-C6alkylene-. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a group, R ^3a represents -C(O)R ¹⁰ and R ¹⁰ represents C 1 -C ₆ alkyl. In some embodiments, a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6- a membered heterocyclyl ring wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)R ¹⁰ and R ¹⁰ is -CH3. In some embodiments, a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said The 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)R ¹⁰ and R ¹⁰ is -CH2CH ₃ . In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted 1 R ^3a group, R ^3a represents -C(O)R ¹⁰ and R ¹⁰ represents -CH ₂ CH ₂ CH ₃ .

In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group and R ^3a is -C(O)OR ⁿ . In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted 1 R ^3a group, R ^3a represents -C(O)OR ⁿ and R ¹¹ represents C1-C6αkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)OR11 and R ¹¹ is -CH3. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted 1 R ^3a group, R ^3a represents -C(O)OR11 and R ¹¹ represents -CH ₂ CH ₃ . In some embodiments, a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said The 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)OR11 and R ¹¹ is -CH2CH2CH3.

In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 0, 1, 2, or 3. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein p is 0. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 1. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein p is 2. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 3. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer where p is 1, 2, or 3. In some embodiments, A compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is represented in the definition, wherein p is 1, 2, or 3 and each R ⁴ is independently halogen, C1-C6αkyl, C1-C6alkenyl, C1-C6haloalkyl, C1-C6αalkoxy or C3C8 cycloalkyl. In some embodiments, a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein p is 1, 2, or 3 and each R ⁴ is independently halo, C1- _C6 alkyl, or _C3 - _C8 cycloalkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 1 and R ⁴ is halo, C1-C6 alkyl, or C3-C8 cycloalkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 2 and each R ⁴ is independently halogen, C1- _C6 alkyl, or ^-C6 alkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 3 and each R ⁴ is independently halogen, C ₁ -C ₆ alkyl, or C ₃ -C ₈ cycloalkyl.

In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 0, 1, or 2. In some embodiments, a compound of formula (Ia) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where q is 0. In some embodiments, a compound

- 25 041942 formula (Ia) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, where q is 1. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where q is 2. In some embodiments, embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 3. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, where q is 1, 2 or 3 and each R ⁵ is independently halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3C8 cycloalkyl. In some embodiments, a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein q is 1, 2, or 3 and each R ⁵ is independently halo, cyano, C1- _C6 alkyl, _C1 -C ₆ haloalkyl or C ₁ -C ₆ alkoxy. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1, 2, or 3 and each R ⁵ is independently halo or C1-C6 alkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1 and R ⁵ is halo or C1-C ₆ alkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 2 and each R ⁵ is independently halo or C1-C6 alkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 3 and each R ⁵ is independently halo or C1-C ₆ alkyl.

In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 0, 1, 2, 3, or 4. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt thereof is provided, a solvate or stereoisomer wherein k is 0, 1, 2, or 3. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 0, 1, or 2. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided wherein k is 0 or 1. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided wherein k is 0. B in some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k p aven 1. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 1 and R ³ is halo, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 2. In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 2, and each R ³ is independently halogen, C 1 -C ₆ alkyl, or C ₁ -C ₆ haloalkyl.

In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

(R ³ ) _k

Formula (Ib);

where is a pyridyl ring;

CD is phenyl;

Z is -(C(R ⁶ )(R ⁷ ))t-;

R ¹ and R ² are selected from (i) and (ii):

(i) R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted from 1 to 4 R ^3a groups; and (ii) R ¹ is hydrogen and R ² is -S(O)2R ¹⁰ , -C1-C ₆ alkyl-S(O) ₂ R ¹⁰ , -N(R ¹¹ )S(O)2R ¹⁰ , or -C1-C ₆ alkyl-N(R ¹¹ )S(O) ₂ R ¹⁰ ;

each R ³ is independently selected from halogen and C ₁ -C ₆ alkyl;

each R ^3a is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C9 heteroaryl, (C2C9 heteroaryl)-C1-C6 alkylene-, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ , -C(O) OR11 and -C(O)N(R11)2, wherein C ₂ -C ₉ heteroaryl and (C ₂ -C ₉ heteroaryl)-C ₁ -C ₆ alkylene- are optionally substituted with 1 to 3 groups independently selected from halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and hydroxyl;

- 26 041942 each R ⁴ and each R ⁵ is independently selected from halogen, cyano, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl,

C1-C ₆ haloalkyl, C ₁ -C ₆ αlkoxy, O ₃ -C ₈ cycloalkyl, -N(R ⁹ )2, -C(O)R ⁸ , -C(O)OR ⁹ , -C(O)N (R ⁹ )2,

-N(R ⁹ )C(O)R ⁸ , -N(R ⁹ )SO2R ⁸ , -SO2R ⁸ , and -SO2N(R ⁸ )2;

each R ⁶ and each R ⁷ independently represent hydrogen, halogen or C ₁ -C ₆ αkil;

each R ⁸ is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

each R ⁹ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

each R ¹⁰ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ αalkyl-O-C ₁ -C ₆ αalkyl-, C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl , phenyl, (phenyl)-C ₁ -C ₆ alkylene-, C ₂ -C ₉ heteroaryl, or (C ₂ C ₉ heteroaryl) -C ₁ -C ₆ alkylene-, where C ₃ -C ₈ cycloalkyl, C ₂ - C ₉ heterocyclyl, phenyl, (phenyl)-C ₁ -C ₆ alkylene-, C ₂ -C ₉ heteroaryl, or (C ₂ -C ₉ heteroaryl) -C ₁ -C ₆ alkylene- are optionally substituted with 1 to 3 groups selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and hydroxyl;

each R ¹¹ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

m is 1, 2, or 3;

n is 1, 2, or 3;

k is 0, 1, 2, 3, or 4;

p is 0, 1, 2, or 3;

q is 0, 1, 2, 3, or 4; and t is 0, 1, 2, or 3.

In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently hydrogen or C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is hydrogen. In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently C1- _C6 alkyl. In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is -CH ₃ . In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently halogen. In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 0. In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. where t is 1, 2, or 3. In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where t is 1. In some embodiments, provided herein is a compound of formula ( Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 2. In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 3.

In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -CH2-. In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is CH2CH2-. In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -CH2CH2CH2-.

In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 1 and n is 1. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 2 and n is 1. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 2 and n is 2. In some embodiments, a compound of formula (Ib) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein m is 3 and n is 1. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 3 and n is 2. In some embodiments, embodiment, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 3 and n is 3. In some embodiments, a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl a ring wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 to 4 R ^3a groups. In some embodiments, a compound of formula (Ib) is provided, or

- 27 041942 its pharmaceutically acceptable salt, solvate or stereoisomer, where R ¹ and R ² together with the carbon atom to which they are attached, form a 4-membered heterocyclyl ring, where the 4-membered heterocyclyl ring is optionally substituted from 1 to 4 R ^3a groups. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ring is optionally substituted with 1 to 4 R ^3a groups. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with 1 to 4 R ^3a groups. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5or 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted 1 R ^3a group. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the 5-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group.

In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups and each R ^3a is selected from C1-C=alkyl, C1-C6 haloalkyl, N-Cdheteroaryl, (C2-C9heteroaryl)-C1-C6αkylene -, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ , -C(O)OR ⁿ and -C(O)N(R ¹¹ )2, where C ₂ -C ₉ heteroaryl and (C ₂ -C ₉ heteroaryl)-C ₁ -C ₆ alkylene is optionally substituted with 1 to 3 groups independently selected from halogen, C ₁ -C ₆ alkyl, C 1 C ₆ haloalkyl and hydroxyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups and each R ^3a is selected from C1-C6 alkyl, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ⁿ . In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups, and each R ^3a is selected from C1-C ₆ alkyl, oxo, -S(O) ₂ R ¹⁰ , -C(O )R ¹⁰ and -C(O)OR ⁿ . In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-membered heterocyclyl ring, wherein the 4-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups, and each R ^3a is selected from C ₁ -C ₆ alkyl, oxo, -S(O) ₂ R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ⁿ . In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt thereof is provided,

- 28 041942 solvate or stereoisomer, where R ¹ and R ² together with the carbon atom to which they are attached, form a 5-membered heterocyclyl ring, where the 5-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups, and each R ^3a is selected from C1-C6 alkyl, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ¹¹ . In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with 1 or 2 R ^3a groups, and each R ^3a is selected from C1C ₆ alkyl, oxo, -S(O) ₂ R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ¹¹ . In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted 1 R ^3a group and R ^3a represents-S(O)2R ¹⁰ . In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said The 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is C1C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-O-C1-C6 alkyl -, C3-C8 cycloalkyl, C2-C9 heterocyclyl, C6-C10 aryl, or (C6-C10 aryl)-C1-C6 alkylene-. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is C1-C6 alkyl or C3-C8 cycloalkyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a group, R ^3a represents -S(O) 2 R ¹⁰ and R ¹⁰ represents C 1 -C 6 alkyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH3. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH2CH3. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH2CH2CH3. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group, R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is ^-C-CHloalkyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said The 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is cyclopropyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted 1 R ^3a group, and R ^3a represents-C(O)R ¹⁰ . In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a group, R ^3a represents -C(O)R ¹⁰ and R ¹⁰ represents C 1 -C ₆ αkyl, C ₁ -C ₆ haloalkyl, C ₁ C ₆ alkyl-O-C ₁ -C ₆ alkyl-, ^-Schloalkyl, C ₂ -C ₉ heterocyclyl, C ₆ -C ₁₀ aryl or (C ₆ -C ₁₀ aryl) -C ₁ -C ₆ alkylene. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where indicated is 4-, 5- or 6

- 29 041942 the membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)R ¹⁰ , and R ¹⁰ is C1-C6 alkyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)R ¹⁰ and R ¹⁰ is -CH3. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)R ¹⁰ and R ¹⁰ is -CH2CH3. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)R ¹⁰ and R ¹⁰ is -CH2CH ₂ CH ₃ .

In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with a 1 R ^3a group and R ^3a is -C(O)OR ⁿ . In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, where the specified 4-, 5 - or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a group, R ^3a represents -C(O)OR11 and R ¹¹ represents C1-C6αkyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)OR11 and R ¹¹ is -CH3. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5- or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)OR11 and R ¹¹ is -CH2CH3. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said The 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 R ^3a , R ^3a is -C(O)OR11 and R ¹¹ is -CH2CH ₂ CH ₃ .

In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 0, 1, or 2. In some embodiments, a compound of formula (Ib) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where p is 0. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 1. In some embodiments, a compound of formula (Ib) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where p is 2. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 3. In some embodiments, a compound of formula (Ib) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where p is 1, 2, or 3. In some embodiments, i is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1, 2, or 3 and each R ⁴ is independently halogen, C1-C6αkyl, C1-C6alkenyl, C1-C6haloalkyl, C1-C6αalkoxy or C3C8 cycloalkyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 1, 2, or 3 and each R ⁴ is independently halogen, C1- _C6 alkyl, or _C3 - _C8 cycloalkyl. In some embodiments, a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein p is 1 and R ⁴ is halo, C1-C6 alkyl, or ^-C6 alkyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 2 and each R ⁴ is independently halogen, C1-C ₆ alkyl, or C ₃ -C ₈ cycloalkyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 3 and each R ⁴ is independently halogen, C 1 -C ₆ alkyl, or C ₃ -C ₈ cycloalkyl.

In some embodiments, a compound of formula (Ib) or pharmaceuticals thereof is provided.

- 30 041942 a pharmaceutically acceptable salt, solvate, or stereoisomer wherein q is 0, 1, 2, or 3. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 0. In some embodiments, embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, where q is 2. embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 3. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, where q is 1, 2 or 3. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable compound thereof is provided. a salt, solvate or stereoisomer wherein q is 1, 2 or 3 and each R ⁵ is independently halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C8 cycloalkyl. In some embodiments, a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein q is 1, 2, or 3 and each R ⁵ is independently halo, cyano, C1- _C6 alkyl, _C1 -C ₆ haloalkyl or C ₁ -C ₆ alkoxy. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1, 2, or 3 and each R ⁵ is independently halo or C1-C6 alkyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1 and R ⁵ is halo or C1-C ₆ alkyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 2 and each R ⁵ is independently halo or C1-C6 alkyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 3 and each R ⁵ is independently halo or C1-C ₆ alkyl.

In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 0, 1, 2, 3, or 4. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt thereof is provided, a solvate or stereoisomer wherein k is 0, 1, 2, or 3. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 0, 1, or 2. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided wherein k is 0 or 1. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided wherein k is 0. B in some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k p aven 1. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 1 and R ³ is halo, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 2. In some embodiments, a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 2 and each R ³ is independently halogen, C 1 -C ₆ alkyl, or C ₁ -C ₆ haloalkyl.

In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Formula (II);

Where

X represents -O-, -NH-, -N(R ^3a )-, -S-, -S(O)- or -S(O) ₂ -;

Z is -(C(R ⁶ )(R ⁷ )) _t -;

each R ³ is independently selected from halogen and C ₁ -C ₆ alkyl;

R ^3a is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C9 heteroaryl, (C2-C9 heteroaryl)-C1-C6 alkylene-, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ , -C(O) OR ¹¹ and -C(O)N(R ⁿ )2, wherein C ₂ -C ₉ heteroaryl and (C ₂ -C ₉ heteroaryl)-C ₁ C ₆ alkylene- are optionally substituted with 1 to 3 groups independently selected from halo , C ₁ C ₆ alkyl, C 1 -C ₆ haloalkyl and hydroxyl;

each R ⁴ and each R ⁵ is independently selected from halogen, cyano, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, -N(R ⁹ )2, -C(O)R ⁸ , -C(O)OR ⁹ , -C(O)N(R ⁹ )2,

- 31 041942

-N(R ⁹ )C(O)R ⁸ , -N(R ⁹ )SO2R ⁸ , -SO2R ⁸ , and -SO2N(R ⁸ )2;

each R ⁶ and each R ⁷ independently represent hydrogen, halogen or C1-C ₆ alkyl;

each R ⁸ is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

each R ⁹ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ¹⁰ is C ₁ -C ₆ αalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ αalkyl-O-C ₁ -C ₆ αalkyl-, C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl, phenyl , (phenyl)-C ₁ -C ₆ alkylene-, C ₂ -C ₉ heteroaryl or (C ₂ -C ₉ heteroaryl) -C ₁ C ₆ alkylene-, where C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl , phenyl, (phenyl)-C ₁ -C ₆ alkylene-, C ₂ -C ₉ heteroaryl or (C ₂ -C ₉ heteroaryl) -C ₁ -C ₆ αkylene- are optionally substituted with 1 to 3 groups selected from halogen , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and hydroxyl;

R ¹¹ independently represents hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

a is 1 or 2;

b is 1 or 2;

m is 1, 2, or 3;

n is 1, 2, or 3;

k is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1, 2, 3, or 4; and t is 0, 1, 2, or 3.

In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently hydrogen or C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is hydrogen. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently C 1 -C ₆ alkyl. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is -CH ₃ . In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently halogen.

In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 0. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof where t is 1, 2, or 3. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where t is 1. In some embodiments, provided herein is a compound of formula ( II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 2. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where t is 3. In some embodiments, in This document provides a compound of formula (II) or and a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is -CH2-. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -CH2CH2-. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -CH2CH2CH2-.

In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 1 and n is 1. In some embodiments, a compound of formula (II) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where m is 2 and n is 1. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein m is 2 and n is 2. In some embodiments, a compound of formula (II) is provided. or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 3 and n is 1. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 3 and n is 2 is provided. in some embodiments, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein m is 3 and n is en 3. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein a is 1, b is 1, m is 2, and n is 2. In some embodiments, a compound of formula (II) is provided. or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein a is 1, b is 2, m is 2, and n is 2. In some embodiments, a compound of formula (II) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein a is 1, b is 2, m is 1 and n is 2. In

- 32 041942 In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein a is 1, b is 1, m is 1, and n is 2. In some embodiments, a compound of formula (II) is provided. or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein a is 2, b is 2, m is 1, and n is 2. In some embodiments, a compound of formula (II) is provided, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein a is 2, b is 2, m is 1, and n is 1. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein a is 2, b is 1, m is 1, and n is 1. In some embodiments, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein a is 1, b is 1, m is 1, and n is 1.

In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is -O-. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is -NH-. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is -N(R ^3a )-. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is -S-. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is -S(O)-. In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is -S(O)2-. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein X is -N(R ^3a )- and R ^3a is selected from C1-C ₆ αalkyl, -S(O)2R ¹⁰ , -C(O)R ¹⁰ , and -C(O)OR11. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein X is -N(R ^3a )- and R ^3a is selected from -S(O)2R ¹⁰ , -C(O) R ¹⁰ and -C(O)OR ⁿ

In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein X is -N(R ^3a )- and R ^3a is -S(O)2R ¹⁰ . In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -S(O)2R ¹⁰ , and R ¹⁰ is C1 -C6alkyl, C1-C6haloalkyl, C1-C6alkyl-O-C1C6alkyl-, C3-C8cycloalkyl, C2-C9heterocyclyl, phenyl, or (phenyl)-C1-C6alkylene-. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -S(O)2R ¹⁰ , and R ¹⁰ is C1 -C ₆ alkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH3 . In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH2CH ₃ . In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -S(O)2R ¹⁰ , and R ¹⁰ is - CH2CH2CH3. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is C1- C6 haloalkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CF3 . In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -S(O) 2 R ¹⁰ , and R ¹⁰ is C3C8 cycloalkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is cyclopropyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein X is -N(R ^3a )- and R ^3a is -C(O)R ¹⁰ . In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -C(O)R ¹⁰ and R ¹⁰ is C1- C ₆ αlkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-O-C ₁ -C ₆ alkyl-, C ₃ -C8 cycloalkyl, C2C ₉ heterocyclyl, phenyl or (phenyl) -C ₁ -C ₆ alkylene- . In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -C(O)R ¹⁰ and R ¹⁰ is C ₁ -C ₆ alkyl. In some embodiments, a compound of formula (II) is provided, or pharmaceutically

- 33 041942 a suitable salt, solvate or stereoisomer, wherein X is -N(R ^3a )-, R ^3a is C(O)R ¹⁰ and R ¹⁰ is -CH3. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -C(O)R ¹⁰ and R ¹⁰ is -CH2CH3 . In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -C(O)R ¹⁰ and R ¹⁰ is -CH2CH _{2CH3 .} In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -C(O)R ¹⁰ and R ¹⁰ is C1- C6alkyl-O-C1-C6alkyl-. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -C(O)R ¹⁰ and R ¹⁰ is C3- C ₈ cycloalkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -C(O)R ¹⁰ and R ¹⁰ is C2C9 heterocyclyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein X is -N(R ^3a )- and R ^3a is -C(O)OR ¹¹ . In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -C(O)OR ¹¹ , and R ¹¹ is C1 -C ₆ alkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -C(O)OR ¹¹ and R ¹¹ is -CH3 . In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -C(O)OR ¹¹ and R ¹¹ is -CH2CH3 . In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein X is -N(R ^3a )-, R ^3a is -C(O)OR ¹¹ and R ¹¹ is -CH2CH2CH3 . In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 0, 1, 2, or 3. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer, where p is 0. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, where p is 1. In some embodiments, a compound of formula (II), or a pharmaceutically acceptable salt, solvate or stereoisomer, where p is 2. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, where p is 3. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer where p is 1, 2, or 3. In some embodiments, The definition is a compound of formula (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein p is 1, 2 or 3 and each R ⁴ is independently halogen, C1-C6 alkyl, C1-C6αalkenyl, C1-C6 haloalkyl, C1- C6αlkoxy, or C3C8cycloalkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 1, 2, or 3 and each R ⁴ is independently halogen, C1-C ₆ alkyl, or C ₃ -C ₈ cycloalkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 1 and R ⁴ is halo, C1-C6 alkyl, or C3-C8 cycloalkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 2 and each R ⁴ is independently halogen, C1- _C6 alkyl, or ^-C6 alkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 3 and each R ⁴ is independently halo, C1-C6αkyl, or C3-C8cycloalkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 0, 1, 2, or 3. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein q is 0. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein q is 2. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 3. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer where q is 1, 2, or 3. In some embodiments, The definition is a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein q is 1, 2 or 3 and each R ⁵ is independently halogen, cyano, C1-C ₆ αkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C3-C ₈ cycloalkyl. In some variants

- 34 041942 implementation represents a compound of formula (II) or its pharmaceutically acceptable salt, solvate or stereoisomer, where q is 1, 2 or 3 and each R ⁵ independently represents halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl or C1- C6alkoxy. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1, 2, or 3 and each R ⁵ is independently halo or C1-C ₆ alkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1 and R ⁵ is halo or C1C6 alkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 2 and each R ⁵ is independently halo or C1-C ₆ alkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 3 and each R ⁵ is independently halo or C ₁ -C ₆ alkyl.

In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 0, 1, 2, 3, or 4. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, a solvate or stereoisomer wherein k is 0, 1, 2, or 3. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 0, 1, or 2. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided wherein k is 0 or 1. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided wherein k is 0. B in some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k p aven 1. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 1 and R ³ is halo, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 2. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 2, and each R ³ is independently halogen, C 1 -C ₆ alkyl, or C ₁ -C ₆ haloalkyl.

In some embodiments, provided herein is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

(R ³ ) _k

Formula (Pa);

Where

Z is -(C(R ⁶ )(R ⁷ ))t-;

each R ³ is independently selected from halogen and C ₁ -C ₆ alkyl;

R ^3a is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C9 heteroaryl, (C2-C9 heteroaryl)-C1-C6 alkylene-, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ , -C(O) OR ¹¹ and -C(O)N(R ¹¹ )2, where C2-C9heteroaryl and ^^heteroaryl)-^C6alkylene- are optionally substituted with 1 to 3 groups independently selected from halogen, C ₁ C ₆ alkyl, C ₁ - C ₆ haloalkyl and hydroxyl;

each R ⁴ and each R ⁵ is independently selected from halogen, cyano, -OH, C ₁ -C ₆ alkyl, C ₁ -C 6 alkenyl, C 1 -C ₆ haloalkyl, ^^ alkoxy, C3-C 8 cycloalkyl, -N(R ⁹ )2 , -C(O)R ⁸ , -C(O)OR ⁹ , -C(O)N(R ⁹ )2, -N(R ⁹ )C(O)R ⁸ , -N(R ⁹ )SO2R ⁸ , -SO2R ⁸ , and -SO2N(R ⁸ ^;

each R ⁶ and each R ⁷ independently represent hydrogen, halogen or C ₁ -C ₆ alkyl;

each R ⁸ is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

each R ⁹ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-O-C ₁ -C ₆ alkyl-, C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl, phenyl , (phenyl)-C ₁ -C ₆ alkylene-, C ₂ -C ₉ heteroaryl, or (C ₂ -C ₉ heteroaryl) -C ₁ C ₆ alkylene-, where C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl, phenyl, (phenyl)-C ₁ -C ₆ alkylene-, C ₂ -C ₉ heteroaryl, or (C ₂ -C ₉ heteroaryl) -C ₁ -C ₆ alkylene- are optionally substituted with 1 to 3 groups selected from from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and hydroxyl;

R ¹¹ independently represents hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

k is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4; and t is 0, 1, 2, or 3.

- 35 041942

In some embodiments, provided herein is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently hydrogen or C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is hydrogen. In some embodiments, provided herein is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently Cl-C6 alkyl. In some embodiments, provided herein is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is -CH3. In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is independently halogen. In some embodiments, provided herein is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 0. In some embodiments, provided herein is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof where t is 1, 2, or 3. In some embodiments, provided herein is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where t is 1. In some embodiments, provided herein is a compound of formula ( IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 2. In some embodiments, provided herein is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, where t is 3.

In some embodiments, provided herein is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -CH2-. In some embodiments, provided herein is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -CH ₂ CH ₂ -. In some embodiments, provided herein is a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -CH2CH2CH2-.

In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ^3a is selected from C1-C6 alkyl, C2-C9 heteroaryl, (C2-C9 heteroaryl)-C1-C6 alkylene-, -S(O)2R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ⁿ . In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ^3a is selected from C 1 -C ₆ alkyl, -S(O) ₂ R ¹⁰ , -C(O)R ¹⁰ , and -C (O)OR ⁿ . In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ^3a is selected from -S(O)2R ¹⁰ , -C(O)R ¹⁰ and -C(O)OR ⁿ . In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ^3a is -S(O)2R ¹⁰ In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer where R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is C1-C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-O-C ₁ C ₆ alkyl-, C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl, phenyl, or (phenyl) -C ₁ -C ₆ alkylene-. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ^3a is —S(O)2R ¹⁰ and R ¹⁰ is C1-C ₆ αkyl. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH3. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CH2CH3. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is S(O)2R ¹⁰ and R ¹⁰ is —CH2CH2CH3. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is —S(O)2R ¹⁰ and R ¹⁰ is C1-C6 haloalkyl. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is -S(O)2R ¹⁰ and R ¹⁰ is -CF3. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ^3a is —S(O)2R ¹⁰ and R ¹⁰ is C ₃ C ₈ cycloalkyl.

In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ^3a is -C(O)R ¹⁰ In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer, where R ^3a is -C(O)R ¹⁰ and R ¹⁰ is C1C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ αkyl-O-C ₁ -C ₆ αkyl-, C ₃ - C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl, phenyl or

- 36 041942 (phenyl)-C1-Sbalkylene-. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is C(O)R ¹⁰ and R ¹⁰ is C1-C=alkyl. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is -C(O)R ¹⁰ and R ¹⁰ is -CH3. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is -C(O)R ¹⁰ and R ¹⁰ is -CH2CH3. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ^3a is -C(O)R ¹⁰ and R ¹⁰ is -CH2CH2CH3. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ^3a is -C(O)R ¹⁰ and R ¹⁰ is C1-C6 alkyl-O-C1-C6 alkyl-. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ^3a is -C(O)R ¹⁰ and R ¹⁰ is C3-C ₈ cycloalkyl. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is —C(O)R ¹⁰ and R ¹⁰ is C2-C9 heterocyclyl. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is -C(O)OR11. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein R ^3a is -C(O)OR11 and R ¹¹ is C1-C ₆ alkyl. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is -C(O)OR11 and R ¹¹ is -CH3. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is -C(O)OR11 and R ¹¹ is -CH2CH3. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein R ^3a is C(O)OR11 and R ¹¹ is -CH2CH2CH3.

In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 0, 1, 2, or 3. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein p is 0. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 1. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein p is 2. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 3. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer, where p is 1, 2, or 3. In some embodiments, oc the compound of formula (IIa) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is represented, wherein p is 1, 2 or 3 and each R ⁴ is independently halogen, C1-C6αkyl, C1-C6alkenyl, C1-C6haloalkyl, C1-C6αalkoxy or C3C8 cycloalkyl. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 1, 2, or 3 and each R ⁴ is independently halogen, C1-C ₆ alkyl, or O ₃ -C ₈ cycloalkyl . In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 1 and R ⁴ is halo, C1-C6 alkyl, or C3C8 cycloalkyl. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 2 and each R ⁴ is independently halo, C1- _C6 αkyl, or _C3 - _C8 cycloalkyl. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein p is 3 and each R ⁴ is independently halo, C ₁ -C ₆ alkyl, or C ₃ C ₈ cycloalkyl.

In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 0, 1, 2, or 3. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein q is 0. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer wherein q is 2. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 3. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer where q is 1, 2, or 3. In some embodiments, the the compound of formula (IIa) or its pharmaceutically

- 37 041942 a suitable salt, solvate or stereoisomer wherein q is 1, 2 or 3 and each R ⁵ is independently halogen, cyano, Cl-C6 alkyl, Cl-C6 haloalkyl, Cl-C6 alkoxy or C3-C8 cycloalkyl. In some embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, wherein q is 1, 2, or 3 and each R ⁵ is independently halo, cyano, Cl-C6 alkyl, Cl-C ₆ haloalkyl or Cl-C ₆ alkoxy. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1, 2, or 3 and each R ⁵ is independently halo or Cl-C6 alkyl. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 1 and R ⁵ is halo or Cl-C6 alkyl. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 2 and each R ⁵ is independently halo or Cl-C6 alkyl. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein q is 3 and each R ⁵ is independently halo or Cl-C6 alkyl.

In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 0, 1, 2, 3, or 4. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt thereof is provided, a solvate or stereoisomer wherein k is 0, 1, 2, or 3. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 0, 1, or 2. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided wherein k is 0 or 1. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided wherein k is 0. B in some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, g de k is 1. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 1 and R ³ is halo, Cl-C6 alkyl, or Cl-C6 haloalkyl. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 2. In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided, wherein k is 2, and each R ³ is independently halogen, Cl-C6 alkyl, or Cl-C ₆ haloalkyl.

In some embodiments, provided herein is a compound of Formula I selected from the following:

2-(3',6'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(3',5'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-ethyl-4'-((4-((methylsulfonyl)methyl)piperidin-1-yl)methyl)-[1,G-biphenyl]-4-yl)1,1,1,3, 3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((4-(methylsulfonyl)piperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1,1,1,3,3 ,3hexafluoropropan-2-ol;

6-((4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2'-methyl-[1,1'-biphenyl]4- yl)methyl)-2-thia-6-azaspiro[3,4]octane 2,2-dioxide;

6-((4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2'-methyl-[1,1'-biphenyl]4- yl)methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide;

2-(2'-ethyl-4'-((6-(methylsulfonyl)-2-azaspiro[3.3]heptan-2-yl)methyl)-[1,G-biphenyl]-4yl)-1,1,1 ,3,3,3-hexafluoropropan-2-ol;

2-(2'-(sec-butyl)-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoro propan-2-ol;

- 38 041942

2-(2',3'-difluoro-6'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(2'-fluoro-6'-isopropyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2-yl) methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol;

6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2'-methyl-[1,1'-biphenyl]-4yl )methyl)-2-thia-6-azaspiro[3,4]octane 2,2-dioxide;

6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -2thia-6-azaspiro[3,4]octane 2,2-dioxide;

6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2'-methyl-[1,1'-biphenyl]-4yl )methyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide;

2-(2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-2-yl)methyl)-[1,G-biphenyl]4-yl)-1, 1,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)methyl)-[1,G-biphenyl]4-yl)-1, 1,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((6-(isobutylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl)-1,1 ,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((6-(propylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl)-1,1 ,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((6-(ethylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4yl)-1, 1,1,3,3,3-hexafluoropropan-2-ol;

2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- [1,1'-biphenyl]-4-yl)methyl) -7thia-2-azaspiro[3.5]nonane 7,7-dioxide;

2-(2'-(tert-butyl)-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoro propan-2-ol;

2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -6thia-2-azaspiro[3,4]octane 6,6-dioxide;

2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -6thia-2-azaspiro[3,4]octane 6-oxide;

6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -2thia-6-azaspiro[3.3]heptane 2,2-dioxide;

6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -2thia-6-azaspiro[3.3]heptane 2-oxide;

2-(4'-((2-thia-6-azaspiro[3.3]heptan-6-yl)methyl)-2'-ethyl-[1,1'-biphenyl]-4-yl)-1.1, 1,3,3,3hexafluoropropan-2-ol;

- 39 041942

N-((l -((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4yl) methyl)azetidin-3-yl)methyl)-X-methylmethanesulfonamide;

2-(2'-ethyl-4'-((2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)-[1,G-biphenyl]-4yl)-1,1 ,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-ethyl-4'-((7-(methylsulfonyl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-[1,G-biphenyl]4-yl)-1 ,1,1,3,3,3 - hexafluoro propan-2-ol;

N-((l -((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4yl) methyl)azetidin-3-yl)methyl)methanesulfonamide;

2-(2'-ethyl-4'-((7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-[1,G-biphenyl]4-yl)-1 ,1,1,3,3,3 - hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((2-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-[1,G-biphenyl]4-yl)-1 ,1,1,3,3,3 - hexafluoro propan-2-ol;

2-(2'-ethyl-2-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-2-yl)methyl)-[1,G-biphenyl]-4yl)-1,1 ,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-ethyl-6'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl )-1,1,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-5'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'biphenyl]-4 -yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-ethyl-3'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl )-1,1,1,3,3,3-hexafluoro propan-2-ol;

tert-butyl 2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4yl)methyl )-2,6-diazaspiro[3.4]octane-6-carboxylate;

2-(2'-ethyl-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoro propan-2-ol;

methyl 6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4yl)methyl)- 2,6-d iazaspiro[3.3] heptane-2-carboxylate;

2-(4'-((6-(cyclopropylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2'-ethyl-[1,Hbiphenyl]-4-yl)-1,1 ,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-cyclopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl)-1,1 ,1,3,3,3-hexafluoro propan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan2-yl)methyl)-[ 1 ,1'-biphenyl]-4-yl)propan-2-ol;

- 40 041942 tert-butyl 6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- 4 yl)methyl)-2,6-d iazaspiro[3.3]heptan-2-carboxylate;

1,1,1,3,3,3-hexafluoro-2-(4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)2'-(prop- 1-en-2-yl)-[1,1'-biphenyl]-4-yl)propan-2-ol;

2-(2'-bromo-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,G-biphenyl]4-yl)-1, 1,1,3,3,3-hexafluoro propan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)2'-(trifluoromethyl) -[ 1,1'-biphenyl]-4-yl)propan-2-ol;

2-(2'-chloro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,G-biphenyl]4-yl)-1, 1,1,3,3,3-hexafluoro propan-2-ol;

-(6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl) methyl)2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one;

2-(2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,G-biphenyl]4-yl)-1, 1,1,3,3,3-hexafluoro propan-2-ol;

-(6-((4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1'-biphenyl]-4yl)methyl) -2,6-d iazaspiro[3.3]heptan-2-yl)ethan-1-one;

1,1,1,3,3,3-hexafluoro-2-(2'-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)- [ 1 ,1'-biphenyl]-4-yl)propan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(2'-methyl-4'-((6-(pyridin-4-ylmethyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl )-[1,1'-biphenyl]-4-yl)propan-2-ol;

2-(4-(3-ethyl-5-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2yl)phenyl)-1,1,1,3 ,3,3-hexafluoro propan-2-ol;

7-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- [1,1'-biphenyl]-4-yl)methyl) 2,7-diazaspiro[4.4]nonan-1-one;

7-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- [1,1'-biphenyl]-4-yl)methyl) 2,7-diazaspiro[4.4]nonan-3-one;

4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-X,X-dimethyl-4-((6-(methylsulfonyl)2,6-diazaspiro[3.3] heptan-2-yl)methyl)-[1,H-biphenyl]-2-carboxamide;

2-(2'-ethyl-2-methoxy-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'biphenyl]-4- yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(2'-methoxy-2-methyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2-yl)methyl )-[1,1'-biphenyl]-4-yl)propan-2-ol;

7-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- [1,1'-biphenyl]-4-yl)methyl) -2thia-7-azaspiro[4.4]nonane 2,2-dioxide;

- 41 041942

2-(5-(2-ethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)phenyl)pyridin-2-yl)-1,1,1,3 ,3,3-hexafluoro propan-2-ol;

2-(4-(4-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3yl)phenyl)-1,1,1,3 ,3,3-hexafluoro propan-2-ol;

4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4-((6-(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2-yl)methyl )-[1,1'-biphenyl]-3-ol;

2-(2'-cyclopropyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-cyclopropyl-2,3',6'-trifluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1'- biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-chloro-2'-cyclopropyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan2-yl)methyl)- [1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(2,3',6'-trifluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3 ]heptane -2-yl)methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol;

2-(2'-cyclopropyl-2-ethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan2-yl)methyl)- [1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-cyclopropyl-3',6'-difluoro-2-methyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2-yl)methyl)- [1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-chloro-5'-fluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl ]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(5'-fluoro-2'-isopropyl-2-methyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3] heptane- 2-yl)methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol;

2-(2,5'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl] - 4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-chloro-3', 6'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-ethyl-3', 6'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(3',6'-difluoro-2'-isopropyl-2-methyl-4'-((6-(methylsulfonyl

2-(2'-ethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[1,1'-biphenyl ]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2,2'-diethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1'- biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-chloro-2'-ethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

- 42 041942

2-(2-chloro-2'-ethyl-5'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[1,1'- biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2'-ethyl-2,5'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[1,1'-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(5'-fluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2-yl) methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol;

2-(2,2'-diethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl)-1 ,1,1,3,3,3-hexafluoro propan-2-ol;

2-(2'-ethyl-2,3',6'-trifluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[1,1' -biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(2-ethyl-2'-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoro propan-2-ol;

2-(2-chloro-2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,Hbiphenyl]-4-yl) -1,1,1,3,3,3-hexafluoro propan-2-ol;

2-(3',6'-difluoro-2'-isopropyl-4'-((2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6yl)methyl)-[1,1'-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(4-(2-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3yl)-3-methylphenyl)-1,1, 1,3,3,3-hexafluoropropan-2-ol;

2-(2'-ethyl-3',6'-difluoro-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2'-ethyl-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3]heptane -2-yl)methyl)-[1, T-biphenyl]-2-carbonitrile;

2-(4-(4-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3yl)-3-methylphenyl)-1,1, 1,3,3,3-hexafluoropropan-2-ol;

2-(6-(2-ethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)phenyl)pyridin-3-yl)-1,1,1, 3,3,3-hexafluoro propan-2-ol;

2-(4-(3-ethyl-5-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2yl)-3-methylphenyl)-1,1, 1,3,3,3-hexafluoropropan-2-ol;

1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)pyridine-2- yl)phenyl)propan-2-ol; And

2-(2,2'-dimethyl-3'-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-[1,G-biphenyl]-4yl)-1,1, 1,3,3,3-hexafluoropropan-2-ol;

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, in a RORy Gal4 ligand binding assay, the compounds provided herein were found to have IC50 values of about or less than 50 nM. In some embodiments, in a RORy Gal4 ligand binding assay, the compounds provided herein were found to have IC ₅₀ values of about or less than 100 nM. In some embodiments of a compound in a RORy Gal4 ligand binding assay, the compounds provided herein were found to have IC ₅₀ values of about 10 nM or less, about 20 nM or less, about 25 nM or less, about 50 nM or less , about 100 nM or less, about 250 nM or less, or about 500 nM or less. In another embodiment, the compounds provided herein selectively modulate RORy over ROR-alpha.

This document considers any combination of the groups described above for various variables. Throughout the description, their groups and substituents can be chosen by the person skilled in the art to obtain stable fragments and compounds. In some embodiments, a compound described herein is present in a pharmaceutical composition as a pharmaceutically acceptable salt. In some embodiments, any compound described above is suitable for any method or composition described herein.

In some embodiments, the compounds provided herein have one or more stereocenters, and each center independently exists in either the R or S configuration. Compounds presented herein include all diastereomeric, enantiomeric and

- 43 041942 epimeric forms, as well as suitable mixtures thereof. If desired, stereoisomers are obtained by techniques such as stereoselective synthesis and/or separation of stereoisomers on chiral chromatographic columns. In some embodiments, a compound of formula (I), (Ia), (Ib), (II), or (IIa) is used as a single enantiomer. In some embodiments, a compound of formula (I), (Ia), (Ib), (II), or (IIa) is used as a racemic mixture. The methods and formulations described herein include the use of N-oxides (if appropriate) or pharmaceutically acceptable salts of compounds having the structures provided herein, as well as active metabolites of these compounds having the same type of activity. In some situations, the compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented here. In specific embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated form.

In some embodiments, the compounds of formula (I), (Ia), (b), (II), or (IIa) described herein include their solvent addition forms. The solvates contain either stoichiometric or non-stoichiometric amounts of solvent with pharmaceutically acceptable solvents such as water, ethanol and the like. When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed. In some embodiments, the sites of the compounds of formula (I), (Ia), (Ib), (II) or (IIa) disclosed herein are subject to various metabolic reactions. Therefore, the inclusion of appropriate substituents at the sites of metabolic reactions will reduce, minimize, or eliminate metabolic pathways. In specific embodiments, an appropriate substituent to reduce or eliminate the metabolic susceptibility of an aromatic ring is, by way of example only, a halogen, deuterium, or alkyl group. In some embodiments, the compounds of formula (I), (Ia), (Ib), (II), or (IIa) disclosed herein are isotopically labeled and identical to the compounds set forth in the various formulas and structures provided herein. except that one or more atoms are replaced by an atom whose atomic mass or mass number is different from the atomic mass or mass number normally found in nature. In some embodiments, one or more hydrogen atoms are replaced by deuterium. In some embodiments, the metabolic sites on the compounds described herein are deuterated. In some embodiments, deuterium substitution provides certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements and thus reduced toxicity or reduced potential for drug interactions.

Synthesis of compounds

In some embodiments, the synthesis of the compounds described herein is carried out using the means described in the chemical literature, using the methods described herein, or by a combination of both. In addition, solvents, temperatures, and other reaction conditions presented here may vary.

In other embodiments, the starting materials and reagents used to synthesize the compounds described herein are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals) and AcrosOrganics.

In additional embodiments, the compounds described herein and other related compounds containing other substituents are synthesized using the techniques and materials described herein, as well as those known in the art, such as those described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry ^4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry ^4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis ^3rd Ed., (Wiley 1999) (all of which are incorporated herein by reference). General methods for preparing a compound as disclosed herein can be derived from reactions, and reactions can be modified by using appropriate reagents and conditions to introduce the various moieties found in the formulas provided herein. The following synthesis methods may be used as a guide.

Application of protecting groups

In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio, or carboxy groups, if desired in the final product, to avoid their undesirable participation in the reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protecting group is removed. It is preferable that each

- 44 041942 the protective group was removed in a different way. Protecting groups that are cleaved off under completely different reaction conditions satisfy the requirement for different removal. The protecting groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are acid-labile and can be used to protect carboxy and hydroxy-reactive moieties in the presence of amino groups protected by Cbz groups, which are removed by hydrogenolysis, and Fmoc groups, which are base-labile. . The carboxylic acid and hydroxy-reactive moieties can be capped with base-labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines capped with acid-labile groups such as t-butyl carbamate, or carbamates that are both acid and and bases, but are removed hydrolytically. Reactive carboxylic acid and hydroxyl groups can also be blocked with hydrolyzable protecting groups such as the benzyl group, while amino groups capable of hydrogen bonding with acids can be blocked with base-labile groups such as Fmoc . Reactive carboxylic acid moieties may be protected by conversion to ethers as illustrated herein, which includes conversion to alkyl esters, or they may be blocked by oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, in while coexisting amino groups can be blocked with fluoride-labile silyl carbamates.

Allyl blocking groups are suitable in the presence of acidic and basic protecting groups because the former are stable and can be removed sequentially with metal or picacid catalysts. For example, the removal of allyl protection from a carboxylic acid can be carried out by a Pd ⁰ catalyzed reaction in the presence of acid-labile tert-butyl carbamates or basic-labile acetylamino protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, the functional group is blocked and cannot react. When the residue is freed from the resin, the functional group will become available to react. Typical blocking/protecting groups can be selected from

RMB trityl tert-butyl

fmoc

Other protecting groups and detailed descriptions of techniques applicable to the creation and removal of protecting groups are described in Greene and Wuts, Protective Groups in Organic Synthesis, ^3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein for such disclosure by reference.

Methods of treatment and prevention

In one embodiment, provided herein are methods for modulating RORy activity in a cell by contacting the cell with a RORy modulator. Examples of such RORy modulators are described above.

In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is selected from psoriasis, psoriatic arthritis, uveitis, ulcerative colitis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, vitiligo, vesiculobullous dermatosis, rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, arthritis associated with inflammatory bowel disease, juvenile rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, lupus, lupus nephritis, multiple sclerosis, axial spodiloarthritis, hidradenitis suppurativa, Sjögren's syndrome, regional enteritis, Tholos-Hunt's syndrome, undifferentiated diseaseconnective tissue, obesity, obesity-induced insulin resistance, atherosclerosis, and type II diabetes mellitus.

In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutic

- 45 041942 a clinically effective amount of a compound of formula (I), (Ia), (Ib), (II) or (IIa) or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is psoriasis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically effective amount thereof. an acceptable salt or solvate, wherein the disease, disorder or condition is psoriatic arthritis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically effective amount thereof. an acceptable salt or solvate, wherein the disease, disorder, or condition is uveitis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically effective amount thereof. an acceptable salt or solvate, wherein the disease, disorder, or condition is ulcerative colitis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is asthma. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is allergic rhinitis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is chronic obstructive pulmonary disease (COPD). In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is atopic dermatitis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is vitiligo. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is vesiculobullous dermatosis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is rheumatoid arthritis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is ankylosing spondylitis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is reactive arthritis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is arthritis associated with inflammatory bowel disease. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is juvenile rheumatoid arthritis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising

- 46 041942 administration to this individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, where the disease, disorder or condition is Crohn's disease. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is an inflammatory bowel disease. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is lupus. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is lupus nephritis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is multiple sclerosis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is axial spondyloarthritis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is hidradenitis suppurativa. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is Sjögren's syndrome. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is regional enteritis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is Tholos-Hunt syndrome. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is an undifferentiated connective tissue disease. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is obesity. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is obesity-induced insulin resistance. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is atherosclerosis. In some embodiments, a method is provided for treating a disease, disorder, or condition in an individual in need thereof, comprising administering to that individual a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate, wherein the disease, disorder or condition is type II diabetes.

- 47 041942

Pharmaceutical Compositions and Methods for Administering RORy Modulators

The RORy modulators described herein are administered to subjects in a biocompatible form suitable for administration to treat or prevent diseases, disorders or conditions. Administration of the RORy modulators as described herein may be in any pharmacological form, including a therapeutically effective amount of the RORy modulator alone or in combination with a pharmaceutically acceptable carrier.

In some embodiments, the compounds described herein are administered as the pure chemical. In other embodiments, the compounds described herein are combined with a pharmaceutically acceptable or acceptable carrier (also referred to herein as a pharmaceutically acceptable (or acceptable) excipient, a physiologically acceptable (or acceptable) excipient, or a physiologically acceptable (or acceptable) carrier) selected based on the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)).

Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or appropriate if the carrier is compatible with the other ingredients of the composition and is not harmful to the recipient (i.e., subject) of the composition. In some embodiments, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, a pharmaceutical composition is provided, consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (I), (Ia), (Ib), (II), or (IIa), or a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition is provided, consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided, consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided, consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided, consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided, consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, a compound described herein is substantially pure as it contains less than about 5%, or less than about 1%, or less than about 0.1%, other organic small molecules, such as polluting intermediates or by-products which are formed, for example, in one or more stages of the synthesis process.

These formulations include formulations suitable for oral, topical, buccal, parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) or aerosol administration.

The exemplary pharmaceutical compositions are administered in the form of a medicament, for example in solid, semi-solid or liquid form, which comprises one or more of the compounds described as the active ingredient in admixture with an organic or inorganic carrier or excipient suitable for topical, enteral or parenteral applications. In some embodiments, the active ingredient is combined, for example,

- 48 041942 with conventional non-toxic pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use.

The active compound is included in the pharmaceutical composition in an amount sufficient to obtain the desired effect on the course or condition of the disease.

In some embodiments, to prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate. or gums, and other pharmaceutical diluents, for example, water, to form a solid pre-composition containing a homogeneous mixture of the described compound or its non-toxic pharmaceutically acceptable salt. When referring to these preformulation compositions as being homogeneous, it is meant that the active ingredient is uniformly dispersed throughout the composition so that the composition is easily divided into equally effective unit dosage forms such as tablets, pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the composition in question is admixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and/or any of the following:

(1) fillers or diluents such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol and/or silicic acid;

(2) binders such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum;

(3) humectants such as glycerin;

(4) disintegrants such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate;

(5) mortar set retarders such as paraffin;

(6) absorption accelerators such as quaternary ammonium compounds;

(7) wetting agents such as, for example, sodium docusate, cetyl alcohol, and glycerol monostearate;

(8) absorbents such as kaolin and bentonite clay;

(9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) dyes.

In the case of capsules, tablets, and pills, in some embodiments, the compositions contain buffering agents. In some embodiments, solid compositions of this type are also used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

In some embodiments, the tablet is made by compression or moulding, optionally with one or more additional ingredients. In some embodiments, compressed tablets are prepared using a binder (for example, gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant, or a dispersing agent. In some embodiments, shaped tablets are prepared by shaping the test composition moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets and other solid dosage forms such as dragees, capsules, pills, and granules are scored or prepared with coatings and shells, such as enteric coatings, and other coatings. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures and powders thereof. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the present composition, in some embodiments, liquid dosage forms contain inert diluents such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 butylene glycol, oils (particularly cottonseed, peanut, corn, wheat germ, olive, castor and sesame oils), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

In some embodiments, the suspensions, in addition to the composition in question, contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and their mixtures.

In some embodiments, the powders and sprays contain, in addition to the composition in question, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. In some embodiments, the sprays additionally contain standard propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

The compositions and compounds disclosed herein are alternatively administered as an aerosol. This is achieved by preparing an aqueous aerosol, liposomal preparation or particulate matter containing the compound. In some embodiments, a non-aqueous suspension (eg, a fluorocarbon propellant) is used. In some embodiments, ultrasonic nebulizers are used because they minimize the shearing effect on the agent, which leads to the destruction of the compounds contained in the compositions in question. Typically, an aqueous aerosol is prepared by formulating an aqueous solution or suspension of the composition in question, together with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular formulation in question, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), non-toxic proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine , buffers, salts, sugars or sugar alcohols. Aerosols are usually prepared from isotonic solutions.

Pharmaceutical compositions suitable for parenteral administration comprise the composition in question in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders which are reconstituted into sterile injectable solutions or dispersions shortly before use, which in some embodiments contain antioxidants, buffers, bacteriostatic agents, solutes that render the composition isotonic with the blood of the intended recipient, or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers that are used in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Appropriate fluidity is maintained, for example, by the use of coating agents such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

The dose of a composition containing at least one compound described herein differs depending on the condition of the patient (eg, human), namely, the stage of the disease, general health, age, and other factors. Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dosage and the appropriate duration and frequency of administration will be determined by factors such as the condition of the patient, the type and severity of the patient's condition, the particular form of the active ingredient, and the route of administration. In general, a suitable dosage and treatment regimen will provide the composition(s) in an amount sufficient to provide a therapeutic and/or prophylactic effect (e.g., an optimized clinical outcome such as more frequent complete or partial remissions, or longer disease absence and/or overall survival, or reduction in the severity of symptoms). Optimal doses are generally determined using experimental models and/or clinical studies. In some embodiments, the implementation of the optimal dose depends on the body weight, weight or blood volume of the patient. Oral doses typically range from about 1.0 mg to about 1000 mg one to four times or more per day.

Dose administration may be repeated depending on the pharmacokinetic parameters of the dosage form and the route of administration employed.

It is particularly advantageous to formulate the compositions in unit dosage form for ease of administration and dosage uniformity. Unit dosage form, as used herein, refers to physically discrete units suitable as unit doses for mammals to be treated; each unit containing a predetermined amount of the active compound is calculated to achieve the desired therapeutic effect in combination with the required pharmaceutical carrier. The specification for unit dosage forms is dictated by and directly dependent on:

(a) the characteristics of the RORy modulator and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of preparing a compound, such as an active compound, for the treatment of hypersensitivity in humans.

- 50 041942

A person skilled in the art can easily calculate a specific dose, for example, in accordance with the approximate body weight, or body surface area of the patient, or the amount of space occupied by the body. The dose will also be calculated depending on the particular route of administration selected. Further refinement of the calculations needed to determine the appropriate dosage for treatment is usually performed by those skilled in the art. Such calculations can be made by one of skill in the art without undue investigation in light of the RORy modulator activities described herein in target cell assay solutions. Exact dosages are determined in conjunction with standard dose-response studies. It should be understood that the amount of composition actually administered will be determined by the practitioner in light of the relevant circumstances, including the condition or conditions to be treated, the choice of composition to be administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration. The toxicity and therapeutic efficacy of such RORy modulators can be determined using standard pharmaceutical techniques in cell cultures or experimental animals, for example, to determine LD50 (dose lethal to 50% of the population) and ED50 (dose therapeutically effective to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD ₅₀ /ED ₅₀ . RORy modulators that exhibit large therapeutic indices are preferred. Although RORy modulators that exhibit toxic side effects can be used, care should be taken to develop a delivery system that targets such modulators to the affected tissue site in such a way as to minimize potential damage to uninfected cells and thus reduce side effects.

Data obtained from cell culture assays and animal studies can be used to determine the dosage range for use in humans. The dosage of such RORy modulators is preferably within a circulating concentration range that includes the ED ₅₀ with little or no toxicity. The dosage may vary within this range depending on the dosage form used and the route of administration used. For any RORy modulator used in the method described here, the therapeutically effective dose can be initially calculated from cell culture assays. The dose can be designed in animal models to achieve a range of circulating plasma concentrations that includes the IC ₅₀ (ie, the RORy modulator concentration that provides half the inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful human doses. Plasma levels can be measured, for example, using high performance liquid chromatography.

Examples

The following examples are offered for purposes of illustration and are not intended to limit the scope of the claims presented herein. All references to the literature in these examples and throughout the description are incorporated herein by reference for all purposes of a legal nature that serve. The starting materials and reagents used to synthesize the compounds described herein can be synthesized or can be obtained from commercial sources such as, without limitation, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

The standard abbreviations and abbreviations used in this document are as defined in J. Org. Chem. 2007 72(1): 23A-24A. Other abbreviations and abbreviations used in this document are as follows: __________________________________

ASON acetic acid DCM dichloromethane DMP Dess-Martin periodinan dppf (diphenylphosphino)ferrocene EtOAc ethyl acetate HBTU Ν, Ν, Ν', A-tetramethyl-O-(1 //-benzotriazol-1 yl)uronium hexafluorophosphate LC-MS liquid chromatography-mass spectrometry Meon methanol TEA triethylamine rt room temperature

- 51 041942

General synthesis scheme:

General way:

Aldehyde (1) (1.0 eq.) and secondary amine (2) (1.2 eq.) were combined in 1,2-DCE with a catalytic amount of an acid such as acetic acid or TFA. The mixture was stirred at room temperature for 1-3 hours. NaBH(OAc) ₃ (3.0 eq.) was added to the solution. The resulting mixture was stirred at room temperature overnight. The reaction was stopped with MeOH and was extracted with ethyl acetate (2x20 ml). The crude mixture was purified on a silica gel column to give the purified product (3).

Example A Synthesis of an Aldehyde Intermediate

Synthesis of Intermediate 1, Intermediate 2 and Intermediates 2A-2D

Stage A.

A solution of NaNO2 (4.4 g, 1.1 eq.) in 30 ml of water. The mixture was cooled to 0°C over 15 min. To the reaction mixture was added dropwise 6 N. HCl (29 ml, 3.0 eq.) for 15 min at 0°C. The resulting mixture was stirred at 0° C. for 1 hour. KI (10.1 g, 1.05 eq.) was added portionwise (over 15 minutes). The reaction mixture was stirred at 0°C for 1 h and then at room temperature overnight. The reaction was diluted with water (~500 ml) and extracted with EtOAc/hexane (2:1, 3x150 ml). The combined organic phase was washed with NaHSO ₃ , water and brine. The crude mixture was purified on a silica gel column to give 1,1,1,3,3,3-hexafluoro-2-(4iodophenyl)propan-2-ol (intermediate 1) (18.9 g, 88% yield) as pale yellow oil.

Method 1, stage B.

To a solution of intermediate 1 (1.0 g, 1.0 eq.) in anhydrous 1,4-dioxane (20 ml) was added bis(pinacolato)diborone (0.89 g, 1.3 eq.), potassium acetate ( 0.265 g, 3.0 eq.) and Pd(dppf) ₂ Cl ₂ (100 mg, 0.05 eq.). The mixture was degassed and then N2 was bubbled through for 5 minutes, then stirred at 90° C. overnight. After cooling to room temperature, the mixture was poured into a solution of NH ₄ Cl and was extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified by silica gel column chromatography to give 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl1,3, 2-dioxaborolan-2-yl)phenyl)propan-2-ol (intermediate 2) (450 mg, 45% yield) as a white solid.

R=-CH ₃ intermediate 2A;

R=-CH ₂ CH ₃ intermediate 2B;

R=F intermediate 2C;

R=Cl intermediate 2D.

1,1,1,3,3,3-Hexafluoro-2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan- 2ol (intermediate 2A) was prepared as described in step B, replacing 2-(4-bromo-3methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol with intermediate 1.

2-(3-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2 -ol (intermediate 2B) was prepared as described in step B, replacing 2-(4-bromo-3-ethylphenyl)1,1,1,3,3,3-hexafluoropropan-2-ol with intermediate 1.

1,1,1,3,3,3-Hexafluoro-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan- 2-ol (intermediate 2C) was prepared as described in step B, replacing 2-(4-bromo-3-fluorophenyl)1,1,1,3,3,3-hexafluoropropan-2-ol with intermediate 1.

2-(3-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2 -ol

- 52 041942 (Intermediate 2D) was prepared as described in Step B, replacing 2-(4-bromo-3-chlorophenyl)1,1,1,3,3,3-hexafluoropropan-2-ol with Intermediate 1.

Example B Synthesis of 2-(4-bromo-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (intermediate 3) and 2-(4-bromo-3-methylphenyl) -1,1,1,3,3,3-hexafluoropropan-2-ol intermediate 4

Methyl 4-bromo-3-methylbenzoate (5) (1.0 g, 1.0 eq) was dissolved in 20 ml THF and TMSCF3 (3.1 g, 5.0 eq) was added. The mixture was cooled at -15°C. To the mixture was added 1 M TBAF (13 ml, 3.0 eq.) dropwise over 20 minutes. After the addition of TMSCF3, 1N was added slowly. HCl (80 ml). The mixture was stirred at room temperature for 15 minutes and then extracted with 2x40 ml of hexane. The organic phase was dried over MgSO ₄ and concentrated in vacuo to give (6) (0.98 g) which was then used in the next reaction without purification. Intermediate (6) and TMSCF3 (3.0 g) were dissolved in anhydrous THF (20 ml) and cooled with ice water. TBAF (1M, 5 ml) was added dropwise. The resulting mixture was stirred at 0°C for 2 hours. The reaction was stopped with 1 N. HCl (80 ml). The mixture was extracted with 2x40 ml of hexane. The crude mixture was purified on a silica gel column to give 2-(4-bromo-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (intermediate 4) (420 mg, 29% yield in two steps) as a white solid.

2-(4-Bromo-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (intermediate 3) was synthesized as described in Example B by replacing methyl 4-bromo-3 -methylbenzoate to 4-bromo-3-fluorobenzoate.

Example C Synthesis of 2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (aldehyde intermediate 5 )

Stage A.

4-Bromo-3-ethylbenzoic acid (7) (5.0 g, 1.0 eq.), N,O-dimethylhydroxylamine hydrochloride (3.2 g, 1.5 eq.) and HBTU (9.6 g, 1.0 eq.) 15 eq.) were combined in 80 ml of DMF at room temperature. Et ₃ N (11.2 g, 4.0 eq.) was added dropwise to the reaction mixture. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with 200 ml of ethyl acetate and 100 ml of hexane, then washed with 2x150 ml of water, 2x100 ml of 1N. HCl, 2x100 ml saturated NaHCO ₃ and brine. The organic phase was dried over MgSO ₄ and concentrated in vacuo to give 4-bromo-3-ethylN-methoxy-N-methylbenzamide (8) (5.8 g, 98% yield) as a pale yellow oil which was used without further purification. .

Stage B.

4-Bromo-3-ethyl-N-methoxy-N-methylbenzamide (8) (3.0 g, 1.0 equiv.) and 4,4,4',4',5,5,5',5'-octamethyl -2,2'bi(1,3,2-dioxaborolane) (3.2 g, 1.15 equiv.) was dissolved in dry dioxane (25 ml). The mixture was degassed by bubbling N ₂ for 5 minutes. PdCl ₂ (dppf) (0.81 g, 0.1 eq.) and potassium acetate (1.6 g, 1.5 eq.) were added to the reaction mixture. The resulting mixture was heated at 100° C. in a sealed tube for 15 hours. The reaction mixture was diluted with 80 ml of acetate and 80 ml of hexane, washed with 3x80 ml of water and 50 ml of brine. The crude mixture was purified on a silica gel column to give 3-ETHYL-Nmethoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (9) (3.3 g, 95% yield) as a pale yellow oil.

Stage C.

3-Ethyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (9) (2.24 g, 1.0 equiv.), 1,1,1,3,3,3-hexafluoro-2-(4-iodophenyl)propan-2-ol (2.85 g, 1.1 equiv.), Pd(PPh ₃ ) ₄ ( 0.81 g, 0.1 eq.) and K ₂ CO ₃ (2.9 g, 3.0 eq.) were combined in 35 ml of dioxane and 10 ml of water. The mixture was purged with N ₂ for 5 min and then heated at 95° C. for 14 h under N ₂ . The reaction was extracted with EtOAc (2x200 ml). The combined organic phase was washed with 1 N. HCl and brine. The crude mixture was purified on a silica gel column to give 2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl[1, 1'-biphenyl]-4-carboxamide (2.28 g, 75% yield) as a white solid.

2-Ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1'-biphenyl]-4- carboxamide (2.0 g, 1.0 eq.) was dissolved in dry THF (20 ml) and the solution was cooled to -50° C. under N 2 atmosphere. Added dropwise LAH (4.6 ml, 1.0 eq.). The mixture was stirred at -30°C to -10°C for an additional 40 minutes. The reaction was stopped with 1 ml of water at -10°C and then diluted with 50 ml of 2N. HCl. The mixture was extracted with 2x50 ml of ethyl acetate. The crude mixture was purified on a silica gel column to give 2ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (aldehyde intermediate 5) (1.41 g, 82% yield) as a white solid.

Example D Synthesis of 2-ethyl-6-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4carbaldehyde ( aldehyde intermediate 6)

To a solution of 3-fluoro-2-hydroxybenzaldehyde (1.4 g, 10 mmol) in THF (20 ml) was added MeMgCl (8 ml, 24 mmol) at 0°C. The reaction mixture was stirred at 0°C to room temperature for 1 h, diluted with EtOAc and the reaction was stopped with a saturated solution of NH ₄ Cl. The organic layer was dried and evaporated to give crude 2-fluoro-6-(1-hydroxyethyl)phenol (1.4 g).

To a solution of 2-fluoro-6-(1-hydroxyethyl)phenol (1.4 g) in MeOH (20 ml) was added 10% Pd/C (100 mg) and hydrogenated under hydrogen (50 PSI) overnight. The mixture was filtered through celite and the filtrate was concentrated to give 2-ethyl-6-fluorophenol (1.0 g).

To a solution of 2-ethyl-6-fluorophenol (1 g, 7.1 mmol) in AcOH (10 ml) was added NBS (1.3 g) at 0°C. The reaction mixture was stirred at 0°C to room temperature for 1 h, diluted with EtOAc and washed with water. The organic layer was concentrated and purified on a silica gel column to give 4-bromo-2-ethyl-6-fluorophenol (0.9 g). A mixture of 4-bromo-2-ethyl-6-fluorophenol (0.88 g, 4 mmol), Zn(CN) ₂ (0.93 g, 8 mmol) and Pd(PPh ₃ ) ₄ (100 mg, 0.09 mmol) in toluene (10 ml) was heated at 90° C. under N2 overnight. The mixture was cooled to room temperature and washed with water and brine. The organic layer was concentrated and purified on a silica gel column to give 3-ethyl-5-fluoro-4hydroxybenzonitrile (0.35 g).

To a solution of 3-ethyl-5-fluoro-4-hydroxybenzonitrile (0.34 g, 2.0 mmol) in CH ₂ Cl ₂ (10 ml) was added DIBAL (4.5 ml, 4.5 mmol) at -78° C in an N2 atmosphere. The reaction mixture was stirred at -78°C to 0°C for 2 h and then stopped with 1N. HCl. The organic layer was concentrated and purified on a silica gel column to give 3-ethyl-5-fluoro-4-hydroxybenzaldehyde (0.17 g).

To a solution of 3-ethyl-5-fluoro-4-hydroxybenzaldehyde (0.17 g, 1 mmol) in CH ₂ Cl ₂ (10 ml) was added N(Et) ₃ (0.2 g, 2 mmol) at 0°C followed by the addition of (Tf) ₂ O (0.28 g, 1 mmol) under N2 atmosphere. The reaction mixture was stirred at 0°C for 2 h and stopped with water. The organic layer was concentrated and purified on a silica gel column to give 2-ethyl-6-fluoro-4-formylphenyl trifluoromethanesulfonate (0.15 g).

A mixture of 2-ethyl-6-fluoro-4-formylphenyl trifluoromethanesulfonate (0.15 g, 0.5 mmol), 1,1,1,3,3,3hexafluoro-2-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (intermediate 2) (0.15 g), Pd(PPh ₃ ) ₄ (55 mg) and Na ₂ CO ₃ (2 n solution, 0.5 ml) in dioxane (10 ml) was heated at 90° C. under N2 overnight. The mixture was cooled to room temperature and washed with water and brine. The organic layer was concentrated and purified on a silica gel column to give 2-ethyl-6-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[ 1,1 '-biphenyl]-4-carbaldehyde (aldehyde intermediate 6) (85 mg).

Example E Synthesis of 2-ethyl-5-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4carbaldehyde ( aldehyde intermediate 7)

To a solution of 1-(4-fluoro-3-nitrophenyl)ethan-1-one (1.8 g, 10 mmol) in THF (20 ml) was added NaBH ₄ (0.38 g, 10 mmol) at 0°C. The reaction mixture was stirred at 0° C. to room temperature for 1 h, diluted with EtOAc and quenched with saturated NH4Cl solution. The organic layer was dried and evaporated to give 1-(4-fluoro-3-nitrophenyl)ethan-1-ol (1.5 g).

To a solution of 1-(4-fluoro-3-nitrophenyl)ethan-1-ol (1.5 g) in MeOH (20 ml) was added 10% Pd/C (100 mg) and hydrogenated under hydrogen atmosphere (50 PSI) for throughout the night. The mixture was filtered through Celite and the filtrate was concentrated to give 5-ethyl-2-fluoroaniline (1.0 g).

To a solution of 5-ethyl-2-fluoroaniline (0.62 g, 4.4 mmol) in DMF (10 ml) was added NBS (0.83 g) at 0°C.

- 54 041942

The reaction mixture was stirred at 0°C to room temperature for 1 h, diluted with EtOAc and washed with water. The organic layer was concentrated and purified using a flash cartridge (ISCO) to give 4-bromo-5-ethyl-2-fluoroaniline (0.92 g). To a solution of 4-bromo-5-ethyl-2-fluoroaniline (0.88 g, 4 mmol) in H ₂ O (15 ml) was added H ₂ SO ₄ (4 ml, 2N solution). The mixture was sonicated for 30 min and cooled to 0°C. NaNO ₂ (0.3 g, 4.4 mmol) in water (10 ml) was added dropwise. After stirring at 0°C for 1 h, Na ₂ CO ₃ was added to bring the pH to 7. The aqueous mixture was added to KCN (0.52 g, 8 mmol) and CuCN (0.36 g, 4 mmol) in water at 70°C, and the mixture was stirred at 70°C for 2 h and was extracted with EtOAc. The organic layer was washed with water, brine and concentrated, the residue was purified using a flash cartridge (ISCO) to obtain 4-bromo-5-ethyl-2fluorobenzonitrile (0.35 g). To a solution of 4-bromo-5-ethyl-2-fluorobenzonitrile (0.34 g, 2 mmol) in CH ₂ Cl ₂ (10 ml) was added DIBAL (2.2 ml, 2.2 mmol) at -78°C in N ₂ atmosphere. The reaction mixture was stirred at -78°C to 0°C for 2 h and stopped with 1N. HCl. The organic layer was concentrated and purified using a flash cartridge (ISCO) to give 4-bromo-5-ethyl-2-fluorobenzaldehyde (0.15 g).

A mixture of 4-bromo-5-ethyl-2-fluorobenzaldehyde (0.11 g, 0.5 mmol), 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5, 5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (0.15 g), Pd(PPh ₃ ) ₄ (55 mg) and Na ₂ CO ₃ (2 N solution, 0 .5 ml) in dioxane (10 ml) was heated at 90° C. under N ₂ overnight. The mixture was cooled to room temperature and washed with water and brine. The organic layer was concentrated and purified using a flash cartridge (ISCO) to give 2-ethyl-5-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)-[1 ,1'-biphenyl]-4-carbaldehyde (52 mg).

Example F Synthesis of 2-ethyl-3-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4carbaldehyde ( aldehyde intermediate 8)

To a solution of 4-bromo-2-fluoro-1-iodobenzene (3.0 g, 10 mmol) in THF (20 ml) was added LDA (12 ml, 12 mmol) at -78°C under N ₂ atmosphere. The reaction was slowly heated to -20°C and then cooled to -78°C. EtI (4.7 g, 30 mmol) was added. The mixture was stirred from -78°C to room temperature overnight, diluted with EtOAc and washed with water. The organic layer was concentrated and purified using a flash cartridge (ISCO) to give 1-bromo-2-ethyl-3-fluoro-4-iodobenzene (1.2 g).

A mixture of 1-bromo-2-ethyl-3-fluoro-4-iodobenzene (1.0 g, 3.0 mmol), Zn(CN) ₂ (0.19 g, 1.6 mmol) and Pd(PPh ₃ ) ₄ ( 0.17 g, 0.15 mmol) in toluene (10 ml) was heated at 70° C. under N ₂ overnight. The mixture was cooled to room temperature and washed with water and brine. The organic layer was concentrated and purified using a flash cartridge (ISCO) to give 4-bromo-3-ethyl-2-fluorobenzonitrile (0.25 g).

To a solution of 4-bromo-3-ethyl-2-fluorobenzonitrile (0.17 g, 1.0 mmol) in CH ₂ Cl ₂ (10 ml) was added DIBAL (1.1 ml, 1.1 mmol) at -78° C in an N2 atmosphere. The reaction mixture was stirred at -78°C to 0°C for 2 h and stopped with 1N. HCl. The organic layer was concentrated and purified using a flash cartridge (ISCO) to give 4-bromo-3-ethyl-2-fluorobenzaldehyde (0.12 g).

A mixture of 4-bromo-3-ethyl-2-fluorobenzaldehyde (0.11 g, 0.5 mmol), 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5, 5 tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (intermediate 2) (0.15 g), Pd(PPh3)4 (55 mg) and Na2CO3 (2N solution , 0.5 ml) in dioxane (10 ml) was heated at 90° C. under N2 overnight. The mixture was cooled to room temperature and washed with water followed by brine. The organic layer was concentrated and purified using a flash cartridge (ISCO) to give 2-ethyl-3-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- [1,1'-biphenyl]-4-carbaldehyde (48 mg).

Example G Synthesis of 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1'-biphenyl]-4carbaldehyde (aldehyde intermediate 9 ) and 2-(sec-butyl)-4'-(1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (intermediate aldehyde 10)

Stage A.

To a solution of 2-isopropylphenol (6.5 g, 48 mmol, 1.0 eq.) in 50% aqueous NaOH (30 ml) was added powdered Cu (240 mg) and carbon tetrachloride (6.7 ml, 62 mmol, 1. 3 eq.). The mixture was heated to reflux for 16 hours. After cooling, the mixture was acidified to pH 2 by adding concentrated HCl and extracted with EtOAc. The organic phase was then extracted

- 55 041942 with saturated NaHCO ₃ solution and the aqueous layer was acidified to pH 2 by careful titration with concentrated HCl. The solution was extracted with EtOAc. The organic layer was washed with water, separated and concentrated to dryness to give 4-hydroxy-3-isopropylbenzoic acid (4 g) as a bright red solid which was used without further purification.

Stage B.

To a mixture of 4-hydroxy-3-isopropylbenzoic acid (2.0 g, 11 mmol, 1 eq.), triethylamine (3.30 g, 33 mmol, 3 eq.) and N,O-dimethylhydroxylamine hydrochloride (1.08 g, 110 mmol, 10 eq.) in DCM (100 ml) was added HBTU (6.25 g, 1.65 mmol, 1.5 eq.). The mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO ₃ solution, 2N. HCl and water. The organic phase was dried over MgSO ₄ and concentrated in vacuo to give 4-hydroxy-3-isopropylN-methoxy-N-methylbenzamide (4.5 g) as a pale red solid which was used without further purification.

Stage C.

To a mixture of 4-hydroxy-3-isopropyl-N-methoxy-N-methylbenzamide (500 mg, 2.2 mmol, 1 eq.) and pyridine (525 µl, 6.6 mmol, 3 eq.) in DCM (30 ml ) trifluoromethanesulfonic acid anhydride (0.93 g, 3.3 mmol, 1.5 eq.) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 h and washed with saturated NaHCO ₃ solution and water. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 2-isopropyl-4-(methoxy(methyl)carbamoyl)phenyl trifluoromethanesulfonate (680 mg) as a white solid.

Stage D

Bis(pinacolato)diborone (0. 63 g, 2.5 mmol, 1.3 eq.), potassium acetate (0.56 g, 5.7 mmol, 3 eq.) and Pd(dppf) ₂ Cl ₂ (70 mg, 0.095 mmol, 0.05 equiv.). The mixture was degassed and then sparged with N ₂ for 5 min, and then stirred at 90°C for 3 h. After cooling to room temperature, the mixture was poured into a solution of NH ₄ Cl and was extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 3-isopropyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)benzamide (500 mg) as a white solid.

Stage E.

To a solution of 3-isopropyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (100 mg, 0.3 mmol, 1 eq.) in anhydrous 1,4-dioxane (2 ml) was added 1,1,1,3,3,3-hexafluoro-2-(4iodophenyl)propan-2-ol (intermediate 1) (145 mg, 0. 39 mmol, 1.3 eq.), 2 M potassium carbonate solution (0.45 ml, 0.9 mmol, 3 eq.) and Pd(PPh ₃ ) ₄ (17 mg, 0.015 mmol, 0.05 eq.) . The mixture was degassed and then sparged with N ₂ for 5 min, and then stirred at 90°C for 3 h. After cooling to room temperature, the mixture was poured into a solution of NH ₄ Cl and was extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 3isopropyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )benzamide (100 mg) as a white solid.

Stage F

To a solution of 3-isopropyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (100 mg, 0.22 mmol, 1 0 eq.) in anhydrous THF (2 ml) was added 1.0 M solution of LAH in THF (220 μl, 1.0 eq.) at -78°C. The reaction was stirred at -78°C for 1 h, stopped by adding EtOAc and then warmed to room temperature. The mixture was poured into NH4Cl solution and extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1, 1'-biphenyl]-4carbaldehyde (aldehyde intermediate 9) (90 mg) as a white solid.

Aldehyde intermediate 10 was prepared using a similar method, but replacing 2(sec-butyl)phenol with 2-isopropanolphenol.

Example H Synthesis of 3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1'biphenyl]-4 -carbaldehyde (aldehyde intermediate 11)

Stage A.

2,5-Difluoro-4-methoxybenzoic acid (500 mg) was treated with BBr ₃ at room temperature for 24 h. HCl and purified on a silica gel column to give 2,5difluoro-4-hydroxybenzoic acid.

Stage B.

To a mixture of 2,5-difluoro-4-hydroxybenzoic acid (380 mg, 2.18 mmol, 1 eq.), triethylamine (660 mg, 6.6 mmol, 3 eq.) and N,O-dimethylhydroxylamine hydrochloride (2, 14 g, 21.8 mmol, 10 eq) in DCM

- 56 041942 (20 ml) HBTU (1.25 g, 3.27 mmol, 1.5 eq.) was added. The mixture was stirred at room temperature overnight, then washed with saturated NaHCO ₃ , 2N. HCl and water. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give

2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (190 mg) as a colorless oil.

Step C To a solution of 2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (190 mg, 0.87 mmol, 1 eq) in acetic acid (4 ml) was added NBS (190 mg, 1. 05 mmol, 1.2 eq.) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 h. The solvent was removed under high vacuum, the residue was dissolved in EtOAc, washed with water, concentrated and purified on a silica gel column to give 3-bromo-2,5-difluoro-4-hydroxy- N-methoxy-N-methylbenzamide (240 mg) as a white solid.

Stage D

Pinacol ether was added to a solution of 3-bromo-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (240 mg, 0.81 mmol, 1 eq.) in anhydrous 1,4-dioxane (9 ml) isopropenylboronic acid (204 mg, 1.22 mmol, 1.5 eq.), 2 M potassium carbonate solution (1.2 ml, 2.4 mmol, 3 eq.) and Pd(PPh ₃ ) ₄ (45 mg, 0 .04 mmol, 0.05 eq.). The mixture was degassed, then N2 was bubbled through for 5 minutes, and then stirred at 90° C. overnight. After cooling to room temperature, the mixture was poured into a solution of NH ₄ Cl and was extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 2,5-difluoro-4-hydroxy-N-methoxy-N-methyl-3-(prop-1-en-2yl)benzamide (180 mg) as a white solid.

Stage E.

To a mixture of 2,5-difluoro-4-hydroxy-N-methoxy-N-methyl-3-(prop-1-en-2-yl)benzamide (180 mg, 0.7 mmol, 1 eq.) and pyridine ( 0.5 ml) in DCM (50 ml) was added dropwise trifluoromethanesulfonic acid anhydride (0.33 g, 1.05 mmol, 1.5 eq.) at 0°C. The mixture was stirred at 0°C for 1 h and washed with saturated NaHCO ₃ solution and water. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 3,6-difluoro-4-(methoxy(methyl)carbamoyl)2-(prop-1-en-2-yl)phenyl trifluoromethanesulfonate (240 mg) as a pale yellow oil.

Stage F

To a solution of 3,6-difluoro-4-(methoxy(methyl)carbamoyl)-2-(prop-1-en-2-yl)phenyl trifluoromethanesulfonate (240 mg, 0.61 mmol, 1 eq.) in anhydrous 1, 4-dioxane (10 ml) was added 1,1,1,3,3,3-hexafluoro-2(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl )propan-2-ol (340 mg, 0.93 mmol, 1.5 eq.), 2 M potassium carbonate solution (1.0 ml, 1.8 mmol, 3 eq.) and Pd(PPh ₃ ) ₄ ( 35 mg, 0.03 mmol, 0.05 eq.). The mixture was degassed, then N2 was bubbled through for 5 minutes, and then stirred at 90° C. overnight. After cooling to room temperature, the mixture was poured into a solution of NH ₄ Cl and was extracted with DCM. The organic phase was dried over MgSO4, concentrated and purified on a silica gel column to give 3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxy-propan-2-yl)-N- methoxy-N-methyl-2-(nprop-1 en-2-yl)-[1,1'-biphenyl]-4-carboxamide (140 mg) as a white solid.

Stage G

To a solution of 3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxynronan-2-yl)-N-methoxy-N-methyl-2(prop-1-ene -2-yl)-[1,1'-biphenyl]-4-carboxamide (140 mg, 0.29 mmol, 1 eq) in MeOH (10 ml) was added Pd/C (10 wt%, 14 mg) . The reaction was shaken under _H2 (50 psi) for 4 hours. The mixture was filtered to remove the catalyst and concentrated to give 3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2hydroxypropane- 2-yl)-2-isopropyl-N-methoxy-N-methyl-[1,1'-biphenyl]-4-carboxamide (120 mg) as a white solid.

stage N.

To a solution of 3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-N-methoxy-Nmethyl-[1,1' -biphenyl]-4-carboxamide (120 mg, 0.25 mmol, 1 eq.) in anhydrous THF (2 ml) was added 1.0 M solution of LAH in THF (250 μl, 1.0 eq.) at -78° WITH. The reaction was stirred at -78°C for 1 h and stopped by adding EtOAc, after which it was warmed to room temperature. The mixture was poured into NH4Cl solution and extracted with DCM. The organic phase was dried over MgSO4, concentrated and purified on a silica gel column to give 3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)-2-isopropyl- [1,1'-biphenyl]-4-carbaldehyde (aldehyde intermediate 11) (100 mg) as a white solid.

Synthesis of 3,5-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1'-biphenyl]-4carbaldehyde (intermediate aldehyde compound 12)

The aldehyde intermediate 12 was prepared using the above methods by replacing 2,6-difluoro-4-hydroxybenzoic acid with 2,5-difluoro-4-hydroxybenzoic acid.

Example I Synthesis of 2-(tert-butyl)-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- 57 041942 carbaldehyde (aldehyde intermediate 13)

Stage A.

To a mixture of 3-(tert-butyl)-4-hydroxybenzoic acid (300 mg, 1 eq.), TEA (470 mg, 3 eq.) and HOdimethylhydroxylamine hydrochloride (1.51 g, 10 eq.) in DCM (20 ml ) was added HBTU (0.88 g, 1.5 eq.). The mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO ₃ solution, 2N. HCl and water. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 3-(tert-butyl)-4-hydroxy-N-methoxy-N-methylbenzamide (202 mg, 55% yield) as a colorless oil.

Stage B.

Trifluoromethanesulfonic acid anhydride (0. 36 g, 1.5 eq.) dropwise at 0°C. The mixture was stirred at 0°C for 1 h and washed with saturated NaHCO ₃ solution and water. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 2-(tert-butyl)-4-(methoxy(methyl)carbamoyl)phenyl trifluoromethanesulfonate (220 mg) as a pale yellow oil.

Stage C.

1,1,1,3,3 ,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)propan-2-ol (330 mg, 1.5 eq.), 2 M solution of potassium carbonate (1.1 ml, 3 eq.) and Pd(PPh ₃ ) ₄ (38 mg, 0.05 eq.). The mixture was degassed, then N2 was bubbled through for 5 minutes and then stirred at 90° C. overnight. After cooling to room temperature, the mixture was poured into a solution of NH ₄ Cl and was extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 2-(tert-butyl)-4'-(1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)-N -methoxy-N-methyl-[1,1'-biphenyl]-4-carboxamide (183 mg, 75% yield) as a white solid.

Stage D

To a solution of 2-(tert-butyl)-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl[1,1'- biphenyl]-4-carboxamide (183 mg, 1.0 eq.) in anhydrous THF (2 ml) was added a 1.0 M solution of LAH in THF (450 μl, 1.0 eq.) at -78°C. The reaction was stirred at -78°C for 1 h and stopped by adding EtOAc, after which it was warmed to room temperature. The mixture was poured into a solution of NH ₄ Cl and was extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 2-(tert-butyl)-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) [1,1'-biphenyl]-4-carbaldehyde (120 mg) as a white solid.

Example J.

Synthesis of 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1'-biphenyl]-4-carbaldehyde (aldehyde intermediate 14) , 2-chloro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'biphenyl]-4-carbaldehyde (aldehyde intermediate 15), and 4'-(1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)-2-(trifluoromethyl)-[1,1'-biphenyl]-4-carbaldehyde (aldehyde intermediate 16)

ooo

Intermediate 14 Intermediate 15 Intermediate 16 (4-Formyl-2-methylphenyl)boronic acid (6.65 g, 1.0 eq.), 4iodophenyl)propan-2-ol (3.2 g, 1.2 eq.), Pd(PPh ₃ ) ₄ (2.05 g, 0.1 eq.) and K2CO3 (7.4 g, 3.0 eq.) were combined into dioxane (150 ml) and water (40 ml). The mixture was purged with N2 for 5 minutes and then heated at 80° C. for 8 hours under N2. The reaction was extracted with EtOAc (2x200 ml). The combined organic phase was washed with 1 N. HCl and brine. The crude mixture was purified on a silica gel column to give 4'(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1'-biphenyl]-4- carbaldehyde (4.6 g, 73% yield) as a white solid.

Aldehyde intermediate 15 was prepared using a similar method, but replacing (2chloro-4-formylphenyl)boronic acid with (4-formyl-2-methylphenyl)boronic acid.

Aldehyde intermediate 16 was prepared using a similar method, but replacing (4-formyl-2-(trifluoromethyl)phenyl)boronic acid with (4-formyl-2-methylphenyl)boronic acid.

- 58 041942

Example K Synthesis of 2-bromo-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (aldehyde intermediate 17 ) ^CF 3 il^ ^Br O

Stage A.

Methyl 3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.0 g, 1.0 eq.), 1,1,1, 3,3,3hexafluoro-2-(4-iodophenyl)propan-2-ol (1.6 g, 1.2 eq.), Pd(PPh ₃ ) ₄ (0.42 g, 0.1 eq.) and K ₂ CO ₃ (1.5 g, 3.0 equiv.) was combined in dioxane (30 ml) and water (10 ml). The mixture was purged with N ₂ for 5 minutes and then heated at 80° C. for 8 hours under N ₂ . The reaction was extracted with EtOAc (2x60 ml). The combined organic phase was washed with 1 N. HCl and brine. The crude mixture was purified on a silica gel column to give methyl 2-amino-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]- 4-carboxylate (1.16 g, 82% yield).

Stage B.

To a solution of methyl 2-amino-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4aniline carboxylate (1.16 g , 1.0 eq.) in DMF (15 ml) was added a solution of NaNO ₂ (0.23 g, 1.1 eq.) in water (10 ml). The mixture was cooled to 0°C over 15 min. To the reaction mixture was added dropwise 6 N. H ₂ SO ₄ (9 ml, 3.0 equiv.) for 15 min at 0°C. The resulting mixture was stirred at 0° C. for 1 hour. CuBr (0.64 g, 1.5 eq.) was added. The reaction mixture was stirred at 0°C for 1 h and then at room temperature overnight. The reaction was diluted with water (~500 ml) and extracted with EtOAc/hexane (2:1, 3x150 ml). The combined organic phase was washed with NaHSO ₃ , water and brine. The crude mixture was purified on a silica gel column to give methyl 2-bromo-4'-(1,1,1,3,3,3hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4- carboxylate (650 mg, 48% yield).

Stage C.

Methyl 2-bromo-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carboxylate was converted to the corresponding acid by treatment 2 n. LiOH to MeOH. This acid was coupled with N,O-dimethylhydroxylamine hydrochloride to give 2-bromo-4'-(1,1,1,3,3,3-hexafluoro-2hydroOxCypropan-2-yl)-N-methoxy-N-methyl-[ 1,1'-biphenyl]-4-carboxamide. 2-Bromo-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1'-biphenyl]-4- carboxamide was converted to 2bromo-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde by reduction with LAH at -70 °C.

Example L Synthesis of 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(prop-1-en-2-yl)-[1,1' biphenyl]-4-carbaldehyde (aldehyde intermediate 18)

By a Suzuki coupling reaction between the intermediate 2-bromo-4'-(1,1,1,3,3,3heksafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1'- biphenyl]-4-carboxamide from step C of example K and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane under the reaction conditions described in step Example K (except heating to 90° C. overnight) gave 4'(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl -2-(prop-1-en-2-yl)-[1,1'-biphenyl]-4carboxamide, which was converted to the corresponding aldehyde, 4'-(1,1,1,3,3,3-hexafluoro -2hydroxypropan-2-yl)-2-(prop-1-en-2-yl)-[1,1'-biphenyl]-4-carbaldehyde, with LAH reduction at 70°C.

Example M Synthesis of 2-cyclopropyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]4-carbaldehyde (aldehyde intermediate 19) ^F3C x ^OH zet (| V o ^v

By a Suzuki coupling reaction between the intermediate 2-bromo-4'-(1,1,1,3,3,3heksafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1'- biphenyl]-4-carboxamide from step C of example K and cyclopropylboronic acid under the reaction conditions described in step A of example K (except heating to 90° C. overnight) gave 2-cyclopropyl-4'-(1,1, 1,3,3,3hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1'-biphenyl]-4-carboxamide which was converted to the corresponding aldehyde, 2-cyclopropyl-4 '-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2yl)-[1,1'-biphenyl]-4-carbaldehyde, with LAH reduction at 70°C.

- 59 041942

Example N Synthesis of 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2'-methyl-[1,1'biphenyl]-4- carbaldehyde (aldehyde intermediate 20)

By standard Suzuki coupling reaction between 3-isopropyl-N-methoxy-N-methyl-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, Example F Intermediate, step E, and intermediate 4 gave 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2isopropyl-N-methoxy-N,2'-dimethyl-[1, 1'-biphenyl]-4-carboxamide which was converted to the corresponding aldehyde with LAH reduction in anhydrous THF at -78°C.

Example O Synthesis of 2-ethyl-2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]4- carbaldehyde (aldehyde intermediate 21) and 2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)-2'-methyl-[1,1'-biphenyl] -4-carbaldehyde (aldehyde intermediate 22)

By a standard Suzuki coupling reaction between 3-ethyl-N-methoxy-N-methyl-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide from Step B of Example C and 2- (4-bromo-3-fluorophenyl)1,1,1,3,3,3-hexafluoropropan-2-ol (intermediate 3) gave 2-ethyl-2'-fluoro-4'(1,1,1, 3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1'-biphenyl]-4-carboxamide, which was converted to the corresponding aldehyde, 2-ethyl-2 '-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (aldehyde intermediate 21), with reduction LAH in anhydrous THF at -70°C.

By a standard Suzuki coupling reaction between 3-ethyl-N-methoxy-N-methyl-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide from Step B of Example C and 2- (4-bromo-3-methylphenyl)1,1,1,3,3,3-hexafluoropropan-2-ol (intermediate 4) gave 2-ethyl-4'-(1,1,1,3,3, 3hexafluoro-2-hydroxypropan-2-yl)-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde, which was converted to the corresponding aldehyde, 2-ethyl-4'-(1,1,1, 3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2'-methyl-[1,1'biphenyl]-4-carbaldehyde (aldehyde intermediate 22), with LAH reduction in anhydrous THF at -70° WITH.

Example P Synthesis of 2-(pyridin-4-ylmethyl)-2,6-diazaspiro[3.3]heptane, TFA (amine intermediate 1)

Commercially available oxalate (100 mg, 1.2 eq.) and tert-butyl 2,6-diazaspiro[3.3]heptane-2carboxylate were suspended in 1,2-DCE (15 ml), then Et ₃ N (42 mg, 2 0 eq.) and stirred at room temperature for 30 minutes. Isonicotinaldehyde (40 mg, 1.0 eq.) was added followed by acetic acid (30 μl). The mixture was stirred at room temperature for 3 h and NaBH(OAc) ₃ (240 mg, 3.0 equiv.) was added to the solution. The resulting mixture was stirred at room temperature overnight. The reaction was stopped with MeOH and diluted with saturated NaHCO ₃ solution, then extracted with 2x20 ml DCM. The crude mixture was purified on a silica gel column to give tert-butyl 6-(pyridin-4-ylmethyl)-2,6-diazaspiro[3.3]heptane-2carboxylate (70 mg, 65% yield). The resulting carboxylate was treated with TFA (3 ml) in DCM (80 v/v%) to give 2-(pyridin-4-ylmethyl)-2,6-diazaspiro[3.3]heptane which was used without purification.

Example Q Synthesis of 2-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane, TFA (amine intermediate 2), 2-(ethylsulfonyl)-2,6-diazaspiro[3.3]heptane, TFA (amine intermediate 3) ), 2-(cyclopropylsulfonyl)-2,6-diazaspiro[3.3]heptane, TFA (amine intermediate 4), 2(propylsulfonyl)-2,6-diazaspiro[3.3]heptane, TFA (amine intermediate 5) and 2 (isobutylsulfonyl)-2,6-diazaspiro[3.3]heptane, TFA (amine intermediate 6).

- 60 041942

R=CH3 amine intermediate 2;

Et is an amine intermediate 3;

1> - amine intermediate 4;

- amine intermediate 5;

''•-X· - amine intermediate 6.

tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as oxalate salt (5.0 g, 1.0 eq.) was suspended in CH ₂ Cl ₂ (150 ml). To the mixture was added a saturated solution of NaHCO ₃ (50 ml) at 0°C. The mixture was stirred at 0° C. for 10 min and a solution of MsCl (4.7 g, 2.0 eq.) in CH ₂ Cl ₂ (10 ml) was added dropwise. The resulting mixture was stirred at 0° C. for 1 hour and then at room temperature overnight. The organic phase was separated and washed with brine, then concentrated in vacuo to give t-butyl 6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane-2carboxylate as a white solid (5.0 g, 88% yield), which used without further purification.

tert-Butyl 6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate was treated with TFA in DCM (80 v/v%) to give 2-(methylsulfonyl)-2,6-diazaspiro[3.3 ]heptane (amine intermediate 2), which was used without purification. 2-(Ethylsulfonyl)-2,6-diazaspiro[3.3]heptane (amine intermediate 3) was synthesized by analogous methods using ethanesulfonyl chloride instead of MsCl. 2-(Cyclopropylsulfonyl)-2,6-diazaspiro[3.3]heptane (amine intermediate 4) was synthesized by analogous methods using cyclopropanesulfonyl chloride instead of MsCl.

2-(Propylsulfonyl)-2,6-diazaspiro[3.3]heptane (amine intermediate 5) was synthesized by similar methods using propane-1-sulfonyl chloride instead of MsCl.

2-(Isobutylsulfonyl)-2,6-diazaspiro[3.3]heptane (amine intermediate 6) was synthesized by analogous methods using 2-methylpropane-1-sulfonyl chloride instead of MsCl.

Example R Synthesis of 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one, TFA (amine intermediate 7) and methyl 2,6-diazaspiro[3.3]heptan-2-carboxylate, TFA (amine intermediate 8)

ABOUT . . V

Amine Intermediate 7 Amine Intermediate 8

tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as oxalate salt (100 mg, 1.0 eq.) was suspended in CH ₂ Cl ₂ (15 ml). A saturated solution of NaHCO ₃ (5 ml) was added to the mixture at 0°C. The mixture was stirred at 0°C for 10 min and a solution of acetyl chloride (84 mg, 5.0 eq.) in CH2Cl2 (2 ml) was added dropwise. The resulting mixture was stirred at 0° C. for 1 h. The organic phase was separated and washed with brine, then concentrated in vacuo to give tert-butyl 6acetyl-2,6-diazaspiro[3.3]heptane-2-carboxylate as a white solid (39 mg, 75% yield), which was used without further purification.

tert-Butyl 6-acetyl-2,6-diazaspiro[3.3]heptane-2-carboxylate was treated with TFA in DCM (80 v/v%) to give 1-(2,6-diazaspiro[3.3]heptan-2- yl)ethan-1-one (amine intermediate 7), which was used without purification.

Methyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (amine intermediate 8) was synthesized in a similar manner using methyl chloroformate instead of acetyl chloride.

Example S Synthesis of 2-thia-6-azaspiro[3.3]heptane 2-oxide (amine intermediate 9) and 6thia-2-azaspiro[3.4]octane 6-oxide (amine intermediate 10) h h >—N.TFA ^-NH.TFA

Amine Intermediate 9 Amine Intermediate 10

Et ₃ N (3.0 equiv.) and (Boc) ₂ O (1.5 equiv.) were added to a solution of 2-thia-6-azaspiro[3.3]heptane (100 mg, 1.0 equiv.) in DCM (8 ml). ). The resulting mixture was stirred at room temperature overnight. The mixture was dried under vacuum and purified on a silica gel column to give tert-butyl 2-thia-6-azaspiro[3.3]heptane-6-carboxylate (170 mg, 91% yield).

tert-Butyl 2-thia-6-azaspiro[3.3]heptane-6-carboxylate (60 mg, 1.0 eq.) was dissolved in DCM (5 ml) and cooled to -30°C. mCPBA (64 mg, 72%, 0.95 eq) was added. The mixture was stirred at -30°C for 10 min, then at 0°C for 1 h. The reaction mixture was diluted with DCM (20 ml) and washed with 3x10 ml of saturated NaHCO3 solution. The crude mixture was purified on a silica gel column to give tert-butyl 2-thia-6-azaspiro[3.3]heptane-6-carboxylate 2-oxide (48 mg, 74% yield). tert-Butyl 2-thia-6azaspiro[3.3]heptane-6-carboxylate 2-oxide was treated with TFA in DCM (80 v/v%) to give 2-thia6-azaspiro[3.3]heptane 2-oxide (amine intermediate 9), which was used without purification.

The amine intermediate 10 was synthesized by analogous methods using 6-thia-2-61 041942 azaspiro[3.4]octane instead of 2-thia-6-azaspiro[3.3]heptane.

Example T Synthesis of 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, TFA (amine intermediate 11) and 6-thia-2-azaspiro[3.4]octane 6,6-dioxide, TFA (amine intermediate 11) amine 12)

Yag O ^{7 l} nh.tfa ^nh.tfa

Amine Intermediate 11 Amine Intermediate 12 tert-Butyl 2-thia-6-azaspiro[3.3]heptane-6-carboxylate (60 mg, 1.0 eq.) was dissolved in DCM (5 ml) and cooled to 0°C. mCPBA (166 mg, 72%, 2.5 eq) was added. The mixture was stirred at 0°C for 10 min, and then at room temperature for 1 h. The reaction mixture was diluted with DCM (20 ml) and washed with 3x10 ml of saturated NaHCO ₃ . The crude mixture was purified on a silica gel column to give tert-butyl 2-thia-6-azaspiro[3.3]heptane-6-carboxylate 2,2-dioxide (56 mg, 80% yield). tert-Butyl 2-thia-6-azaspiro[3.3]heptane-6-carboxylate 2,2-dioxide was treated with TFA in DCM (80 v/v%) to give 2-thia-6-azaspiro[3.3]heptane 2 ,2-dioxide, salt of TFA (amine intermediate 11), which was used without purification.

The amine intermediate 12 was synthesized by analogous methods, using tert-butyl 6-thia-2-azaspiro[3.4]octane-2-carboxylate instead of tert-butyl 2-thia-6-azaspiro[3.3]heptane-6carboxylate.

Example U Synthesis of N-(azetidin-3-ylmethyl)methanesulfonamide, TFA (amine intermediate 13)

V

HN—h ^NH. TFA

Stage A.

tert-Butyl 3-(aminomethyl)azetidine-1-carboxylate (300 mg, 1.0 eq.) and pyridine (1 ml) were combined in DCM (20 ml) at 0°C. MsCl (1.1 eq.) was added dropwise. The mixture was stirred at 0° C. for 3 hours. The reaction mixture was diluted with DCM (30 ml), washed with 3x30 ml of 1N. HCl, water and brine to give tert-butyl 3-(methylsulfonamidomethyl)azetidine-1-carboxylate (390 mg, 91% yield) which was used without further purification.

Stage B.

tert-Butyl 3-(methylsulfonamidomethyl)azetidine-1-carboxylate was treated with TFA in DCM (80 v/v%) to give N-(azetidin-3-ylmethyl)methanesulfonamide, TFA (amine intermediate 13), which was used without cleaning.

Example V Synthesis of N-(azetidin-3-ylmethyl)-N-methylmethanesulfonamide, TFA (amine intermediate 14)

NaH (60%, 23 mg, 1.5 eq.) .). The mixture was stirred at room temperature for 30 minutes and then cooled to 0°C. CH ₃ I (81 mg, 1.5 eq.) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 ml) and hexane (20 ml). The mixture was washed with 3x30 ml of water and brine. The crude mixture was purified on a silica gel column to give tert-butyl 3-((Nmethylmethylsulfonamido)methyl)azetidine-1-carboxylate (72 mg, 68% yield). tert-Butyl 3-((Nmethylmethylsulfonamido)methyl)azetidine-1-carboxylate was treated with TFA in DCM (80 v/v%) to give amine intermediate 14 which was used without purification.

Example W Synthesis of 2-(methylsulfonyl)-2,6-diazaspiro[3.4]octane, TFA (amine intermediate 15)

Commercially available tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was treated with MsCl in the presence of TEA to give tert-butyl 2-(methylsulfonyl)-2,6-diazaspiro[3.4]octane-6carboxylate, which was then treated with TFA in DCM (80 v/v%) to give Amine Intermediate 15 which was used without purification.

Example X Synthesis of 7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonane, TFA (amine intermediate 16)

- 62 041942

Commercially available tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate was treated with MsCl in the presence of TEA to give tert-butyl 7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonane-2carboxylate, which was then treated with TFA in DCM (80 v/v%) to give Amine Intermediate 16 as TFA salt, which was used without purification.

Example Y Synthesis of 6-(methylsulfonyl)-2,6-diazaspiro[3.5]nonane, TFA (amine intermediate 17)

Commercially available tert-butyl 2,6-diazaspiro[3.5]nonane-2-carboxylate was treated with MsCl in the presence of TEA to give tert-butyl 6-(methylsulfonyl)-2,6-diazaspiro[3.5]nonane-2carboxylate, which was then treated with TFA in DCM (80 v/v%) to give the amine intermediate 17 as the TFA salt, which was used without purification.

Example Z Synthesis of 2-(methylsulfonyl)-2,7-diazaspiro[4.4]nonane, TFA (amine intermediate 19)

Commercially available tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate was treated with MsCl in the presence of TEA to give tert-butyl 7-(methylsulfonyl)-2,7-diazaspiro[4.4]nonane-2carboxylate, which was then treated with TFA in DCM (80 v/v%) to give the amine intermediate 19 as the TFA salt, which was used without purification.

AA example. Synthesis of 6-(methylsulfonyl)-2-azaspiro[3.3]heptane, TFA (amine intermediate 20)

Commercially available tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.0 eq.), TEA (360 mg, 3.0 eq.) and DMAP (10 mg) were combined in DCM ( 25 ml) at 0°C. MsCl (162 mg, 1.2 eq.) was added dropwise. The mixture was stirred at 0° C. for 3 hours. The reaction mixture was diluted with DCM (30 ml) and then washed with 1 N. HCl, water and brine to give tert-butyl 6((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (324 mg, 95% yield) which was used without further purification. tert-Butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (324 mg, 1.0 eq.) and NaSMe (160 mg, 2.0 eq.) were combined in DMF (15 ml). The mixture was heated at 60° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and hexane (30 ml) and then washed with 3x40 ml of water and brine. The crude mixture was purified on a silica gel column to give tert-butyl 6(methylthio)-2-azaspiro[3.3]heptane-2-carboxylate (144 mg, 53% yield).

tert-Butyl 6-(methylthio)-2-azaspiro[3.3]heptane-2-carboxylate (144 mg, 1.0 eq.) was dissolved in DCM (10 ml) and cooled with ice water. m-CPBA (355 mg, 2.5 eq.) was added. The resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM (20 ml) and washed with 3x30 ml of saturated NaHCO ₃ solution. The crude mixture was purified on a silica gel column to give tert-butyl 6-(methylsulfonyl)-2-azaspiro[3.3]heptane-2-carboxylate (98 mg, 60% yield). tert-Butyl 6-(methylsulfonyl)-2-azaspiro[3.3]heptane-2-carboxylate was treated with TFA in DCM (80 v/v%) to give 6-(methylsulfonyl)-2-azaspiro[3.3]heptane, TFA (intermediate amine compound 20), which was used without purification.

VV example. Synthesis of 4-((methylsulfonyl)methyl)piperidine, TFA (amine intermediate 21) and 4-(2-(methylsulfonyl)ethyl)piperidine, TFA (amine intermediate 22)

Amine intermediate 21 was synthesized using the methods described in Example AA using commercially available tert-butyl 4-hydroxypiperidine-1-carboxylate in place of tert-butyl 6hydroxy-2-azaspiro[3.3]heptane-2-carboxylate. Amine intermediate 22 was synthesized using the methods described in Example AA using commercially available tert-butyl 4-(2-63041942 hydroxyethyl)piperidine-1-carboxylate in place of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane- 2 carboxylates.

SS example. Synthesis of 2,3-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-6-isopropyl-[1,1' biphenyl]-4-carbaldehyde ( aldehyde intermediate 23) and 2-fluoro-4'-(1,1,1,3,3,3-hexafluoro2-hydroxypropan-2-yl)-6-isopropyl-[1,1'-biphenyl]-4- carbaldehyde (aldehyde intermediate 24)

The aldehyde intermediate 23 was prepared using the methods described in Example H, but replacing 2,3-difluoro-4-hydroxybenzoic acid with 2,5-difluoro-4-hydroxybenzoic acid in step B.

The aldehyde intermediate 23 was prepared using the methods described in Example H, but replacing 3-fluoro-4-hydroxybenzoic acid with 2,5-difluoro-4-hydroxybenzoic acid in step B.

DD example. Synthesis of 4-ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)picolinaldehyde (aldehyde intermediate 25)

Stage A.

To a solution of 4-ethylpyridine-2-amine (1 g, 8.2 mmol, 1 eq.) in DCM (30 ml) was added NBS (1.45 g, 8.2 mmol, 1 eq.) at -40°C . The reaction mixture was stirred at -40°C for 30 min. The reaction was stopped with 50 ml of water and extracted with DCM. The organic phase was separated and concentrated. The residue was purified on a silica gel column (hexane/ethyl acetate) to give 5-bromo-4-ethylpyridin-2-amine (1.3 g) as a white solid.

Stage B.

To a solution of 5-bromo-4-ethylpyridine-2-amine (1.0 g, 5.0 mmol, 1.0 eq.), NaNO ₂ (860 mg, 12.5 mmol, 2.5 eq.) in 40 % solution of HBr (30 ml) was added Br ₂ (1.8 g, 2.0 eq.) at 0°C. The mixture was then heated to 70° C. for 2 hours. The reaction mixture was poured into DCM (100 ml) and water (100 ml). The organic phase was washed with water and saturated NaHCO ₃ solution. The crude material was purified on a silica gel column (hexane/ethyl acetate) to give 2,5-dibromo-4-ethylpyridine (1.1 g) as a white solid.

Stage C.

CuCN (340 mg, 3.8 mmol, 1 equiv.) and NaCN (190 mg, 3.8 mmol, 1 equivalent). The mixture was stirred at 150°C for 5 hours After cooling to room temperature, the reaction mixture was diluted with EtOAc/hexane (8:1, 100 ml) and washed with water, saturated NaHCO ₃ solution and water. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 5-bromo-4-ethylpicolinonitrile (580 mg) as a white solid.

Stage D

To a solution of 5-bromo-4-ethylpicolinonitrile (300 mg, 1.4 mmol, 1 eq.) in 1,4-dioxane (10 mL) was added intermediate 2 from Example A (570 mg, 1.54 mmol, 1, 1 eq.), 2 M potassium carbonate solution (2.1 ml, 4.2 mmol, 3 eq.) and Pd(PPh ₃ ) ₄ (80 mg, 0.07 mmol, 0.05 eq.). The mixture was degassed and then N ₂ was bubbled through for 5 minutes. The resulting mixture was stirred at 90°C for 3 hours After cooling to room temperature, the mixture was poured into a solution of NH ₄ Cl and was extracted with DCM. The organic phase was dried over MgSO4, concentrated and purified on a silica gel column to give 4-ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)picolinonitrile (380 mg) as a white solid.

Stage E.

4-Ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)picolinonitrile (200 mg, 0.53 mmol, 1 eq) was dissolved in 6 n. HCl solution. The reaction was stirred at 100°C for 3 hours and then concentrated to give 4-ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2yl)phenyl)picolinic acid, which was used without purification.

Stage F

To a mixture of 4-ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)picolinic acid

- 64 041942 (200 mg, 0.5 mmol, 1 eq.), triethylamine (150 mg, 1.5 mmol, 3 eq.) and N,Ο-dimethylhydroxylamine hydrochloride (73 mg, 0.75 mmol, 1.5 eq.) in DCM (10 ml) was added HBTU (285 mg, 0.75 mmol, 1.5 eq.). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (20 ml) and washed with saturated NaHCO ₃ , 2N. HCl and water. The organic phase was dried over MgSO ₄ and concentrated in vacuo to give 4-ethyl-5-(4-(1,1,1,3,3,3-hexafluoro2-hydroxypropan-2-yl)phenyl)-N-methoxy-N -methylpicolinamide (170 mg) as a pale red solid, which was used without further purification.

Stage G

To a solution of 4-ethyl-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-methoxy-Nmethylpicolinamide (170 mg, 0.39 mmol , 1 eq.) in anhydrous THF (2 ml) was added a 1.0 M solution of LAH in THF (0.39 ml, 1.0 eq.) at -78°C. The reaction was stirred at -78°C for 1 h and stopped by adding EtOAc, then warmed to room temperature. The mixture was poured into a solution of NH ₄ Cl and was extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give Alaldehyde Intermediate 25 (90 mg) as a white solid.

Example EE:

Synthesis of 5-ethyl-6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)nicotinaldehyde (aldehyde intermediate 26)

NBS (1.45 g, 8.2 mmol, 1 eq.). The resulting mixture was stirred at 0° C. for 2 hours. The reaction mixture was diluted with water (50 ml) and extracted with DCM. The organic phase was separated and concentrated. The residue was purified on a silica gel column (hexane/EtOAc) to give 5-bromo-3-ethylpyridine-2-amine (1.5 g) as a white solid.

5-Bromo-3-ethylpyridine-2-amine (1 g, 1 eq.), Zn(CN) ₂ (1.5 eq.) and PdCl ₂ (dppf) (10%) were combined in dry DMF (18 ml) . The resulting mixture was heated at 120° C. overnight. The reaction mixture was poured into DCM (100 ml) and washed with water and saturated NaHCO ₃ solution. The organic phase was dried over MgSO4 and concentrated. The residue was purified on a silica gel column (hexane/EtOAc) to give 6-amino-5-ethylnicotinonitrile (0.7 g) as a white solid. To a solution of 6-amino-5-ethylnicotinonitrile (0.7 g, 1 eq.) in CH3CN (15 ml) was added CuCl ₂ (2 eq.) and CuCl (2 eq.). n-Butyl nitrite (1.3 eq.) was added to the mixture at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then heated to reflux overnight. The reaction mixture was diluted with CH2Cl2 and washed with water, saturated NaHCO ₃ solution and water. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 6-chloro-5-ethylnicotinonitrile (0.42 g) as a white solid.

6-Chloro-5-ethylnicotinonitrile (200 mg, 0.53 mmol, 1 eq.) was dissolved in 6N. HCl solution. The reaction was stirred at 100° C. for 3 hours and then concentrated to give 6-chloro-5-ethylnicotinic acid, which was used without purification.

To a mixture of 6-chloro-5-ethylnicotinic acid (220 mg, 1 eq.), triethylamine (150 mg, 3 eq.) and N,Qdimethylhydroxylamine hydrochloride (85 mg, 1.5 eq.) in DCM (10 ml) was added HBTU (280 mg, 1.4 eq.). The mixture was stirred at room temperature overnight. The reaction was washed with a saturated solution of NaHCO ₃ , 2N. HCl and water. The organic phase was dried over MgSO ₄ and concentrated in vacuo to give 6-chloro-5-ethyl-N-methoxy-N-methylnicotinamide (150 mg) which was used without further purification.

6-Chloro-5-ethyl-N-methoxy-N-methylnicotinamide was replaced by 5-bromo-4-ethylpicolinonitrile in the Suzuki coupling reaction described in Step D of Example DD to give 5-ethyl-6-(4-(1, 1,1,3,3,3hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-methoxy-N-methylnicotinamide. 5-Ethyl-6-(4-(1,1,1,3,3,3hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-methoxy-N-methylnicotinamide was treated with 1 M LAH solution (1.2 eq. .) at -78°C to give aldehyde intermediate 26.

FF example.

Synthesis of 2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2'-methoxy-[1,1'-biphenyl]-4carbaldehyde (intermediate aldehyde 27)

- 65 041942

Aldehyde Intermediate 27

Stage A.

4-Bromo-3-methoxybenzaldehyde (400 mg, 1.0 eq.) and TMSCF ₃ (1.5 eq.) were dissolved in dry THF (15 ml), cooled with ice water under N2 atmosphere. CsF (1.0 eq.) was added to the mixture. The mixture was stirred at room temperature for 2 hours. The reaction was stopped with 1 M HCl (30 ml). The mixture was extracted with ethyl acetate and hexane (1:4). The crude mixture was purified on a silica gel column to give 1-(4bromo-3-methoxyphenyl)-2,2,2-trifluoroethan-1-ol (280 mg).

Stage B.

1-(4-Bromo-3-methoxyphenyl)-2,2,2-trifluoroethan-1-ol (200 mg, 1.0 eq.) was dissolved in dry DCM (10 ml) and cooled to 0°C. DMP (2.0 eq.) was added. The mixture was stirred at room temperature for 2 hours. The crude mixture was purified on a silica gel column to give 1-(4-bromo-3-methoxyphenyl)2,2,2-trifluoroethan-1-one (190 mg).

Stage C.

To a solution of 1-(4-bromo-3-methoxyphenyl)-2,2,2-trifluoroethan-1-one (150 mg, 1.0 eq.) and TMSCF3 (1.5 eq.) in dry THF (8 ml ) at 0° C., TBAF (1 M, 0.1 eq.) was added dropwise. The mixture was stirred at 0°C for 20 min, then stopped with 1 M HCl (10 ml). The crude mixture was purified on a silica gel column to give 2-(4-bromo-3-methoxyphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (80 mg).

Stage D

Preparation of intermediate 3-ethyl-N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzamide: 4-bromo-3-ethylbenzoic acid (5 0 g, 1.0 eq.), N,Odimethylhydroxylamine hydrochloride (3.2 g, 1.5 eq.) and HBTU (9.6 g, 1.15 eq.) were combined in DMF (80 ml) at room temperature. TEA (11.2 g, 4.0 eq.) was added dropwise to the reaction mixture. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (200 ml) and hexane (100 ml), then washed with 2x150 ml of water, 2x100 ml of 1N. HCl, 2x100 ml saturated NaHCO ₃ and brine. The organic phase was dried over MgSO ₄ and concentrated in vacuo to give 4-bromo-3-ethyl-N-methoxy-N-methylbenzamide as a pale yellow oil (5.8 g, 98% yield) which was used without further purification. 4-Bromo-3-ethyl-N-methoxy-N-methylbenzamide (3.0 g, 1.0 eq) and 4,4,4',4',5,5,5',5'-octamethyl-2,2' -bi(1,3,2-dioxaborolane) (3.22 g, 1.15 equiv.) was dissolved in dry dioxane (25 ml). The mixture was degassed by bubbling N ₂ for 5 minutes. PdCl ₂ (dppf) (0.81 g, 0.1 eq) and potassium acetate (1.63 g, 1.5 eq) were added to the reaction mixture. The resulting mixture was heated at 100° C. in a sealed tube for 15 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and hexane (80 ml) and washed with 3x80 ml of water and 50 ml of brine. The crude mixture was purified on a silica gel column to give 3-ethyl-N-methoxy-N-methyl-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (3.34 g, yield 95%) as a pale yellow oil.

Stage E.

2-(4-Bromo-3-methoxyphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol was substituted for Intermediate 1 in the Suzuki coupling reaction described in Step C of Example C to give 2- ethyl 4'-(1,1,1,3,3,3hexafluoro-2-hydroxypropan-2-yl)-N,2'-dimethoxy-N-methyl-[1,1'-biphenyl]-4-carboxamide . 2-Ethyl-4'(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N,2'-dimethoxy-N-methyl-[1,1'-biphenyl]- 4-carboxamide was treated with 1 M LAH (1.2 eq) at -78°C to give aldehyde intermediate 27.

GG example.

Synthesis of 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methoxy-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde ( aldehyde intermediate 28)

Intermediate 4 was replaced by Intermediate 1 in Step B of Example A to give 1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol.

1,1,1,3,3,3-Hexafluoro-2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan- 2ol was replaced with intermediate 2 and 4-bromo-3-methoxybenzaldehyde was replaced with 5-bromo-4-ethylpicolinonitrile in the Suzuki coupling described in Step D of Example DD to give

- 66 041942 aldehyde intermediate 28.

An example of NN.

Synthesis of 3-ethyl-4-(6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)benzaldehyde (aldehyde intermediate 29)

Methyl 5-bromopicolinate (1.0 g, 1.0 eq.) and TMSCF3 (6.5 g, 10 eq.) were combined in dry THF (20 ml). The mixture was cooled at 0°C for 5 min. To the solution was added 1 M TBAF (23 ml) dropwise over 10 minutes. The mixture was then stirred at 0°C for 2 hours, the Reaction was stopped with 1 M HCl (50 ml) at 0°C. The mixture was extracted with 3x30 ml of hexane. The crude material was purified on a silica gel column to give 2-(5-bromopyridin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (450 mg).

2-(5-Bromopyridin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol was substituted for Intermediate 1 in the Suzuki coupling reaction described in Step C of Example C to give 3- ethyl 4-(6-(1,1,1,3,3,3hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)-N-methoxy-N-methylbenzamide, which was then treated with 1 M LAH (1.2 eq.) at -78°C to give aldehyde intermediate 29.

Example II. Synthesis of 4-formyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N,N-dimethyl-[1,1'biphenyl]-2-carboxamide ( aldehyde intermediate 30)

Methyl 2-bromo-5-formylbenzoate was replaced by 5-bromo-4-ethylpicolinonitrile in the Suzuki coupling reaction described in Step D of Example DD to give methyl 4-formyl-4'-(1,1,1,3,3, 3-hexafluoro-2hydroxypropan-2-yl)-[1,1'-biphenyl]-2-carboxylate. Methyl 4-formyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-carboxylate was treated with a solution of LiOH in water and MeOH to give 4-formyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-carboxylic acid. 4-Formyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-carboxylic acid was coupled with N, O-dimethylhydroxylamine hydrochloride in the presence of HBTU to give aldehyde intermediate 30.

JJ example. Synthesis of 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3-hydroxy-[1,1'-biphenyl]-4carbaldehyde (aldehyde intermediate 31)

4-Bromo-2-hydroxybenzaldehyde was replaced by 5-bromo-4-ethylpicolinonitrile in the Suzuki coupling reaction described in Step D of Example DD to give the aldehyde intermediate 31.

Example 1 Synthesis of tert-butyl 6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'biphenyl]- 4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-carboxylate

Commercially available tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate salt (62 mg, 1.2 eq.) was suspended in 1,2-DCE (15 ml), Et ₃ N (26 mg, 2.0 eq.) and stirred at room temperature for 30 minutes. Aldehyde intermediate 5 (80 mg, 1.0 eq.) was added followed by acetic acid (20 μl). The mixture was stirred at room temperature for 3 h and NaBH(OAc) ₃ (136 mg, 3.0 equiv.) was added to the solution. The resulting mixture was stirred at room temperature overnight. The reaction was stopped with MeOH, diluted with 20 ml of saturated NaHCO ₃ and was extracted with 2x20 ml of ethyl acetate. The crude mixture was purified on a silica gel column to give the title compound (65 mg, 55% yield) as a white solid. LC-MS (ESI) m/z 559.2 (M+H)+.

Example 2 Synthesis of 2-(2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'biphenyl]-4- yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

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Amine intermediate 20 (3.7 g, TFA salt, 1.2 eq) was suspended in 1,2-DCE (50 ml) and aldehyde intermediate 5 (4.0 g, 1.0 eq) was added. The mixture was stirred at room temperature for 3 hours. Then solid NaBH(OAc) ₃ (6.76 g, 3.0 eq.) was added to the reaction mixture. The resulting mixture was stirred at room temperature overnight. The reaction was stopped with MeOH (10 ml) and washed with saturated NaHCO ₃ solution, water and brine. The crude mixture was purified on a silica gel column to give the title compound (3.5 g, 61.4% yield) as a white solid. LC-MS (ESI) m/z 537.4 (M+H) ⁺ .

Example 3 Synthesis of 2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4yl) methyl)-7-thia-2-azaspiro[3.5]nonane 7,7-dioxide

7-Thia-2-azaspiro[3.5]nonane 7,7-dioxide (50 mg, 1.2 eq.) and aldehyde intermediate 5 (90 mg, 1.0 eq.) were combined to form 1,2-DCE (25 ml). Acetic acid (40 µl) was added to the mixture. The reaction mixture was stirred at room temperature for 3 h. NaBH(OAc) ₃ (155 mg, 3.0 equiv.) was added. The resulting mixture was stirred at room temperature overnight. The reaction was stopped with MeOH, washed with saturated NaHCO ₃ solution and extracted with 2x20 ml DCM. The crude mixture was purified on a silica gel column to give the title compound (28 mg, 22% yield). LC-MS (ESI) m/z 536.4 (M+H) ⁺ .

Example 4 Synthesis of 2-(2'-ethyl-4'-((2-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-[1,1'biphenyl]-4- yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

tert-Butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (100 mg, 1.2 eq.) and aldehyde intermediate 5 (85 mg, 1.0 eq.) were combined in 1,2-DCE (15 ml). Acetic acid (20 µl) was added to the mixture. The reaction mixture was stirred at room temperature for 3 h. NaBH(OAc) ₃ (145 mg, 3.0 equiv.) was added. The resulting mixture was stirred at room temperature overnight. The reaction was stopped with MeOH, washed with saturated NaHCO ₃ solution, and extracted with 2x20 ml DCM. The crude mixture was purified on a silica gel column to give tert-butyl 7-((2ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[ 1,1' -biphenyl]-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (103 mg, 78% yield).

tert-Butyl 7-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl )methyl)2,7-diazaspiro[3.5]nonane-2-carboxylate (103 mg) was treated with 4 ml (80% TFA in DCM) for 1 h. The solvent was removed in vacuo to give 2-(4'-((2 ,7-diazaspiro[3.5]nonan-7-yl)methyl)-2'-ethyl[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2- ol (106 mg) as TFA salt, which was used without purification. 2-(4'-((2,7-Diazaspiro[3.5]nonan-7-yl)methyl)-2'-ethyl-[1,1'-biphenyl]-4-yl)-1,1,1, 3,3,3-hexafluoropropan-2-ol, TFA salt (53 mg) was suspended in DCM (10 ml) and saturated NaHCO ₃ solution (5 ml) was added. To the mixture was added MsCl (3.0 equiv.) in DCM (5 ml) dropwise over 20 min at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with water and brine. The crude material was purified on a silica gel column to give the title compound (25 mg, 51% yield). LC-MS (ESI) m/z 565.6 (M+H)+.

Example 5 Synthesis of 2-(2'-ethyl-4'-((2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)methyl)-[1,1'biphenyl]-4- yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

- 68 041942

The title compound was prepared using the method described in Example 4 but replacing t-butyl 2,6-diazaspiro[3.5]nonane-2-carboxylate with t-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate. LC-MS (ESI) m/z 565.5 (M+H)+.

Example 6 Synthesis of 2-(2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-2-yl)methyl)-[1,1'biphenyl]-4- yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared using the method described in Example 4, but replacing t-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate with t-butyl 2,7-diazaspiro[3.5]nonane-2carboxylate. LC-MS (ESI) m/z 551.4 (M+H) ⁺ .

Examples 7-61: the following compounds in the table. 1 was synthesized using the methods described in the previous examples, where an aldehyde intermediate (sp. com. aldehyde) (1.0 eq.) and an amine intermediate (sp. com. amine) (1.2 eq.) were combined to give header connections.

Table 1

Example No. Structure Chemical name Applicable Intermediates LC-MS (ESI) m/z (M+H) ⁺ 7 ^F V he Oh 2-(3',6'-difluoro-2'- isopropyl-4'-((6(methylsulfonyl)-2,6diazaspiro[3,3]heptan-2yl)methyl)-[1,1'-biphenyl]- 4-yl)-1,1,1,3,3,3- hexafluoropropan-2-ol Etc. conn. aldehyde 11 Ex. conn. amine 2 587.2 8 O F ^nQxQn-S— ^ό /Mf ^F HOA _F 2-(3',5'-difluoro-2'isopropyl-4'-((6(methylsulfonyl)-2,6diazaspiro[3,3]heptan-2yl)methyl)-[1,1'-biphenyl]4- yl)-1,1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 12 Ex. conn. amine 2 587.4 9 about Va \ \7 f—'z. O \—/ II / — II O 2-(2'-ethyl-4'-((4((methylsulfonyl)methyl)p-iperidin-1-yl)methyl)[1,1-biphenyl]-4-yl)1,1,1,3,3 ,3hexafluoropropan-2-ol Etc. conn. aldehyde 5 Ex. conn. amine 21 538.5

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10 T LL i. ° X UCH "R /'° 2-(2'-ethyl-4'-((4(methylsulfonyl)piperide in-1-yl)methyl)- [ 1,1'biphenyl]-4-yl)-1,1,1,3,3, 3hexafluoropropan-2-ol Etc. conn. aldehyde 5 Ex. conn. amine 21 524.4 And R Ζ—' y} vX -p zao π I 6-((4-(1,1,1,3,3,3hexafluoro-2hydroxypropan-2-yl)-2isopropyl-2'-methyl-[1, Hbiphenyl]-4-yl)methyl)-2thia-6- azaspiro[3,4]octane 2,2-dioxide Etc. conn. 20 Aldehyde Commercial and available 2-thia-6azaspiro[3.4]octane 2,2dioxide 550.5 12 ZE LL and O N' ⁷ UCH < 6-((4-(1,1,1,3,3,3hexafluoro-2hydroxypropan-2-yl)-2isopropyl-2'-methyl-[1, Hbiphenyl]-4-yl)methyl)-2thia-6- azaspiro[3.3] heptane 2,2-dioxide Etc. conn. aldehyde 20 Ex. conn. amine 11 536.4 13 R / X on Lo 0 ^F ό pv^ \ 2-(2'-(sec-butyl)-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2yl)methyl)-[1,1'-biphenyl]4-yl)-1, 1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 10 Ex. conn. amine 2 565.5 14 F _x Z ^F X PH ^f χ> _F su ^f ° ^f xC/ %?~νΛ^α οχ ο CyN-\ 2-(2',3'-difluoro-6'isopropyl-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2yl)methyl)-[1,1'-biphenyl]- Etc. conn. aldehyde 23 Ex. conn. amine 2 587.3

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4-yl)-1,1,1,3,3,3- hexafluoropropan-2-ol 15 VoH //../ _F J> ^F ^ ^N CX>v ^x 1,1,1,3,3,3-hexafluoro-2-(2'fluoro-6'-isopropyl-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2yl)methyl)-[ 1,1'-biphenyl]4-yl)propan-2-ol Etc. conn. aldehyde 24 Ex. conn. amine 2 569.4 16 fho f f-H+ ^F l V WT O' 6-((2-ethyl-4'-(1,1,1,3,3,3hexafluoro-2hydroxypropan-2-yl)-2'methyl-[1,1'-biphenyl]-4yl)methyl)-2 -thia-6azaspiro[3.4]octane 2,2 dioxide Etc. conn. aldehyde 22 Commercial and available 2-thia-6azaspiro[3.4]octane 2,2dioxide 536.5 17 O il Z^O z^ o' Qy Xv 6-((2-ethyl-4'-(1,1,1,3,3,3hexafluoro-2hydroxypropan-2-yl)[1,H-biphenyl]-4yl)methyl)-2-thia-6azaspiro[3.4 ]octane 2,2 dioxide Etc. conn. aldehyde 5 Commercial and available 2-thia-6azaspiro[3.4]octane 2,2dioxide 522.4 18 4,o $ UQ wy, ^m )< o 6-((2-ethyl-4'-(1,1,1,3,3,3hexafluoro-2hydroxypropan-2-yl)-2'methyl-[1,1'-biphenyl]-4yl)methyl)-2 -thia-6- Etc. conn. aldehyde 22 Etc. conn. amine 11 522.5

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azaspiro[3.3]heptane 2,2 dioxide 19 pt Г} ' WV ¹¹ Xo π Til 2-(2'-ethyl-4'-((6(methylsulfonyl)-2,6diazaspiro[3.5]nonan-2yl)methyl)-[1,1'-biphenyl]4-yl)-1,1,1, 3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 5 Ex. conn. amine 17 565.6 20 >0 y y} ' Uulu X% -P nl 2-(2'-ethyl-4'-((6- (isobutylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2 yl)methyl)-[1,1'-biphenyl]4-yl)-1,1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 5 Ex. conn. amine 6 579.6 21 f—UF ^'° y _F 2-(2'-ethyl-4'-((6(propylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2 yl)methyl)-[1,1'-biphenyl]- 4-yl)-1,1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 5 Ex. conn. amine 5 565.6 22 T U-1, o X UCH . _U O 2-(2'-ethyl-4'-((6- (ethylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2 yl)methyl)-[1,1'-biphenyl]4-yl)-1,1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 5 Ex. conn. amine 3 551.5 23 T U- . o X x/ UCH ^z o. , ^z ω. /Ό 2-(2'-(tert-butyl)-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2yl)methyl)-[1,1'-biphenyl]4-yl)-1, 1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 13 Ex. conn. amine 2 565.4

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24 o \ Q _V LO n -p I 2-((2-ethyl-4'-(1,1,1,3,3,3- hexafluoro-2hydroxypropan-2-yl)[1,1'-biphenyl]-4yl)methyl)-6-thia-2azaspiro[3.4]octane 6,6- dioxide Etc. conn. aldehyde 5 Ex. conn. amine 12 522.5 25 R / X P ^{n F} X/ ^F 0 _h 's-λ^ O-U V\ _Z N'?^ 2-((2-ethyl-4'-(1,1,1,3,3,3hexafluoro-2hydroxypropan-2-yl)[1,H-biphenyl]-4yl)methyl)-6-thia-2azaspiro[3.4 ]octane 6-oxide Etc. conn. aldehyde 5 Ex. conn. amine 10 506.3 26 O G”' ⁰ O kl / L / p - Ho ^{41 41} - P I 6-((2-ethyl-4'-(1,1,1,3,3,3hexafluoro-2hydroxypropan-2-yl)[1,H-biphenyl]-4yl)methyl)-2-thia-6azaspiro[3.3 ]heptane 2,2 dioxide Etc. conn. aldehyde 5 Ex. conn. amine 11 508.2 27 O // $ KX Ho P -p ¹ 6-((2-ethyl-4'-(1,1,1,3,3,3hexafluoro-2hydroxypropan-2-yl)[1,H-biphenyl]-4yl)methyl)-2-thia-6azaspiro[3.3 ]heptane 2 oxide Etc. conn. aldehyde 5 Ex. conn. amine 9 492.3 28 ω y) \ NC ¹ to -P -p I 2-(4'-((2-thia-6azaspiro[3.3 ]heptan-6yl)methyl)-2'-ethyl-[ 1, Hbiphenyl]-4-yl)-1,1,1,3,3,3hexafluoropropane -2-ol Etc. conn. aldehyde 5 Commercial and available 2-thia-6- 476.3

- 73 041942

azaspiro[3.3 ] heptane 29 IU-u. OU X-((1-((2-ethyl-4'- (1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)[1,G-biphenyl]-4yl)methyl)azetidin-3 yl)methyl)-Mmethylmethanesulfonamide Etc. conn. aldehyde 5 Ex. conn. amine 14 539.6 thirty I u-u. O V ^z R Z-D ' Λ 2-(2'-ethyl-4'-((2- (methylsulfonyl)-2,6diazaspiro[3,4]octan-6yl)methyl)-[1,1'-biphenyl]4-yl)-1,1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 5 Ex. conn. amine 15 551.6 31 IU-U. About X <7 θ Г \ and /^L / o 2-(2'-ethyl-4'-((7- (methyl sulfonyl)-2,7 diazaspiro[4.4]nonan-2yl)methyl)-[1,1'-biphenyl]- 4-yl)-1,1,1,3,3,3- hexafluoropropan-2-ol Etc. conn. aldehyde 5 Ex. conn. amine 19 565.6 32 I LL ,, ° v \7 ^z Ck ^z (/k / O X-((1-((2-ethyl-4'(1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)[1,G-biphenyl]-4yl)methyl)azetidine-3 yl)methyl)methanesulfone id Etc. conn. aldehyde 5 Ex. conn. amine 13 525.6

- 74 041942

33 T.LL.. LL°JV \ About me UK /Ό 2-(2'-ethyl-4'-((7- (methyl sulfonyl)-2,7 diazaspiro[3.5]nonan-2yl)methyl)-[1,1'-biphenyl]- 4-yl)-1,1,1,3,3,3- hexafluoropropan-2-ol Etc. conn. aldehyde 5 Ex. conn. amine 16 565.7 34 T IL IL ^{O W} \/ ..X ω ₄ / Ό 2-(2'-ethyl-2-fluoro-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2 yl)methyl)-[1,1'-biphenyl]4-yl)-1 ,1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 21 Ex. conn. amine 2 555.2 35 ζ zr MT \Oy Ho -p -p I 2-(2'-ethyl-6'-fluoro-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl]4-yl)- 1,1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 6 Ex. conn. amine 2 555.3 36 I LL ., O V M/L ch j /Ό 2-(2'-ethyl-5'-fluoro-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl]4-yl)- 1,1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 7 Ex. conn. amine 2 555.3 37 SC / 2'° Z^ 2-(2'-ethyl-3'-fluoro-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2yl)methyl)-[1,1'-biphenyl]4-yl)-1 ,1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 8 Ex. conn. amine 2 555.3

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38 midrange /%/ F F tert-butyl 2-((2-ethyl-4'(1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)[1,G-biphenyl]-4yl)methyl)-2,6 - diazaspiro[3,4]octane-6carboxylate Etc. conn. 5 Aldehyde Commercially available from /?ot-butyl 2,6diazaspiro[ 3.4]octane-6carboxylate 573.4 39 V OH F%C ^{F F} yJ- ⁷ 2-(2'-ethyl-2-methyl-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl]4-yl)-1, 1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 22 Ex. conn. amine 2 551.3 40 . . 0 / ^- Ν X YD ° lCh r/\=/ Ύ\/ F F methyl 6-((2-ethyl-4'(1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)[1,G-biphenyl]-4yl)methyl)-2,6diazaspiro[3.3 ]heptane-2carboxylate Etc. conn. aldehyde 5 Ex. conn. amine 8 517.5 41 О γ ^ν Χ ^ν Ή ° лЧ x/w /4/ F 'ho/^f 2-(4'-((6(cyclopropylsulfonyl)2,6-diazaspiro[3.3]heptan2-yl)methyl)-2'-ethyl-[ 1,1 biphenyl]-4-yl)-1,1,1, 3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 5 Ex. conn. amine 4 563.6 42 0 -S-N X N-\ 0 \ Qv f V( f-VYhT 2-(2'-cyclopropyl-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl]- Etc. conn. aldehyde 19 Ex. conn. amine 2 549.2

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4-yl)-1,1,1,3,3,3- hexafluoropropan-2-ol 43 O NS— ° X/F ^F HoV _F 1,1,1,3,3,3-hexafluoro-2-(2'isopropyl-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2yl)methyl)- [ 1,1 '- biphenyl]4-yl)propan-2-ol Etc. conn. aldehyde 20 Ex. conn. amine 2 551.5 44 O^L-p V z z Ο=ω=ο 1 1,1,1,3,3,3-hexafluoro-2-(4'((6-(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2yl)methyl)-2'-(prop-1-ene -2yl)-[1,1'-biphenyl]-4yl)propan-2-ol Etc. conn. aldehyde 18 Ex. conn. amine 2 549.2 45 0 -s-nTXJn^ 0 /=\ Br Br \=x Mv _F VW 2-(2'-bromo-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2yl)methyl)-[1,1'-biphenyl]4-yl)-1,1,1, 3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 17 Ex. conn. amine 2 587.589 (1:1) 46 0 _{l l} -SN XN -< o )=\ O d VY _F yoif 1,1,1,3,3,3-hexafluoro-2-(4'((6-(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2yl)methyl)-2'(trifluoromethyl)-[ 1, Hbiphenyl ]-4-yl)propan-2-ol Etc. conn. aldehyde 16 Ex. conn. amine 2 577.3 47 0 -s-nQxQn^ δ )=\ st Cl \=χ v/V \ νν f-VohT 2-(2'-chloro-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2yl)methyl)-[1,1'-biphenyl]4-yl)-1,1,1, 3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 15 Ex. conn. amine 2 543, 545 (3:1)

- 77 041942

48 /\ /\ R ^%H lH %>/ /%/ F ^F H0y4 1-(6-((2-ethyl-4'-(1,1,1,3,3,3hexafluoro-2hydroxypropan-2-yl)[1,G-biphenyl]-4yl)methyl)-2,6diazaspiro[ 3.3]heptan-2 yl)ethan-1-one Etc. conn. aldehyde 5 Ex. conn. amine 7 501.2 49 0 . . Str O ^f _V f 5TVa f%ohF 1-(6-((4'-(1,1,1,3,3,3hexafluoro-2hydroxypropan-2-yl)-2methyl-[1,1'-biphenyl]-4yl)methyl)-2,6diazaspiro[ 3.3]heptan-2 yl)ethan-1-one Etc. conn. aldehyde 14 Ex. conn. amine 7 487.3 50 p NS— / \z \/ II ~O ⁰ lH F%\=/ ^f hoVt 1,1,1,3,3,3-hexafluoro-2-(2'methyl-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2yl)methyl)-[1,1' -biphenyl]4-yl)propan-2-ol Etc. conn. aldehyde 14 Ex. conn. amine 2 523.6 51 h5 o \=/ X^ _N r/W %/”f W/f 1,1,1,3,3,3-hexafluoro-2-(2'methyl-4'-((6-(pyridin-4ylmethyl)-2,6diazaspiro[3.3]heptan-2yl)methyl)-[1, 1'-biphenyl]4-yl)propan-2-ol Etc. conn. aldehyde 14 Ex. conn. amine 1 536.3 52 %O% ^ιίη z z Ο=ω=ο 1 2-(4-(3-ethyl-5-((6(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2yl)methyl)pyridin-2yl)phenyl)-1,1,1,3,3,3hexafluoropropane- 2-ol Etc. conn. aldehyde 26 Ex. conn. amine 2 538.3

- 78 041942

53 nO^-NH J, 0 jO fQf f-h-H FOHF 7-((2-ethyl-4'-(1,1,1,3,3,3hexafluoro-2hydroxypropan-2-yl)[1,G-biphenyl]-4yl)methyl)-2,7diazaspiro[4.4]nonane -1-he Etc. conn. aldehyde 5 Commercial and available 2,7diazaspiro[4.4]nonan-1one 501.3 54 i—\Λ ^ΝΗ ,nXvL Г ⁰ ό fQf fX—rb ^F F OHF 7-((2-ethyl-4'-(1,1,1,3,3,3- hexafluoro-2hydroxypropan-2-yl)[1,G-biphenyl]-4yl)methyl)-2,7diazaspiro[4.4]nonan-3-one Etc. conn. aldehyde 5 Commercial and available 2,7diazaspiro[4.4]nonan-3one 501.3 55 0 / _r N%TN-S- ^-l \x4 ° o' \=/ /4 fju X/ f ^F HOy^ _F 4'-(1,1,1,3,3,3-hexafluoro-2hydropoκc and πpopan-2-yl)X,X-dimethyl-4-((6(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2yl) methyl)-[1,1'-biphenyl]2-carboxamide Etc. conn. aldehyde 30 Ex. conn. amine 2 580.3 56 ABOUT N-s-° f.x4 w/f 2-(2'-ethyl-2-methoxy-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3 ]heptan-2yl)methyl)-[1,1'-biphenyl]4-yl)-1, 1,1,3,3,3hexafluoropropan-2-ol Etc. conn. aldehyde 27 Ex. conn. amine 2 567.5

- 79 041942

57 O f ^y H_ fJ\=/ _F 1,1,1,3,3,3-hexafluoro-2-(2'methoxy-2-methyl-4'-((6(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2yl)methyl)-[ 1 ,1'-biphenyl]4-yl)propan-2-ol Etc. conn. aldehyde 28 Ex. conn. amine 2 553.5 58 lCXZs=O £ 6 £7 ^F F OHF 7-((2-ethyl-4'-(1,1,1,3,3,3- hexafluoro-2hydroxypropan-2-yl)[1,1'-biphenyl]-4yl)methyl)-2-thia-7 azaspiro[4.4]nonane 2,2- dioxide Etc. conn. aldehyde 5 Commercial and available 2-thia-7azaspiro[4.4 ]nonane 2,2dioxide 536.3 59 0 ^nQxjn-s— C/t 2-(5-(2-ethyl-4-((6(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2yl)methyl)phenyl)pyridin2-yl)-1,1,1,3,3,3hexafluoropropan- 2-ol Etc. conn. aldehyde 29 Ex. conn. amine 2 538.4 60 0 NS- / \Z \z II A 0 /-\ ^N F^/w/ /%/F ^F H0y^ F 2-(4-(4-ethyl-6-((6(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2yl)methyl)pyridin-3yl)phenyl)-1,1,1,3,3, 3hexafluoropropan-2-ol Etc. conn. aldehyde 25 Ex. conn. amine 2 538.4 61 0 —S-nGA^ oh 6 \_/ ABOUT mv e 4'-(1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)-4((6-(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2yl)methyl)-[1, 1'-biphenyl]3-ol Etc. conn. aldehyde 31 Ex. conn. amine 2 525.4

Example 62 Synthesis of 2-(4-(3-ethyl-5-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-3-methylphenyl )-1,1,1,3,3,3-hexafluoropropan-2-ol o ν ν-s— \Ζ X/ ii O

NBS (1.45 g, 8.2 mmol, 1 eq.). The resulting mixture was stirred at 0° C. for 2 hours. The reaction was diluted with water (50 ml) and extracted with DCM. The organic phase was separated and concentrated. The residue was purified on a silica gel column (hexane/ethyl acetate) to give 5-bromo3-ethylpyridin-2-amine (1.5 g) as a white solid.

5-Bromo-3-ethylpyridine-2-amine (1 g, 1 eq.), Zn(CN)2 (1.5 eq.) and PdCl ₂ (dppf) (10%) were combined in dry DMF (18 ml) . The resulting mixture was heated to 120° C. overnight. The reaction mixture was poured into DCM (100 ml) and washed with water and saturated NaHCO ₃ solution. The organic phase was dried over MgSO ₄ and concentrated. The residue was purified on a silica gel column (hexane/ethyl acetate) to give 6-amino-5-ethylnicotinonitrile (0.7 g) as a white solid.

To a solution of 6-amino-5-ethylnicotinonitrile (0.7 g, 1 eq.) in CH3CN (15 ml) was added CuCl ₂ (2 eq.) and CuCl (2 eq.). n-Butyl nitrite (1.3 eq.) was added to the mixture at room temperature. The resulting mixture was stirred at room temperature for 1 h and then heated to boiling

- 80 041942 reflux overnight. The reaction mixture was diluted with CH ₂ Cl ₂ and washed with water, saturated NaHCO3 solution and water. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 6-chloro-5-ethylnicotinonitrile (0.42 g) as a white solid.

6-Chloro-5-ethylnicotinonitrile (200 mg, 0.53 mmol, 1 eq.) was dissolved in 6N. HCl solution. The reaction was stirred at 100° C. for 3 hours and then concentrated to give 6-chloro-5-ethylnicotinic acid, which was used without purification.

To a mixture of 6-chloro-5-ethylnicotinic acid (220 mg, 1 eq.), triethylamine (150 mg, 3 eq.) and N,Odimethylhydroxylamine hydrochloride (85 mg, 1.5 eq.) in DCM (10 ml) was added HBTU (280 mg, 1.4 eq.). The mixture was stirred at room temperature overnight. The reaction was washed with a saturated solution of NaHCO ₃ , 2N. HCl and water.

The organic phase was dried over MgSO ₄ and concentrated in vacuo to give 6chloro-5-ethyl-N-methoxy-N-methylnicotinamide (150 mg) which was used without further purification.

6-Chloro-5-ethyl-N-methoxy-N-methylnicotinamide was subjected to a standard Suzuki coupling reaction with 1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol to give 5-ethyl-6-(4-(1,1,1,3,3,3-hexafluoro- 2-hydroxypropan-2-yl)-2-methylphenyl)-N-methoxy-N-methylnicotinamide. 5-Ethyl-6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-propan-2-yl)-2-methylphenyl)-N-methoxy-N-methylnicotinamide (Compound 7) was treated 1 M LAH (1.2 eq) at -78°C to give the aldehyde intermediate 5-ethyl-6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2- yl)-2methylphenyl)nicotinaldehyde.

The title compound was prepared using the reductive amination method described in the General Method with the aldehyde intermediate from the previous step and the amine intermediate 2 from Example Q.

Example 63 Synthesis of 2-(6-(2-ethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyridin-3-yl)-1 ,1,1,3,3,3-hexafluoropropan-2-ol

To a solution of methyl 6-bromonicotinate (1.0 eq.) in THF (20 ml) was added TMSCF3 (5.0 eq.). The mixture was cooled at -15°C. To the mixture was added 1 M TBAF in THF (3.0 eq.) dropwise over 20 min. After adding TMSCF3, a saturated solution of NH ₄ Cl (50 ml) was slowly added. The mixture was stirred at room temperature for 15 minutes and extracted with 2x40 ml of hexane. The organic phase was dried over MgSO ₄ and concentrated in vacuo to give 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethan-1-one, which was used in the next step without purification.

1-(6-Bromopyridin-3-yl)-2,2,2-trifluoroethan-1-one and TMSCF3 (5.0 eq.) were dissolved in THF (20 ml) and cooled to 0°C. TBAF (1 M, 5 ml) was added dropwise. The resulting mixture was stirred at 0°C for 2 hours the Reaction was stopped with a saturated solution of NH ₄ Cl (80 ml). The mixture was extracted with 2x40 ml of hexane. The crude mixture was purified on a silica gel column to give 2-(6bromopyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol.

2-(6-Bromopyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol was substituted for Intermediate 1 in the Suzuki coupling reaction described in Step C of Example C to give 3- ethyl 4-(5-(1,1,1,3,3,3hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)-N-methoxy-N-methylbenzamide. 3-Ethyl-4-(5-(1,1,1,3,3,3hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)-N-methoxy-N-methylbenzamide was reduced to 3ethyl-4- (5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)benzaldehyde with LAH.

The title compound was prepared using the reductive amination method described in the General Method with the aldehyde intermediate from the previous step and the amine intermediate 2 from Example Q.

Example 64 Synthesis of 2-(4-(4-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)-3-methylphenyl )-1,1,1,3,3,3-hexafluoropropan-2-ol

Commercially available 5-bromo-4-ethylpicolinaldehyde (1.0 eq) and 2-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane (amine intermediate 2) (1.2 eq) were combined in 1 ,2-DCE (3 ml), the mixture was stirred at room temperature for 2 h, then NaBH(OAc) ₃ (2.5 eq.) was added. The resulting mixture was stirred at room temperature overnight. Standard work-up and purification on a silica gel column gave 2-((5-bromo-4-ethylpyridin-2-yl)methyl)6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane.

By a standard Suzuki coupling reaction between 2-((5-bromo-4-ethylpyridin-2-yl)methyl)-6(methylsulfonyl)-2,6-diazaspiro[3.3]heptane and 1,1,1,3,3, 3-hexafluoro-2-(3-methyl-4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol under the conditions described in step A of example K gave the title compound.

Example 65 Synthesis of 2'-ethyl-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4'-((6-(methylsulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile o n^\Qn-s— o

_-F '

Step A. Synthesis of intermediate 3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzaldehyde. 4-Bromo-3-ethylbenzoic acid (5.0 g, 1.0 eq.), N,O-dimethylhydroxylamine hydrochloride (3.2 g, 1.5 eq.) and HBTU (9.6 g, 1.15 eq. ) were combined in DMF (80 ml) at room temperature. TEA (11.2 g, 4.0 eq.) was added dropwise to the reaction mixture. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (200 ml) and hexane (100 ml), then washed with 2x150 ml of water, 2x100 ml of 1N. HCl, 2x100 ml saturated NaHCO ₃ solution and brine. The organic phase was dried over MgSO ₄ and concentrated in vacuo to give 4-bromo-3-ethyl-N-methoxy-N-methylbenzamide (5.8 g, 98% yield) as a pale yellow oil which was used without further purification.

4-Bromo-3-ethyl-N-methoxy-N-methylbenzamide (1.0 eq.) was dissolved in dry THF and cooled to -50°C. 1 M LAH in THF (0.6 eq.) was added to the solution. The reaction was stirred at -30°C for 1 h and then stopped with 1N. HCl at -10° C. to give 4-bromo-3-ethylbenzaldehyde which was used without purification.

4-Bromo-3-ethylbenzaldehyde (1.0 eq.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (1.15 eq.) was dissolved in dry toluene (25 ml). The mixture was degassed by bubbling N2 for 5 minutes. PdCl ₂ (dppf (0.1 eq.) and potassium acetate (1.5 eq.) were added to the reaction mixture. The resulting mixture was heated at 100° C. in a sealed tube for 15 hours. The reaction mixture was dried under vacuum. The crude mixture was purified on a silica gel column to give 3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde.

Stage B.

Synthesis of the intermediate 2-bromo-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2yl)benzonitrile. 2-Bromo-5-formylbenzonitrile (1.0 eq) was dissolved in THF to which TMSCF3 (2.0 eq) was added and the mixture cooled to 0°C. CsF (0.3 eq.) was added to the mixture. The resulting mixture was stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. 1 M TBAF (2.0 eq.) was added to the mixture. The reaction was then stopped with a saturated solution of NH ₄ Cl (50 ml) and was extracted with 2x40 ml of hexane. The organic phase was dried over MgSO ₄ and concentrated in vacuo to give 2-bromo-5-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile as an oil which was used without purification. 2-Bromo-5-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile was dissolved in DCM, then DMP (1.5 eq.) was added at room temperature. The mixture was stirred at room temperature for 1 h and then stopped with a saturated solution of NaHCO ₃ . The crude mixture was purified on a silica gel column to give 2-bromo-5-(2,2,2-trifluoroacetyl)benzonitrile.

2-Bromo-5-(2,2,2-trifluoroacetyl)benzonitrile and TMSCF3 (2.0 eq.) were dissolved in THF anhydride (20 ml) and cooled to 0°C. 1M TBAF in THF (1.0 eq.) was added dropwise. The resulting mixture was stirred at 0°C for 2 hours the Reaction was stopped with a saturated solution of NH ₄ Cl (80 ml). The mixture was extracted with 2x40 ml of hexane. The crude mixture was purified on a silica gel column to give 2-bromo-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzonitrile.

Step C: Synthesis of the aldehyde intermediate. Through the Suzuki coupling reaction between

- 82 041942

2-bromo-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzonitrile from the previous step and 3-ethyl-4(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzaldehyde from Step A under the reaction conditions described in Step A of Example K gave the aldehyde intermediate 2'-ethyl-4'-formyl-4(1,1,1,3 ,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-carbonitrile.

Stage D:

The title compound was prepared using the reductive amination method described in the General Method with the aldehyde intermediate from Step C and the amine intermediate 2 from Example Q.

Example 66 Synthesis of 2-(2,2'-dimethyl-3'-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-[1,1'biphenyl]-4-yl )-1,1,1,3,3,3-hexafluoropropan-2-ol

1,3-Dibromo-2-methylbenzene (1.2 eq.) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate of oxalic acid (1.0 eq.) were suspended in 5 ml of dry toluene, to to which was added Pd ₂ (dba) ₃ (0.05 eq.), RuPhos (0.1 eq.) and sodium tert-butyl oxide (2.5 eq.). The mixture was sparged with N2 for 5 minutes. The resulting mixture was heated at 100° C. for 5 hours. The solvent was removed under high vacuum. The residue was purified on a silica gel column to give tert-butyl 6-(3-bromo-2-methylphenyl)-2,6diazaspiro[3.3]heptane-2-carboxylate.

tert-Butyl 6-(3-bromo-2-methylphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate from the previous step was treated with 50% TFA in DCM to give the corresponding amine as the TFA salt. The amine salt of TFA was suspended in DCM and water and adjusted to pH > 10 with 2M K2CO3. The mixture was cooled to 0° C. and MsCl (2.0 eq.) was added. The mixture was stirred at room temperature for 2 hours. The crude mixture was purified on a silica gel column to give 2-(3-bromo-2-methylphenyl)-6(methylsulfonyl)-2,6-diazaspiro[3.3]heptane.

Standard Suzuki coupling reaction between 2-(3-bromo-2-methylphenyl)-6(methylsulfonyl)-2,6-diazaspiro[3.3]heptane and Intermediate 2A under the reaction conditions described in Step A of Example K gave connection header.

Example 67 Synthesis of 1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl )pyridin-2-yl)phenyl)propan-2-ol

The title compound was prepared using the method described in Example 66 but replacing 2,6-dibromopyridine with 1,3-dibromo-2-methylbenzene in the first step.

Example 68 Synthesis of 2-(2'-ethyl-3',6'-difluoro-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl )-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

Stage A.

2,5-Difluoro-4-methoxybenzoic acid (500 mg) was treated with BBr ₃ at room temperature for 24 hours. HCl and purified on a silica gel column to give 2,5-difluoro-4-hydroxybenzoic acid.

Stage B.

To a mixture of 2,5-difluoro-4-hydroxybenzoic acid (1 eq.), triethylamine (3 eq.) and N,Odimethylhydroxylamine hydrochloride (10 eq.) in DCM (20 ml) was added HBTU (2.5 eq.). The mixture was stirred at room temperature overnight. The mixture was washed with 2N. HCl and water. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide as a colorless oil.

Stage C.

To a solution of 2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (1.0 eq.) in acetic acid (4

- 83 041942 ml) was added NBS (1.1 eq.) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in

EtOAc, washed with water, concentrated and purified on a silica gel column to give 3-bromo2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide as a white solid.

Stage D

4,4,5,5-Tetramethyl-2 -vinyl-1,3,2-dioxaborolane (1.5 eq.), 2 M potassium carbonate solution (3 eq.), and Pd(PPh ₃ ) ₄ (0.05 eq.). The mixture was degassed, then N2 was bubbled through for 5 minutes and then stirred at 90° C. overnight. After cooling to room temperature, the mixture was poured into a solution of NH ₄ Cl and was extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 2,5-difluoro-4-hydroxy-N-methoxy-N-methyl-3-vinylbenzamide as a white solid.

Stage E.

Trifluoromethanesulfonic acid anhydride (1.0 eq.) and pyridine (0.5 ml) in DCM (10 ml) .5 eq.) dropwise at 0°C. The mixture was stirred at 0°C for 1 h and washed with saturated NaHCO ₃ solution and water. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 3,6-difluoro-4-(methoxy(methyl)carbamoyl)-2-vinylphenyl trifluoromethanesulfonate as a pale yellow oil.

Stage F

To a solution of 3,6-difluoro-4-(methoxy(methyl)carbamoyl)-2-vinylphenyl trifluoromethanesulfonate (1.0 eq.) in anhydrous 1,4-dioxane (10 ml) was added intermediate 2A from 5 eq.), 2 M potassium carbonate solution (3 eq.) and Pd(PPh ₃ ) ₄ (0.05 eq.). The mixture was degassed, then N2 was bubbled through for 5 minutes and then stirred at 90° C. overnight. After cooling to room temperature, the mixture was poured into NH4Cl solution and extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 3,6-difluoro-4'(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N- methoxy-.N-methyl-2-vinyl-[1,1'-biphenyl]-4-carboxamide as a white solid.

Stage G

To a solution of 3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-2vinyl-[1,1' -biphenyl]-4-carboxamide (1.0 eq.) in MeOH (10 ml) was added Pd/C (10 wt.%). The reaction was shaken under H2 (50 psi) for 4 h. The mixture was filtered to remove the catalyst and concentrated to give 2-ethyl-3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro -2-hydroxypropan-2-yl)-Nmethoxy-N-methyl-[1,1'-biphenyl]-4-carboxamide as a white solid.

stage N.

To a solution of 2-ethyl-3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-Nmethyl-[1,1' -biphenyl]-4-carboxamide (120 mg, 0.25 mmol, 1 eq.) in anhydrous THF (2 ml) was added a 1.0 M solution of LAH in THF (1.0 eq.) at -78°C. The reaction was stirred at -78°C for 1 h and stopped by adding EtOAc, then warmed to room temperature. The mixture was poured into a solution of NH ₄ Cl and was extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 2-ethyl-3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2yl) -[1,1'-biphenyl]-4-carbaldehyde as a white solid.

Stage I

The title compound was prepared using the reductive amination method described in the General Method with the Aldehyde Intermediate from the previous step and the Amine Intermediate 2 from Example Q.

Example 69 Synthesis of 2-(2'-ethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared as described in Example 68, replacing Intermediate 2 with Intermediate 2A in step F.

Example 70 Synthesis of 2-(2'-ethyl-2,3',6'-trifluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1 ,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

- 84 041942

The title compound was prepared as described in Example 68, replacing Intermediate 2B with Intermediate 2A in step F.

Example 71 Synthesis of 2-(2,2'-diethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[ 1 ,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared as described in Example 68, replacing Intermediate 2C with Intermediate 2A in step F.

Example 72 Synthesis of 2-(2-chloro-2'-ethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl )-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared as described in Example 68, replacing Intermediate 2D with Intermediate 2A in step F.

Example 73 Synthesis of 2-(4-(2-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)-3-methylphenyl )-1,1,1,3,3,3-hexafluoropropan-2-ol

5-Bromo-6-ethylpicolinaldehyde (1.0 eq.) and amine intermediate 2 from Example Q (1.2 eq.) were combined in 1,2-DCE (3 ml). The mixture was stirred at room temperature for 2 h and then NaBH(OAc) ₃ (2.5 eq.) was added. The resulting mixture was stirred at room temperature overnight. Standard work-up and purification on a silica gel column gave 2-((5-bromo-6-ethylpyridin-2-yl)methyl)-6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane.

By standard Suzuki coupling reaction between 2-((5-bromo-6-ethylpyridin-2-yl)methyl)-6(methylsulfonyl)-2,6-diazaspiro[3.3]heptane and Intermediate 2A from Example A under the conditions described in Step A of Example K, 2-(4-(2-ethyl-6-((6-(methylsulfonyl)-2,6diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)-3- methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol.

Example 74 Synthesis of 2-(3',6'-difluoro-2'-isopropyl-4'-((2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan6-yl)methyl)-[1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared using the reductive amination method described in the General Method with aldehyde intermediate 11 from example H and amine intermediate 15 from example W.

- 85 041942

Example 75 Synthesis of 2-(2-chloro-2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared using the method described in Example 65, but replacing 4-bromo-3-chlorobenzaldehyde with 2-bromo-5-formylbenzonitrile in step A.

Example 76 Synthesis of 2-(2-ethyl-2'-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1'-biphenyl] -4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared using the method described in steps B and C of Example 65, but replacing 4-bromo-3-ethylbenzaldehyde with 2-bromo-5-formylbenzonitrile in step B and replacing (4-formyl-2-methylphenyl)boronic acid with 3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzaldehyde in step C.

Example 77 4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The aldehyde intermediate 2,2'-diethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2yl)-[1,1'-biphenyl]-4-carbaldehyde was prepared using the method described in step C of example C, but replacing 2-(4-bromo-3-ethylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol with intermediate 1 and replacing 3-ethyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde for compound 9.

The title compound was prepared using the general method using the aldehyde from the previous step and the amine intermediate 2 from Example Q.

Example 78 Synthesis of 1,1,1,3,3,3-hexafluoro-2-(5'-fluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6diazaspiro[3.3]heptane- 2-yl)methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol

acids

Stage A.

To a mixture of 2-fluoro-4-hydroxybenzoic (1.0 eq.), triethylamine (3.0 eq.) and PHOdimethylhydroxylamine hydrochloride (10.0 eq.) in DMF (10 ml) was added HBTU (2.5 eq.). The mixture was stirred at room temperature overnight.

The reaction mixture was diluted with 40 ml of EtOAc and 20 ml of hexane and washed with 2 N. HCl, water and brine. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 2-fluoro-4-hydroxy-N-methoxy-N-methylbenzamide.

Stage B.

To a solution of 2-fluoro-4-hydroxy-N-methoxy-N-methylbenzamide (1.0 eq.) in AcOH (10 ml) was added NBS (1.0 g) at 0°C. The reaction mixture was stirred at 0°C to room temperature for 1 h, diluted with EtOAc and washed with water.

The organic layer was concentrated and purified on a silica gel column to give 5-bromo-2fluoro-4-hydroxy-N-methoxy-N-methylbenzamide.

Stage C.

5-Bromo-2-fluoro-4-hydroxy-N-methoxy-N-methylbenzamide was dissolved in DMF, to which was added

- 86 041942

K2CO3 (3.0 eq.) and benzyl bromide (1.2 eq.). The resulting mixture was heated at 50°C for

h. The reaction was diluted with ethyl acetate and washed with water. The crude mixture was purified on a silica gel column to give 4-(benzyloxy)-5-bromo-2-fluoro-N-methoxy-N-methylbenzamide.

Stage D

By standard Suzuki coupling reaction between 4-(benzyloxy)-5-bromo-2-fluoro-N-methoxy-N-methylbenzamide and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)- 1,3,2-dioxaborolan gave 4(benzyloxy)-2-fluoro-N-methoxy-N-methyl-5-(prop-1-en-2-yl)benzamide.

Stage E.

4-(Benzyloxy)-2-fluoro-N-methoxy-N-methyl-5-(prop-1-en-2-yl)benzamide in MeOH was hydrogenated at 50 PSI in the presence of Pd/C (10% by weight) in for 5 hours to obtain 2-fluoro-4-hydroxy-5-isopropyl-Nmethoxy-N-methylbenzamide.

Stage F

To a mixture of 2-fluoro-4-hydroxy-5-isopropyl-N-methoxy-N-methylbenzamide (1.0 eq.) and pyridine (3.0 eq.) in DCM (10 ml) was added trifluoromethanesulfonic anhydride (1.5 eq. .) drop by drop at 0°C. The mixture was stirred at 0°C for 1 h and washed with saturated NaHCO ₃ solution and water. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 5-fluoro-2-isopropyl-4-(methoxy(methyl)carbamoyl)phenyl trifluoromethanesulfonate as a white solid.

Stage G

To a solution of 5-fluoro-2-isopropyl-4-(methoxy(methyl)carbamoyl)phenyl trifluoromethanesulfonate (1.0 eq.) in anhydrous 1,4-dioxane (2 ml) was added boronic ester of Intermediate 2 (1.3 eq. .), 2 M potassium carbonate solution (3.0 eq.), and Pd(PPh ₃ ) ₄ (0.05 eq.). The mixture was sparged with N2 for 5 min and then stirred at 90° C. in a sealed tube for 3 h. After cooling to room temperature, the mixture was poured into a solution of NH ₄ Cl and extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 5-fluoro-4'(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl- N-methoxy-N-methyl-[1,1'-biphenyl]-4-carboxamide as a white solid.

stage N.

To a solution of 5-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-N-methoxy-Nmethyl-[1,1'-biphenyl ]-4-carboxamide (1 eq.) in anhydrous THF (2 ml) was added a 1.0 M solution of LAH in THF (1.0 eq.) at -78°C. The reaction was stirred at -78°C for 1 h and stopped by adding EtOAc, then warmed to room temperature. The mixture was poured into a solution of NH ₄ Cl and was extracted with DCM. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 5-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl -[1,1'biphenyl]-4-carbaldehyde as a white solid.

Stage I

The title compound was prepared using the general method using the aldehyde intermediate from the previous step and the amine intermediate 2.

Example 79 Synthesis of 1,1,1,3,3,3-hexafluoro-2-(5'-fluoro-2'-isopropyl-2-methyl-4'-((6-(methylsulfonyl)2,6-diazaspiro [3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol

The title compound was prepared using the method described in Example 78, but replacing Intermediate 2A with Intermediate 2 in Step G.

Example 80 Synthesis of 2-(2,5'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan2-yl)methyl)-[1,1' -biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared using the method described in Example 78, but replacing Intermediate 2C with Intermediate 2 in Step G.

Example 81 Synthesis of 2-(2-chloro-5'-fluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[ 1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

- 87 041942

The title compound was prepared using the method described in Example 78, but replacing Intermediate 2D with Intermediate 2 in Step G.

Example 82 Synthesis of 2-(2'-ethyl-2,5'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1,1' -biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was synthesized using the methods described in steps D-I of Example 78, but replacing 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane with 4,4,5,5- tetramethyl-2-(prop-1en-2-yl)-1,3,2-dioxaborolane and replacing intermediate 2C with intermediate 2 in step G.

Example 83 Synthesis of 2-(2-chloro-2'-ethyl-5'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl)-[1, 1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was synthesized using the methods described in steps D-I of Example 78, but replacing 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane with 4,4,5,5- tetramethyl-2-(prop-1en-2-yl)-1,3,2-dioxaborolane and replacing intermediate 2D with intermediate 2 in step G.

Example 84 Synthesis of 2-(3',6'-difluoro-2'-isopropyl-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl )-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

Aldehyde intermediate 3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2yl)-2-isopropyl-2'-methyl-[1,1'-biphenyl ]-4-carbaldehyde was prepared using the method described in example H, but replacing 1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2yl)phenyl)propan-2-ol on 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol in step F. The title compound was prepared using the general method using the aldehyde intermediate from the previous step and the amine intermediate 2.

Example 85 Synthesis of 2-(2-ethyl-3',6'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl )-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

- 88 041942

Aldehyde intermediate 2'-ethyl-3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)-2-isopropyl-[1,1'-biphenyl ]-4-carbaldehyde was obtained using the method described in example H, but replacing 2-(3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl )1,1,1,3,3,3-hexafluoropropan-2-ol on 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2yl)phenyl)propan-2-ol in step F. The title compound was prepared using the general method using the aldehyde intermediate from the previous step and the amine intermediate 2.

Example 86 Synthesis of 1,1,1,3,3,3-hexafluoro-2-(2,3',6'-trifluoro-2'-isopropyl-4'-((6-(methylsulfonyl)2,6- diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol _Λ o fA-zo

Aldehyde intermediate 2',3,6-trifluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2yl)-2-isopropyl-[1,1'-biphenyl]- 4-carbaldehyde was obtained using the method described in example H, but replacing 1,1,1,3,3,3-hexafluoro-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)propan-2ol on 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)phenyl)propan-2-ol in step F. The title compound was prepared using the general method using the aldehyde intermediate from the previous step and the amine intermediate 2.

Example 87 Synthesis of 2-(2-chloro-3',6'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl )-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

Aldehyde intermediate 2'-chloro-3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-[1,1' -biphenyl]-4-carbaldehyde was obtained using the method described in example H, but replacing 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl)-1,1,1,3,3,3hexafluoropropan-2-ol on 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol in step F. The title compound was prepared using the general method using the aldehyde intermediate from the previous step and the amine intermediate 2.

Example 88 Synthesis of 2-(2'-cyclopropyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[ 1 ,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol o —S-N;V\^

O >=\

Thu

Ον fVohT

Stage A.

2,5-Difluoro-4-methoxybenzoic acid (500 mg) was treated with BBr ₃ at room temperature for 24 hours. HCl, and purified on a silica gel column to give the corresponding 2,5-difluoro-4-hydroxybenzoic acid.

Stage B.

To a mixture of 2,5-difluoro-4-hydroxybenzoic acid (380 mg, 2.18 mmol, 1.0 eq.), triethylamine (660 mg, 6.6 mmol, 3.0 eq.) and N,O-dimethylhydroxulamine hydrochloride ( 2.14 g, 21.8 mmol, 10.0 eq.) in DCM (20 ml) was added HBTU (1.25 g, 3.27 mmol, 1.5 eq.). The mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO ₃ solution, 2N. HCl and water. The organic phase was dried over MgSO ₄ , concentrated and purified on a silica gel column to give 2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (190 mg) as a colorless oil.

Stage C.

NBS (190 mg, 1.05 mmol, 1.2 equiv.) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc, washed with water, concentrated and purified on a column of

- 89 041942 silica gel to obtain 3-bromo-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (240 mg) as a white solid.

Stage D

3-Bromo-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide (1.0 eq.) and potassium cyclopropyl trifluoroborate (2.5 eq.) were combined in dioxane (5 ml) and water (2 ml ), then K ₂ CO ₃ (3.0 equiv.) and Pd(PPh ₃ ) ₄ (0.08 equiv.) were added. The resulting mixture was sparged with N2 for 5 min, then heated at 90° C. in a sealed tube for 14 h. The reaction mixture was diluted with ethyl acetate and washed with saturated NH4Cl solution and water. The crude mixture was purified on a silica gel column to give 3-cyclopropyl-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide.

Stage E.

3-Cyclopropyl-2,5-difluoro-4-hydroxy-N-methoxy-N-methylbenzamide was treated with trifluoromethanesulfonic anhydride (1.5 eq.) in the presence of pyridine (1.5 eq.) as base at 0° C. with obtaining 2-cyclopropyl-3,6-difluoro-4-(methoxy(methyl)carbamoyl)phenylatrifluoromethanesulfonate.

Stage F

By a Suzuki coupling reaction between 2-cyclopropyl-3,6-difluoro-4-(methoxy(methyl)carbamoyl)phenyl trifluoromethanesulfonate and intermediate 2 under the conditions described in step A of Example K, except for heating to 90° C. overnight, obtained 2cyclopropyl-3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl-[1,1'- biphenyl]-4-carboxamide.

Stage G

2-Cyclopropyl-3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-methoxy-N-methyl[1,1'- biphenyl]-4-carboxamide from the previous step was reduced to the aldehyde intermediate 2-cyclopropyl-3,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) -[1,G-biphenyl]-4carbaldehyde with LAH at -78°C.

stage N.

The title compound was prepared using the general method using the aldehyde intermediate from the previous step and the amine intermediate 2.

Example 89 [ 1,1 '-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared using the method described in Example 88 but replacing Intermediate 2A with Intermediate 2 in Step F.

Example 90 Synthesis of 2-(2'-cyclopropyl-2-ethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl )-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared using the method described in Example 88, but replacing Intermediate 2B with Intermediate 2 in Step F.

Example 91 Synthesis of 2-(2'-cyclopropyl-2,3',6'-trifluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared using the method described in Example 88, but replacing Intermediate 2C with Intermediate 2 in Step F.

Example 92 Synthesis of 2-(2-chloro-2'-cyclopropyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diaza-90 041942 spiro[3.3]heptane-2 -yl)methyl)-[1,G-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared using the method described in Example 88, but replacing Intermediate 2D with Intermediate 2 in Step F.

Example 93 Gal4 Ligand Binding Assay

Compounds of the present invention were tested in a human RORy ligand binding assay using a reporter ligand binding assay based on commercially available cells in 96-well format (catalog number IB04001, INDIGO Biosciences, State College, PA). The N-terminal DNA binding domains (DBDs) of the native RORy and RORyt receptors were replaced with the GAL4-DBD domains of the yeast GAL4 protein and stably transfected into HEK293T cells, which also stably express luciferase under the control of the yeast Gal4 activating sequence.

These cells constitutively express a high level of RORy activity due to the binding of endogenous cofactors. Both agonistic activity and inverse agonist activity can be detected. The assay was performed according to the kit manufacturer's instructions as described below. 10 mM stock compounds were serially diluted 1:3 with DMSO and the resulting medium was further diluted to obtain 10 titration points from 60 μM to 3 nM. These compounds with these processing conditions were added to the plates in the form of 2x medium in a volume of 100 μl. Each plate contained a positive control with 10 titration points, as well as 6 negative control wells with vehicle only, with a final concentration of 0.2% DMSO. RORy reporter cells were rapidly thawed and added to the plates in a volume of 100 µl. The plates were incubated for 24 hours in a humidified incubator with 5% CO ₂ at 37°C. The medium was removed before the addition of the luciferin substrate for detection at room temperature. After a 5 min incubation, relative light units (RLU) were quantified using a luminometer to read the plates. Data were normalized to positive control wells with 0.2% DMSO only. Before establishing internal controls, ursolic acid was used as a control.

Table 2. IC ₅₀ values for RORyt inverse agonists in the RORyt Gal fusion assay

Example No. RORyt (1С ₅₀ ) Example No. RORyt (1С ₅₀ ) Example No. RORyt (1С ₅₀ ) Example No. RORyt (1С ₅₀ ) 1 IN 2 A 3 A 4 A 5 A 6 IN 7 A 8 A 9 IN 10 A AND A 12 IN 13 A 14 A 15 A 16 A 17 IN 18 A 19 IN 20 IN 21 IN 22 IN 23 A 24 IN 25 WITH 26 IN 27 IN 28 WITH 29 With thirty A 31 A 32 With 33 V 34 A 35 A 36 A 37 A 38 IN 39 A 40 IN 41 IN 42 A 43 A 44 A 45 V 46 IN 47 WITH 48 WITH 49 With 50 IN 51 WITH 52 IN 53 V 54 IN 55 WITH 56 V 57 A 58 A 59 V 60 A 61 IN 62 IN 63 V 64 A 65 A 66 V 67 With 68 A 69 A 70 A 71 A 72 A 73 WITH 74 IN 75 A 76 A 77 A 78 A 79 A 80 A 81 A 82 A 83 A 84 A 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A

A: IC ₅₀ <50 nM; B: IC ₅₀ =50 nM - 250 nM; C: IC ₅₀ > 250 nM

- 91 041942

Example 94 Th17 Cell Differentiation Assay in Human PBMC

This assay tested compounds for their modulating effect on RORyt, as measured by the production of IL-17 by CD4+ T cells under conditions that promote Th17 differentiation. Fresh healthy donor peripheral blood mononuclear cells (PBMCs) were isolated using a ficoll gradient. CD4+ T cells were purified using the negative selection and magnetic separation kit from Stemcell Technologies according to the manufacturer's instructions (catalog number 17952, Vancouver, Canada). 2.5x10 ⁴ CD4+ T cells per well were incubated in a 96-well plate at a 1:1 ratio with anti-CD3/CD28 stimulation beads (catalog number 11131D, Gibco DYNAL, Waltham, MA) in the presence of rhIL-6 (50 ng /ml), rhIL-1b (10 ng/ml), rhTGF-b1 (1 ng/ml), rhIL-23 (5 ng/ml), anti-1b-4 (10 µg/ml) and anti-IFNg ( 10 µg/ml). Compounds were added 1 h before the onset of differentiation at various concentrations with a final concentration of 0.1% DMSO. Cells were incubated at 37°C and 5% CO ₂ for 3 days before collecting the supernatant for U-plex human IL-17A ELISA (catalog number K151ATA-4, Meso Scale Discovery, Rockville, MD). Data were normalized for DMSO control wells. Cell viability was also measured after removal of the supernatant using an MTT assay kit (catalog number 11465007001, Sigma-Aldrich, St. Louis, MO).

In one embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 500 nM. In another embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 250 nM. In another embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 200 nM. In another embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 150 nM. In another embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 100 nM.

Example 95 IL-17A Inhibition Assay in Patient PBMC

This assay is designed to screen compounds for their inhibitory effect on IL-17 release from isolated human Th17 cells. Peripheral blood mononuclear cells (PBMCs) from patients with psoriasis, systemic lupus erythematosus, Crohn's disease, and rheumatoid arthritis were purchased from Precision For Medicine (Frederick, MD). 4x105 cells per well were incubated in a 96-well plate with Cytostim, human (catalog number 130-092-172, Miltenyi Biotec, Bergisch Gladbach, Germany) according to the manufacturer's instructions.

Cells were incubated in the presence or absence of various concentrations of compounds with a final concentration of 0.1% DMSO and starting from the moment of stimulation. After 48 hours incubation at 37° C. and 5% CO2, the supernatant was removed for IL-17A determination by ELISA (catalog number BMS2017, ThermoFisher Scientific, Waltham, MA). Data were normalized for DMSO control wells. Cell viability was also measured after removal of the supernatant using the CellTiter-Glo Fluorescent Cell Viability Assay Kit (catalog number G7570, Promega, Madison, WI).

In one embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 5 μM. In one embodiment, the compounds provided herein were found to have IC ₅₀ values of less than about 2.5 μM. In one embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 2 μM. In one embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 1 μM. In another embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 1500 nM. In another embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 500 nM. In another embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 250 nM. In another embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 300 nM. In another embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 200 nM. In another embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 150 nM. In another embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 100 nM. In another embodiment, the compounds provided herein have been found to have IC ₅₀ values of less than about 50 nM.

The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications or changes are to be included within the scope of the disclosure and the scope of the appended claims.

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Claims (19)

CLAIM 1. Compound of formula (I) CF ₃ ^F 3^-OH ( ^R5 )q _R 1 U ^m V~ ^(R<I ' ^R2 /4 (R ³ ) _k Formula (I); or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A represents phenyl or a 5-membered or 6-membered heteroaryl ring; A represents phenyl or a 5-membered or 6-membered heteroaryl ring; Z is -(C(R ⁶ )(R ⁷ ))t-; R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 to 4 R ^3a groups; and each R ³ is independently selected from halo and C ₁ -C ₆ alkyl; each R ^3a is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C9 heteroaryl, (C2C9 heteroaryl)-C1-C6 alkylene-, oxo, -S(O)2R ¹⁰ , -C(O)R ¹⁰ , -C(O) OR11 and -C(O)N(R11)2, wherein C ₂ -C ₉ heteroaryl and (C ₂ -C ₉ heteroaryl)-C 1 -C ₆ alkylene- are optionally substituted with 1 to 3 groups independently selected from halo, C1 -C ₆ alkyl, C 1 -C ₆ haloalkyl and hydroxyl; each R ⁴ and each R ⁵ is independently selected from halogen, cyano, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, -N(R ⁹ )2, -C(O) R ⁸ , -C(O)OR ⁹ , -C(O)N(R ⁹ )2, -N(R ⁹ )C(O)R ⁸ , -N(R ⁹ )SO2R ⁸ , -SO2R ⁸ and - SO2N(R ⁸ ) ₂ ; each R ⁶ and each R ⁷ independently represent hydrogen, halogen or C1-C ₆ alkyl; each R ⁸ is independently C1-C ₆ alkyl or C1-C ₆ haloalkyl; each R ⁹ is independently hydrogen, C1-C ₆ alkyl or C1-C ₆ haloalkyl; each R ¹⁰ is independently C 1 -C ₆ alkyl, C 1 -C ₆ haloalkyl, C ₁ -C ₆ alkyl-O-C ₁ -C ₆ alkyl-, C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl, phenyl , (phenyl)-C1-C ₆ alkylene-, C ₂ -C ₉ heteroaryl or (C ₂ C ₉ heteroaryl) -C1-C ₆ alkylene-, where C ₃ -C ₈ cycloalkyl, C ₂ -C ₉ heterocyclyl, phenyl , (phenyl)-C1-C ₆ alkylene-, C ₂ -C ₉ heteroaryl or (C ₂ -C ₉ heteroaryl)-C 1 -C ₆ alkylene- are optionally substituted with 1 to 3 groups selected from halo, C 1 -C ₆ alkyl, C1- _C6 haloalkyl and hydroxyl; each R ¹¹ independently represents hydrogen, C1-C ₆ alkyl or C1-C ₆ haloalkyl; m is 1, 2, or 3; n is 1, 2, or 3; k is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3, or 4; and t is 0, 1, 2, or 3; where heteroaryl or heterocyclyl contains from one to five heteroatoms, each of which is independently selected from O, S or N, while the remaining ring atoms are carbon atoms. (B) 2. A compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein O is phenyl. ( A ) 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is phenyl. 4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ and R ² , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring, wherein said 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with 1 to 2 R ^3a groups. 5. A compound according to claim 4 having formula (II), or a pharmaceutically acceptable salt or stereoisomer thereof - 93 041942 (R ³ )k Formula (II); Where X represents -O-, -NH-, -N(R ^3a )-, -S-, -S(O)- or -S(O) ₂ -; a has a value of 1 or 2; and b has a value of 1 or 2. 6. Compound according to claim 5 having formula (IIa) (R ³ ) _k Formula (Pa); or a pharmaceutically acceptable salt or stereoisomer thereof. 7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ^3a is -S(O)2R ¹⁰ , -C(O)R ¹⁰ or -C(O)OR ¹¹ . 8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ^3a is -S(O)2R ¹⁰ . 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹⁰ is C ₁ -C ₆ alkyl. 10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R ⁶ and each R ⁷ is hydrogen. 11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein t is 1. 12. A compound according to any one of claims 1-11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein p is 0, 1, 2, or 3. 13. A compound according to any one of claims 1-12, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R ⁴ is independently halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ haloalkyl, C1C ₆ alkoxy or C ₃ -C ₈ cycloalkyl. 14. A compound according to any one of claims 1-13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein q is 0, 1, or 2. 15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R ⁵ is independently halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C 1 C 6 alkoxy. 16. A compound according to any one of claims 1-15, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein k is 0. 17. Connection selected from the following: 2-(2'-ethyl-4'-((4-((methylsulfonyl)methyl)piperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1,1,1, 3,3,3hexafluoropropan-2-ol; 2-(2'-ethyl-4'-((4-(methylsulfonyl)piperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1,1,1,3,3 ,3-hexafluoropropan-2-ol; N-(( 1 -((2-ethyl-4'-( 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[ 1,1 '-biphenyl]-4- yl)methyl)azetidin-3-yl)methyl)-N-methylmethanesulfonamide; N-(( 1 -((2-ethyl-4'-( 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[ 1,1 '-biphenyl]-4- yl)methyl)azetidin-3-yl)methyl)methanesulfonamide; 2-(3',6'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'biphenyl ]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(3',5'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'biphenyl ]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 6-((4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2'-methyl-[1,1'-biphenyl]-4 -yl)methyl)-2-thia-6-azaspiro[3.4]octane 2,2-dioxide; 6-((4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-isopropyl-2'-methyl-[1,1'-biphenyl]-4 -yl)methyl- 94 041942 tyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide; 2-(2'-(sec-butyl)-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4yl )-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2',3'-difluoro-6'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'biphenyl ]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 1,1,1,3,3,3-hexafluoro-2-(2'-fluoro-6'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl) methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol; 6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2'-methyl-[1,1'-biphenyl]-4 -yl)methyl)-2thia-6-azaspiro[3.4]octane 2,2-dioxide; 6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -2-thia-6-azaspiro[3.4]octane 2,2-dioxide; 6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2'-methyl-[1,1'-biphenyl]-4 -yl)methyl)-2thia-6-azaspiro[3.3]heptane 2,2-dioxide; 2-(2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-4'-((2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-4'-((6-(isobutylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-4'-((6-(propylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-4'-((6-(ethylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -7-thia-2azaspiro[3.5]nonane 7,7-dioxide; 2-(2'-(tert-butyl)-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4yl )-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -6-thia-2-azaspiro[3.4]octane 6,6-dioxide; 2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -6-thia-2-azaspiro[3.4]octane 6-oxide; 6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -2-thia-6-azaspiro[3.3]heptane 2,2-dioxide; 6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -2-thia-6-azaspiro[3.3]heptane 2-oxide; 2-(4'-((2-thia-6-azaspiro[3.3]heptan-6-yl)methyl)-2'-ethyl-[1,1'-biphenyl]-4-yl)-1.1, 1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-4'-((2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-4'-((7-(methylsulfonyl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-4'-((7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-4'-((2-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-2-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4yl )-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-6'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl] - 4yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-5'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl] - 4yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-3'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl] - 4yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; tert-butyl 2-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl )methyl)2,6-diazaspiro[3.4]octane-6-carboxylate; 2-(2'-ethyl-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4yl )-1,1,1,3,3,3-hexafluoropropan-2-ol; methyl 6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl )-2,6diazaspiro[3.3]heptane-2-carboxylate; 2-(4'-((6-(cyclopropylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2'-ethyl-[1,1'-biphenyl]-4- 95 041942 yl )-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-cyclopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4yl)-1, 1,1,3,3,3-hexafluoropropan-2-ol; 1,1,1,3,3,3-hexafluoro-2-(2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)- [1,1'-biphenyl]-4-yl)propan-2-ol; tert-butyl 6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl )methyl)2,6-diazaspiro[3.3]heptane-2-carboxylate; 1,1,1,3,3,3-hexafluoro-2-(4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2'-(prop -1en-2-yl)-[1,1'-biphenyl]-4-yl)propan-2-ol; 2-(2'-bromo-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 1,1,1,3,3,3-hexafluoro-2-(4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-2'-(trifluoromethyl )-[1,1'-biphenyl]-4-yl)propan-2-ol; 2-(2'-chloro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 1 -(6-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl )methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one; 2-(2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)1 ,1,1,3,3,3-hexafluoropropan-2-ol; 1-(6-((4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1'-biphenyl]-4-yl )methyl)-2,6diazaspiro[3.3]heptan-2-yl)ethan-1-one; 1,1,1,3,3,3-hexafluoro-2-(2'-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[ 1,1'-biphenyl]-4-yl)propan-2-ol; 1,1,1,3,3,3-hexafluoro-2-(2'-methyl-4'-((6-(pyridin-4-ylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl )methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol; 2-(4-(3-ethyl-5-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)phenyl)1,1,1, 3,3,3-hexafluoropropan-2-ol; 7-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -2,7-diazaspiro[4.4]nonan-1-one; 7-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -2,7-diazaspiro[4.4]nonan-3-one; 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-I,H-dimethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide; 2-(2'-ethyl-2-methoxy-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl] -4 -yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 1,1,1,3,3,3-hexafluoro-2-(2'-methoxy-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl)methyl )-[1,1'-biphenyl]-4-yl)propan-2-ol; 7-((2-ethyl-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl) -2-thia-7 azaspiro[4.4]nonane 2,2-dioxide; 2-(5-(2-ethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyridin-2-yl)1,1,1, 3,3,3-hexafluoropropan-2-ol; 2-(4-(4-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)phenyl)1,1,1, 3,3,3-hexafluoropropan-2-ol; 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl )methyl)-[ 1,1'-biphenyl]-3-ol; 2-(2'-cyclopropyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[1,1'-biphenyl ]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-cyclopropyl-2,3',6'-trifluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[1,1' -biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2-chloro-2'-cyclopropyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1 ,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 1,1,1,3,3,3-hexafluoro-2-(2,3',6'-trifluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3 ]heptan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol; 2-(2'-cyclopropyl-2-ethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1 ,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-cyclopropyl-3',6'-difluoro-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1 ,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2-chloro-5'-fluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[1,1'- biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 1,1,1,3,3,3-hexafluoro-2-(5'-fluoro-2'-isopropyl-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3] heptan-2-yl)methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol; 2-(2,5'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-96 041942 biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2-chloro-3',6'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1 ,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2-ethyl-3',6'-difluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1 ,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(3',6'-difluoro-2'-isopropyl-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1 ,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'- biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2,2'-diethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1 'biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2-chloro-2'-ethyl-3',6'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1 ,1'biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2-chloro-2'-ethyl-5'-fluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1' -biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-2,5'-difluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl ]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 1,1,1,3,3,3-hexafluoro-2-(5'-fluoro-2'-isopropyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2yl) methyl)-[1,1'-biphenyl]-4-yl)propan-2-ol; 2-(2,2'-diethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4-yl )1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-2,3',6'-trifluoro-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,G -biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2-ethyl-2'-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4yl )-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(2-chloro-2'-ethyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[1,1'-biphenyl]-4yl )-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(3',6'-difluoro-2'-isopropyl-4'-((2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)-[1,Hbiphenyl] - 4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2-(4-(2-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)-3-methylphenyl)-1, 1,1,3,3,3-hexafluoropropan-2-ol; 2-(2'-ethyl-3',6'-difluoro-2-methyl-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)[1, 1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 2'-ethyl-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4'-((6-(methylsulfonyl)-2,6-diazaspiro[3.3] heptan-2-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile; 2-(4-(4-ethyl-6-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-3-yl)-3-methylphenyl)-1, 1,1,3,3,3-hexafluoropropan-2-ol; 2-(6-(2-ethyl-4-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)phenyl)pyridin-3-yl)1,1,1, 3,3,3-hexafluoropropan-2-ol; 2-(4-(3-ethyl-5-((6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyridin-2-yl)-3-methylphenyl)-1, 1,1,3,3,3-hexafluoropropan-2-ol; 1,1,1,3,3,3-hexafluoro-2-(3-methyl-4-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2 -yl)phenyl)propan-2-ol and 2-(2,2'-dimethyl-3'-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-[1,1'-biphenyl]-4-yl)1, 1,1,3,3,3-hexafluoropropan-2-ol or a pharmaceutically acceptable salt thereof. 18. Pharmaceutical composition for the treatment of psoriasis, psoriatic arthritis, uveitis, ulcerative colitis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, vitiligo, vesiculobullous dermatosis, rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, arthritis, associated with inflammatory bowel disease, juvenile rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, lupus, lupus nephritis, multiple sclerosis, axial spondiloarthritis, suppurative hidradenitis, Sjögren's syndrome, regional enteritis, Tholos-Hunt syndrome, undifferentiated connective tissue disease, obesity, insulin resistance caused by obesity, atherosclerosis, or type II diabetes mellitus, wherein the composition comprises a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 19. The use of a compound according to any one of claims 1-17, or a pharmaceutically acceptable salt or stereoisomer thereof, in the treatment of a disorder or condition selected from psoriasis, psoriatic arthritis, uveitis, ulcerative colitis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, vitiligo, vesiculobullous dermatosis, rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, arthritis associated with inflammatory bowel disease, juvenile rheumatoid arthritis, Crohn's disease, inflammatory bowel disease - 97 041942 cervical, lupus, lupus nephritis, multiple sclerosis, axial spodilitis, purulent hydradenitis, Sjögren's syndrome, regional enteritis, Tholos-Hunt syndrome, undifferentiated connective tissue disease, obesity, insulin resistance caused by obesity, atherosclerosis and type II diabetes mellitus. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2