Bicyclic indazole glucocorticoid receptor antagonists

Abstract

The present disclosure provides compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2. The compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2 may be used in pharmaceutical preparations and may be used to modulate the glucocorticoid receptor.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 368,409, filed July 14, 2022, and U.S. Provisional Patent Application No. 63 / 292,089, filed December 21, 2021, each of which is incorporated herein in its entirety for all purposes. [Background technology]

[0002] In most species, including humans, the physiological glucocorticoid is cortisol (hydrocortisone). In rodents, the physiological glucocorticoid is corticosterone. Glucocorticoids are secreted in response to ACTH (corticotropin) and show both circadian rhythmic changes and elevations in response to stress and feeding. Cortisol levels respond within minutes to many physical and psychological stresses, including trauma, surgery, exercise, anxiety, and depression. Cortisol is a steroid and acts by binding to the intracellular glucocorticoid receptor (GR). In humans, the glucocorticoid receptor exists in two forms: the ligand-binding GR-alpha of 777 amino acids, and the GR-beta isoform, which lacks the 50 carboxy-terminal residues. Because these residues contain the ligand-binding domain, GR-beta cannot bind natural ligands and is constitutively localized in the nucleus.

[0003] The biological effects of cortisol, including those caused by hypercortisolism, can be modulated at the GR level using receptor modulators such as agonists, partial agonists, and antagonists. Several different classes of drugs can block the physiological effects of GR-agonist binding. These antagonists include compositions that bind to GR, thereby inhibiting the ability of agonists to effectively bind to and / or activate GR. One such known GR antagonist, mifepristone, has been found to be an effective antiglucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to GR with high affinity, with a dissociation constant (K d ) is 10 -9 M (Cadepond (1997) Annu. Rev. Med 48:129).

[0004] Cortisol (and corticosterone) also binds to the mineralocorticoid receptor MR. Cortisol has a higher affinity for the MR than the GR, and the MR is usually thought to be fully occupied under normal physiological conditions. Under stress conditions, cortisol concentrations increase and the GR becomes occupied. The MR also binds the mineralocorticoid aldosterone, and aldosterone and cortisol have similar affinities for the MR. However, glucocorticoids circulate at approximately 100-fold the mineralocorticoid levels. An enzyme (11-β hydroxysteroid dehydrogenase 1) that inactivates cortisol (and corticosterone) is present in mineralocorticoid target tissues and prevents overstimulation by glucocorticoids.

[0005] Steroids, when administered to a subject in need thereof, may provide negative side effects as well as the intended therapeutic effect. There is a need in the art for new compounds and methods for selectively modulating GR. Surprisingly, the present invention meets these and other needs. Summary of the Invention

[0006] In one embodiment, the present invention provides a compound of formula I, [ka] During the ceremony, R 1 are heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms each being N, O, or S, phenyl, or heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each being N, O, or S, each independently consisting of 0 to 5 R 1a is substituted with a group, Each R 1a became independent, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -OH, oxo, -CN, -C(O)N(R 1b )(R 1c ), C 3-10 cycloalkyl or heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each of which is N, O, or S; Each R 1b and R 1c are independently hydrogen, C 1-6 alkyl, or a 3-8 membered heterocycloalkyl having 1-3 heteroatoms, each independently being N, O, or S; Each A 1 , A 2 , A 3 , and A 4 Independently, =CR 2 - or =N-, Each R 2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, Hydroxy, C 1-6 hydroxyalkyl, or -CN; Ring A is C 3-6 is cycloalkyl, L 2 is absent, -C(O)-, -C(O)O-, -C(O)N(R 3 )-, -S(O) 2 - or -S(O) 2 N(R 3 )-and R 3 is hydrogen or C 1-6 is alkyl, R 4 But, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, -(CH 2 CH 2 O) 2-6 CH 3 , C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 5 R 4a is substituted with a group, Alternatively, R 3 and R 4 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C1-6 substituted with an alkyl group, Each R 4a became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, -OH, oxo, -C(O)R 4b , -C(O)OR 4b , -OC(O)R 4b , -OC(O)OR 4b , -C(O)N(R 4b )(R 4c ), -N(R 4b )C(O)R 4c , -OC(O)N(R 4b )(R 4c ), -N(R 4b )C(O)OR 4c , -S(O) 2 R 4b , -S(O) 2 N(R 4b )(R 4c ), -N(R 4b )S(O) 2 R 4c , C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0, 1, or 2 C 1-6substituted with an alkyl group, Each R 4b and R 4c is hydrogen or C 1-6 is alkyl, Each L 5 is independent, absent or C 1-6 is alkylene, Each R 5 became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, oxo, -OR 5a , -C(O)R 5a , -C(O)OR 5a , -OC(O)R 5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , -OC(O)N(R 5a )(R 5b ), -N(R 5a )C(O)OR 5b , -S(O) 2 R 5a , -S(O) 2 N(R 5a )(R 5b ), -N(R 5a )S(O) 2 R 5b , C 3-8 Cycloalkyl, heterocycloalkyl, C 6-12 aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms which are each independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5c is substituted with a group, Each R5a and R 5b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5d is substituted with a group, Alternatively, R 5a and R 5b are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5c became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, oxo, -OH, -C(O)R5c1 , -C(O)OR 5c1 , -OC(O)R 5c1 , -OC(O)OR 5c1 , -C(O)N(R 5c1 )(R 5c2 ), -N(R 5c1 )C(O)R 5c2 , -OC(O)N(R 5c1 )(R 5c2 ), -N(R 5c1 )C(O)OR 5c2 , -S(O) 2 R 5c1 , -S(O) 2 N(R 5c1 )(R 5c2 ), -N(R 5c1 )S(O) 2 R 5c2 , C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5c1 and R 5c2 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Alternatively, R 5c1 and R 5c2 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5d became independent, C 1-6 is alkyl or halogen; Each R 6 became independent, C 1-6 Alkoxy, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, or C 1-6 is haloalkoxy; the subscript m is 0, 1, 2, 3, 4, or 5; The subscript n is 1 or 2, or a pharma- ceutically acceptable salt thereof.

[0007] In another embodiment, the present invention provides a compound of formula I, [ka] During the ceremony, R 1are heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms each being N, O, or S, phenyl, or heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each being N, O, or S, each independently consisting of 0 to 5 R 1a is substituted with a group, Each R 1a became independent, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -OH, oxo, -CN, -C(O)N(R 1b )(R 1c ), C 3-10 cycloalkyl or heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each of which is N, O, or S; Each R 1b and R 1c are independently hydrogen, C 1-6 alkyl, or a 3-8 membered heterocycloalkyl having 1-3 heteroatoms, each independently being N, O, or S; Each A 1 , A 2 , A 3 , and A 4 Independently, =CR 2 - or =N-, Each R 2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, Hydroxy, C 1-6 hydroxyalkyl, or -CN; Ring A is C 3-6 is cycloalkyl, L 2 is -C(O)-, -C(O)O-, -C(O)N(R 3 )-, -S(O) 2 - or -S(O) 2N(R 3 )-and R 3 is hydrogen or C 1-6 is alkyl, R 4 But, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 5 R 4a is substituted with a group, Alternatively, R 3 and R 4 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4a became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C1-6 Haloalkoxy, -CN, -OH, oxo, -C(O)R 4b , -C(O)OR 4b , -OC(O)R 4b , -OC(O)OR 4b , -C(O)N(R 4b )(R 4c ), -N(R 4b )C(O)R 4c , -OC(O)N(R 4b )(R 4c ), -N(R 4b )C(O)OR 4c , -S(O) 2 R 4b , -S(O) 2 N(R 4b )(R 4c ), -N(R 4b )S(O) 2 R 4c , C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4b and R 4c is hydrogen or C 1-6 is alkyl, Each L 5 is independent, absent or C 1-6 is alkylene, Each R 5 became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, oxo, -OR 5a , -C(O)R 5a , -C(O)OR 5a , -OC(O)R 5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , -OC(O)N(R 5a )(R 5b ), -N(R 5a )C(O)OR 5b , -S(O) 2 R 5a , -S(O) 2 N(R 5a )(R 5b ), -N(R 5a )S(O) 2 R 5b , C 3-8 Cycloalkyl, heterocycloalkyl, C 6-12 aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms which are each independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5c is substituted with a group, Each R 5a and R 5b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5d is substituted with a group, Alternatively, R 5a and R 5b are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5c became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, oxo, -OH, -C(O)R 5c1 , -C(O)OR 5c1 , -OC(O)R 5c1 , -OC(O)OR 5c1 , -C(O)N(R 5c1 )(R 5c2 ), -N(R 5c1 )C(O)R 5c2 , -OC(O)N(R 5c1 )(R 5c2 ), -N(R 5c1 )C(O)OR5c2 , -S(O) 2 R 5c1 , -S(O) 2 N(R 5c1 )(R 5c2 ), -N(R 5c1 )S(O) 2 R 5c2 , C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5c1 and R 5c2 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Alternatively, R 5c1 and R 5c2 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5d became independent, C 1-6 is alkyl or halogen; Each R 6 became independent, C 1-6 Alkoxy, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, or C 1-6 is haloalkoxy; the subscript m is 0, 1, 2, 3, 4, or 5; The subscript n is 1 or 2, or a pharma- ceutically acceptable salt thereof.

[0008] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharma- ceutically acceptable excipient.

[0009] In another embodiment, the present invention provides a method of treating a disorder or condition by modulating the glucocorticoid receptor, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition of the present invention, thereby treating the disorder or condition.

[0010] In another embodiment, the present invention provides a method of treating a disorder or condition by antagonizing the glucocorticoid receptor, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutical composition of the present invention.

[0011] In another embodiment, the present invention provides a compound or pharmaceutical composition for use in a method of treating a disorder or condition by modulating the glucocorticoid receptor.

[0012] In another embodiment, the present invention provides a compound or pharmaceutical composition for use in a method of treating a disorder or condition by antagonizing the glucocorticoid receptor.

[0013] In another embodiment, the present invention provides the use of a compound or pharmaceutical composition of the present invention in the manufacture of a medicament for treating a disorder or condition by modulating the glucocorticoid receptor.

[0014] In another embodiment, the present invention provides the use of a compound or pharmaceutical composition of the present invention in the manufacture of a medicament for treating a disorder or condition by antagonizing the glucocorticoid receptor. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] I. Overview The present invention provides compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2 that can modulate and / or antagonize the glucocorticoid receptor, thereby providing beneficial therapeutic effects. The present invention also provides methods for treating disorders and conditions by modulating or antagonizing the glucocorticoid receptor. The present invention also provides the use of the compounds of the present invention in the manufacture of a medicament for treating disorders or conditions by modulating, agonizing, or antagonizing the glucocorticoid receptor.

[0016] II. Definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In addition, any methods or materials similar or equivalent to those described herein can be used in the practice of the present invention. For purposes of the present invention, the following terms are defined:

[0017] As used herein, "a," "an," or "the" includes embodiments having one member as well as embodiments having multiple members. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, reference to "the agent" includes reference to one or more agents known to those of skill in the art, and so forth.

[0018] "Alkyl" refers to a straight or branched chain saturated aliphatic radical having the indicated number of carbon atoms. 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6 For example, C 1-6Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, including, but not limited to, heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.

[0019] "Alkylene" means an alkyl group having the indicated number of carbon atoms (i.e., C 1-6 means 1 to 6 carbons) and at least two other groups, i.e., divalent hydrocarbon radicals. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For example, a straight chain alkylene is -(CH 2 ) n- where n is 1, 2, 3, 4, 5, or 6. Representative C 1-4 Alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, and sec-butylene.

[0020] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl is defined as any one of the following: 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C 6Alkenyl groups can include any number of carbons, such as 1, 2, 3, 4, 5, or more. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5, or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

[0021] "Alkynyl" refers to either a straight or branched chain hydrocarbon having at least two carbon atoms and at least one triple bond. Alkynyl is a C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C 6 Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted.

[0022] "Deuteroalkyl" refers to an alkyl group as defined above in which at least one of the hydrogen atoms is replaced with deuterium. With respect to the alkyl group, a deuteroalkyl group is any group that is selected from the group consisting of C 1 - 6 Exemplary C can have any suitable number of carbon atoms, such as 1-4 Deuteroalkyl groups include -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 These include, but are not limited to:

[0023] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment, i.e., alkyl-O-. With respect to the alkyl group, an alkoxy group is a C 1-6 Alkoxy groups can have any suitable number of carbon atoms, such as, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like. Alkoxy groups can be further substituted with a variety of substituents as described herein. Alkoxy groups can be substituted or unsubstituted.

[0024] "Alkoxyalkyl" refers to a radical having an alkyl and alkoxy moiety, where the alkyl moiety links the alkoxy moiety to a point of attachment. The alkyl moiety is as defined above, except that the alkyl moiety is at least a divalent alkylene to link the alkoxy moiety to a point of attachment. The alkyl moiety is as defined above, except that the alkyl moiety is at least a divalent alkylene to link the alkoxy moiety to a point of attachment. 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6 The alkoxy moiety is as defined above. Examples of alkyl-alkoxy groups include, but are not limited to, 2-ethoxy-ethyl and methoxymethyl.

[0025] "Hydroxyalkyl" or "alkylhydroxy" refers to an alkyl group as defined above in which at least one of the hydrogen atoms is replaced with a hydroxy group. With respect to an alkyl group, hydroxyalkyl or alkylhydroxy can be any of the C 1 - 6 Exemplary C can have any suitable number of carbon atoms, such as 1-4 Hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (hydroxy in the 1- or 2-position), hydroxypropyl (hydroxy in the 1-, 2-, or 3-position), hydroxybutyl (hydroxy in the 1-, 2-, 3-, or 4-position), 1,2-dihydroxyethyl, and the like.

[0026] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0027] "Haloalkyl" refers to an alkyl as defined above in which some or all of the hydrogen atoms are replaced with halogen atoms. With respect to the alkyl group, a haloalkyl group is one having a C 1-6 For example, haloalkyl includes trifluoromethyl, fluoromethyl, and the like. In some cases, the term "perfluoro" can be used to define a compound or radical in which all hydrogens are replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0028] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced with halogen atoms. With respect to the alkyl group, the haloalkoxy group is 1-6 The alkoxy group may have any suitable number of carbon atoms, such as 1, 2, 3, or more halogens. If all hydrogens are replaced with halogens, such as fluorine, the compound is fully substituted, such as perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, and the like.

[0029] "Amino" refers to -N(R) where the R group can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, among others. 2 refers to the group. The R groups can be the same or different. Amino groups can be primary (each R is hydrogen), secondary (one R is hydrogen), or tertiary (each R is other than hydrogen).

[0030] "Oxo" refers to the carbonyl group =O.

[0031] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic, or bridged polycyclic ring assembly having 3 to 12 ring atoms or the indicated number of atoms. Cycloalkyl is defined as any of the following: 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12Cycloalkyl groups can contain any number of carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3-isomer and 1,4-isomer), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-isomer, 1,4-isomer, and 1,5-isomer), norbornene, and norbornadiene. Cycloalkyl groups can be saturated monocyclic C 3-8 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 When it is cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.

[0032] "Alkyl-cycloalkyl" refers to a radical having an alkyl and cycloalkyl component, where the alkyl component links the cycloalkyl component to a point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene to link the cycloalkyl component to the point of attachment. The alkyl component is selected from the group consisting of C 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C3-6 , C 4-5 , C 4-6 , and C 5-6 The cycloalkyl moiety is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0033] "Heterocycloalkyl" or "heterocyclyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 5 heteroatoms which are N, O, and S. The heteroatoms are -S(O)- and -S(O) 2- Heterocycloalkyl groups can include any number of ring atoms, such as, but not limited to, 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Any suitable number of heteroatoms may be included in the heterocycloalkyl group, for example, 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5. Heterocycloalkyl groups include, but are not limited to, C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12Heterocycloalkyl groups can include any number of carbons, such as aziridine, azetidine, pyrrolidine, piperidine, azepane, diazepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-isomer, 1,3-isomer, and 1,4-isomer), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members, including, but not limited to, indoline. Heterocycloalkyl groups can also form spiro structures, such as, but not limited to, diazabicycloheptane, diazabicyclooctane, diazaspirooctane, or diazaspirononane. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups include, among others, C 1-6 It may be substituted with alkyl or oxo (=O). Heterocycloalkyl groups may also contain double or triple bonds, such as, but not limited to, dihydropyridine or 1,2,3,6-tetrahydropyridine.

[0034] The heterocycloalkyl group may be linked through any position on the ring. For example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or 2-azetidine, pyrrolidine can be 1-, 2-, or 3-pyrrolidine, piperidine can be 1-, 2-, 3-, or 4-piperidine, pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3-, or 4-imidazolidine, and piperazine can be 1-, 2-, 3-, or 4-piperazine. where tetrahydrofuran can be 1- or 2-tetrahydrofuran, oxazolidine can be 2-, 3-, 4-, or 5-oxazolidine, isoxazolidine can be 2-, 3-, 4-, or 5-isoxazolidine, thiazolidine can be 2-, 3-, 4-, or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4-, or 5-isothiazolidine, and morpholine can be 2-, 3-, or 4-morpholine.

[0035] When the heterocycloalkyl contains 3 to 12 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxzoalidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. The heterocycloalkyl can also form a ring having 5 to 6 ring members and 1 to 2 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0036] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component links the heterocycloalkyl component to a point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene to link the heterocycloalkyl component to the point of attachment. The alkyl component is selected from the group consisting of C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6 The heterocycloalkyl moiety is as defined above. The alkyl-heterocycloalkyl group can be substituted or unsubstituted.

[0037] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. An aryl group can contain any suitable number of ring atoms, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms and 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linking group. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. Aryl groups can be substituted or unsubstituted.

[0038] "Alkyl-aryl" refers to a radical having an alkyl and aryl moiety, where the alkyl moiety links the aryl moiety to a point of attachment. The alkyl moiety is as defined above, except that the alkyl moiety is at least divalent alkylene to link the aryl moiety to a point of attachment. The alkyl moiety is as defined above, except that the alkyl moiety is at least divalent alkylene to link the aryl moiety to a point of attachment. 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6 The aryl moiety is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene. The alkyl-aryl group may be substituted or unsubstituted.

[0039] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly having 5 to 16 ring atoms, where one to five of the ring atoms are heteroatoms such as N, O, or S. Heteroatoms include -N(O)-, -S(O)-, and -S(O)-. 2-Heteroaryl groups can include any number of ring atoms, such as, but not limited to, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Any suitable number of heteroatoms may be included in the heteroaryl group, for example, 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5. Heteroaryl groups can have 5-8 ring members and 1-4 heteroatoms, or 5-8 ring members and 1-3 heteroatoms, or 5-6 ring members and 1-4 heteroatoms, or 5-6 ring members and 1-3 heteroatoms. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer, and 1,3,5-isomer), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also be fused to aromatic ring systems such as phenyl rings to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0040] The heteroaryl group may be linked through any position on the ring. For example, pyrrole includes 1-, 2-, and 3-pyrrole, pyridine includes 2-, 3-, and 4-pyridine, imidazole includes 1-, 2-, 4-, and 5-imidazole, pyrazole includes 1-, 3-, 4-, and 5-pyrazole, triazole includes 1-, 4-, and 5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5-, and 6-pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-, 5-, and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2- and 3-thiophene, and furan includes 2- and 3-furan. , thiazoles include 2-, 4-, and 5-thiazoles, isothiazoles include 3-, 4-, and 5-isothiazoles, oxazoles include 2-, 4-, and 5-oxazoles, isoxazoles include 3-, 4-, and 5-isoxazoles, indoles include 1-, 2-, and 3-indoles, isoindoles include 1- and 2-isoindoles, quinolines include 2-, 3-, and 4-quinolines, isoquinolines include 1-, 3-, and 4-isoquinolines, quinazolines include 2- and 4-quinoazolines, cinnolines include 3- and 4-cinnolines, benzothiophenes include 2- and 3-benzothiophenes, and benzofurans include 2- and 3-benzofurans.

[0041] Some heteroaryl groups include those having 5 to 10 ring members and 1 to 3 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer, and 1,3,5-isomer), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those having 5 to 10 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer, and 1,3,5-isomer), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those having 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Still other heteroaryl groups include those having 5 to 6 ring members and 1 to 2 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0042] "Alkyl-heteroaryl" refers to a radical having an alkyl and heteroaryl component, where the alkyl component links the heteroaryl component to a point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene to link the heteroaryl component to the point of attachment. The alkyl component is selected from the group consisting of C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6 The heteroaryl moiety is as defined herein. An alkyl-heteroaryl group can be substituted or unsubstituted.

[0043] "Pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject and the absorption of the active agent by the subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, surfactants, coatings, sweeteners, flavorings, and colorings. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0044] "Treate", "treating", and "treatment" refer to any indication of successful treatment or amelioration of an injury, pathology, or condition, including any objective or subjective parameter, such as remission; remission; reducing symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; improving the physical or mental health of the patient. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical exam, a neuropsychiatric exam, and / or a psychiatric evaluation.

[0045] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, or subcutaneous administration, intrathecal administration, or implantation of a sustained release device, e.g., a mini-osmotic pump, to a subject.

[0046] "Therapeutically effective amount" refers to a dose that produces a therapeutic effect when administered. The exact dose depends on the purpose of treatment and can be ascertained by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective dose is often lower than the conventional therapeutically effective dose in non-sensitized cells.

[0047] "Glucocorticoid receptor" ("GR") refers to a family of intracellular receptors that specifically bind cortisol and / or cortisol analogs, such as dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292). The glucocorticoid receptor is also called the cortisol receptor. The term includes isoforms of GR, recombinant GR, and mutant GR.

[0048] The cortisol receptor is the glucocorticoid receptor (GR), in particular the type II GR, which specifically binds cortisol and / or cortisol analogues such as dexamethasone (see, for example, Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292).

[0049] "Mineralocorticoid receptor" (MR) refers to the type I glucocorticoid receptor (GR I), which is activated by aldosterone in humans.

[0050] "Glucocorticoid receptor modulator" (GRM) refers to any compound that modulates any biological response associated with the binding of glucocorticoid receptor to an agonist. As used herein, with respect to GRM, the glucocorticoid receptor may be GR. For example, GRM acting as an agonist, such as dexamethasone, increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human liver hepatocellular carcinoma cell line, ECACC, UK). GRM acting as an antagonist, such as mifepristone, inhibits the agonist-induced increase in the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity can be measured as outlined in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0051] "Glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits any biological response associated with the binding of the glucocorticoid receptor to an agonist. As used herein, with respect to GRA, the glucocorticoid receptor may be GR. Thus, GR antagonists can be identified by measuring the ability of a compound to inhibit the effects of dexamethasone. TAT activity can be measured as outlined in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. Inhibitors have an IC of less than 10 micromolar. 50 (50% inhibitory concentration). See Example 1 of U.S. Patent No. 8,685,973, the entire contents of which are incorporated herein by reference in their entirety.

[0052] "Modulate" and "modulating" are used according to their plain and ordinary meaning and refer to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, when applied to the effect of a modulator on a target protein, modulating means altering by increasing or decreasing the property or function of the target molecule or the amount of the target molecule.

[0053] "Modulator" refers to a composition that increases or decreases the level of a target molecule, or the function of a target molecule, or the physical state of a target of the molecule.

[0054] "Antagonize" and "antagonizing" refer to inhibiting the binding of an agonist at a receptor molecule or inhibiting the signal produced by the receptor-agonist. Receptor antagonists inhibit or suppress an agonist-mediated response, such as gene expression.

[0055] "Antagonist" refers to a substance that can detectably reduce the expression or activity of a given gene or protein. Antagonists can inhibit expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or less, compared to a control in the absence of antagonist. In some embodiments, inhibition is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more, over expression or activity in the absence of antagonist.

[0056] "Inhibit," "inhibit," and "inhibitor" refer to a compound that prohibits a particular action or function or a method of inhibiting the same.

[0057] "Disorder" or "condition" refers to a condition or health state of a patient or subject that can be treated with a glucocorticoid receptor modulator of the present invention. In some embodiments, examples of disorders or conditions include, but are not limited to, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), antipsychotic-induced weight gain, cancer, Cushing's disease, Cushing's syndrome, psychotic major depression, nonalcoholic steatohepatitis, and obesity. In some embodiments, the disorder or condition includes nonalcoholic liver disease and / or nonalcoholic steatohepatitis. In some embodiments, the disorder or condition includes cancer.

[0058] "Medicine" refers to a composition or substance used in the treatment of a disease or condition.

[0059] "Subject" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, horses, and other non-mammalian animals. In some embodiments, the patient is a human.

[0060] III.Compound The present invention provides a compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof. In some embodiments, the present invention provides a compound of formula I, [ka] During the ceremony, R 1 are heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms each being N, O, or S, phenyl, or heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each being N, O, or S, each independently consisting of 0 to 5 R 1a is substituted with a group, Each R 1a became independent, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -OH, oxo, -CN, -C(O)N(R 1b )(R 1c ), C 3-10 cycloalkyl or heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each of which is N, O, or S; Each R 1b and R 1c are independently hydrogen, C 1-6 alkyl, or a 3-8 membered heterocycloalkyl having 1-3 heteroatoms, each independently being N, O, or S; Each A 1 , A 2 , A 3 , and A 4 Independently, =CR 2 - or =N-, Each R 2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, Hydroxy, C 1-6 hydroxyalkyl, or -CN; Ring A is C 3-6 is cycloalkyl, L 2 is absent, -C(O)-, -C(O)O-, -C(O)N(R 3 )-, -S(O) 2 - or -S(O) 2 N(R 3 )-and R 3 is hydrogen or C 1-6 is alkyl, R 4 But, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, -(CH 2 CH 2 O) 2-6 CH 3 , C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 5 R 4a is substituted with a group, Alternatively, R 3 and R 4 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4a became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, -OH, oxo, -C(O)R 4b , -C(O)OR 4b , -OC(O)R 4b , -OC(O)OR 4b , -C(O)N(R 4b )(R 4c ), -N(R 4b )C(O)R 4c , -OC(O)N(R 4b )(R 4c ), -N(R 4b )C(O)OR 4c , -S(O) 2 R 4b , -S(O) 2 N(R 4b )(R 4c ), -N(R 4b )S(O) 2 R 4c , C 3-8Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4b and R 4c is hydrogen or C 1-6 is alkyl, Each L 5 is independent, absent or C 1-6 is alkylene, Each R 5 became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, oxo, -OR 5a , -C(O)R 5a , -C(O)OR 5a , -OC(O)R 5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , -OC(O)N(R 5a )(R 5b ), -N(R 5a )C(O)OR 5b , -S(O) 2 R 5a, -S(O) 2 N(R 5a )(R 5b ), -N(R 5a )S(O) 2 R 5b , C 3-8 Cycloalkyl, heterocycloalkyl, C 6-12 aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms which are each independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5c is substituted with a group, Each R 5a and R 5b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5d is substituted with a group, Alternatively, R 5a and R 5bare combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5c became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, oxo, -OH, -C(O)R 5c1 , -C(O)OR 5c1 , -OC(O)R 5c1 , -OC(O)OR 5c1 , -C(O)N(R 5c1 )(R 5c2 ), -N(R 5c1 )C(O)R 5c2 , -OC(O)N(R 5c1 )(R 5c2 ), -N(R 5c1 )C(O)OR 5c2 , -S(O) 2 R 5c1 , -S(O) 2 N(R 5c1 )(R 5c2 ), -N(R 5c1 )S(O) 2 R 5c2 , C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5c1 and R 5c2 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Alternatively, R 5c1 and R 5c2 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5d became independent, C 1-6 is alkyl or halogen; Each R 6 became independent, C 1-6 Alkoxy, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, or C 1-6 is haloalkoxy; the subscript m is 0, 1, 2, 3, 4, or 5; The subscript n is 1 or 2, or a pharma- ceutically acceptable salt thereof.

[0061] In some embodiments, the present invention provides a compound of formula I, [ka] During the ceremony, R 1 are heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms each being N, O, or S, phenyl, or heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each being N, O, or S, each independently consisting of 0 to 5 R 1a is substituted with a group, Each R 1a became independent, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -OH, oxo, -CN, -C(O)N(R 1b )(R 1c ), C 3-10 cycloalkyl or heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each of which is N, O, or S; Each R 1b and R 1c are independently hydrogen, C 1-6 alkyl, or a 3-8 membered heterocycloalkyl having 1-3 heteroatoms, each independently being N, O, or S; Each A 1 , A 2 , A3 , and A 4 Independently, =CR 2 - or =N-, Each R 2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, Hydroxy, C 1-6 hydroxyalkyl, or -CN; Ring A is C 3-6 is cycloalkyl, L 2 is -C(O)-, -C(O)O-, -C(O)N(R 3 )-, -S(O) 2 - or -S(O) 2 N(R 3 )-and R 3 is hydrogen or C 1-6 is alkyl, R 4 But, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 5 R4a is substituted with a group, Alternatively, R 3 and R 4 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4a became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, -OH, oxo, -C(O)R 4b , -C(O)OR 4b , -OC(O)R 4b , -OC(O)OR 4b , -C(O)N(R 4b )(R 4c ), -N(R 4b )C(O)R 4c , -OC(O)N(R 4b )(R 4c ), -N(R 4b )C(O)OR 4c , -S(O) 2 R 4b , -S(O) 2 N(R 4b )(R 4c ), -N(R 4b )S(O) 2 R 4c , C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4b and R 4c is hydrogen or C 1-6 is alkyl, Each L 5 is independent, absent or C 1-6 is alkylene, Each R 5 became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, oxo, -OR 5a , -C(O)R 5a , -C(O)OR 5a , -OC(O)R 5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , -OC(O)N(R 5a )(R 5b ), -N(R 5a )C(O)OR 5b , -S(O) 2 R 5a , -S(O) 2 N(R 5a )(R 5b ), -N(R 5a )S(O) 2 R 5b , C 3-8 Cycloalkyl, heterocycloalkyl, C 6-12aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms which are each independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5c is substituted with a group, Each R 5a and R 5b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5d is substituted with a group, Alternatively, R 5a and R 5b are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R5c became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, oxo, -OH, -C(O)R 5c1 , -C(O)OR 5c1 , -OC(O)R 5c1 , -OC(O)OR 5c1 , -C(O)N(R 5c1 )(R 5c2 ), -N(R 5c1 )C(O)R 5c2 , -OC(O)N(R 5c1 )(R 5c2 ), -N(R 5c1 )C(O)OR 5c2 , -S(O) 2 R 5c1 , -S(O) 2 N(R 5c1 )(R 5c2 ), -N(R 5c1 )S(O) 2 R 5c2 , C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5c1 and R 5c2are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Alternatively, R 5c1 and R 5c2 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5d became independent, C 1-6 is alkyl or halogen; Each R 6 became independent, C 1-6 Alkoxy, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, or C 1-6 is haloalkoxy; the subscript m is 0, 1, 2, 3, 4, or 5; The subscript n is 1 or 2, or a pharma- ceutically acceptable salt thereof.

[0062] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 1 are heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms each being N, O, or S, phenyl, or heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each being N, O, or S, each independently consisting of 0 to 5 R 1a groups, each R 1a became independent, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -OH, oxo, -CN, -C(O)N(R 1b )(R 1c ), C 3-10 cycloalkyl or heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each of which is N, O, or S; 1b and R 1c are independently hydrogen, C 1-6 alkyl, or 3-8 membered heterocycloalkyl having 1-3 heteroatoms, each independently being N, O, or S.

[0063] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 1 In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 1In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 1 is a compound where: [ka]

[0064] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, 1 , A 2 , A 3 , and A 4 Independently, =CR 2 - or =N-, and each R 2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, Hydroxy, C 1-6 In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each A is -hydroxyalkyl, -CN, or -CN. 1 , A 2 , A 3 , and A 4 GA=CR 2 - is a compound.

[0065] In some embodiments, a compound of Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, or Formula Ic, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 2 are independently hydrogen or C 1-6 In some embodiments, a compound of Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, or Formula Ic, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 2is independently hydrogen, methyl, ethyl, n-propyl, or iso-propyl. In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, or Formula Ic, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 2 In some embodiments, the compound of formula Ia, formula Ib, formula Ib-1, formula Ib-2, or formula Ic, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 2 is methyl.

[0066] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, 1 , A 2 , and A 4 is =CH-, and A 3 In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each A 1 , A 2 , and A 4 is =CH-, and A 3 is =C(Me)-.

[0067] A described herein 1 , A 2 , A 3 , A 4 , and R 2 Each embodiment of the formula (I) is a cyclic alkyl group as described herein. 1 It can be combined with each of the above embodiments.

[0068] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, has the formula Ia [ka] It is a compound having the structure:

[0069] In some embodiments, the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, is a compound, wherein ring A is C 3-6 In some embodiments, the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, is a compound, wherein ring A is C 3-5 In some embodiments, the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, is a compound, wherein ring A is C 3 Cycloalkyl or C 5 A compound that is cycloalkyl.

[0070] Each embodiment of ring A described herein can be any of the R 1 , A 1 , A 2 , A 3 , A 4 , and R 2 It can be combined with each of the above embodiments.

[0071] In some embodiments, the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, is represented by formula Ib [ka] It is a compound having the structure:

[0072] In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is represented by the formula Ib-1 [ka] It is a compound having the structure:

[0073] In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is represented by the formula Ib-2: [ka] It is a compound having the structure:

[0074] In some embodiments, the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, is a compound having the structure of Formula Ic, [ka] wherein the subscript m is 0 or 1.

[0075] In some embodiments, the compound of Formula I, Formula Ia, or Formula Ic, or a pharma- ceutically acceptable salt thereof, is a compound having the structure of Formula Ic-1, [ka] wherein the subscript m is 0 or 1.

[0076] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein L 2 is absent, -C(O)-, -C(O)O-, -C(O)N(R 3 )-, -S(O) 2 - or -S(O) 2 N(R 3 )- and R 3 is hydrogen or C 1-6 In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein L is an alkyl group. 2 is absent, -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )- and R 3 is hydrogen or C 1-6 In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein L is an alkyl group. 2is -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )- and R 3 is hydrogen or C 1-6 In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein L is an alkyl group. 2 is absent, -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )- and R 3 In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein L 2 is -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )- and R 3 In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein L 2 is absent, -C(O)-, or -S(O) 2 In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein L 2 is -C(O)- or -S(O) 2 In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein L 2In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein L is -C(O)-. 2 But -S(O) 2 - is a compound.

[0077] The L described herein 2 and R 3 Each embodiment of the formula (I) is a cyclic alkyl group as described herein. 1 , A 1 , A 2 , A 3 , A 4 , R 2 and each of the embodiments of ring A.

[0078] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 4 But, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, -(CH 2 CH 2 O) 2-4 CH 3 , C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 5 R 4a is substituted with a group, Alternatively, R 3 and R 4 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4a became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, -OH, oxo, -C(O)R 4b , -C(O)OR 4b , -OC(O)R 4b , -OC(O)OR 4b , -C(O)N(R 4b )(R 4c ), -N(R 4b )C(O)R 4c , -OC(O)N(R 4b )(R 4c ), -N(R 4b )C(O)OR 4c , -S(O) 2 R 4b , -S(O) 2 N(R 4b )(R 4c ), -N(R 4b )S(O) 2 R 4c , C 3-8Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4b and R 4c is hydrogen or C 1-6 It is a compound that is alkyl.

[0079] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 4 But, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, -(CH 2 CH 2 O) 2-4 CH 3 , C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently have 0 to 5 R 4a is substituted with a group, Alternatively, R 3 and R 4 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4a became independent, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, -OH, -S(O) 2 R 4b , C 3-6 cycloalkyl, and heterocycloalkyl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; Each R 4b But, C 1-6 It is a compound that is alkyl.

[0080] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 4 But, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 3-8Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 5 R 4a substituted with an alkyl group, Alternatively, R 3 and R 4 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4a became independent, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 haloalkoxy, -CN, or -OH.

[0081] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 4 But, C 1-4 Alkyl, C 2-4 Alkoxyalkyl, -(CH 2 CH 2 O) 2-4CH 3 , C 3-6 Cycloalkyl, C 1-2 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 aryl or heteroaryl; wherein each heterocycloalkyl independently has 3 to 6 ring members and 1 to 3 heteroatoms which are each independently N or O; and each heteroaryl independently is having 5 to 6 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 3 R 4a is substituted with a group, Each R 4a became independent, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkoxyalkyl, halogen, -CN, -S(O) 2 R 4b , C 3-6 cycloalkyl, and heterocycloalkyl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; Each R 4b But, C 1-6 It is a compound that is alkyl.

[0082] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 4 are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, methoxymethyl, methoxyethyl, -(CH 2 CH 2 O) 2 CH 3 , C 3-6 Cycloalkyl, C 1-2 Alkyl-C 3-6Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 aryl or heteroaryl; wherein each cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each heterocycloalkyl is azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, or morpholine; each heteroaryl is pyrrole, pyridine, pyrazole, imidazole, pyridazine, pyrimidine, pyrazine, isoxazole, oxazole, isothiazole, thiazole, or triazole; Each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently represents 0 to 2 R 4a is substituted with a group, Each R 4a are independently methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, n-propoxy, iso-propoxy, methoxymethyl, methoxyethyl, fluoro, chloro, bromo, -CH 2 F, -CHF 2 , -CF 3 , -CN, -S(O) 2 Me, -S(O) 2 Et, cyclopropyl, cyclobutyl, cyclopentyl, piperidine, tetrahydropyran, or morpholine.

[0083] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 4 Methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, methoxymethyl, methoxyethyl, C 3-6 Cycloalkyl, C 1-2 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12aryl or heteroaryl; wherein each cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each heterocycloalkyl is azetidine, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, or morpholine; each heteroaryl is pyrrole, pyridine, pyrazole, imidazole, pyridazine, pyrimidine, pyrazine, isoxazole, oxazole, isothiazole, thiazole, or triazole; Each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently represents 0 to 2 R 4a is substituted with a group, Each R 4a is independently methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, n-propoxy, iso-propoxy, methoxymethyl, methoxyethyl, fluoro, chloro, bromo, or -CN.

[0084] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 4 Methyl, ethyl, iso-propyl, iso-butyl, t-butyl, methoxymethyl, methoxyethyl, -(CH 2 CH 2 O) 2 CH 3 , [ka] [ka] is a compound.

[0085] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 4Methyl, ethyl, iso-propyl, iso-butyl, t-butyl, methoxymethyl, methoxyethyl, [ka] is a compound.

[0086] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 4 Methyl, ethyl, isopropyl, isobutyl, methoxymethyl, methoxyethyl, CH 2 (CH 2 OCH 2 ) 2 H, [ka] [ka] is a compound.

[0087] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 4 Methyl, ethyl, isopropyl, isobutyl, methoxymethyl, methoxyethyl, [ka] is a compound.

[0088] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 4 Methyl, iso-propyl, t-butyl, methoxyethyl, [ka] is a compound.

[0089] R as described herein 4 , R 4a , R 4b , and R 4c Each embodiment of the formula (I) is a cyclic alkyl group as described herein. 1 , A 1 , A 2 , A 3 , A 4 , R 2 , ring A, L 2 , and R 3 It can be combined with each of the above embodiments.

[0090] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: Each L 5 is independent, absent or C 1-6 is alkylene, Each R 5 became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, oxo, -OR 5a , -C(O)R 5a , -C(O)OR 5a , -OC(O)R 5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , -OC(O)N(R 5a )(R 5b ), -N(R 5a )C(O)OR 5b , -S(O) 2 R 5a , -S(O) 2 N(R 5a )(R5b ), -N(R 5a )S(O) 2 R 5b , C 3-8 Cycloalkyl, heterocycloalkyl, C 6-12 aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms which are each independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5c is substituted with a group, Each R 5a and R 5b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5d is substituted with a group, Alternatively, R 5a and R 5bare combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5c became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, oxo, -OH, -C(O)R 5c1 , -C(O)OR 5c1 , -OC(O)R 5c1 , -OC(O)OR 5c1 , -C(O)N(R 5c1 )(R 5c2 ), -N(R 5c1 )C(O)R 5c2 , -OC(O)N(R 5c1 )(R 5c2 ), -N(R 5c1 )C(O)OR 5c2 , -S(O) 2 R 5c1 , -S(O) 2 N(R 5c1 )(R 5c2 ), -N(R 5c1 )S(O) 2 R 5c2 , C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5c1 and R 5c2 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C 1-6 substituted with an alkyl group, Alternatively, R 5c1 and R 5c2 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5d became independent, C 1-6It is a compound in which the aryl group is an alkyl or halogen.

[0091] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: Each L 5 is independent, absent or C 1-6 is alkylene, Each R 5 became independent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, Hydroxy, C 1-6 Hydroxyalkyl, oxo, -OR 5a , -C(O)R 5a , -C(O)OR 5a , -OC(O)R 5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , -OC(O)N(R 5a )(R 5b ), -N(R 5a )C(O)OR 5b , -S(O) 2 R 5a , -S(O) 2 N(R 5a )(R 5b ), -N(R 5a )S(O) 2 R 5b , C 3-8 Cycloalkyl, heterocycloalkyl, C 6-12 aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms which are each independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5c is substituted with a group, Each R5a and R 5b are independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5d is substituted with a group, Alternatively, R 5a and R 5b are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 5c became independent, C 1-6 Alkyl, halogen, or C 1-6 is haloalkyl, Each R 5d became independent, C 1-6 It is a compound in which the aryl group is an alkyl or halogen.

[0092] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: Each L 5 is independent, absent or C 1-2 is alkylene, Each R 5 became independent, C 1-3Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, oxo, -OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , heterocycloalkyl, C 6-12 aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5c is substituted with a group, Each R 5a and R 5b are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-12 Aryl, C 1-2 Alkyl-C 6-12 aryl, or heteroaryl, where each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5d is substituted with a group, Alternatively, R 5a and R 5b are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 6 ring members and one additional heteroatom that is N or O, where the heterocycloalkyl is selected from 0, 1, or 2 C 1-3 substituted with an alkyl group, Each R 5c became independent, C 1-3 Alkyl, halogen, or C 1-3 is haloalkyl, Each R 5d became independent, C 1-3 It is a compound in which the aryl group is an alkyl or halogen.

[0093] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: Each L 5 is independent, absent or C 1-2 is alkylene, Each R 5 became independent, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, oxo, -OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , C 6-12 aryl, or heteroaryl, where each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each aryl and heteroaryl independently has 0 to 4 R 5c is substituted with a group, Each R 5a and R 5b are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-12 Aryl, C 1-2 Alkyl-C 6-12 aryl, or heteroaryl, where each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5d is substituted with a group, Alternatively, R 5a and R 5b are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 6 ring members and one additional heteroatom that is N or O, where the heterocycloalkyl is selected from 0, 1, or 2 C 1-3 substituted with an alkyl group, Each R 5c became independent, C1-3 Alkyl or C 1-3 is haloalkyl, Each R 5d are independently halogen.

[0094] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: Each L 5 is independently absent or -CH 2 - and Each R 5 are independently methyl, -C≡CH, -C≡CCH 3 , -CH 2 C≡CCH 3 , methoxy, ethoxy, n-propoxy, iso-propoxy, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, oxo, -OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , heterocycloalkyl, C 6-12 aryl or heteroaryl; wherein each heterocycloalkyl is azetidine, pyrrolidine, piperidine, or morpholine; the aryl is phenyl; each heteroaryl is pyrrole, pyridine, pyrazole, imidazole, pyridazine, pyrimidine, pyrazine, isoxazole, oxazole, benzoxazole, isothiazole, thiazole, benzothiazole, triazole, oxadiazole, or thiadiazole; Each heterocycloalkyl, aryl, and heteroaryl independently represents 0 to 2 R 5c is substituted with a group, Each R 5a and R 5bare independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, C 3-6 Cycloalkyl, C 6-12 Aryl, C 1-2 Alkyl-C 6-12 aryl or heteroaryl; wherein each cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each aryl is phenyl; each heteroaryl is pyrrole, pyridine, pyrazole, imidazole, pyridazine, pyrimidine, or pyrazine; Each cycloalkyl, aryl, and heteroaryl is selected from 0 to 2 R 5d is substituted with a group, Alternatively, R 5a and R 5b taken together with the atom to which they are attached form a heterocycloalkyl which is azetidine, pyrrolidine, or piperidine; wherein the heterocycloalkyl is selected from the group consisting of 0, 1, or 2 C 1-3 substituted with an alkyl group, Each R 5c are independently methyl, ethyl, n-propyl, iso-propyl, fluoro, chloro, -CH 2 F, -CHF 2 , -CF 3 , or -CH 2 CF 3 and Each R 5d is independently methyl, ethyl, n-propyl, iso-propyl, fluoro, chloro, or bromo.

[0095] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: Each L 5 is independently absent or -CH 2 - and Each R 5are independently -C≡CH, -C≡CCH 3 , -CH 2 C≡CCH 3 , methoxy, ethoxy, n-propoxy, iso-propoxy, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, oxo, -OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , C 6-12 aryl or heteroaryl; wherein the aryl is phenyl; each heteroaryl is pyrrole, pyridine, pyrazole, imidazole, pyridazine, pyrimidine, pyrazine, isoxazole, oxazole, benzoxazole, isothiazole, thiazole, benzothiazole, triazole, oxadiazole, or thiadiazole; Each aryl and heteroaryl independently represents 0 to 2 R 5c is substituted with a group, Each R 5a and R 5b are independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, C 3-6 Cycloalkyl, C 6-12 Aryl, C 1-2 Alkyl-C 6-12 aryl or heteroaryl; wherein the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each aryl is phenyl; each heteroaryl is pyrrole, pyridine, pyrazole, imidazole, pyridazine, pyrimidine, or pyrazine; Each cycloalkyl, aryl, and heteroaryl is selected from 0 to 2 R 5d is substituted with a group, Alternatively, R5a and R 5b taken together with the atom to which they are attached form a heterocycloalkyl which is azetidine, pyrrolidine, or piperidine; wherein the heterocycloalkyl is selected from the group consisting of 0, 1, or 2 C 1-3 substituted with an alkyl group, Each R 5c are independently methyl, ethyl, n-propyl, iso-propyl, -CH 2 F, -CHF 2 , -CF 3 , or -CH 2 CF 3 and Each R 5d is independently fluoro, chloro, or bromo.

[0096] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 5 -L 5 - group is methyl, -C≡CCH 3 , methoxy, -CH 2 OH, oxo, [ka] is a compound.

[0097] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 5 -L 5 - group is -C≡CCH 3 , methoxy, -CH 2 OH, oxo, [ka] is a compound.

[0098] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 5 -L 5 - group is methyl, -CH 2 OH, [ka] is a compound.

[0099] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 5 -L 5 - group is -CH 2 OH, [ka] is a compound.

[0100] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 5 -L 5 - group is methoxy, -C≡CCH 3 , oxo, [ka] is a compound.

[0101] The L described herein 5 , R 5 , R 5a , R 5b , R 5c , R 5c1 , R 5c2 , and R 5d Each embodiment of the formula (I) is a cyclic alkyl group as described herein. 1 , A 1 , A 2 , A 3 , A 4 , R 2 , ring A, L2 , R 3 , R 4 , R 4a , R 4b , and R 4c It can be combined with each of the above embodiments.

[0102] In some embodiments, the compound of formula I, formula Ia, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 6 became independent, C 1-6 Alkoxy, Hydroxy, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, or C 1-6 In some embodiments, the compound of Formula I, Formula Ia, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 6 became independent, C 1-6 alkoxy, hydroxy, or halogen; and the subscript m is 0 or 1.

[0103] In some embodiments, the compound of formula I, formula Ia, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein the subscript m is 0 or 1. In some embodiments, the compound of formula I, formula Ia, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 6 is independently -OMe, -OEt, -OPr, -OiPr, hydroxy, F, Cl, or Br, and subscript m is 0 or 1. In some embodiments, a compound of Formula I, Formula Ia, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein each R 6 is independently -OMe, -OEt, hydroxy, or F, and the subscript m is 0 or 1.

[0104] In some embodiments, the compound of Formula I, Formula Ia, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound wherein the subscript m is 0.

[0105] R as described herein 6 and each embodiment of the subscript m is R 1 , A 1 , A 2 , A 3 , A 4 , R 2 , ring A, L 2 , R 3 , R 4 , R 4a , R 4b , R 4c , L 5 , R 5 , R 5a , R 5b , R 5c , R 5c1 , R 5c2 , and R 5d It can be combined with each of the above embodiments.

[0106] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound where the subscript n is 1 or 2. In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound where the subscript n is 1.

[0107] Each embodiment of subscript n described herein can be any of the R 1 , A 1 , A 2 , A 3 , A 4 , R 2 , ring A, L 2 , R 3 , R 4 , R 4a , R 4b , R 4c , L 5 , R5 , R 5a , R 5b , R 5c , R 5c1 , R 5c2 , R 5d , R 6 , and each embodiment of subscript m.

[0108] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 1 is phenyl substituted with fluoro, and each A 1 , A 2 , and A 4 is =CH-, and A 3 is a compound in which =C(Me)-.

[0109] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 1 is phenyl substituted with fluoro, and each A 1 , A 2 , and A 4 is =CH-, and A 3 is =C(Me)- and ring A is C 3 Cycloalkyl or C 5 A compound that is cycloalkyl.

[0110] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 1 is phenyl substituted with fluoro; Each A 1 , A 2 , and A 4 is =CH-, A 3 , =C(Me)-, Ring A is C 3 Cycloalkyl or C5 is cycloalkyl, L 2 is absent, -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )- and R 3 is hydrogen or C 1-6 is alkyl, R 4 But, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 5 R 4a is substituted with a group, Alternatively, R 3 and R 4 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4a became independent, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6haloalkoxy, -CN, or -OH.

[0111] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 1 is phenyl substituted with fluoro; Each A 1 , A 2 , and A 4 is =CH-, A 3 , =C(Me)-, Ring A is C 3 Cycloalkyl or C 5 is cycloalkyl, L 2 is absent, -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )- and R 3 is hydrogen or C 1-6 is alkyl, R 4 But, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 5 R 4a is substituted with a group, Alternatively, R 3 and R 4 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4a became independent, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 haloalkoxy, -CN, or -OH; Each L 5 is independent, absent or C 1-2 is alkylene, Each R 5 became independent, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, oxo, -OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , heterocycloalkyl, C 6-12 aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5c is substituted with a group, Each R 5a and R 5b are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-12 Aryl, C 1-2 Alkyl-C6-12 aryl, or heteroaryl, where each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5d is substituted with a group, Alternatively, R 5a and R 5b are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 6 ring members and one additional heteroatom that is N or O, where the heterocycloalkyl is selected from 0, 1, or 2 C 1-3 substituted with an alkyl group, Each R 5c became independent, C 1-3 Alkyl, halogen, or C 1-3 is haloalkyl, Each R 5d became independent, C 1-3 It is a compound in which the aryl group is an alkyl or halogen.

[0112] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 1 is phenyl substituted with fluoro; Each A 1 , A 2 , and A 4 is =CH-, A 3 , =C(Me)-, Ring A is C 3 Cycloalkyl or C 5 is cycloalkyl, L 2 is absent, -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )- and R 3 is hydrogen or C 1-6 is alkyl, R 4 But, C 1-6Alkyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 5 R 4a is substituted with a group, Alternatively, R 3 and R 4 are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently N, O, or S, where the heterocycloalkyl has 0, 1, or 2 C 1-6 substituted with an alkyl group, Each R 4a became independent, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 haloalkoxy, -CN, or -OH; Each L 5 is independent, absent or C 1-2 is alkylene, Each R 5 became independent, C 1-3 Alkyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, oxo, -OR5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , heterocycloalkyl, C 6-12 aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5c is substituted with a group, Each R 5a and R 5b are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-12 Aryl, C 1-2 Alkyl-C 6-12 aryl, or heteroaryl, where each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5d is substituted with a group, Alternatively, R 5a and R 5b are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 6 ring members and one additional heteroatom that is N or O, where the heterocycloalkyl is selected from 0, 1, or 2 C 1-3 substituted with an alkyl group, Each R 5c became independent, C 1-3 Alkyl, halogen, or C 1-3 is haloalkyl, Each R 5d became independent, C 1-3 is alkyl or halogen; Each R 6 became independent, C 1-6 alkoxy, hydroxy, or halogen; The subscript m is 0 or 1.

[0113] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 1 is phenyl substituted with fluoro, and each A 1 , A 2 , and A 4 is =CH-, and A 3 is =C(Me)- and ring A is C 3 A compound that is cycloalkyl.

[0114] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 1 is phenyl substituted with fluoro; Each A 1 , A 2 , and A 4 is =CH-, A 3 , =C(Me)-, Ring A is C 3 is cycloalkyl, L 2 is absent, -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )-and R 3 is hydrogen or methyl.

[0115] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 1 is phenyl substituted with fluoro; Each A 1 , A 2 , and A 4 is =CH-, A 3 , =C(Me)-, Ring A is C 3 is cycloalkyl, L 2 is absent, -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )-and R 3 is hydrogen or methyl; R 4 Methyl, ethyl, iso-propyl, iso-butyl, t-butyl, methoxymethyl, methoxyethyl, -(CH 2 CH 2 O) 2 CH 3 , [ka] [ka] is a compound.

[0116] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 1 is phenyl substituted with fluoro; Each A 1 , A 2 , and A 4 is =CH-, A 3 , =C(Me)-, Ring A is C 3 is cycloalkyl, L 2 is absent, -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )-and R 3 is hydrogen or methyl; R 4Methyl, ethyl, iso-propyl, iso-butyl, t-butyl, methoxymethyl, methoxyethyl, -(CH 2 CH 2 O) 2 CH 3 , [ka] [ka] and Each R 5 -L 5 - group is -CH 2 OH, [ka] and The compound in which the subscript m is 0.

[0117] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 1 is phenyl substituted with halogen; Each A 1 , A 2 , and A 4 is =CH-, A 3 is ═CH— or ═C(Me)—, Ring A is C 3-5 is cycloalkyl, L 2 is absent, -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )-and R 3 is hydrogen or C 1-3 is alkyl, R 4 But, C 1-4 Alkyl, C 2-4 Alkoxyalkyl, -(CH 2 CH 2O) 2-4 CH 3 , C 3-6 Cycloalkyl, C 1-2 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 aryl or heteroaryl; wherein each heterocycloalkyl independently has 3 to 6 ring members and 1 to 3 heteroatoms which are each independently N or O; and each heteroaryl independently is having 5 to 6 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 3 R 4a is substituted with a group, Each R 4a became independent, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkoxyalkyl, halogen, -CN, -S(O) 2 R 4b , C 3-6 cycloalkyl, and heterocycloalkyl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; Each R 4b But, C 1-6 is alkyl, Each L 5 is independent, absent or C 1-2 is alkylene, Each R 5 became independent, C 2-4 Alkynyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, oxo, -OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5a )C(O)R 5b , heterocycloalkyl, C 6-12aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5c is substituted with a group, Each R 5a and R 5b are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-12 Aryl, C 1-2 Alkyl-C 6-12 aryl, or heteroaryl, where each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; and each cycloalkyl, aryl, and heteroaryl independently has 0 to 4 R 5d is substituted with a group, Alternatively, R 5a and R 5b are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 6 ring members and one additional heteroatom that is N or O, where the heterocycloalkyl is selected from 0, 1, or 2 C 1-3 substituted with an alkyl group, Each R 5c became independent, C 1-3 Alkyl, halogen, or C 1-3 is haloalkyl, Each R 5d became independent, C 1-3 is alkyl or halogen; Each R 6 became independent, C 1-6 alkoxy, hydroxy, or halogen; the subscript m is 0 or 1; The compound in which the subscript n is 1.

[0118] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 1 but, [ka] and Each A 1 , A 2 , and A 4 is =CH-, A 3 is ═CH— or ═C(Me)—, Ring A is C 3 Cycloalkyl or C 5 is cycloalkyl, L 2 is absent, -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )-and R 3 is hydrogen or methyl; R 4 Methyl, ethyl, iso-propyl, iso-butyl, t-butyl, methoxymethyl, methoxyethyl, CH 2 (CH 2 OCH 2 ) 2 H, [ka] [ka] and Each R 5 -L 5 - group is methyl, -C≡CCH 3 , methoxy, -CH 2 OH, oxo, [ka] and Each R 6are independently -OMe, -OEt, hydroxy, or F; the subscript m is 0 or 1; The compound in which the subscript n is 1.

[0119] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 1 but, [ka] and Each A 1 , A 2 , and A 4 is =CH-, A 3 is ═CH— or ═C(Me)—, Ring A is C 3 Cycloalkyl or C 5 is cycloalkyl, L 2 is -C(O)-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 3 )-and R 3 is hydrogen or methyl; R 4 Methyl, ethyl, iso-propyl, iso-butyl, t-butyl, methoxymethyl, methoxyethyl, [ka] and Each R 5 -L 5 - group is -C≡CCH 3 , methoxy, -CH 2 OH, oxo, [ka] and Each R 6are independently -OMe, -OEt, hydroxy, or F; the subscript m is 0 or 1; The compound in which the subscript n is 1.

[0120] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 4 Methyl, ethyl, isopropyl, isobutyl, methoxymethyl, methoxyethyl, CH 2 (CH 2 OCH 2 ) 2 H, [ka] [ka] and Each R 5 -L 5 - group is methyl, -CH 2 OH, [ka] is a compound.

[0121] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 4 Methyl, ethyl, isopropyl, isobutyl, methoxymethyl, methoxyethyl, [ka] and Each R 5 -L 5 - group is -CH 2 OH, [ka] is a compound.

[0122] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 4 Methyl, iso-propyl, t-butyl, methoxyethyl, [ka] and Each R 5 -L 5 - group is methoxy, -C≡CCH 3 , oxo, [ka] is a compound.

[0123] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound, wherein: R 4 Methyl, iso-propyl, t-butyl, methoxyethyl, [ka] and Each R 5 -L 5 - group is methoxy, -C≡CCH 3 , oxo, [ka] is a compound.

[0124] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, or formula Ib-2, or a pharma- ceutically acceptable salt thereof, is represented by formula Id-1 or Id-2: [ka] It is a compound having the structure:

[0125] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 4 But, C 6-12 aryl or heteroaryl having 5-6 ring members and 1-4 heteroatoms each independently being N, O, or S, where the aryl and heteroaryl are independently selected from 0-3 R 4a groups, each R 4a became independent, C 1-3 Alkyl, C 1-3 Alkoxy, halogen, C 1-3 Haloalkyl, -CN, -S(O) 2 R 4b , C 3-6 cycloalkyl, and heterocycloalkyl, where each heterocycloalkyl independently has 5 to 6 ring members and 1 to 2 heteroatoms, each independently being N, O, or S; and each R 4b But, C 1-3 It is a compound that is alkyl.

[0126] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 4 But 0 to 2 R 4a R is a phenyl, pyridine, pyridazine, pyrimidine, or pyrazine substituted with a group; 4a are independently methyl, isopropyl, methoxy, fluoro, -CHF 2 , -CF 3 , -CN, -S(O) 2 Me, cyclopropyl, or morpholine.

[0127] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 4 But 0 to 1 R 4a phenyl or pyridine, substituted with R 4a is -CN.

[0128] In some embodiments, Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, Formula Ic-1, Formula Id-1, or Formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound, wherein R 4 but, [ka] is a compound.

[0129] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1A.

[0130] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0131] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1B.

[0132] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0133] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1C.

[0134] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8]

[0135] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1D.

[0136] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7]

[0137] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, Formula Ic-1, Formula Id-1, or Formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1E.

[0138] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9]

[0139] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, Formula Ic-1, Formula Id-1, or Formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1F.

[0140] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6]

[0141] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, Formula Ic-1, Formula Id-1, or Formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1G.

[0142] [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6]

[0143] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, or Table 1G. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1A, Table 1B, Table 1C, Table 1D, or Table 1E. In some embodiments, the compound of formula I, formula Ia, formula Ic, or formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1A or Table 1B. In some embodiments, the compound of Formula I, Formula Ia, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1A. In some embodiments, the compound of Formula I, Formula Ia, Formula Ic, or Formula Ic-1, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1B.

[0144] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2 is a compound of Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, or Table 1G. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, or formula Id-2 is a compound of Table 1A, Table 1B, Table 1C, Table 1D, or Table 1E. In some embodiments, the compound of formula I, formula Ia, formula Ic, or formula Ic-1 is a compound of Table 1A or Table 1B. In some embodiments, the compound of formula I, formula Ia, formula Ic, or formula Ic-1 is a compound of Table 1A. In some embodiments, the compound of Formula I, Formula Ia, Formula Ic, or Formula Ic-1 is a compound of Table 1B.

[0145] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1C, Table 1D, or Table 1E, Table 1F, or Table 1G. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1C, Table 1D, or Table 1E. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1C. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1D. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1E. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1F. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1G.

[0146] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2 is a compound of Table 1C, Table 1D, or Table 1E, Table 1F, or Table 1G. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2 is a compound of Table 1C, Table 1D, or Table 1E. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2 is a compound of Table 1C. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2 is a compound of Table 1D. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2 is a compound of Table 1E. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2 is a compound of Table 1F. In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2 is a compound of Table 1G.

[0147] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is [ka] [ka] It is a compound having the structure:

[0148] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is [ka] It is a compound having the structure:

[0149] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is [ka] It is a compound having the structure:

[0150] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is [ka] It is a compound having the structure:

[0151] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is [ka] It is a compound having the structure:

[0152] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is [ka] It is a compound having the structure:

[0153] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is [ka] It is a compound having the structure:

[0154] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is [ka] It is a compound having the structure:

[0155] In some embodiments, the compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Id-1, or formula Id-2, or a pharma- ceutically acceptable salt thereof, is [ka] It is a compound having the structure:

[0156] The compounds of the present invention may exist as salts. The present invention includes such salts, which may be pharma- ceutically acceptable salts. Examples of applicable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof, including racemic mixtures), succinate, benzoate, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art. Also included are base addition salts, such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. In cases where the compounds of the present invention contain relatively basic functional groups, acid addition salts can be prepared by converting the neutral forms of such compounds, either neat or in a suitable inert solvent. The acid addition salts can be obtained by contacting the compound with a sufficient amount of the desired acid, either in a solvent or in a solvent medium. Examples of acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galactunoric acid. Certain certain compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0157] Other salts include acid salts or base salts of the compounds used in the method of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (such as methyl iodide, ethyl iodide, etc.) salts. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0158] Pharmaceutically acceptable salts include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein.When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.Examples of pharma-ceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as arginic acid, and salts of organic acids such as glucuronic acid or galactunoric acid (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

[0159] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0160] Certain compounds of the present invention can exist in unsolvated or solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or non-crystalline forms.

[0161] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds, and enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L)- relative to the amino acids, and individual isomers are encompassed within the scope of the present invention. Compounds of the present invention do not include those known in the art to be too unstable to synthesize and / or isolate. The present invention is intended to include compounds in racemic and optically pure form. Optically active (R)- and (S)-isomers or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or using conventional techniques.

[0162] Isomers include compounds that have the same number and kinds of atoms, and thus the same molecular weight, but differ with regard to the structural or spatial arrangement of the atoms.

[0163] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0164] Unless otherwise specified, the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds of the present invention may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), Fluorine-18( 18 F), Nitrogen-15( 15N), oxygen-17( 17 O), oxygen-18( 18 O), Carbon-13( 13 C), or carbon-14 ( 14 The compound may be labeled with a radioactive or stable isotope, such as C. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0165] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that undergo easy chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with suitable enzymes or chemical reagents.

[0166] IV. Composition In some embodiments, the invention provides a pharmaceutical composition comprising a compound, which is any one of the compounds of the invention, and a pharma- ceutically acceptable excipient.

[0167] The compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, troches, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by the patient. The compounds of the present invention can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. The compounds described herein can also be administered by inhalation, for example, intranasally. In addition, the compounds of the present invention can be administered transdermally. The compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2 of the present invention can also be administered by intraocular, intravaginal, and intrarectal routes, including suppositories, insufflations, powders, and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J.Clin.Pharmacol.35:1187-1193,1995; Tjwa, Ann.Allergy Asthma Immunol.75:107-111,1995). Thus, the present invention also provides pharmaceutical compositions comprising one or more pharma-ceutically acceptable carriers and / or excipients and a compound of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2, or any of its pharma-ceutically acceptable salts.

[0168] For preparing pharmaceutical compositions from the compounds of the present invention, pharma- ceutically acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.Solid carriers can be one or more substances, and can also act as diluents, flavoring agents, surfactants, binders, preservatives, tablet disintegrating agents, or encapsulating materials.Details regarding formulation and administration techniques are fully explained in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0169] In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties and additional excipients as required in suitable proportions and compacted in the shape and size desired.

[0170] Powders, capsules, and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound with an encapsulating material as a carrier, in which the active ingredient is surrounded by a carrier with or without other excipients, thus providing a capsule therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0171] Suitable solid excipients are carbohydrate or protein fillers, including, but not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starches from corn, wheat, rice, potato, or other plants; celluloses, such as methylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose; and gums, including arabic and tragacanth; and proteins, such as gelatin and collagen. If desired, disintegrating or solubilizing agents, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate, may be added.

[0172] Dragee cores are provided with suitable coatings such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and concentrated sugar solutions, which may also contain suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or dragee coatings to identify the product or to characterize the amount of active compound (i.e., dosage). The pharmaceutical preparations of the present invention can also be used orally, for example, using push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a coating such as glycerin or sorbitol. Push-fit capsules can contain the compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2 mixed with fillers or binders such as lactose or starch, lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the compounds of Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, Formula Ic-1, Formula Id-1, and Formula Id-2 may be dissolved or suspended in a suitable liquid, such as fatty acid liquid, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.

[0173] For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0174] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in aqueous polyethylene glycol solution.

[0175] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active ingredient in water containing a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, as well as dispersing or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, aspartame, or saccharin. The preparations may be adjusted for osmolality.

[0176] Also included are solid form preparations that are intended to be converted immediately prior to use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0177] In oil suspensions, the compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2 can be formulated by suspending them in vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oils, such as liquid paraffin, or mixtures thereof. Oil suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners can be added to provide a palatable oral preparation, such as glycerol, sorbitol, or sucrose. These preparations can be preserved by the addition of antioxidants, such as ascorbic acid. For an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical preparations of the present invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, as described above, or mixtures thereof. Suitable emulsifying agents include naturally occurring gums such as gum acacia and gum tragacanth, naturally occurring phosphatides such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweetening and flavoring agents, as found in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, preservative, or coloring agent.

[0178] The compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2 of the present invention can be delivered transdermally by the topical route and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0179] The compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1 and formula Id-2 of the present invention and compositions may be delivered as microspheres for sustained release in the body.For example, microspheres can be administered by intradermal injection of drug-containing microspheres for sustained subcutaneous release (see Rao, J.Biomater Sci.Polym.Ed.7:623-645,1995), or as biodegradable and injectable gel formulations (see Gao Pharm.Res.12:857-863,1995), or as microspheres for oral administration (see Eyles, J.Pharm.Pharmacol.49:669-674,1997).Both transdermal and intradermal routes can provide constant delivery over weeks or months.

[0180] Pharmaceutical formulations of the compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2 of the present invention can be provided as salts and can be formed with a number of acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. In other cases, the preparations can be lyophilized powders of 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, in a pH range of 4.5 to 5.5, which is combined with a buffer prior to use.

[0181] Pharmaceutical formulations of the compounds of Formula I, Ia, Ib, Ib-1, Ib-2, Ic, Ic-1, Id-1, and Id-2 of the present invention can be provided as salts, which can be formed with bases, i.e., cationic salts, such as alkali and alkaline earth metal salts, e.g., sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, trimethyl-ammonium salts, diethylammonium salts, and tris-(hydroxymethyl)-methyl-ammonium salts.

[0182] In some embodiments, formulations of compounds of Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2, Formula Ic, Formula Ic-1, Formula Id-1, and Formula Id-2 of the invention can be delivered by the use of liposomes that fuse with the cell membrane or are endocytosed, i.e., by using a ligand attached to the liposome or directly attached to the oligonucleotide that binds to a surface membrane protein receptor of the cell that effects endocytosis. The use of liposomes can focus the delivery of GR modulators to target cells in vivo, especially if the liposome surface carries a ligand specific to the target cell or is otherwise preferentially directed to a particular organ. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0183] The pharmaceutical preparation is preferably in unit dosage form.In such dosage form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredient.The unit dosage form can be a packaged preparation, i.e., a package containing discrete amounts of preparation, such as tablets, capsules, and powders, packaged in vials or ampoules.The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0184] The quantity of active ingredient in a unit dose preparation may vary or be adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 1,000 mg, and most typically from 10 mg to 500 mg, depending on the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[0185] Dosing regimens also take into account pharmacokinetic parameters, i.e., absorption, bioavailability, metabolism, clearance rates, etc., which are well known in the art (see, e.g., Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; latest edition of Remington's, supra). State-of-the-art technology allows the clinician to determine the dosing regimen for each individual patient, GR and / or MR modulator, and disease or condition being treated.

[0186] Single or multiple administrations of the compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2 can be administered depending on the dosage and frequency required and tolerated by the patient. The formulation should provide a sufficient amount of active agent to effectively treat the condition. Thus, in one embodiment, pharmaceutical formulations for oral administration of the compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2 are in a daily dose of about 0.5 to about 30 mg per kilogram of body weight per day. In an alternative embodiment, the dosage is about 1 mg to about 20 mg per kg of body weight per patient per day. In contrast to oral administration, administration into the bloodstream, administration into a body cavity, or administration into the lumen of an organ, smaller dosages can be used, especially when the drug is administered to an anatomically isolated site such as the cerebrospinal fluid (CSF) cavity. Local administration can use substantially higher dosages. The actual methods for preparing formulations containing the compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2 for parenteral administration are known or apparent to those skilled in the art and are described in more detail in publications such as Remington's (see above). See also Nieman, "Receptor Mediated Antisteroid Action," Agarwal, et al., eds., De Gruyter, New York (1987).

[0187] The compounds described herein can be used in combination with each other, in combination with other active agents known to be useful in modulating the glucocorticoid receptor, or in combination with adjunct agents that may not be effective alone but may contribute to the effectiveness of the active agent.

[0188] In some embodiments, simultaneous administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Simultaneous administration includes administering two active agents simultaneously, at about the same time (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, simultaneous administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition that includes both active agents. In some embodiments, the active agents can be formulated separately. In some embodiments, the active agents and / or adjuncts can be linked to each other or conjugated to each other.

[0189] After the pharmaceutical compositions comprising the compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2 of the present invention have been formulated in one or more acceptable carriers, they can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of the compounds of formula I, formula Ia, formula Ib, formula Ib-1, formula Ib-2, formula Ic, formula Ic-1, formula Id-1, and formula Id-2, such labeling would include, for example, instructions regarding the amount, frequency, and method of administration.

[0190] In some embodiments, the compositions of the present invention are useful for parenteral administration, such as intravenous (IV) administration or administration into a cavity of a body or organ. Formulations for administration generally comprise a solution of the compositions of the present invention dissolved in one or more pharma- ceutically acceptable carriers. Acceptable vehicles and solvents that can be used include water and Ringer's solution, isotonic sodium chloride. In addition, sterile, fixed oils can be used in conventional manner as a solvent or suspending medium. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables as well. These solutions are sterile and generally free of undesirable substances. These formulations can be sterilized by conventional, well-known sterilization techniques. The formulations may contain pharma-ceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting and buffering agents, osmolality adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like. The concentration of the composition of the present invention in these formulations can vary widely and is selected primarily based on fluid volume, viscosity, body weight, etc., depending on the particular administration method selected and the patient's needs. For intravenous (IV) administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution.

[0191] V. METHODS AND USES In some embodiments, the present invention provides a method of treating a disorder or condition by modulating the glucocorticoid receptor, comprising administering to a subject in need of such treatment a therapeutically effective amount of any one of the compounds of the present invention or a pharmaceutical composition of the present invention, thereby treating the disorder or condition.

[0192] In an exemplary embodiment, the GR modulator is an antagonist of GR activity (also referred to herein as a "glucocorticoid receptor antagonist"). As used herein, a glucocorticoid receptor antagonist refers to any composition or compound that partially or completely inhibits (antagonizes) the binding of a glucocorticoid receptor (GR) agonist (e.g., cortisol and synthetic or natural cortisol analogs) to GR, thereby inhibiting any biological response associated with the binding of GR to the agonist.

[0193] In some embodiments, the GR modulator is a specific glucocorticoid receptor antagonist. As used herein, a specific glucocorticoid receptor antagonist refers to a composition or compound that inhibits any biological response associated with the binding of GR to an agonist by preferentially binding to GR rather than another nuclear receptor (NR). In some embodiments, a specific glucocorticoid receptor antagonist preferentially binds to GR rather than to the mineralocorticoid receptor (MR), aldosterone receptor (AR), or progesterone receptor (PR). In an exemplary embodiment, a specific glucocorticoid receptor antagonist preferentially binds to GR rather than to the mineralocorticoid receptor (MR). In another exemplary embodiment, a specific glucocorticoid receptor antagonist preferentially binds to GR rather than to the progesterone receptor (PR). In another exemplary embodiment, a specific glucocorticoid antagonist preferentially binds to GR rather than to the aldosterone receptor (AR).

[0194] In some embodiments, a specific glucocorticoid receptor antagonist binds to GR with an association constant (Kd) that is at least 10-fold lower than the association constant (Kd) of any other NR. In some embodiments, a specific glucocorticoid receptor antagonist binds to GR with a Kd that is at least 100-fold lower than the association constant (Kd) of any other NR. In some embodiments, a specific glucocorticoid receptor antagonist binds to GR with a Kd that is at least 1000-fold lower than the association constant (Kd) of any other NR.

[0195] In some embodiments, the present invention provides a method of treating a disorder or condition by antagonizing the glucocorticoid receptor, comprising administering to a subject in need of such treatment an effective amount of any one of the compounds of the present invention or a pharmaceutical composition of the present invention.

[0196] In some embodiments, the disorder or condition is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), antipsychotic-induced weight gain, cancer, Cushing's disease, Cushing's syndrome, psychotic major depression, nonalcoholic steatohepatitis, and obesity. In some embodiments, the disorder or condition can be ovarian cancer, breast cancer, non-small cell lung cancer, or prostate cancer.

[0197] In some embodiments, the method includes administering one or more second agents (e.g., therapeutic agents). In some embodiments, the method includes administering a therapeutically effective amount of one or more second agents (e.g., therapeutic agents). In some embodiments, the second agent is an agent known to be useful in modulating the glucocorticoid receptor. In some embodiments, the second agent is an agent for treating Alzheimer's disease, amyotrophic lateral sclerosis (ALS), antipsychotic-induced weight gain, cancer, Cushing's disease, Cushing's syndrome, psychotic major depression, nonalcoholic steatohepatitis, and obesity. In some embodiments, the second agent is an agent for treating psychotic major depression, stress disorder, or antipsychotic-induced weight gain. In some embodiments, the second agent is an agent for treating nonalcoholic fatty liver disease and / or nonalcoholic steatohepatitis. In some embodiments, the second agent is an agent for treating cancer. In some embodiments, the second agent is an anti-cancer agent. In some embodiments, the second agent is a chemotherapeutic agent.

[0198] In some embodiments, any one of the compounds of the present invention or the pharmaceutical composition of the present invention can be used in a method for treating a disorder or condition by modulating the glucocorticoid receptor.

[0199] In some embodiments, any one of the compounds of the present invention or the pharmaceutical composition of the present invention can be used in a method for treating a disorder or condition by antagonizing the glucocorticoid receptor.

[0200] In some embodiments, any one of the compounds of the present invention or the pharmaceutical composition of the present invention can be used in the manufacture of a medicament for treating a disorder or condition by modulating the glucocorticoid receptor.

[0201] In some embodiments, any one of the compounds of the present invention or the pharmaceutical composition of the present invention can be used in the manufacture of a medicament for treating a disorder or condition by antagonizing the glucocorticoid receptor.

[0202] VI. Compound Examples General Procedure All starting materials and solvents were either obtained from commercial sources or prepared according to literature references. All reactions were stirred unless otherwise stated. Organic solutions were routinely dried over anhydrous magnesium sulfate. Hydrogenations were carried out in a Thales H-cube flow reactor under the conditions stated or under pressure in a gas autoclave (bomb).

[0203] Column chromatography was performed on pre-packed silica (230-400 mesh, 40-63 μm) cartridges using the volumes indicated. SCX was purchased from Supelco and treated with 1 M hydrochloric acid before use. Unless otherwise stated, the reaction mixture to be purified was first diluted with MeOH and acidified with a few drops of AcOH. This solution was directly loaded onto the SCX and washed with MeOH. The desired material was then purified by elution with 1% NH 3 The mixture was washed with and eluted with 100% MeOH.

[0204] Preparative reversed-phase high performance liquid chromatography. Preparative HPLC was performed over 10 min. 2Waters X-Select Prep-C18, 5 μm, 19 × 50 mm column (Method A) eluted with a gradient of O-MeCN (containing 0.1% v / v formic acid) or H over 10 min. 2 Analysis was performed on either a Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column (Method B) eluted with a gradient of O-MeCN (containing 0.1% ammonium bicarbonate) using UV detection at 215 nm and 254 nm. [ka]

[0205] 4-(benzylthio)-2-methyl-2H-1,2,3-triazole was prepared according to the procedure described in Example 1 of US Pat. No. 10,494,349, which is incorporated herein in its entirety for all purposes. [ka]

[0206] 2-Methyl-2H-1,2,3-triazole-4-sulfonyl chloride was prepared according to the procedure described in Intermediate 5A of US Pat. No. 10,047,082, incorporated herein in its entirety for all purposes. [ka]

[0207] 4-(benzylthio)-2-isopropyl-2H-1,2,3-triazole was prepared according to the procedure described in Example 2 of US Pat. No. 10,494,349, which is incorporated herein in its entirety for all purposes. [ka]

[0208] 2-Isopropyl-2H-1,2,3-triazole-4-sulfonyl chloride was prepared according to the procedure described in Intermediate 5D of US Pat. No. 10,494,349, which is incorporated herein in its entirety for all purposes.

[0209] Analysis method Reversed-phase high-performance liquid chromatography. Method 1: Waters XSelect CSH UPLC C18 1.7 μm (2.1 × 30 mm), 40 °C, flow rate 0.77 mL / min -1 , 3 minutes H 2 Elute with a gradient of 0-MeCN (containing 0.1% v / v formic acid) with UV detection at 210-400 nm. Gradient information: 95% H from 0 to 0.11 min. 2 Hold in 5% MeCN-HO, 95% H2O, 0.11–2.15 min 2 O-5% MeCN to 5% H 2 Gradient to O-95% MeCN, 5% H 2 Hold in O-95% MeCN, 5% H 2 O-95%MeCN to 95%H 2 Gradient to 5% O-MeCN, 95% H2O from 2.56 to 3.00 min. 2 Hold in O-5% MeCN.

[0210] Method 2: Waters XSelect CSH C18 2.5μm (4.6×30mm), 40℃, flow rate 2.5~4.5mL / min -1 , 4 minutes H 2 Elute with a gradient of 0-MeCN (containing 0.1% v / v formic acid) with UV detection at 254 nm and 215 nm. Gradient information: 95% H from 0 to 3.00 min. 2 O-5% MeCN to 5% H 2 Gradient to O-95% MeCN, 5% H2O from 3.00 to 3.01 min. 2 Maintain flow rate at 4.5 mL / min with O-95% MeCN -1 Increase to 5% H for 3.01 to 3.50 min. 2 Hold in O-95% MeCN, 3.50–3.60 min in 95% H 2 Change back to O-5% MeCN, flow rate to 3.50 mL / min-1 Reduce to 95% H for 3.60-3.90 min. 2 Hold in 5% MeCN / HO, 95% H2O, 3.90–4.00 min. 2 O-5% MeCN, flow rate 2.5 mL / min -1 Reduce to.

[0211] Method 3: Waters XBridge BEH C18 1.7μm (2.1×30mm), 40℃, flow rate 2.5~4.5mL / min -1 , 4 minutes H 2 Elute with a gradient of 10O-MeCN (containing 10 mM ammonium bicarbonate) with UV detection at 254 nm. Gradient information: 95% H from 0 to 0.11 min. 2 Hold in 5% MeCN-HO, 95% H2O, 0.11–2.15 min 2 O-5% MeCN to 5% H 2 Gradient to O-95% MeCN, 5% H 2 Hold in O-95% MeCN, 5% H 2 O-95%MeCN to 95%H 2 Gradient to 5% O-MeCN, 95% H2O from 2.56 to 3.00 min. 2 Hold in O-5% MeCN.

[0212] Method 4: Waters XSelect BEH C18 1.7μm (2.1×30mm), 40℃, flow rate 0.77mL / min -1 , 3 minutes H 2 Elute with a gradient of 10O-MeCN (containing 10 mM ammonium bicarbonate) with UV detection at 210-400 nm. Gradient information: 95% H from 0 to 0.11 min. 2 Hold in 5% MeCN-HO, 95% H2O, 0.11–2.15 min 2 O-5% MeCN to 5% H 2 Gradient to O-95% MeCN, 5% H 2 Hold in O-95% MeCN, 5% H 2 O-95%MeCN to 95%H 2 Gradient to 5% O-MeCN, 95% H2O from 2.56 to 3.00 min.2 Hold in O-5% MeCN.

[0213] Method 5: Waters XSelect CSH UPLC C18 1.7μm (2.1×30mm), 40℃, flow rate 0.77mL / min -1 , 10 minutes H 2 Elute with a gradient of 0-MeCN (containing 0.1% v / v formic acid) with UV detection at 210-400 nm. Gradient information: 95% H at 0.0–9.52 min. 2 O-5% MeCN to 5% H 2 Gradient to O-95% MeCN, 5% H 2 Hold in O-95% MeCN, 5% H 2 O-95%MeCN to 95%H 2 Gradient to O-5% MeCN, 95% H2O from 10.00 to 10.20 min. 2 Hold in O-5% MeCN.

[0214] Method 6: Waters HClass, binary solvent pump, SM-FTN, CMA, PDA: 210-400 nm, QDa: ACQ-QDa ESI, Column: Waters CSH C18, 30 x 2.1 mm, 1.7 μm, Temperature: 40 °C, Flow rate: 0.77 mL / min, Gradient: 0 min = 2% B, 2.5 min = 100% B, 3.0 min = 100% B, Eluent A: 0.1% formic acid in water, Eluent B: acetonitrile.

[0215] Method 7: Waters HClass, quaternary solvent pump, SM-FTN, CMA, PDA: 210-400 nm, QDa: ACQ-QDa ESI, Column: Waters CSH C18, 30 x 2.1 mm, 1.7 μm, Temperature: 40 °C, Flow rate: 0.77 mL / min, Gradient: 0 min = 2% B, 2.5 min = 100% B, 3.0 min = 100% B, Eluent A: 0.1% formic acid in water, Eluent B: acetonitrile.

[0216] Method 8: UPLC_basic, Instrument: Waters HClass, Binary Solvent Pump, SM-FTN, CMA, PDA: 210-400 nm, QDa: ACQ-QDa ESI, Column: Waters BEH C18, 30×2.1 mm, 1.7 μm, Temperature: 40° C., Flow rate: 0.77 mL / min, Gradient: 0 min=2% B, 2.5 min=100% B, 3.0 min=100% B, Eluent A: 0.1% NH3 in water, Eluent B: acetonitrile.

[0217] Method 9: LCMS_acidic, Instrument: Agilent 1260, binary pump, HiP sampler, column compartment, DAD: 260±90 nm, G6150 MSD: ESI, Column: Waters Cortecs C18, 30×2.1 mm, 2.7 μm, Temperature: 40° C., Flow rate: 1.35 mL / min, Gradient: 0 min=5% B, 2.5 min=100% B, 3.0 min=100% B, Eluent A: 0.1% formic acid in water, Eluent B: acetonitrile.

[0218] NMR spectra were recorded using either a Bruker Avance III HD 500 MHz instrument or a Bruker Avance Neo 400 MHz using residual non-deuterated solvent or tetra-methylsilane as a reference, or a Varian Y 400 MHz instrument using tetra-methylsilane as a reference, or a QOne AS400 400 MHz spectrometer using either residual non-deuterated solvent or tetra-methylsilane as a reference.

[0219] All chemical names were generated using ChemDraw. Abbreviation COMU = 1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate DBU = diazabicyclo[5.4.0]undec-7-ene DCM = dichloromethane DIAD = diisopropyl azadicarboxylate DIBAL-H = diisobutylaluminum hydride DIPEA = diisopropylethylamine DMF = Dimethylformamide DMSO = dimethyl sulfoxide EtOAc = ethyl acetate EtOH = ethanol H, hr, HR, Hr=time HATU = Hexafluorophosphate azabenzotriazole tetramethyluronium MeCN = acetonitrile MeOH = methanol min=minutes MgSO 4 = Magnesium sulfate NaHCO 3 = Sodium bicarbonate NaOH = Sodium hydroxide Na 2 SO 4 = Sodium sulfate NH 4 Cl = Ammonium chloride RT, rt=room temperature sat.=saturated SFC = Supercritical Fluid Chromatography TBME = t-butyl methyl ether THF = tetrahydrofuran Wt=weight

[0220] Example 1: tert-Butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ka] Pyridine (18.7 g, 19.1 mL, 237 mmol) was added to a solution of 5-bromo-6-methyl-1H-indazole (25.0 g, 118 mmol), (4-fluorophenyl)boronic acid (33.1 g, 237 mmol), and copper(II) acetate (21.5 g, 118 mmol) in DCM (500 mL). The reaction mixture was stirred at 20° C. for 21 h. The reaction mixture was concentrated under reduced pressure, redissolved in EtOAc (500 mL), and washed with water (200 mL), 1N HCl (200 mL), saturated sodium bicarbonate (2×200 mL), and brine (100 mL). The organic layer was concentrated and washed with MgSO 4 The mixture was dried using a 50 mL hexanes water bath, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (330 g cartridge, 0-10% EtOAc / isohexane) to give 5-bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (Intermediate A) (34.2 g, 0.11 mol, 81% yield) as a yellow solid. t 2.33 min (Method 7); m / z 305.3 and 307.5 (M+H) + (ES + );δH(DMSO-d6,400MHz)δ 8.30(d,J=0.9Hz,1H), 8.16(s,1H), 7.81(s,1H), 7.80-7.76(m,2H), 7.50-7.38(m,2H), 2.50(s,3H).

[0221] Alternatively, 5-bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole can be prepared according to the method for Intermediate C of PCT Publication No. WO2021 / 262587.

[0222] [ka] 5-Bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (Intermediate A) (5.00 g, 16.4 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2-2'-bi(1,3,2-dioxaborolane) (6.24 g, 24.6 mmol), potassium acetate (8.04 g, 81.9 mmol), and Pd(dppf)Cl 2 DCM (1.34 g, 1.64 mmol) was suspended in 1,4-dioxane (30 mL). The mixture was evacuated and back-filled with nitrogen (3 times) then heated to 80° C. for 16 h. The mixture was cooled to room temperature then filtered through Celite eluting with EtOAc (50 mL). The filtrate was washed with water (2×50 mL) and brine (50 mL) then dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-50% EtOAc / isohexane) to give 1-(4-fluorophenyl)-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate B) (6.8 g, 13 mmol, 79% yield) as a pale yellow crystalline solid. t 2.05 minutes (method 1); m / z 353.4 (M+H) + (ES + );δH(DMSO-d6,500MHz)δ 8.35(d,J=0.9Hz,1H), 8.22(s,1H), 7.83-7.76(m,2H), 7.58(br.d,J=0.9Hz,1H), 7.46-7.40(m,2H), 2.62(d,J=0.9Hz,3H), 1.33(s,12H).

[0223] Example 1: tert-Butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ka] A solution of 1-(4-fluorophenyl)-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate B, 3.82 g, 10.3 mmol), 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (3.86 g, 9.86 mmol), and triethylamine (4.08 g, 5.62 mL, 40.3 mmol) in 1,4-dioxane (22.5 mL) and water (2.50 mL) was stirred at 4°C for 12 h at 20°C for 30 min. 2 Hydroxy(cyclooctadiene)rhodium(I) dimer (461 mg, 1.01 mmol) was added and the solution was sparged with N 2 The mixture was sparged with 500 ml of ethyl acetate for 5 min, then heated to 80° C. and stirred for 5 h. The reaction mixture was allowed to cool to room temperature and stand over the weekend. The reaction mixture was diluted with saturated NH 4 It was diluted with aqueous Cl (50 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (4 x 50 mL). The combined organics were washed with MgSO 4 The crude product was purified by chromatography on silica gel (220 g cartridge, 0-20% EtOAc / DCM) to give tert-butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (6.32 g, 13 mmol, 63%) as a thick yellow oil. t 1.72 minutes (method 1); m / z 450.4 (M+H) + (ES + ).

[0224] Example 2: 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-(thiazol-2-yl)octahydrocyclopenta[c]pyrrol-5-ol [ka] To a solution of tert-butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Example 1) (3.0 g, 6.7 mmol) in 1,4-dioxane (30 mL) was added 4M 1,4-dioxane solution (2.4 g, 17 mL, 67 mmol). The resulting yellow solution was heated at 50° C. for 18 hours. The solvent was removed under reduced pressure to give a grey solid. The solid was triturated in TBME (10 mL), sonicated, filtered, and washed with TBME (2×5 mL) to give 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)hexahydrocyclopenta[c]pyrrol-5(1H)-one, HCl (Intermediate C) (1.80 g, 4.61 mmol, 69% yield) as a grey solid. t 0.66 min (method 2); m / z 350.2 (M+H) + (ES + ).

[0225] [ka] To a solution of 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)hexahydrocyclopenta[c]pyrrol-5(1H)-one, HCl (Intermediate C) (1.70 g, 4.41 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (1.59 g, 8.81 mmol) in DCM (60 mL) was added triethylamine (1.23 mL, 8.81 mmol) dropwise at 0° C. The resulting deep orange solution was stirred at 0° C. for 2 h, allowed to warm to room temperature and stirred for 18 h. The reaction mixture was concentrated onto silica and purified by chromatography on silica gel (80 g cartridge, 0-100% EtOAc / isohexane, product eluted at 100%) to give 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)hexahydrocyclopenta[c]pyrrol-5(1H)-one (1.52 g, 3.06 mmol, 69.4% yield) (Intermediate D) as a white solid.t 1.23 minutes (method 2); m / z 494.2 (M+H) + (ES + ). δH(DMSO-d6,400MHz)δ 8.21(d,J=0.9Hz,1H), 8.12(s,1H), 7.82-7.76(m,2H), 7.67-7.62(m,3H), 7.48-7.40(m, 2H), 3.78(d,J=11.1Hz,1H), 3.71(dd,J=10.3,7.2Hz,1H), 3.64-3.57(m,1H), 3.55(s,3H) ), 3.50(d,J=11.0Hz,1H), 3.27(dd,J=10.3,4.2Hz,1H), 2.88(d,J=18.6Hz,1H), 2.65(dd ,J=18.9,8.2Hz,1H), 2.47-2.44(m,3H), 2.43-2.36(m,1H), 2.20(dd,J=18.8,6.5Hz,1H).

[0226] Example 2: 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-(thiazol-2-yl)octahydrocyclopenta[c]pyrrol-5-ol [ka] To a solution of 2-bromothiazole (66.5 mg, 36.5 μL, 405 μmol) in THF (2 mL) was added butyllithium (2.5 M in hexanes) (26.0 mg, 162 μL, 405 μmol) dropwise at −78° C. The yellow solution was stirred at −78° C. for 30 min, after which a solution of 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)hexahydrocyclopenta[c]pyrrol-5(1H)-one (Intermediate D) (100 mg, 203 μmol) in THF (4 mL) was added dropwise. The reaction was stirred at −78° C. for 2 h, allowed to warm to room temperature and stirred for 18 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with ethyl acetate (10 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined and washed with MgSO 4The mixture was dried at 40° C. and filtered. The solvent was removed under reduced pressure to give a colorless oil. The crude product was purified by chromatography on silica gel (12 g cartridge, eluting with 0-100% EtOAc / isohexane, 100%) to give 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-(thiazol-2-yl)octahydrocyclopenta[c]pyrrol-5-ol (18 mg, 31 μmol, 15% yield) (Example 2) as a white crystalline solid. t 1.29 minutes (method 3); m / z 579.2 (M+H) + (ES + );δH(DMSO-d6,400MHz)δ 8.21(d,J=0.9Hz,1H), 8.03(s,1H), 7.83-7.76(m,2H), 7.64-7.58(m,3H), 7.55(d,J= 3.2Hz,1H), 7.52(d,J=3.2Hz,1H), 7.47-7.40(m,2H), 6.31(s,1H), 3.84(d,J=10.4Hz) ,1H), 3.77-3.67(m,1H), 3.59(dd,J=10.1,7.6Hz,2H), 3.50(s,3H), 3.35(dd,J=10.1 ,3.0Hz,2H), 2.85(d,J=14.1Hz,1H), 2.47-2.40(m,4H), 2.01(dd,J=13.3,8.4Hz,1H).

[0227] Example 3: 2-(3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-methoxy-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)thiazole [ka] To a solution of 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-(thiazol-2-yl)octahydrocyclopenta[c]pyrrol-5-ol (15 mg, 26 μmol) (Example 2) in THF (2 mL) was added sodium hydride (1.6 mg, 60 wt%, 39 μmol) at 0° C. The resulting yellow solution was stirred at 0° C. for 30 minutes before adding iodomethane (7.4 mg, 3.2 μL, 52 μmol). The reaction mixture was stirred at 0° C. for 1.5 hours, allowed to warm to room temperature, and stirred for 18 hours. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with ethyl acetate (10 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined and washed with MgSO 4 The mixture was dried at 40° C. and filtered. The solvent was removed under reduced pressure to give a yellow oil. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give 2-(3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-methoxy-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)thiazole (10 mg, 16 μmol, 63% yield) (Example 3) as a white solid. t 1.47 minutes (method 4); m / z 593.2 (M+H) + (ES + );δH(DMSO-d6,400MHz)δ 8.16(d,J=0.9Hz,1H), 8.13(s,1H), 7.81-7.76(m,2H), 7.68-7.66(m,2H), 7.62(s ,1H), 7.59(d,J=3.2Hz,1H), 7.54(s,1H), 7.46-7.38(m,2H), 3.70(d,J=10.4Hz,1 H), 3.58(s,3H), 3.56-3.48(m,3H), 3.30(1H, under water signal), 3.00(s,3H), 2.95(d,J=14 .2Hz,1H), 2.59(dd,J=13.1,6.9Hz,1H), 2.50(4H, under DMSO signal), 2.05-1.98(m,1H).

[0228] Example 4: 5-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole [ka] To a solution of diethylaminosulfur trifluoride (11 mg, 9.0 μL, 70 μmol) in THF (1 mL) was added a solution of 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol (20 mg, 35 μmol) (Example 10) in THF (1 mL) at −78° C. The resulting colorless solution was stirred at −78° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with ethyl acetate (10 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined and washed with MgSO 4 The mixture was dried at 40° C. and filtered. The solvent was removed under reduced pressure to give a yellow oil. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give 5-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (4.5 mg, 7.8 μmol, 22%) (Example 5) as a white solid. t 1.88 min (method 5); m / z 574.2 (M+H) + (ES +);δH(400MHz,methanol-d4)δ 8.16(d,J=0.9Hz,1H), 7.82-7.76(m,3H), 7.61(d,J=9.7Hz,2H), 7.52(d,J=0.7Hz,1H), 7.48-7.33(m,7H), 3.95-3.85(m,2H), 3.76(d,J= 11.2Hz,1H), 3.66-3.62(m,2H), 3.43(s,3H), 2.97(dd,J=36.3,15.3Hz,1H), 2.64-2.53(m,2H), 2.51(d,J=0.8Hz,3H), 2.35-2.16(m,1H).

[0229] Example 5: 1-(4-fluorophenyl)-5-((3aR,5R,6aS)-5-methoxy-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole Example 6: 1-(4-fluorophenyl)-5-((3aS,5S,6aR)-5-methoxy-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole Example 7: 1-(4-fluorophenyl)-5-((3aR,5S,6aS)-5-methoxy-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole Example 8: 1-(4-fluorophenyl)-5-((3aS,5R,6aR)-5-methoxy-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole [ka] 1-(4-Fluorophenyl)-5-(5-methoxy-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole (512 mg, 0.88 mmol) (Example 11) was dissolved in MeOH with sonication to 41 mg / mL, filtered and then separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210-400 nm, 40° C., 120 bar. The column was a Chiralpak IH 10×250 mm, 5 um, flow rate 15 mL / min, 40% MeOH (0.1% ammonia), 60% CO 2 The main peak was isolated in 35% EtOH (0.1% ammonia), 65% CO 2 A minor peak was isolated at 1.0. Clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator to give 1-(4-fluorophenyl)-5-((3aR,5R,6aS)-5-methoxy-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole (158 mg, 270 μmol, 30.8%) (Example 5) as a white solid. t 1.77 min (method 6); m / z 586.3 (M+H) + (ES + );δH NMR(400MHz,DMSO-d6)δ 8.19(d,J=0.9Hz,1H), 8.17(s,1H), 7.83-7.77(m,2H), 7.70(s,1H), 7.65(d,J=7.1Hz,2H), 7.4 7-7.39(m,2H), 7.28-7.22(m,2H), 7.19(d,J=7.2Hz,3H), 3.67(d,J=10.1Hz,1H), 3.63(s,4H), 3.59-3.53(m,1H), 3.52-3.44(m,1H), 3.22(dd,J=9.7,3.7Hz,1H), 2.94(d,J=14.3Hz,1H), 2.7 4(s,3H), 2.54(s,3H), 2.35-2.26(m,1H), 2.22(d,J=14.2Hz,1H), 2.05(dd,J=13.4,7.5Hz,1H).

[0230] 1-(4-fluorophenyl)-5-((3aS,5S,6aR)-5-methoxy-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole (156 mg, 266 μmol, 30.5%) was obtained as a white solid (Example 6). t 1.77 minutes (method 6); m / z 586.3 (M+H) + (ES + );δH NMR(400MHz,DMSO-d6)δ 8.19(d,J=0.9Hz,1H), 8.17(s,1H), 7.83-7.77(m,2H), 7.70(s,1H), 7.66(s,1H), 7.64(s,1H), 7 .47-7.39(m,2H), 7.28-7.22(m,2H), 7.19(d,J=7.2Hz,3H), 3.68(d,J=10.1Hz,1H), 3.63(s,4H) , 3.60-3.53(m,1H), 3.53-3.44(m,1H), 3.22(dd,J=9.7,3.7Hz,1H), 2.94(d,J=14.2Hz,1H), 2.7 4(s,3H), 2.54(s,3H), 2.35-2.26(m,1H), 2.22(d,J=14.2Hz,1H), 2.05(dd,J=13.4,7.6Hz,1H).

[0231] 1-(4-fluorophenyl)-5-((3aR,5S,6aS)-5-methoxy-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole (1.4 mg, 2.3 μmol, 0.26%) was obtained as a white solid (Example 7). t 1.77 minutes (method 6); m / z 586.3 (M+H) + (ES +);δH NMR(400MHz, methanol-d4)δ 8.16(s,1H), 7.82-7.76(m,3H), 7.64(s,1H), 7.61(s,1H), 7.53(s,1H), 7.44-7.34(m,6H), 7.34-7.28(m,1H), 3.82-3.75(m,2H) , 3.64-3.51(m,3H), 3.47(s,3H), 2.80(s,3H), 2.72-2.66(m,2H), 2.58(dd,J=14.2,2.7Hz,1H), 2.54(s,3H), 2.15-2.06(m,1H).

[0232] 1-(4-fluorophenyl)-5-((3aS,5R,6aR)-5-methoxy-2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole (2.2 mg, 3.6 μmol, 0.41%) was obtained as a white solid (Example 8). t 1.77 minutes (method 6); m / z 586.4 (M+H) + (ES + );δH NMR(400MHz, methanol-d4)δ 8.16(s,1H), 7.82-7.77(m,3H), 7.64(s,1H), 7.61(s,1H), 7.53(s,1H), 7.43-7.30(m,7H), 3.79(d,J=10.9Hz,2H), 3. 65-3.50(m,3H), 3.47(s,3H), 2.80(s,3H), 2.74-2.67(m,2H), 2.58(d,J=16.5Hz,1H), 2.54(s,3H), 2.15-2.05(m,1H).

[0233] Examples 9 to 16 Table 2: The examples shown in the following table were prepared by methods similar to those described for Examples 1 and 2.

[0234] [Table 8-1] [Table 8-2] [Table 8-3]

[0235] Example 17: tert-Butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ka] A 2M solution of phenylmagnesium chloride in THF (8.28 mL, 16.6 mmol) was added to a solution of tert-butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Example 1) (1.55 g, 2.76 mmol) in THF (10 mL) at 0° C. The reaction was stirred at 0° C. for 30 min, after which phenylmagnesium chloride (2M in THF) (2.76 mL, 5.52 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with saturated NH 4 It was quenched with Cl solution (25 mL), the layers were separated and the aqueous layer was then extracted with EtOAc (3×25 mL). The combined organic phases were washed with brine (25 mL) and MgSO 4 The crude product was concentrated onto silica and purified by chromatography on silica gel (80 g cartridge, 0-60% EtOAc / isohexane) to give tert-butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Example 17) (1.34 g, 2.54 mmol, 53.1% yield) as a colorless oil. t 2.32 minutes (method 6); m / z 528.4 (M+H) + (ES +);δH NMR(400MHz,DMSO-d6)δ 8.26(s,1H), 7.85-7.78(m,3H), 7.70(s,1H), 7.45-7.40(m,2H), 7.29-7 .24(m,2H), 7.23-7.18(m,2H), 7.15-7.11(m,1H), 5.40(s,1H), 4.08(d,J 11.0,1H), 3.78-3.70(m,1H), 3.68(d,J 11.0,1H), 3.54-3.49(m,1H), 3.49-3.42(m,1H), 2.89(d,J 14.1,1H), 2.48(s,3H), 2.39-2.32(m,2H), 2.18-2.10(m,1H), 1.38-1.27(m,9H).

[0236] Example 18: 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-methoxy-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-butyl [ka] To a solution of tert-butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-hydroxy-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.34 g, 2.54 mmol) (Example 17) in THF (15 mL) was added sodium hydride (305 mg, 60 wt%, 7.62 mmol) at 0° C. The resulting yellow solution was stirred at 0° C. for 30 min before adding methyl iodide (1.44 g, 635 μL, 10.2 mmol). The reaction mixture was allowed to warm to 20° C. and stirred for 17 h. The reaction mixture was diluted with saturated NH 4 It was quenched with aqueous Cl (25 mL), the layers were separated, and the aqueous layer was then extracted with EtOAc (3×25 mL). The combined organic phases were washed with brine (25 mL) and MgSO 4The crude product was dried at 70° C., filtered and concentrated in vacuo. The crude product was redissolved in DCM, concentrated onto silica and purified by chromatography on silica gel (40 g gold cartridge, 0-20% (3:1 EtOAc / EtOH) / isohexane) to give tert-butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-methoxy-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.30 g, 2.4 mmol, 79% yield) (Example 18) as a pale yellow solid. R t 2.55 minutes (method 6); m / z 542.5 (M+H) + (ES + ). δ 8.22(s,1H), 7.79(dd,J=8.7,4.9Hz,2H), 7.71(d,J=13.0Hz,2H), 7.42(t,J=8.8Hz,2H), 7.31-7.15(m,5H), 3.91(d,J=11.5Hz,1H), 3.71(d,J=1 1.1Hz,2H), 3.45(d,J=10.1Hz,1H), 2.98(d,J=14.2Hz,1H), 2.92(s,3H) , 2.55(s,3H), 2.47-2.38(m,3H), 2.29-2.17(m,1H), 1.39-1.24(m,9H).

[0237] Example 19: 1-(4-fluorophenyl)-5-(5-methoxy-2-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole [ka] tert-Butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-methoxy-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.30 g, 2.4 mmol) (Example 18) was separated by chiral SFC on a Waters prep 100 at 40° C. with PDA at 40° C. and 120 bar as well as UV detection over all wavelengths with QDA. The column was a Phenomenex Lux® 5 μM amylose-1 LC column 250×50 mm, packed with AXIA™, flow rate 65 mL / min, 25% MeOH / MeCN (0.03% ammonia, 75% CO 2 ) to give tert-butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-methoxy-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (535 mg, 988 μmol, 32.8%) (Intermediate E) as an off-white partial solid. t 2.58 minutes (method 6); m / z 542.5 (M+H) + (ES + ).

[0238] [ka] Zinc bromide (2.440 g, 10.83 mmol) was added to a solution of tert-butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-methoxy-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1630 mg, 2.708 mmol) in DCM (60 mL) (Intermediate E). The suspension was sonicated for 1 min, then the cloudy reaction mixture was stirred vigorously at 20° C. for 7 h with intermittent sonication. The reaction mixture was treated with DCM (30 mL), excess saturated sodium bicarbonate solution (60 mL 0.9 M). The mixture was agitated by sonication, spatula, and stirring to ensure dissolution of all reaction precipitates. The mixture was passed through a phase separation cartridge directly onto a pre-wetted SCX column with DCM, and the mixture was transferred onto the column by vacuum. Once loaded, the column was washed with MeOH (100 mL) and eluted using a 0.7 M ammonia / MeOH solution. The eluate was concentrated under reduced pressure to give 1-(4-fluorophenyl)-5-(5-methoxy-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole 54 mg, 1.9 mmol, 71%) (Intermediate F) as a brown gum. t 1.56 min (method 6); m / z 442.5 (M+H) + (ES + ).

[0239] Example 19: 1-(4-fluorophenyl)-5-(5-methoxy-2-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole [ka] To a solution of 1-(4-fluorophenyl)-5-(5-methoxy-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole (Intermediate F) (19.0 mg, 33.6 μmol) in DCM (0.50 mL) was added N-ethyl-N-isopropylpropan-2-amine (30.0 μL, 172 μmol) followed by 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride (12.2 mg, 67.1 μmol). The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with aqueous (1 mL). The layers were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The combined organic phases were dried on a hydrophobic frit and concentrated in vacuo. The crude product was purified by preparative HPLC (Waters, basic (0.1% aqueous ammonia), basic, Waters XBridge BEH C18 ODB prep column, 50-80% MeCN / water). The fractions were dissolved in MeCN, concentrated in vacuo and dried in a desiccator for 1 h to give 1-(4-fluorophenyl)-5-(5-methoxy-2-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole (Example 19) (11 mg, 18 μmol, 53% yield) as an off-white solid. R t 2.23 minutes (method 6); m / z 587.3 (M+H) + (ES + );δH(DMSO-d6,400MHz)δ 8.20(d,J=0.9Hz,1H), 8.08(s,1H), 7.84-7.77(m,2H), 7.65(s,1H), 7.57(s,1H) ), 7.48-7.40(m,2H), 7.30-7.22(m,2H), 7.22-7.16(m,3H), 3.92-3.69(m,6H), The 3.52-3.36 (m, 2H), 2.96 (d, J = 14.4 Hz, 1H), 2.80 (s, 3H), 2.52 (s, 3H), 2.41-2.31 (m, 1H), 2.23 (d, J = 14.3 Hz, 1H), and 2.11 (dd, J = 13.3, 8.7 Hz, 1H) rotamers were revealed.

[0240] Example 20: (3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-methoxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(phenyl)methanone [ka] To a solution of 1-(4-fluorophenyl)-5-(5-methoxy-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole (25.0 mg, 48.7 μmol) (Intermediate F) in DCM (0.50 mL) was added N-ethyl-N-isopropylpropan-2-amine (31.5 mg, 42.4 μL, 243 μmol) followed by benzoyl chloride (13.7 mg, 97.4 μmol). The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with aqueous solution (1 mL). The layers were separated and the aqueous layer was extracted with DCM (3×1 mL). The combined organic phases were dried through a hydrophobic frit and concentrated in vacuo to give (3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-methoxy-5-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(phenyl)methanone (10.71 mg, 19 μmol, 38%) (Example 20) as a white solid. t 2.43 minutes (method 4); m / z 546.4 (M+H) + (ES + ).

[0241] Examples 21 to 33 Table 3: The examples shown in the following table were prepared by methods similar to those described for Examples 19 and 20.

[0242] [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5]

[0243] Example 34: 1-(4-fluorophenyl)-5-(5-methoxy-2-(methylsulfonyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole [ka] Sodium borohydride (2.7 mg, 70 μmol) was added to a solution of 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-(methylsulfonyl)hexahydrocyclopenta[c]pyrrol-5(1H)-one (prepared using the same method as in Example 2) (20 mg, 47 μmol) in DCM (1 mL) and the reaction was stirred overnight. The reaction mixture was quenched with 1M HCl (10 mL) and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-80% EtOAc / isohexane) to give an 89:11 distereomeric mixture of 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-ol (Intermediate G) (20 mg, 46 μmol, 99% yield) as a white solid, as a major and minor pair of diastereoisomers. t 1.30 min (major) and 1.27 min (minor) (Method 1); m / z 430.7 (M+H) + (ES + ).

[0244] Example 34: 1-(4-fluorophenyl)-5-(5-methoxy-2-(methylsulfonyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole [ka] Sodium hydride (2.8 mg, 60 wt%, 70 μmol) was added to a solution of 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-ol (Intermediate G) (20 mg, 47 μmol) in THF (1 mL) at 0 °C and the mixture was stirred for 30 min. Methyl iodide (7.9 mg, 3.5 μL, 56 μmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was then quenched with water (10 mL). The aqueous phase was extracted with EtOAc (3 × 15 mL) and the combined organics were washed with MgSO 4 The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to give a 9:1 diastereomeric mixture, 1-(4-fluorophenyl)-5-(5-methoxy-2-(methylsulfonyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-6-methyl-1H-indazole (Example 34) (7.0 mg, 15 μmol, 33% yield) as a white solid. t 1.53 min (major) and 1.50 min (minor) (Method 1); m / z 444.4 (M+H) + (ES +);δH(DMSO-d6,500MHz) (Main diastereomer data) 8.27(d,J 0.9,1H), 7.82-7.77(m,3H), 7.69(s,1H), 7.45-7.40(m,2H), 3.86(d,J 9.9,1H), 3.74(p,J 7.2,1H), 3.63(dd,J 9.7,7.5,1H), 3.41(d,J 10.0,2H), 3.30(d,J 4.4,1H), 3.20(s,3H), 2.81(s,3H), 2.52(s,3H), 2.42(dt,J 13.9,7.3,1H), 2.31(dd,J 13.4,7.3,1H), 2.22(dd,J 13.4,7.2,1H), 1.64(dt,J 13.0,7.4,1H).

[0245] Example 35: tert-Butyl 5-(benzyloxy)-3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ka] This compound was prepared by a method similar to that described for Example 34 to give tert-butyl 5-(benzyloxy)-3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (6 mg, 0.01 mmol, 20%) (Example 35) as a white solid. Rt 2.44 min (Method 4); m / z 542.4 (M+H)+ (ES+). δH(DMSO-d6,500MHz)δ 8.25(s,1H), 7.82-7.76(m,2H), 7.73(s,1H), 7.67(s,1H), 7.42(t,J 8.8,2H), 7.32(m,4H), 7.27(td,J 6.0,2.5,1H), 4.44(s,2H), 4.01(p,J 7.0,1H), 3.91-3.85(m,1H), 3.74-3.69(m,1H), 3.58-3.51(m,1H), 3.44-3.34(m,1H), 3.30-3.21(m,1H), 2.44(dt,J) 13.8, 7.2, 1H), 2.31 (d, J 7.1, 2H), 1.74-1.64 (m, 1H), 1.40-1.25 (br.m, 9H). The CH3 peak is below the DMSO-d6 signal.

[0246] Examples 36 and 37: 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole [ka] DIAD (104 μL, 536 μmol) was added to a solution of tert-butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (220 mg, 487 μmol) (prepared using the same method as intermediate G using intermediate A), phenol (59.6 mg, 633 μmol), and triphenylphosphine (153 mg, 585 μmol) in toluene (3 mL) at 0° C., and the mixture was stirred at room temperature overnight. Phenol (59.6 mg, 633 μmol), DIAD (104 μL, 536 μmol), and triphenylphosphine (153 mg, 585 μmol) were added, and the reaction was stirred for 2 hours. The reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organics were washed with saturated NaHCO 3 Wash with aqueous solution (20 mL) of MgSO 4 The crude product was purified by chromatography on silica gel (12 g cartridge, 0-30% EtOAc / isohexane) to give a 93:7 diastereomeric mixture, tert-butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Intermediate H) (309 mg, 0.48 mmol, 99% yield) as an off-white solid. t 2.09 min (major) and 2.14 min (minor); (Method 1); m / z 528.8 (M+H) + (ES + ).

[0247] Example 36: 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole Example 37: 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole [ka] HCl (4 molar, 0.19 mL, 0.76 mmol) was added to a solution of tert-butyl 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (137 mg, 260 μmol) (Intermediate H) in 1,4-dioxane (4 mL) and the reaction mixture was stirred for 1 h. The reaction was concentrated in vacuo and the residue was taken up in pyridine (0.1 mL, 1.3 mmol) and DCM (3 mL). Methanesulfonyl chloride (44.6 mg, 30.1 μL, 389 μmol) was added and the mixture was stirred at room temperature for 2 h. Water (10 mL) and DCM (10 mL) were added, the layers were separated and the organic layer was washed with water (10 mL) and MgSO 4 The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to give 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole (28 mg, 54 μmol, 21%), which was dissolved in DCM:MeOH by sonication to 50 mg / mL, filtered, and then separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210-400 nm, 40° C., 120 bar. Column: IH 10×250 mm, 5 um, flow rate 15 mL / min, 40% MeOH (neutral), 60% CO 2Clean fractions were pooled, rinsed with methanol and concentrated to dryness using a rocket evaporator at 40° C. The residue was redissolved in methanol:DCM, transferred to a final vial and evaporated on a Biotage V10. The sample was then further dried overnight in a vacuum oven at 30° C. / 5 mbar to give isomer 1, 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole (3.3 mg) (Example 36) (R t 1.86 min (method 5); m / z 506.4 (M+H) + (ES + )) and 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole 3.4 mg) (Example 37) (R t 1.86 min (method 5); m / z 506.4 (M+H) + (ES + )) was obtained.

[0248] Examples 38 to 45 Table 4: The examples shown in the following table were prepared by methods similar to those described for Examples 36 and 37.

[0249] [Table 10-1] [Table 10-2] [Table 10-3]

[0250] Example 46: 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole [ka] Phenylmagnesium chloride (2M in THF) (38.4 mg, 140 μL, 281 μmol) was added to a solution of 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-(methylsulfonyl)hexahydrocyclopenta[c]pyrrol-5(1H)-one (100 mg, 234 μmol) (prepared using the same method as in Example 2) in THF (1 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was diluted with H 2 The mixture was quenched with O (10 mL) and the layers were separated. The aqueous phase was extracted with DCM (3 x 10 mL) and the combined organics were washed with MgSO 4 The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to give a 96.5:3.55 diastereomeric mixture, 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-(methylsulfonyl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol (34 mg, 65 μmol, 28%) (Intermediate I) as a colorless gum. t 1.86 min (method 5); m / z 506.4 (M+H) + (ES + ).

[0251] [ka] HCl (4 M in dioxane) (25 mg, 0.17 mL, 4.00 mol, 0.67 mmol) was added to a solution of 3a-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-(methylsulfonyl)-5-phenyloctahydrocyclopenta[c]pyrrol-5-ol (34 mg, 67 μmol) (Intermediate I) in 1,4-dioxane (0.5 mL) and the reaction was stirred for 2 h. The reaction was concentrated in vacuo and the crude product purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to give an inseparable mixture of 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenyl-2,3,6,6a-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole and 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenyl-2,3,4,6a-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole (30 mg, 29 μmol, 43%) (Intermediate J) as a colourless glass. t 1.86 min and 1.86 min (Method 1); m / z 488.8 (M+H) + (ES + ).

[0252] Example 46: 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole [ka] 10% Palladium on carbon (15 mg, 5.5 μmol) was added to a solution of 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenyl-2,3,6,6a-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole and 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenyl-2,3,4,6a-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole (27 mg, 28 μmol) in EtOH (1 mL) and the reaction mixture was stirred under a hydrogen atmosphere (5 bar) overnight. The reaction was filtered through Celite and concentrated in vacuo to give a 1:1 diastereomeric mixture, 1-(4-fluorophenyl)-6-methyl-5-(2-(methylsulfonyl)-5-phenylhexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-1H-indazole (24 mg, 47 μmol, 84%) as an off-white foam. t 1.84 min and 1.85 min (Method 1); m / z 506.4 (M+H) + (ES + ).

[0253] Example 47: (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol [ka] Intermediate K: 1-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1H-pyrrole-2,5-dione 1-Benzyl-3-bromo-1H-pyrrole-2,5-dione (2.11 g, 7.94 mmol), 1-(4-fluorophenyl)-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (2.33 g, 6.62 mmol) (Intermediate B), and potassium phosphate tribasic (2.81 g, 13.2 mmol) were dissolved in 1,4-dioxane (30 mL) and water (6 mL). The mixture was purged with nitrogen for 5 min. PdCl 2 (dppf)-CH 2 Cl 2 The adduct (270 mg, 331 μmol) was added and the mixture was purged with nitrogen for an additional 5 min before being heated to 80° C. overnight. The reaction was cooled, diluted with EtOAc (60 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried using sodium sulfate and concentrated to give a dark brown oil. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-30% EtOAc / isohexane) to give 1-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1H-pyrrole-2,5-dione (1.44 g, 3.3 mmol, 50%) as a bright yellow solid. Rt 2.19 min (Method 7); m / z 412.2 (M+H)+ (ES+). δH (400 MHz, DMSO-d 6 )8.44(d,J=0.9Hz,1H), 8.07(s,1H), 7.87-7.78(m,2H), 7.76(s,1H), 7.50-7.25(m,7H), 7.13(s,1H), 4.71(s,2H), 2.52(s,3H).

[0254] [ka] To a solution of 1-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1H-pyrrole-2,5-dione (1444 mg, 3.51 mmol) in toluene (25 mL) was added 15% ethyl 2-diazoacetate / toluene solution (8.1 g, 8.9 mL, 10.53 mmol) and the reaction was heated to 100° C. for 18 h. The solvent was removed in vacuo and the residual solid was purified by chromatography on silica gel (80 g cartridge, 0-25% EtOAc / isohexane) to give ethyl 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (1210 mg, 2.3 mmol, 64%) as a yellow solid. Rt 2.26 min (Method 7); m / z 498.2(M+H)+(ES+).

[0255] [ka] To a solution of ethyl 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (3.54 g, 5.62 mmol) in 1,4-dioxane (50 mL) was added DIBAL-H (1 M hexane solution) (8.5 g, 60 mL, 60 mmol) slowly at 0° C. The reaction mixture was stirred overnight while warming to room temperature. The reaction mixture was cooled to 0° C. and quenched with 2 M NaOH solution (5 mL) followed by water (6 mL). The reaction mixture was stirred for 15 minutes while warming to room temperature. Na 2 SO 4was added and stirring was continued for 15 min. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-10% (0.7 M ammonia / MeOH) / DCM) to give two separate enantiomeric pairs, (3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (437 mg, 0.61 mmol, 11%) (Intermediate M) (Rt 1.35 min (Method 7); m / z 428.4 (M+H)+(ES+)) as an off-white solid, and (3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (1.33 g, 2.8 mmol, 50%) (Intermediate N) (Rt 1.3 min (Method 7); m / z 428.3 (M+H)+(ES+)) was obtained. δH (400 MHz, DMSO-d 6 )δ 8.24-8.19(m,1H), 7.80-7.74(m,2H), 7.70(s,1H), 7.61-7.54(m,1H), 7.41(t,J=8.8Hz,2H) , 7.34-7.19(m,5H), 4.32(t,J=5.1Hz,1H), 3.68-3.52(m,2H), 3.37(d,J=8.7Hz,1H), 3.19-3 .08 (m, 1H), 3.03 (d, J = 8.6 Hz, 1H), 2.96-2.78 (m, 1H), 2.70-2.56 (m, 1H), 2.45 (s, 1H), 2.23 (d, J = 8.5 Hz, 1H), 1.95-1.85 (m, 1H), 1.78-1.71 (m, 1H) - One CH was obscured by DMSO and no OH was observed.

[0256] [ka] (3-Benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (535 mg, 1.25 mmol) (Intermediate N) was dissolved in EtOH (20 mL) and treated with 10% palladium on carbon (133 mg, 1.25 mmol). The mixture was purged with nitrogen (3 times) then hydrogen (3 times) before being hydrogenated at 5 atmospheres for 4 hours. The reaction was heated to 60° C. and stirred overnight. The sample was cooled and continued to stir under hydrogen for a further 48 hours. The catalyst was removed by filtration and washed with EtOH (20 mL). The solvent was removed in vacuo to give (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (428 mg, 1.27 mmol, 101%) as a hazy glass. Rt 1.07 min (90%) and 1.12 min (10%) (Method 7); m / z 428.3 (M+H)+ (ES+).

[0257] Example 47: (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol [ka] A solution of (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (425 mg, 1.26 mmol) in DCM (10 mL) was treated with triethylamine (191 mg, 263 μL, 1.89 mmol) and 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride (274 mg, 1.51 mmol). The reaction was stirred for 60 min. The reaction was diluted with DCM (10 mL) and water (2 mL) and the phases separated. The aqueous layer was washed with DCM (10 mL) and the combined organic layers were concentrated in vacuo to give a colorless glass. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (350 mg, 700 μmol, 55.6%, 96.5% pure) (Example 47) (Rt 1.79 min (Method 7); m / z 483.3 (M+H)+ (ES+). δH (400 MHz, DMSO-d 6, VT90)δ 8.20(m,2H), 7.80-7.62(m,3H), 7.62-7.55(m,1H), 7.45-7.33(m,2H), 4.35-4.13(m ,3H), 3.96(m,1H), 3.65(m,2H), 3.17(m,2H), 2.93(m,1H), 2.52(m,3H), 2.26(m,1H) , 2.05 (m, 1H), 1.38 (m, 1H)), and (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl 2-methyl-2H-1,2,3-triazole-4-sulfonate (75 mg, 96 μmol, 7.6%) (Intermediate P) (Rt 2.04 min (Method 7); m / z 627.2 (M+H)+(ES+)) as a colorless gum.

[0258] Example 48: (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol [ka] This compound was prepared by a method similar to that described for Example 47 using intermediate M to give (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (4.3 mg, 8.5 μmol, 14%) (Example 48). Rt 1.81 min (Method 7); m / z 483.6 (M+H)+ (ES+). δH(DMSO-d6,400MHz)δ 8.22-8.20(m,2H), 7.79-7.70(m,3H), 7.54(s,1H), 7.38(t,J=8.8Hz,2H), 4.51(t,J=5.3Hz,1H), 4.28(s,3H) ), 3.88-3.73(m,4H), 3.62(m,1H), 3.37(m,1H), 2.30(s,3H), 2.08(dd,J=8.7,5.1Hz,1H), 1.55-1.45(m,1H).

[0259] Example 49: 1-(4-fluorophenyl)-6-methyl-5-(3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-6-(phenoxymethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole [ka] A solution of (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl 2-methyl-2H-1,2,3-triazole-4-sulfonate (80 mg, 0.13 mmol) (Intermediate P) in THF (3 mL) was treated with sodium phenolate (30 mg, 0.25 mmol) and stirred at room temperature for 24 h. The reaction was heated to 60° C. for 18 h. The reaction was diluted with DCM (15 mL) and water (5 mL). The phases were separated and the organic phase was concentrated to dryness. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give 1-(4-fluorophenyl)-6-methyl-5-(3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-6-(phenoxymethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (16 mg, 29 μmol, 22%) as a white solid. Rt 2.30 min (Method 7); m / z 559.3 (M+H)+(ES+). δH (400 MHz, DMSO-d 6, VT90)8.20(m,2H), 8.01-7.65(m,3H), 7.57(s,1H), 7.46-7.31(m,2H), 7.18(m,2H), 6.79(m,3H), 4.26(s,3H), 4.0 5(m,1H), 3.88(m,1H), 3.70(s,3H), 3.54(m,1H), 3.24(m,1H), 3.04(m,1H), 2.59(m,1H), 2.28(m,1H), 1.66(s,1H).

[0260] Example 50: 1-(4-fluorophenyl)-6-methyl-5-(3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-6-((pyridin-2-yloxy)methyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole [ka] A solution of (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (150 mg, 311 μmol) (Intermediate N) was dissolved in DCM (8 mL) and cooled to 0° C. before adding triethylamine (94.4 mg, 130 μL, 933 μmol) and methanesulfonyl chloride (107 mg, 72.7 μL, 933 μmol). The reaction was allowed to warm to room temperature overnight. The reaction was diluted with DCM (10 mL) and washed with water before passing through a phase separation cartridge. The organic phase was concentrated to dryness to give (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl methanesulfonate (160 mg, 285 μmol, 91.8%) (Intermediate Q) as a colorless gum. Rt 1.92 min (Method 7); m / z 561.3 (M+H)+ (ES+).

[0261] Example 50: 1-(4-fluorophenyl)-6-methyl-5-(3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-6-((pyridin-2-yloxy)methyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole [ka] A solution of (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl methanesulfonate (90 mg, 0.16 mmol) (Intermediate Q) in DMF (3 mL) was treated with cesium fluoride (80 mg, 0.53 mmol) and pyridin-2-ol (31 mg, 0.32 mmol) and stirred at room temperature for 24 hours. The reaction was heated to 50° C. for 16 hours. The reaction was treated with pyridin-2-ol (31 mg, 0.32 mmol) and cesium fluoride (80 mg, 0.53 mmol) and continued stirring at 80° C. for 4 hours. The reaction was cooled, diluted with water (10 mL) and the solid collected by filtration to give a cream solid. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give 1-(4-fluorophenyl)-6-methyl-5-(3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-6-((pyridin-2-yloxy)methyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (6 mg, 0.01 mmol, 7%) as a white solid. Rt 1.84 min (Method 7); m / z 560.1 (M+H)+(ES+). δH (400 MHz, DMSO-d 6, VT90)8.25(d,J=0.9Hz,1H), 8.18(s,1H), 7.83-7.71(m,3H), 7.62(s,1H), 7.46-7.31(m,3H), 7.26(m,1H), 6.34(m,1H), 6.13( m,1H), 4.26(s,3H), 4.00(m,1H), 3.76(m,1H), 3.64(m,1H), 3.56(m,1H), 3.20(m,2H), 2.50(s,3H), 2.35(m,1H), 1.66(m,1H).

[0262] Example 51: 1-(4-fluorophenyl)-5-(6-(isopropoxymethyl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-6-methyl-1H-indazole [ka] A solution of (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl methanesulfonate (85 mg, 0.15 mmol) (Intermediate Q) in THF (3 mL) was treated with sodium propan-2-olate (0.12 g, 1.5 mmol) and stirred at room temperature for 24 h. The reaction was heated to 60° C. for 4 h. DMF (2 mL) was added and the reaction was heated to 70° C. overnight. The temperature was increased to 100° C. and continued to stir overnight. The reaction was cooled, diluted with water (10 mL) and the solid was collected by filtration to give a cream colored solid. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give 1-(4-fluorophenyl)-5-(6-(isopropoxymethyl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-6-methyl-1H-indazole (10 mg, 19 μmol, 13%) as a white solid. Rt 2.04 min (Method 7); m / z 525.1 (M+H)+ (ES+).

[0263] Example 52: 5-(6-((4-chlorophenoxy)methyl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole Example 53: 5-(6-((4-chlorophenoxy)methyl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole [ka] A solution of (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (90 mg, 0.19 mmol) (Intermediate N) in THF (4 mL) was treated with 4-chlorophenol (36 mg, 0.28 mmol), triphenylphosphine (73 mg, 0.28 mmol) followed by DIAD (57 mg, 54 μL, 0.28 mmol) and the mixture was stirred for 16 h. The mixture was diluted with DCM (10 mL) and washed with water (5 mL). The organic phase was concentrated in vacuo to give a colourless gum. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-20% EtOAc / isohexane) then dissolved in MeOH / THF to 12 mg / mL, filtered and then separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210-400 nm, 40° C., 120 bar. Column: A1 10×250 mm, 5 um, flow rate 15 mL / min, 45% IPA (0.03% ammonia), 55% CO 2Clean fractions were pooled, rinsed with MeOH / THF and concentrated to dryness using a rotary evaporator. The residue was redissolved in MeOH / THF, transferred to a final vial and evaporated on a Biotage V10. The sample was then further dried overnight in a vacuum oven at 30° C. / 5 mbar to give 5-(6-((4-chlorophenoxy)methyl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (11 mg, 18 μmol, 9.8%) (Example 52) (Rt 2.42 min (Method 7); m / z 593.7 (M+H)+(ES+)) to give 5-(6-((4-chlorophenoxy)methyl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (12 mg, 20 μmol, 11%) (Example 53) (Rt 2.42 min (Method 7); m / z 593.7 (M+H)+(ES+)) as a colorless glass.

[0264] Example 54: 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(5-fluoropyridin-2-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide [ka] To a solution of (3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (1.25 g, 59%, 1.73 mmol) (Intermediate N) in acetone (10.5 mL) was added a solution of chromium(VI) oxide (690 mg 6.90 mmol) and sulfuric acid (1.18 g, 644 μL, 12.1 mmol) in water (6.5 mL) at 0° C. The reaction mixture was stirred overnight while warming to room temperature. The reaction mixture was diluted with saturated NaHCO 3The mixture was quenched with aqueous solution of MgSO, and the excess chromium was removed by filtration and washed with EtOAc (50 mL) and water (50 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (2×50 mL). The combined organic layers were diluted with MgSO 4 The mixture was dried using HCl, filtered and concentrated under reduced pressure. The aqueous layer was reacidified with 1M HCl solution and further extracted with EtOAc (3×50 mL). The combined organic layers were washed with MgSO 4 The mixture was dried using hexanes, filtered and concentrated under reduced pressure. The crude products were combined and purified by chromatography on silica gel (24 g cartridge, 0-10% MeOH / DCM) to give 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (349 mg, 0.71 mmol, 41%) as a yellow glass. Rt 1.33 min (Method 7); m / z 442.4 (M+H)+ (ES+).

[0265] [ka] To a solution of 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (157 mg, 320 μmol) in DCM (2 mL) was added HATU (134 mg, 352 μmol) and DIPEA (137 mg, 184 μL, 1.06 mmol) and the reaction mixture was stirred at room temperature for 5 min. Then 5-fluoropyridin-2-amine (43 mg, 0.38 mmol) was added and stirring was continued for 2 h. DCM was removed under reduced pressure and the crude material was redissolved in DMF (2 mL). The reaction mixture was heated at 60° C. for 18 h. The reaction mixture was diluted with DCM (10 mL) and washed with water (3×10 mL) and brine (10 mL). The organic layer was removed by filtration using MgSO 4The mixture was dried using a hexanes water bath, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(5-fluoropyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (117 mg, 0.19 mmol, 61%) as a yellow solid. Rt 1.48 min (Method 7); m / z 536.4 (M+H)+ (ES+).

[0266] Example 54: 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(5-fluoropyridin-2-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide [ka] This compound was prepared by a method similar to that described for Example 47 using intermediate S to give 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(5-fluoropyridin-2-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (28.03 mg, 45 μmol, 67%) (Example 54). Rt 2.03 min (Method 7); m / z 591.6 (M+H)+ (ES+). δH(DMSO-d6,400MHz)δ 11.14-10.79(m,1H), 8.46-8.05(m,3H), 7.86-7.65(m,4H), 7.63-7.31(m,4H), 4.39-4.20(m,3H), 4.12-3. 95(m,1H), 3.87-3.47(m,2H), 3.18-3.04(m,1H), 2.92-2.61(m,2H), 2.48-2.45(m,2H), 2.18-2.07(m,1H).

[0267] Example 55: (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)(pyrrolidin-1-yl)methanone [ka] To a solution of 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (30 mg, 52 μmol) (prepared using a method similar to that described for Example 47 using intermediate R) and DIPEA (13 mg, 18 μL, 0.10 mmol) in DCM (0.5 mL) was added COMU (27 mg, 62 μmol). The reaction mixture was stirred at room temperature for 5 minutes, after which pyrrolidine (4.1 mg, 4.8 μL, 57 μmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated onto silica gel and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)(pyrrolidin-1-yl)methanone (6.65 mg, 11 μmol, 22%) as a white solid. Rt 1.98 min (Method 7); m / z 550.2 (M+H)+(ES+). δH(DMSO-d6,400 MHz) δ 8.24(s,1H), 8.18(d,J=1.0Hz,1H), 7.78-7.70(m,2H), 7.55-7.48(m,2H), 7.3 8(t,J=8.8Hz,2H), 4.28(s,3H), 3.97(d,J=10.4Hz,1H), 3.81-3.71(m,3H), 3.6 3-3.49(m,1H), 3.32(d,J=10.2Hz,1H), 3.24-3.13(m,1H), 2.62-2.57(m,1H), 2 .35-2.29(m,4H), 2.10(d,J=4.0Hz,1H), 2.04-1.94(m,2H), 1.86-1.73(m,2H).

[0268] Example 56: 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(5-fluoropyridin-2-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide Example 57: 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(5-fluoropyridin-2-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide [ka] 1-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(5-fluoropyridin-2-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (75 mg, 42 μmol) (Example 54) was dissolved in DCM / MeOH / DMSO with sonication to 11 mg / mL, filtered and then separated by chiral SFC on a Sepiatec with UV detection by DAD at 220 nm, 40° C., 120 bar. The column was a Chiralpak IC 10×250 mm, 5 um, flow rate 20 mL / min, 55% MeOH / (0.1% ammonia), 45% CO 2Clean fractions were pooled, rinsed with methanol / DCM and concentrated to dryness using a rocket evaporator at 40° C. The residue was redissolved in methanol / DCM, transferred to a final vial and evaporated on a Biotage V10. The sample was then further dried overnight in a vacuum oven at 30° C. / 5 mbar to give 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(5-fluoropyridin-2-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (0.99 mg, 1.6 μmol, 3.0%) Example 56 (Rt 2.02 min (Method 7); m / z 591.5 (M+H)+ (ES+). δH(400 MHz, MeOD) δ 8.28-7.99(m,3H), 7.88-7.64(m,4H), 7.58-7.27(m,4H), 4.38-4.27(m,3H), 4.23(d,J=9.7Hz,1H), 3. 96-3.79(m,2H), 3.76-3.42(m,1H), 3.28(d,J=9.8Hz,1H), 2.90-2.62(m,2H), 2.57(s,2H), 2.32(s,1H) ), and 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(5-fluoropyridin-2-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (2.24 mg, 3.0 μmol, 5.7%) as an off-white solid Example 57 (Rt 2.02 minutes (method 7); m / z 591.6(M+H)+(ES+);δH(400MHz,MeOD)δ 8.28-7.99(m,3H), 7.88-7.64(m,4H), 7.58-7.27(m,4H), 4.38-4.27(m,3H), 4.23(d,J=9.7Hz,1H), 3.96- 3.79(m,2H), 3.76-3.42(m,1H), 3.28(d,J=9.8Hz,1H), 2.90-2.62(m,2H), 2.57(s,2H), 2.32(s,1H)) were obtained.

[0269] Examples 58 to 67 Table 5: The examples shown in the following table were prepared by methods similar to those described for Examples 54 and 55.

[0270] [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4]

[0271] Example 68: 3-Acetyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(5-fluoropyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide [ka] This compound was prepared in a manner similar to that described for Example 20 using Intermediate S to give 3-acetyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(5-fluoropyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (11.59 mg, 23 μmol). t 1.74 minutes (method 7); m / z 488.4 (M+H) + (ES + ).

[0272] Example 69: 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole [ka] A solution of hydrazine monohydrate (4.25 g, 4.16 mL, 84.8 mmol) in EtOH (30 mL) was treated dropwise over 10 min with benzaldehyde (3.00 g, 2.87 mL, 28.3 mmol). The mixture was stirred for 60 min and treated with water (20 mL). Ethanol was removed under reduced pressure. The aqueous phase was extracted with DCM (3×40 mL). The combined organics were dried using sodium sulfate and concentrated in vacuo to give (Z)-benzylidenehydrazine (3 g, 0.02 mol, 90%) as a pale yellow oil. A solution of benzylidenehydrazine (5.00 g, 41.6 mmol) in 1,4-dioxane (200 mL) was cooled to 15° C. and treated dropwise over 10 min with manganese(IV) oxide (14.5 g, 166 mmol). Cooling was removed and the reaction was allowed to warm to 20° C. over approximately 30 minutes, upon which point the reaction was filtered through a glass fiber filter pad into a cooled receiver flask (ice bath) to give a deep red / orange solution. 1-Benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1H-pyrrole-2,5-dione (6.85 g, 16.6 mmol) (Intermediate T) was added and the reaction was stirred overnight. The reaction was concentrated in vacuo and the crude product purified by chromatography on silica gel (220 g cartridge, 0-40% EtOAc / isohexane) to give a mixture of the major and minor enantiomeric pairs, 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-phenyl-3-azabicyclo[3.1.0]hexane-2,4-dione (7.87 g, 15 mmol, 90%) as an off-white solid. Rt 2.35 min (80%) 2.38 min (20%) (Method 7); m / z 502.5 (M+H)+ (ES+).

[0273] [ka] To a solution of 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-phenyl-3-azabicyclo[3.1.0]hexane-2,4-dione (3.81 g, 7.60 mmol) and 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-phenyl-3-azabicyclo[3.1.0]hexane-2,4-dione (4.07 g, 8.11 mmol) in 1,4-dioxane (100 mL) was slowly added DIBAL-H (1 molar heptane solution) (14.2 g, 100 mL, 100 mmol) at 0° C. The resulting mixture was stirred overnight while warming to room temperature. The reaction mixture was cooled to 0° C. and quenched with 2M NaOH solution (8 mL) followed by water (10 mL). The reaction mixture was allowed to stir at room temperature for 15 minutes and then Na 2 SO 4The mixture was dried at 70° C. for 15 min. After stirring at room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (120 g gold cartridge, 0-50% EtOAc / isohexane) to give 5-(3-benzyl-6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (1.61 g, 3.3 mmol, 21%) (Intermediate V) (Rt 1.77 min (Method 7); m / z 474.5(M+H)+(ES+). 8.29(s,1H), 7.98(s,1H), 7.86-7.76(m,2H), 7.63(s,1H), 7.50-7.28(m,7H), 7.12-6.99(m,3H), 6.52- 6.40(m,2H), 3.36(d,J=3.3Hz,2H), 3.10(d,J=9.3Hz,1H), 3.01(d,J=9.2Hz,1H), 2.90(dd,J=9.3,3.7Hz , 1H), 2.64 (s, 3H), 2.61 (d, J = 9.2 Hz, 1H), 2.40 (d, J = 8.4 Hz, 1H), 2.12 (dd, J = 8.5, 3.5 Hz, 1H)), and 5-(3-benzyl-6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (3.41 g, 6.8 mmol, 44%) (Intermediate U) as a white solid (Rt 1.63 min (Method 7); m / z 474.1 (M+H)+ (ES+). δH (DMSO-d6, 400 MHz) δ 8.28(s,1H), 7.96(s,1H), 7.76-7.67(m,2H), 7.44-7.30(m,8H), 7.29-7.23(m,1H), 7.00-6.88(m,2H), 6.84-6.77(m,2H), 3.78-3.61( m,2H), 3.51(d,J=8.9Hz,1H), 3.20(d,J=8.8Hz,1H), 2.91(d,J=3.9Hz,1H), 2.83-2.75(m,1H), 2.40(d,J=8.4Hz,2H), 2.13(s,3H)).

[0274] [ka] To a solution of 5-(3-benzyl-6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (3.41 g, 6.8 mmol) (Intermediate U) in methanol (50 mL) was added palladium on carbon (766 mg, 10 wt%, 720 μmol). The reaction mixture was heated at 50° C. under a hydrogen atmosphere (5 bar) for 3 h. The catalyst was removed by filtration through glass fiber filter paper and the filtrate was concentrated under reduced pressure to give 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (2.66 g, 6.2 mmol, 87%) as a white solid. Rt 1.39 min (Method 7); m / z 384.5 (M+H)+ (ES+). δH(DMSO-d6,400MHz)δ 8.27(s,1H), 7.95(s,1H), 7.77-7.67(m,2H), 7.44-7.29(m,3H), 7.01-6.88(m,3H), 6.83-6.75(m,2H), 3.47(d,J=11.2Hz, 1H), 3.21-3.10(m,2H), 2.66(d,J=11.1Hz,1H), 2.56-2.52(m,1H), 2.45(d,J=4.2Hz,1H), 2.31-2.25(m,1H), 2.15(s,3H).

[0275] [ka] 1-(4-Fluorophenyl)-6-methyl-5-(6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (2.66 g) was dissolved in MeOH (12 mL), filtered, and then separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210-400 nm, 40 °C, 120 bar. The column was a C4 10 × 250 mm, 5 μM, flow rate 15 mL / min, 55% MeOH (0.03% ammonia), 45% CO 2Clean fractions were pooled, rinsed with methanol and concentrated to dryness using a rotary evaporator. The residue was redissolved in methanol, transferred to a final vial and evaporated on a Biotage V10. The sample was then further dried overnight in a vacuum oven at 30 °C / 5 mbar to give 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (1.28 g, 3.34 mmol, 46.4%) intermediate X (Rt 1.39 min (Method 7); m / z 384.5 (M+H)+ (ES+). δH(DMSO-d6,400 MHz) δ 8.27(s,1H), 7.95(s,1H), 7.77-7.67(m,2H), 7.44-7.29(m,3H), 7.01-6.88(m,3H), 6.83-6.75(m ,2H), 3.47(d,J=11.2Hz,1H), 3.21-3.10(m,2H), 2.66(d,J=11.1Hz,1H), 2.56-2.52(m,1H), 2.45( d, J = 4.2 Hz, 1H), 2.31-2.25 (m, 1H), 2.15 (s, 3H)), and 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (1.09 g, 2.84 mmol, 39.5%) intermediate Y was obtained (data was consistent with that recorded above).

[0276] Example 69: 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole [ka] To a solution of 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (20 mg, 52 μmol) intermediate X in DCM (0.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (20 mg, 27 μL, 0.16 mmol) followed by 1-propyl-1H-pyrazole-4-sulfonyl chloride (13 mg, 63 μmol). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated onto silica gel and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (27.37 mg, 47 μmol, 90%) as a white solid. Rt 2.30 min (Method 7); m / z 556.2 (M+H)+(ES+). δH(DMSO-d6, 400 MHz) δ 8.57-8.46(m,1H), 8.24(s,1H), 7.98-7.92(m,1H), 7.86(s,1H), 7.70(dd,J=8.9,4.9Hz, 2H), 7.41-7.31(m,3H), 7.11-6.89(m,3H), 6.76(d,J=6.8Hz,2H), 4.14(t,J=6.9Hz,2H), 4.03(d,J=9.7Hz,1H), 3.71(d,J=9.7Hz,1H), 3.54-3.41(m,1H), 3.12-2.92(m,1H), 2.69 -2.60(m,1H), 2.39(d,J=4.4Hz,1H), 2.15(s,3H), 1.88-1.69(m,2H), 0.90-0.70(m,3H).

[0277] Examples 70 to 109 Table 6: The examples shown in the following table were prepared by methods similar to those described for Example 69.

[0278] [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] [Table 12-8] [Table 12-9] [Table 12-10] [Table 12-11] [Table 12-12] [Table 12-13] [Table 12-14]

[0279] Example 110: (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-phenyl-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone [ka] To a solution of 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (20 mg, 52 μmol) (Intermediate X) in DCM (0.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (20 mg, 27 μL, 0.16 mmol) followed by benzoyl chloride (8.8 mg, 7.3 μL, 63 μmol). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated onto silica gel and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-phenyl-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone (23.10 mg, 45 μmol, 86%) as a white solid. Rt 2.28 min (Method 7); m / z 488.4 (M+H)+ (ES+).

[0280] Examples 111 to 130 Table 7: The examples shown in the following table were prepared by methods similar to those described for Example 110.

[0281] [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7]

[0282] Example 131: 5-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methyl-1,2,4-oxadiazole [ka] To a solution of 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (50 mg, 87 μmol) (Intermediate R) and carbodiimide (28 mg, 0.17 mmol) in acetonitrile (2 mL) was added (E)-N'-hydroxyacetimide amide (16 mg, 0.22 mmol). The reaction mixture was stirred at room temperature overnight. An additional portion of carbodiimide (28 mg, 0.17 mmol) was added and the reaction mixture was stirred at room temperature for 15 min. Then, N-hydroxyacetimide amide (16 mg, 0.22 mmol) was added and stirring was continued for 1 h. DBU (111 mg, 110 μL, 730 μmol) was added and stirring was continued at 80° C. for 3 h. The reaction mixture was diluted with water (10 mL) and extracted into DCM (3×10 mL). The combined organic layers were washed with MgSO 4The mixture was dried using a 500 rpm evaporator, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give 5-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methyl-1,2,4-oxadiazole (21.49 mg, 38 μmol, 44%) as a yellow solid. Rt 1.98 min (Method 7); m / z 535.5 (M+H)+ (ES+). δH (DMSO-d6, 400 MHz) δ 8.26(s,1H), 8.19(s,1H), 7.77-7.70(m,2H), 7.50(s,1H), 7.41-7.32(m,2H), 4.29(s,3H), 4.12(br.s,1H), 3.94-3.76(m,2H), 3.42-3.31(m,1H), 2.98-2.93(m,1H), 2.82-2.76(m,1H), 2.33(s,3H), 2.06(s,3H) - no ArH peak broadening was observed.

[0283] Example 132: 5-(6-((1H-pyrazol-1-yl)methyl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole [ka] To a solution of 1H-pyrazole (10 mg, 0.15 mmol) in THF (0.5 mL) was added sodium hydride (7.1 mg, 60 wt%, 0.18 mmol) at 0° C. The reaction mixture was stirred at this temperature for 15 min, after which 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl methanesulfonate (40 mg, 71 μmol) (Intermediate Q) was added. The reaction mixture was heated to reflux and stirred overnight. The reaction mixture was quenched with water (10 mL) and extracted into DCM (3×10 mL). The combined organic layers were diluted with MgSO 4 The mixture was dried using a 500 rpm HPLC-MS / HPLC-MS column, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-60% EtOAc / isohexane) to give 5-(6-((1H-pyrazol-1-yl)methyl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (7.79 mg, 14 μmol, 19%) as a white solid. Rt 1.98 min (Method 7); m / z 533.1 (M+H)+ (ES+). δH 8.22(s,1H), 8.19(s,1H), 7.79-7.73(m,3H), 7.60(s,1H), 7.46-7.34(m,4H), 6.18(s,1H), 4.25( s,3H), 4.10-3.88(m,2H), 3.71-3.36(m,4H), 3.28-3.18(m,1H), 2.36(s,3H), 1.78-1.60(m,1H).

[0284] Example 133: 2-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxazole [ka] A solution of N-(2,2-dimethoxyethyl)-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (75 mg, 90 μmol) (prepared in a manner similar to Example 55) in Eaton's reagent (0.83 g, 0.55 mL, 0.45 mmol) was heated at 135° C. for 18 h. An additional portion of Eaton's reagent (0.83 g, 0.55 mL, 0.45 mmol) was added and stirring was continued for an additional 18 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was carefully quenched with aqueous solution (50 mL) and extracted into DCM (3×20 mL). The combined organic layers were washed with MgSO 4 The mixture was dried using hexanes, filtered, and concentrated under reduced pressure to give 2-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)oxazole (48 mg, 71%). This material was redissolved in DCM (1 mL) and DIPEA (29.5 mg, 39.8 μL, 229 μmol) was added followed by 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride (16.6 mg, 91.4 μmol). The reaction mixture was stirred at room temperature for 20 min. The reaction mixture was concentrated onto silica gel and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give 2-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)oxazole (1.54 mg, 2.8 μmol, 6.2%) as a white solid. Rt 2.06 min (Method 7); m / z 520.1 (M+H)+ (ES+). δH 8.22-7.92(m,2H), 7.87-7.58(m,3H), 7.57-7.44(m,1H), 7.40-7.18(m,3H), 7.00-6.7 5(m,1H), 4.41-4.17(m,4H), 4.03-3.43(m,3H), 3.05-2.71(m,2H), 2.47-2.29(m,3H).

[0285] Example 134: 2-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)benzo[d]oxazole [ka] To a solution of 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(2-hydroxyphenyl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (24 mg, 35 μmol) (prepared in a similar manner to Example 55) in toluene (1 mL) was added tosylic acid monohydrate (1.4 mg, 6.9 μmol). The reaction mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and washed with saturated NaHCO 3 The reaction mixture was quenched with aqueous solution of MgSO. The reaction mixture was extracted into DCM (3×20 mL). The combined organic layers were diluted with MgSO 4The mixture was dried using hexanes, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give 2-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)benzo[d]oxazole (6.96 mg, 12 μmol, 33%) as an off-white solid. Rt 2.23 min (Method 7); m / z 570.1 (M+H)+ (ES+). δH 8.27(s,1H), 8.23-7.75(m,2H), 7.76-7.59(m,2H), 7.54-7.37(m,3H), 7.32(t,J=8.8Hz,2H), 7.25-7.10(m,2H), 4.31(s, 3H), 4.27-4.03(m,1H), 4.00-3.78(m,2H), 3.40(d,J=10.3Hz,1H), 3.13-3.03(m,1H), 2.78(d,J=4.2Hz,1H), 2.37(s,3H).

[0286] Example 135: N-((1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)acetamide [ka] To a solution of 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (33 mg, 67 μmol) (prepared using a method similar to that of Example 55) in THF (1 mL) was added borane.THF complex (23 mg, 0.27 mL, 1 mol THF) at 0° C. The reaction mixture was stirred for 4 h while warming to room temperature. An additional portion of borane.THF (23 mg, 0.27 mL, 1 mol THF) was added and stirring was continued for 72 h. Na 2 SO4 .10H 2 The reaction mixture was quenched by the addition of O and stirred at room temperature until effervescence ceased. The solids were removed by filtration, washed with THF (2×10 mL), and the filtrate was concentrated under reduced pressure and purified by chromatography on silica gel (4 g cartridge, 0-10% (0.7 M ammonia / MeOH) / DCM) to give (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methanamine (11 mg, 21 μmol, 24%) as a white solid. This material was dissolved in DCM (0.5 mL) and DIPEA (8.2 mg, 11 μL, 64 μmol) was added followed by acetyl chloride (2.0 mg, 1.8 μL, 25 μmol). The reaction mixture was stirred overnight while warming to room temperature. The reaction mixture was concentrated onto silica gel and purified by chromatography on silica gel (4 g cartridge, 0-10% (0.7 M ammonia / MeOH) / DCM) to give N-((1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)acetamide (8.31 mg, 15 μmol, 71%) as a white solid. Rt 1.74 min (Method 7); m / z 524.3 (M+H)+ (ES+). δH 8.38-8.28(m,1H), 8.28-8.20(m,1H), 8.04-7.82(m,1H), 7.81-7.58(m,4H), 7.47-7.35(m,2H), 4.34-4.19(m,3H), 4.02-3.86(m,1H), 3.70-3.49(m,2H), 3.14-2.89(m,3H), 2.23-1.99(m,3H), 1.86-1.67(m,3H), 1.52-1.34(m,1H) - one proton obscured by DMSO.

[0287] Examples 138 to 140 Table 8: The examples shown in the following table were prepared by methods similar to those described for Example 69.

[0288] [Table 14]

[0289] Examples 141 to 163 Table 9: The examples shown in the following table were prepared by methods similar to those described for Example 110.

[0290] [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6] [Table 15-7] [Table 15-8]

[0291] Example 164: 6-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-phenyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)picolinonitrile [ka] DCM (150 mL) was charged to a stirred reactor under nitrogen at room temperature, followed by the addition of 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (Intermediate X, 7.5 g, 0.02 mol), 6-cyano-2-pyridinecarbonyl chloride (3.3 g, 0.02 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (5.8 g, 0.03 mol), and 1-hydroxybenzotriazole (2.7 g, 0.02 mol). The reaction mixture was stirred at room temperature for at least 2 h, filtered, and the filter cake was washed with DCM (23 mL). The combined filtrate was diluted with 5% aqueous HCl (75 mL), 5% NaHCO 3 The resulting residue was purified by silica chromatography to give 6-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-phenyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)picolinonitrile as an off-white solid (35% yield and >97% purity by HPLC). t 2.19 minutes (method 7). m / z 514.3(M+H) + (ES + ). δH NMR(300MHz,DMSO)δ 8.33-7.97(m,5H), 7.75-7.68(m,2H), 7.41-7.33(m,3H), 7.08-6.84(m,5H), 4.70-4.43(m ,1H), 4.32-4.03(m,2H), 4.00-3.50(m,1H), 2.75-2.36(m,3H), 2.42(s,1H) and 2.09(s,1H).

[0292] Examples 165 to 178 Table 10: The examples shown in the following table were prepared by methods similar to those described for Example 110.

[0293] [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5]

[0294] Example 179: 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-(pyridin-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole [ka] To a solution of 1-(4-fluorophenyl)-6-methyl-5-((1S,5R,6S)-6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (10 mg, 26 μmol) intermediate X in DCM (0.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (17 mg, 23 μL, 0.13 mmol) followed by 2-(bromomethyl)pyridine, HBr (7.9 mg, 31 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated onto silica gel and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give 1-(4-fluorophenyl)-6-methyl-5-((1S,5R,6S)-6-phenyl-3-(pyridin-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole Example 179 (7.76 mg, 16 μmol, 60%) as a white solid. Rt 1.55 min (Method 9); m / z 475.2 (M+H)+(ES+). δH(DMSO-d6,400 MHz)δ 8.49(dd,J=4.9,1.3Hz,1H), 8.28(s,1H), 7.97(s,1H), 7.79(td,J=7.7,1.8Hz,1H), 7.7 2(dd,J=8.9,4.8Hz,2H), 7.49(d,J=7.7Hz,1H), 7.43-7.31(m,3H), 7.27(ddd,J=7.5,4. 8,1.1Hz,1H), 7.10-6.87(m,3H), 6.87-6.76(m,2H), 3.93-3.71(m,2H), 3.61-3.50(m,1 H), 3.29-3.17(m,1H), 3.06-2.83(m,2H), 2.73-2.54(m,1H), 2.42(s,1H), 2.15(s,3H).

[0295] Example 180: (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-(morpholinomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone [ka] To a solution of (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol intermediate O (5.00 g, 82 wt%, 12.2 mmol) in DCM (50 mL) was added DIPEA (4.71 g, 6.35 mL, 36.5 mmol) followed by benzoyl chloride (2.05 g, 1.69 mL, 14.6 mmol) at 0° C. The reaction mixture was stirred for 1 h while warming to room temperature. The reaction mixture was diluted with water and the biphasic mixture was separated using a phase separator. The organic layer was concentrated under reduced pressure and purified by chromatography on silica gel (80 g cartridge, 0-100% EtOAc / isohexane) to give (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone intermediate Y (4.90 g, 10 mmol, 83%) as a white solid. Rt 1.80 min (Method 7); m / z 442.4 (M+H)+ (ES+). δH (DMSO-d6, 400 MHz) δ 8.33-8.16 (m, 1H), 8.00-7.72 (m, 3H), 7.72-7.32 (m, 8H), 4.72-4.36 (m, 1H), 4.34-3.95 (m, 1H), 3.91-3.41 (m, 2H), 3.27-2.81 (m, 2H), 2.60 (s, 1H), 2.58-2.52 (m, 1H), 2.41-2.33 (m, 1H), 2.09-1.66 (m, 1H), 1.35-1.23 (m, 1H) - one proton was not observed.

[0296] [ka] To a solution of oxalyl chloride (1.54 g, 1.06 mL, 12.1 mmol) in dry DCM (50 mL) was added dropwise DMSO (2.05 g, 1.86 mL, 26.3 mmol) at -78°C. The reaction mixture was stirred at this temperature for 10 min, after which a solution of (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone intermediate N (4.90 g, 91 wt%, 10.1 mmol) in dry DCM (10 mL) was added. The reaction mixture was stirred at -78°C for 30 min, after which triethylamine (5.11 g, 7.04 mL, 50.5 mmol) was added. The reaction mixture was stirred overnight while warming to room temperature. The reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel (80 g cartridge, 0-100% EtOAc / isohexane) to give 3-benzoyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-carbaldehyde intermediate Z (2.87 g, 6.1 mmol, 60%) as a white solid. Rt 1.92 min (Method 7); m / z 440.4 (M+H)+ (ES+). δH(DMSO-d6,400MHz)δ 9.06-8.64(m,1H), 8.38-8.18(m,1H), 8.10-7.31(m,11H), 4.72-4.20(m,1H), 4.20-3.81(m,1H) , 3.81-3.40(m,1H), 3.21-2.82(m,1H), 2.69-2.57(m,1H), 2.49-2.40(m,1H), 2.37-2.09(m,3H).

[0297] Example 180: (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-(morpholinomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone [ka] To a solution of (1R,5R,6R)-3-benzoyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-carbaldehyde intermediate Z (10 mg, 23 μmol) in dry THF (1 mL) was added morpholine (5.9 mg, 5.9 μL, 68 μmol). The reaction mixture was stirred at room temperature for 30 min, after which sodium triacetoxyborohydride (9.6 mg, 46 μmol) was added. Stirring was continued at room temperature for 30 min. The reaction mixture was diluted with saturated NaHCO 3 It was quenched with aqueous solution (20 mL) and the product was extracted into DCM (3×20 mL). The combined organic layers were washed with MgSO 4 The mixture was dried using a hexane distillation column, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-10% (0.7M ammonia / MeOH) / DCM) to obtain (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-(morpholinomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone Example 180 (12.21 mg, 23 μmol, 100%) as a white solid. Rt 1.50 min (Method 9); m / z 511.2 (M+H)+ (ES+). δH (DMSO-d6, 400 MHz) δ 8.36-8.18 (m, 1H), 7.90-7.72 (m, 3H), 7.71-7.54 (m, 1H), 7.56-7.33 (m, 7H), 4.63-3.96 (m, 2H), 3.94-3.65 (m, 1H), 3.65-3.41 (m, 5H), 2.77-2.57 (m, 2H), 2.40-1.69 (m, 5H), 1.57-1.37 (m, 1H), 1.32-1.17 (m, 1H) - two protons obscured by solvent.

[0298] Example 181: 5-(6-((4,4-difluoropiperidin-1-yl)methyl)-3-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole Table 11: The examples shown in the following table were prepared by methods similar to those described for Example 180.

[0299] [Table 17]

[0300] Example 182: (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone [ka] To a solution of hydrazine (1.23 g, 1.20 mL, 38.3 mmol) in EtOH (3 mL) was added acetophenone (1.53 g, 1.49 mL, 12.8 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. The crude material was diluted with water (25 mL) and extracted into DCM (3 x 25 mL). The combined organic layers were washed with MgSO 4 The mixture was dried using hexanes and concentrated under reduced pressure to give (E)-(1-phenylethylidene)hydrazine (1.91 g, 12 mmol, 90%) as a colorless oil. Rt 1.50 min (Method 8); m / z 135.4 (M+H)+ (ES+).

[0301] (E)-(1-Phenylethylidene)hydrazine (1.91 g, 12 mmol) was dissolved in 1,4-dioxane (50 mL) and cooled to about 10° C. Manganese(IV) oxide (6.34 g, 72.9 mmol) was added dropwise and the temperature was kept constant. The reaction mixture was stirred for 45 min while warming to room temperature. The reaction mixture was filtered through glass fiber filter paper into a cooled receiver flask and washed with dioxane. To the resulting filtrate was added 1-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1H-pyrrole-2,5-dione (2.50 g, 1 eq, 6.08 mmol) and the reaction mixture was stirred overnight while warming to room temperature. Acetic acid (1 mL) was added and the reaction mixture was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-30% EtOAc / isohexane) to give an inseparable mixture of isomers, 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexane-2,4-dione (3.19 g, 5.7 mmol, 94%) as a yellow solid (total 92% combined, 4 isomers). The ratio of isomers was 4:60:25:11 in order of elution on UPLC). Rt 2.36 min, 2.39 min, 2.42 min, and 2.55 min (Method 7); m / z 516.4 (M+H)+ (ES+).

[0302] [ka] To a solution of 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexane-2,4-dione (3.19 g, 5.69 mmol) in 1,4-dioxane (50 mL) was added DIBAL-H (1 M hexane solution) (7.1 g, 50 mL, 1.00 moles, 50 mmol) dropwise at 0° C. The reaction mixture was stirred overnight while warming to room temperature. The reaction mixture was cooled to 0° C. and quenched with water (2 mL), followed by 15% NaOH solution (2 mL), followed by water (5 mL). The reaction mixture was stirred for 15 minutes while warming to room temperature. MgSO 4 was added and stirring was continued for 15 min. The reaction mixture was filtered, washed with EtOAc and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-20% EtOAc / isohexane) to give 5-(3-benzyl-6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole intermediate AB (93 mg, 0.13 mmol, 2.3%) (Rt 1.73 min (Method 7); m / z 488.4 (M+H)+(ES+)) as a sticky colorless oil, and 5-(3-benzyl-6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole intermediate AC (1.24 g, 2.3 mmol, 40%) (Rt 1.59 min (Method 7); m / z The product was 488.4 (M+H)+ (ES+). δH(DMSO-d6,400MHz)δ 8.07(s,1H), 7.74-7.62(m,2H), 7.54(s,1H), 7.43-7.26(m,7H), 7.27-7.19(m,1H), 7.10(d,J=7.8Hz,2H), 6.96(t,J=7.4Hz,2H), 6.92 -6.80(m,1H), 3.73(s,2H), 3.64-3.52(m,1H), 3.37-3.24(m,1H), 3.23-3.12(m,1H), 2.80(d,J=9.7Hz,2H), 2.41(s,3H), 1.85(s,3H).

[0303] [ka] To a solution of 5-(3-benzyl-6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole intermediate AB (93 mg, 0.13 mmol) in methanol (1 mL) was added Pd / C (14 mg, 10 wt%, 13 μmol). The reaction mixture was stirred under hydrogen atmosphere (5 bar) at room temperature over the weekend. The catalyst was removed by filtration through glass fiber filter paper and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-10% (0.7 M ammonia / MeOH) / DCM) to give 1-(4-fluorophenyl)-6-methyl-5-(6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole intermediate AD (32 mg, 79 μmol, 59%) as a colorless glass which was scraped to give a white solid. Rt 1.45 min and 1.48 min (Method 7); m / z 398.4 (M+H)+ (ES+).

[0304] Example 182: (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone [ka] To a solution of 1-(4-fluorophenyl)-6-methyl-5-(6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (32 mg, 79 μmol) in DCM (1 mL) was added DIPEA (31 mg, 41 μL, 0.24 mmol) followed by benzoyl chloride (13 mg, 11 μL, 95 μmol). The reaction mixture was stirred at room temperature overnight. Water (1 mL) was added and the reaction mixture was passed through a phase separator and washed with DCM (2×1 mL). The reaction mixture was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone (32.12 mg, 61 μmol, 77%) as a white solid. Rt 2.36 min (Method 7); m / z 502.5 (M+H)+ (ES+).

[0305] Example 183: (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone [ka] To a solution of 5-(3-benzyl-6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (1.24 g, 2.29 mmol) in methanol (12 mL) was added Pd / C (244 mg, 10 wt%, 229 μmol). The reaction mixture was stirred under a hydrogen atmosphere (5 bar) at room temperature over the weekend. The catalyst was removed by filtration through glass fiber filter paper and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% (0.7 M ammonia / MeOH) / DCM) to give 1-(4-fluorophenyl)-6-methyl-5-(6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole intermediate AE (896 mg, 2.2 mmol, 97%) as a white solid. Rt 1.40 min (Method 7); m / z 398.5 (M+H)+ (ES+).

[0306] Example 183: (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone [ka] To a solution of 1-(4-fluorophenyl)-6-methyl-5-(6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole (32 mg, 79 μmol) (32 mg, 79 μmol) in DCM (1 mL) was added DIPEA (31 mg, 41 μL, 0.24 mmol) followed by benzoyl chloride (13 mg, 11 μL, 95 μmol). The reaction mixture was stirred at room temperature overnight. Water (1 mL) was added and the reaction mixture was passed through a phase separator and washed with DCM (2×1 mL). The reaction mixture was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-methyl-6-phenyl-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone (28.60 mg, 54 μmol, 69%) as a white solid. Rt 2.28 min (Method 7); m / z 502.5 (M+H)+ (ES+).

[0307] Example 184: (6-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone [ka] To a solution of oxalyl chloride (338 mg, 233 μL, 2.67 mmol) in dry DCM (10 mL) was added DMSO (451 mg, 410 μL, 5.78 mmol) dropwise at −78° C. The reaction mixture was stirred at this temperature for 10 min, after which a solution of (3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol intermediate N (1.00 g, 95 wt%, 2.22 mmol) in dry DCM (2 mL) was added. The reaction mixture was stirred at −78° C. for 30 min, after which Et 3N (1.12 g, 1.55 mL, 11.1 mmol) was added. The reaction mixture was stirred overnight while warming to room temperature. The reaction mixture was concentrated under reduced pressure to give 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-carbaldehyde (1.09 g, 2.2 mmol, 100%) as an orange oil. The product was used crude without purification. Rt 1.39 min (Method 7); m / z 426.4 (M+H)+ (ES+).

[0308] [ka] To a solution of 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-carbaldehyde (500 mg, 87 wt%, 1.02 mmol) in dry THF (10 mL) was added phenylmagnesium chloride (0.15 g, 0.55 mL, 2 mol, 1.1 mmol) dropwise at −78° C. The reaction mixture was stirred for 90 minutes while warming to room temperature. The reaction mixture was diluted with saturated NH 4 It was quenched with aqueous Cl (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with MgSO 4 The mixture was dried using hexanes, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc / isohexane) to give (3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)(phenyl)methanol intermediate AG (290 mg, 0.55 mmol, 54%) as a white solid. Rt 1.44 min (Method 7); m / z 504.4 (M+H)+ (ES+). δH(DMSO-d6,400MHz)δ 8.43-8.19(m,1H), 7.90-7.55(m,4H), 7.53-6.76(m,13H), 5.46-4.75(m,1 H), 3.82-3.39(m,4H), 2.91-2.67(m,2H), 2.51(s,2H), 2.30-1.70(m,3H).

[0309] [ka] To a solution of (3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)(phenyl)methanol (50 mg, 99 μmol) in DCM (0.5 mL) was added DIPEA (38 mg, 52 μL, 0.30 mmol) followed by acetyl chloride (9.4 mg, 8.5 μL, 0.12 mmol). The reaction mixture was stirred at room temperature for 2 h. An additional portion of DIPEA (38 mg, 52 μL, 0.30 mmol) was added followed by acetyl chloride (9.4 mg, 8.5 μL, 0.12 mmol). The reaction mixture was stirred at room temperature overnight. Additional DIPEA (0.26 g, 0.35 mL, 2.0 mmol) was added followed by acetyl chloride (39 mg, 35 μL, 0.50 mmol). Stirring was continued for an additional 5 days. The reaction mixture was diluted with water (5 mL) and extracted into DCM (3×5 mL). The combined organic layers were washed with MgSO 4 The mixture was dried using hexanes, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give (3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)(phenyl)methyl acetate (26.0 mg, 29 μmol, 29%) as a colorless oil. Rt 1.60 min and 1.63 min (Method 7); m / z 546.5 (M+H)+ (ES+).

[0310] [ka] To a solution of (3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)(phenyl)methyl acetate (26 mg, 61 wt%, 29 μmol) in MeOH (0.5 mL) (plus a few drops of DCM to aid dissolution) was added Pd / C (3.1 mg, 10 wt%, 2.9 μmol). The reaction mixture was stirred under a hydrogen atmosphere (5 bar) at room temperature over the weekend. The catalyst was removed by filtration through glass fiber filter paper and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-10% (0.7 M NH 3 / MeOH) / DCM) to give 5-(6-benzyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (3.0 mg, 6.9 μmol, 24%) as a white solid. Rt 1.49 min (Method 7); m / z 398.4 (M+H)+ (ES+).

[0311] Example 184: (6-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone [ka] To a solution of 5-(6-benzyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (3.0 mg, 7.5 μmol) in DCM (0.5 mL) was added DIPEA (1.2 mg, 1.6 μL, 9.1 μmol) followed by benzoyl chloride (3.2 mg, 2.6 μL, 23 μmol). The reaction mixture was stirred at room temperature overnight. Water (0.5 mL) was added and the reaction mixture was passed through a phase separator and washed with DCM (2×0.5 mL). The reaction mixture was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give (6-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone (4.13 mg, 7.8 μmol, 100%) as a white solid. Rt 2.41 min (Method 7); m / z 502.4 (M+H)+ (ES+). δH(DMSO-d6,400MHz)δ 8.35-8.18(m,1H), 7.96-7.57(m,4H), 7.57-7.33(m,7H), 7.35-7.01(m,5H), 4.66-3.97(m,2H), 3.93-3.0 7(m,3H), 2.65-2.55(m,2H), 2.32-2.26(m,1H), 2.18-2.05(m,1H), 1.94-1.74(m,1H), 1.48-1.32(m,1H).

[0312] Example 185: 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole [ka] To a solution of 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole intermediate X (10 mg, 26 μmol) and triethylamine (13 mg, 18 μL, 0.13 mmol) in isopropanol (0.5 mL) was added 2-fluoropyrimidine (5.1 mg, 52 μmol). The reaction mixture was stirred in a microwave at 130° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was diluted with DCM (1 mL) and water (1 mL), passed through a phase separator and washed with DCM (1 mL). The combined organic layers were loaded directly onto a column and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give 1-(4-fluorophenyl)-6-methyl-5-(6-phenyl-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indazole Example 185 (7.69 mg, 16 μmol, 61%) as a yellow solid. Rt 2.41 min (Method 9); m / z 462.1 (M+H)+ (ES+). δH(DMSO-d6, 400 MHz) δ 8.37(d,J=4.8Hz,2H), 8.31(s,1H), 8.08(s,1H), 7.81-7.69(m,2H), 7.4 7-7.32(m,3H), 7.11-6.91(m,3H), 6.89-6.81(m,2H), 6.67(t,J=4.8Hz, 1H), 4.58-4.48(m,1H), 4.21-4.09(m,1H), 3.95(dd,J=11.2,4.2Hz,1H) , 3.51-3.37(m,1H), 2.83-2.75(m,1H), 2.44-2.39(m,1H), 2.24(s,3H).

[0313] Example 186: (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-(pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone [ka] Four identical reactions were set up in parallel. To a microwave vial was added picolinaldehyde (26.0 mg, 23.1 μL, 243 μmol), 4-methylbenzenesulfonohydrazide (54.3 mg, 292 μmol), cesium carbonate (158 mg, 486 μmol), 5,10,15,20-tetraphenyl-21H,23H-porphinecobalt(II) (8.16 mg, 12.2 μmol), 1-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1H-pyrrole-2,5-dione (100 mg, 243 μmol), and dry toluene (2.00 mL). The vial was purged with nitrogen, sealed, and stirred at 80° C. overnight. The reaction mixtures were combined and concentrated under reduced pressure. EtOAc (10 mL) was added and the reaction mixture was filtered through glass fiber filter paper to remove excess inorganics, washing with EtOAc. The filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give 3-benzyl-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-6-(pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2,4-dione intermediate AJ (342 mg, 0.67 mmol, 55%) as a brown oil. Rt 2.13 min (Method 7); m / z 503.4 (M+H)+ (ES+).

[0314] Table 12: The examples shown in the following table were prepared by a method similar to that described for Example 110 using intermediate AJ.

[0315] [Table 18]

[0316] VII. Biological Examples Example 1. GR Binding Assay Binding of test compounds to the glucocorticoid receptor (GR) is determined using a fluorescence polarization (FP) assay utilizing recombinant ligand binding domain (LBD) of GR. Test compounds are assessed by their ability to displace fluorescently labeled ligand and detection of the resulting decrease in fluorescence polarization. Fluorescence polarization values ​​are converted to % inhibition using high (1% DMSO only) and low (1 μM) controls and expressed as IC 50 Values ​​are calculated from non-linear regression curves fitted using Dotmatics software.

[0317] Example 2. Hep G2 TAT Ki Glucocorticoid-mediated activation of TAT occurs by transactivation of the glucocorticoid response element in the TAT promoter by the glucocorticoid receptor-agonist complex. The following protocol describes an assay for measuring the induction of TAT by dexamethasone in HepG2 cells (human hepatocellular carcinoma cell line, ECACC, UK).

[0318] TAT activity was measured as outlined in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. Dexamethasone had a mean EC 50 TAT production was induced at a concentration of 0.01 mg / mL (half maximal effect).

[0319] HepG2 cells were cultured at 37°C in 5% / 95% (v / v) CO 2 HepG2 cells were cultured at 4 °C / air in MEME medium supplemented with 10% (v / v) fetal bovine serum, 2 mM L-glutamine, and 1% (v / v) NEAA. HepG2 cells were counted and cultured at 0.2 × 10 in RPMI 1640 without phenol red, 10% (v / v) charcoal-stripped FBS, 2 mM L-glutamine. 6 Cells were cultured at a density of 10,000 cells / ml and seeded into 96-well sterile tissue culture microtiter plates at 40,000 cells / well in 200 μl and incubated at 37 °C in 5% CO. 2 The mixture was incubated at RT for 24 hours.

[0320] Growth medium was removed and replaced with assay medium {RPMI 1640 without phenol red, 2 mM L-glutamine, and 10 μM forskolin}. Test compounds were screened against 100 nM dexamethasone exposure. Compounds were serially diluted in 100% (v / v) dimethyl sulfoxide from 10 mM stocks. An 8-point half-log dilution curve was then generated, followed by a 1:100 dilution into assay medium to obtain a 10x final assay [compound], which gave a range of final assay [compound] from 10 to 0.003 μM in 0.1% (v / v) dimethyl sulfoxide.

[0321] 100 nM dexamethasone was added to the test compound, which was then incubated at 37°C, 5 / 95 (v / v) CO 2 Incubate at 4°C / air for 18–24 h to allow for optimal TAT induction.

[0322] HepG2 cells were then lysed with 30 μl of cell lysis buffer containing a protease inhibitor cocktail for 15 min at 4° C. Then, 155 μl of substrate mixture containing 5.4 mM tyrosine sodium salt, 10.8 mM alpha-ketoglutarate, and 0.06 mM pyridoxal 5'-phosphate in 0.1 M potassium phosphate buffer (pH 7.4) was added. After 2 h of incubation at 37° C., the reaction was terminated by adding 15 μl of 10 M aqueous potassium hydroxide solution, and the plate was incubated for an additional 30 min at 37° C. TAT activity products were measured by absorbance at λ 340 nm.

[0323] I C 50 Values ​​were calculated by plotting % inhibition (normalized to 100 nM dexamethasone TAT stimulation) versus [compound] and fitting the data to a four-parameter logistic equation. IC 50 Values ​​were converted to Ki (equilibrium dissociation constant) using the Cheng-Prusoff equation.

[0324] [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4]

[0325] The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, but those skilled in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. Additionally, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. In the event of any conflict between this application and any reference provided herein, this application shall control.

Claims

1. A compound of formula I, 【Chemistry 1】 During the ceremony, R １ is heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each of which is N, O, or S; phenyl; or heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms, each of which is N, O, or S; １ａ is substituted with a group, Each R １ａ became independent and C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkoxyalkyl, C １－６ Hydroxyalkyl, halogen, C １－６ Haloalkyl, C １－６ Haloalkoxy, -OH, oxo, -CN, -C(O)N(R １ｂ ) (R １ｃ ), C ３－１０ cycloalkyl or heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each of which is N, O, or S; Each R １ｂ and R １ｃ are independently hydrogen, C １－６ alkyl, or a 3- to 8-membered heterocycloalkyl having 1-3 heteroatoms, each independently N, O, or S; Each A １ , A ２ , A ３ , and A ４ is independent, = CR ２ - or =N-, Each R ２ are independently hydrogen, C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkoxyalkyl, halogen, C １－６ Haloalkyl, C １－６ Haloalkoxy, Hydroxy, C １－６ hydroxyalkyl, or -CN; Ring A is C ３－６ is cycloalkyl, L ２ is absent, -C(O)-, -C(O)O-, -C(O)N(R ３ ) -, -S(O) ２ - or -S(O) ２ N (R ３ ) - and R ３ is hydrogen or C １－６ is alkyl, R ４ But, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ２－６ Alkoxyalkyl, -(CH ２ CH ２ O) ２－６ CH ３ , C １－６ Hydroxyalkyl, C １－６ Haloalkyl, C ３－８ Cycloalkyl, C １－６ Alkyl-C ３－８ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C １－６ Alkyl-C ６－１２ Aryl, heteroaryl, or C １－６ alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently have 0 to 5 R ４ａ is substituted with a group, Alternatively, R ３ and R ４ are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently being N, O, or S, where said heterocycloalkyl has 0, 1, or 2 C １－６ substituted with an alkyl group, Each R ４ａ became independent and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ２－６ Alkoxyalkyl, C １－６ Hydroxyalkyl, halogen, C １－６ Haloalkyl, C １－６ Haloalkoxy, -CN, -OH, oxo, -C(O)R ４ｂ , -C(O)OR ４ｂ , -OC(O)R ４ｂ , -OC(O)OR ４ｂ , -C(O)N(R ４ｂ ) (R ４ｃ ), -N(R ４ｂ ) C(O)R ４ｃ , -OC(O)N(R ４ｂ ) (R ４ｃ ), -N(R ４ｂ ) C(O)OR ４ｃ , -S(O) ２ R ４ｂ , -S(O) ２ N (R ４ｂ ) (R ４ｃ ), -N(R ４ｂ ) S (O) ２ R ４ｃ , C ３－８ Cycloalkyl, C １－６ Alkyl-C ３－８ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C １－６ Alkyl-C ６－１２ Aryl, heteroaryl, or C １－６ alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0, 1, or 2 C １－６ substituted with an alkyl group, Each R ４ｂ and R ４ｃ is hydrogen or C １－６ is alkyl, Each L ５ is independently absent or C １－６ is alkylene, Each R ５ became independent and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ２－６ Alkoxyalkyl, hydroxy, C １－６ Hydroxyalkyl, halogen, C １－６ Haloalkyl, C １－６ Haloalkoxy, -CN, oxo, -OR ５ａ , -C(O)R ５ａ , -C(O)OR ５ａ , -OC(O)R ５ａ , -C(O)N(R ５ａ ) (R ５ｂ ), -N(R ５ａ ) C(O)R ５ｂ , -OC(O)N(R ５ａ ) (R ５ｂ ), -N(R ５ａ ) C(O)OR ５ｂ , -S(O) ２ R ５ａ , -S(O) ２ N (R ５ａ ) (R ５ｂ ), -N(R ５ａ ) S (O) ２ R ５ｂ , C ３－８ Cycloalkyl, heterocycloalkyl, C ６－１２ aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R ５ｃ is substituted with a group, Each R ５ａ and R ５ｂ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ２－６ Alkoxyalkyl, hydroxy, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－８ Cycloalkyl, C １－６ Alkyl-C ３－８ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C １－６ Alkyl-C ６－１２ Aryl, heteroaryl, or C １－６ alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R ５ｄ is substituted with a group, Alternatively, R ５ａ and R ５ｂ are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently being N, O, or S, where said heterocycloalkyl has 0, 1, or 2 C １－６ substituted with an alkyl group, Each R ５ｃ became independent and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ２－６ Alkoxyalkyl, hydroxy, C １－６ Hydroxyalkyl, halogen, C １－６ Haloalkyl, C １－６ Haloalkoxy, -CN, oxo, -OH, -C(O)R ５ｃ１ , -C(O)OR ５ｃ１ , -OC(O)R ５ｃ１ , -OC(O)OR ５ｃ１ , -C(O)N(R ５ｃ１ ) (R ５ｃ２ ), -N(R ５ｃ１ ) C(O)R ５ｃ２ , -OC(O)N(R ５ｃ１ ) (R ５ｃ２ ), -N(R ５ｃ１ ) C(O)OR ５ｃ２ , -S(O) ２ R ５ｃ１ , -S(O) ２ N (R ５ｃ１ ) (R ５ｃ２ ), -N(R ５ｃ１ ) S (O) ２ R ５ｃ２ , C ３－８ Cycloalkyl, C １－６ Alkyl-C ３－８ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C １－６ Alkyl-C ６－１２ Aryl, heteroaryl, or C １－６ alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C １－６ substituted with an alkyl group, Each R ５ｃ１ and R ５ｃ２ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ２－６ Alkoxyalkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, C ３－８ Cycloalkyl, C １－６ Alkyl-C ３－８ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C １－６ Alkyl-C ６－１２ Aryl, heteroaryl, or C １－６ alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C １－６ substituted with an alkyl group, Alternatively, R ５ｃ１ and R ５ｃ２ are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently being N, O, or S, where said heterocycloalkyl has 0, 1, or 2 C １－６ substituted with an alkyl group, Each R ５ｄ became independent and C １－６ is alkyl or halogen; Each R ６ became independent and C １－６ Alkoxy, Hydroxy, C １－６ Hydroxyalkyl, halogen, C １－６ Haloalkyl, or C １－６ is haloalkoxy; subscript m is 0, 1, 2, 3, 4, or 5; A compound, or a pharma- ceutically acceptable salt thereof, wherein the subscript n is 1 or 2.

2. R １ is heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each of which is N, O, or S; phenyl; or heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms, each of which is N, O, or S; １ａ is substituted with a group, Each R １ａ became independent and C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkoxyalkyl, C １－６ Hydroxyalkyl, halogen, C １－６ Haloalkyl, C １－６ Haloalkoxy, -OH, oxo, -CN, -C(O)N(R １ｂ ) (R １ｃ ), C ３－１０ cycloalkyl or heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each of which is N, O, or S; Each R １ｂ and R １ｃ are independently hydrogen, C １－６ alkyl, or a 3- to 8-membered heterocycloalkyl having 1-3 heteroatoms, each independently N, O, or S; Each A １ , A ２ , A ３ , and A ４ is independent, = CR ２ - or =N-, Each R ２ are independently hydrogen, C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkoxyalkyl, halogen, C １－６ Haloalkyl, C １－６ Haloalkoxy, Hydroxy, C １－６ hydroxyalkyl, or -CN; Ring A is C ３－６ is cycloalkyl, L ２ is -C(O)-, -C(O)O-, -C(O)N(R ３ ) -, -S(O) ２ - or -S(O) ２ N (R ３ ) - and R ３ is hydrogen or C １－６ is alkyl, R ４ But, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ２－６ Alkoxyalkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, C ３－８ Cycloalkyl, C １－６ Alkyl-C ３－８ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C １－６ Alkyl-C ６－１２ Aryl, heteroaryl, or C １－６ alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently have 0 to 5 R ４ａ is substituted with a group, Alternatively, R ３ and R ４ are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently being N, O, or S, where said heterocycloalkyl has 0, 1, or 2 C １－６ substituted with an alkyl group, Each R ４ａ became independent and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ２－６ Alkoxyalkyl, C １－６ Hydroxyalkyl, halogen, C １－６ Haloalkyl, C １－６ Haloalkoxy, -CN, -OH, oxo, -C(O)R ４ｂ , -C(O)OR ４ｂ , -OC(O)R ４ｂ , -OC(O)OR ４ｂ , -C(O)N(R ４ｂ ) (R ４ｃ ), -N(R ４ｂ ) C(O)R ４ｃ , -OC(O)N(R ４ｂ ) (R ４ｃ ), -N(R ４ｂ ) C(O)OR ４ｃ , -S(O) ２ R ４ｂ , -S(O) ２ N (R ４ｂ ) (R ４ｃ ), -N(R ４ｂ ) S (O) ２ R ４ｃ , C ３－８ Cycloalkyl, C １－６ Alkyl-C ３－８ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C １－６ Alkyl-C ６－１２ Aryl, heteroaryl, or C １－６ alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0, 1, or 2 C １－６ substituted with an alkyl group, Each R ４ｂ and R ４ｃ is hydrogen or C １－６ is alkyl, Each L ５ is independently absent or C １－６ is alkylene, Each R ５ became independent and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ２－６ Alkoxyalkyl, hydroxy, C １－６ Hydroxyalkyl, halogen, C １－６ Haloalkyl, C １－６ Haloalkoxy, -CN, oxo, -OR ５ａ , -C(O)R ５ａ , -C(O)OR ５ａ , -OC(O)R ５ａ , -C(O)N(R ５ａ ) (R ５ｂ ), -N(R ５ａ ) C(O)R ５ｂ , -OC(O)N(R ５ａ ) (R ５ｂ ), -N(R ５ａ ) C(O)OR ５ｂ , -S(O) ２ R ５ａ , -S(O) ２ N (R ５ａ ) (R ５ｂ ), -N(R ５ａ ) S (O) ２ R ５ｂ , C ３－８ Cycloalkyl, heterocycloalkyl, C ６－１２ aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R ５ｃ is substituted with a group, Each R ５ａ and R ５ｂ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ２－６ Alkoxyalkyl, hydroxy, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－８ Cycloalkyl, C １－６ Alkyl-C ３－８ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C １－６ Alkyl-C ６－１２ Aryl, heteroaryl, or C １－６ alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R ５ｄ is substituted with a group, Alternatively, R ５ａ and R ５ｂ are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently being N, O, or S, where said heterocycloalkyl has 0, 1, or 2 C １－６ substituted with an alkyl group, Each R ５ｃ became independent and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ２－６ Alkoxyalkyl, hydroxy, C １－６ Hydroxyalkyl, halogen, C １－６ Haloalkyl, C １－６ Haloalkoxy, -CN, oxo, -OH, -C(O)R ５ｃ１ , -C(O)OR ５ｃ１ , -OC(O)R ５ｃ１ , -OC(O)OR ５ｃ１ , -C(O)N(R ５ｃ１ ) (R ５ｃ２ ), -N(R ５ｃ１ ) C(O)R ５ｃ２ , -OC(O)N(R ５ｃ１ ) (R ５ｃ２ ), -N(R ５ｃ１ ) C(O)OR ５ｃ２ , -S(O) ２ R ５ｃ１ , -S(O) ２ N (R ５ｃ１ ) (R ５ｃ２ ), -N(R ５ｃ１ ) S (O) ２ R ５ｃ２ , C ３－８ Cycloalkyl, C １－６ Alkyl-C ３－８ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C １－６ Alkyl-C ６－１２ Aryl, heteroaryl, or C １－６ alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C １－６ substituted with an alkyl group, Each R ５ｃ１ and R ５ｃ２ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ２－６ Alkoxyalkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, C ３－８ Cycloalkyl, C １－６ Alkyl-C ３－８ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C １－６ Alkyl-C ６－１２ Aryl, heteroaryl, or C １－６ alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each heterocycloalkyl and heteroaryl independently has 0, 1, or 2 C １－６ substituted with an alkyl group, Alternatively, R ５ｃ１ and R ５ｃ２ are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently being N, O, or S, where said heterocycloalkyl has 0, 1, or 2 C １－６ substituted with an alkyl group, Each R ５ｄ became independent and C １－６ is alkyl or halogen; Each R ６ became independent and C １－６ Alkoxy, Hydroxy, C １－６ Hydroxyalkyl, halogen, C １－６ Haloalkyl, or C １－６ is haloalkoxy; subscript m is 0, 1, 2, 3, 4, or 5; 2. The compound of claim 1, wherein subscript n is 1 or 2, or a pharma- ceutically acceptable salt thereof.

3. R １ 3. The compound of claim 1 or 2, wherein is phenyl substituted with halogen, or a pharma- ceutically acceptable salt thereof.

4. R １ The compound according to any one of claims 1 to 3, wherein: 【Chemistry 2】

5. Each A １ , A ２ , A ３ , and A ４ But, =CR ２ The compound according to any one of claims 1 to 4, wherein R is -, or a pharma- ceutically acceptable salt thereof.

6. Each R ２ are independently hydrogen or C １－６ 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

7. Each R ２ The compound of any one of claims 1 to 6, wherein is independently hydrogen, methyl, ethyl, n-propyl, or iso-propyl, or a pharma- ceutically acceptable salt thereof.

8. Each R ２ The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein: is independently hydrogen or methyl.

9. Each A １ , A ２ , and A ４ is ═CH—, A ３ The compound according to any one of claims 1 to 8, wherein is =CH- or =C(Me)-, or a pharma- ceutically acceptable salt thereof.

10. Each A １ , A ２ , and A ４ is ═CH—, A ３ The compound according to any one of claims 1 to 9, wherein is =C(Me)-, or a pharma- ceutically acceptable salt thereof.

11. Formula Ia 【Chemistry 3】 The compound according to any one of claims 1 to 10, having the structure:

12. Ring A is C ３－５ 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

13. Ring A is C ３ Cycloalkyl or C ５ 13. The compound of any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

14. Formula Ib 【Chemistry 4】 14. The compound according to any one of claims 1 to 13, having the structure:

15. Formula Ib-1 【Chemistry 5】 15. The compound according to any one of claims 1 to 14, having the structure:

16. Formula Ib-2 【Chemistry 6】 15. The compound according to any one of claims 1 to 14, having the structure:

17. having the structure of formula Ic, 【Chemistry 7】 During the ceremony, 14. The compound of any one of claims 1 to 13, wherein subscript m is 0 or 1, or a pharma- ceutically acceptable salt thereof.

18. having the structure of formula Ic-1, 【Chemistry 8】 During the ceremony, 18. The compound of any one of claims 1 to 13 or 17, wherein subscript m is 0 or 1, or a pharma- ceutically acceptable salt thereof.

19. L ２ is absent, -C(O)-, -C(O)O-, -S(O) ２ - or -S(O) ２ N (R ３ ) - and R ３ is hydrogen or C １－３ 19. The compound of any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

20. L ２ is absent, -C(O)-, -C(O)O-, -S(O) ２ - or -S(O) ２ N (R ３ ) - and R ３ The compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or methyl.

21. L ２ is -C(O)- or -S(O) ２ 21. The compound according to any one of claims 1 to 20, wherein:

22. L ２ The compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, wherein: is -C(O)-.

23. L ２ But -S(O) ２ 22. The compound according to any one of claims 1 to 21, wherein: -, or a pharma- ceutically acceptable salt thereof.

24. R ４ But, C １－６ Alkyl, C ２－６ Alkoxyalkyl, -(CH ２ CH ２ O) ２－４ CH ３ , C １－６ Hydroxyalkyl, C ３－８ Cycloalkyl, C １－６ Alkyl-C ３－８ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C １－６ Alkyl-C ６－１２ Aryl, heteroaryl, or C １－６ alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently have 0 to 5 R ４ａ is substituted with a group, Alternatively, R ３ and R ４ are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently being N, O, or S, where said heterocycloalkyl has 0, 1, or 2 C １－６ substituted with an alkyl group, Each R ４ａ became independent and C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkoxyalkyl, C １－６ Hydroxyalkyl, halogen, C １－６ Haloalkyl, C １－６ Haloalkoxy, -CN, -OH, -S(O) ２ R ４ｂ , C ３－６ cycloalkyl, and heterocycloalkyl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; Each R ４ｂ But, C １－６ 24. The compound of any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

25. R ４ But, C １－４ Alkyl, C ２－４ Alkoxyalkyl, -(CH ２ CH ２ O) ２－４ CH ３ , C ３－６ Cycloalkyl, C １－２ Alkyl-C ３－６ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ aryl or heteroaryl; wherein each heterocycloalkyl independently has 3 to 6 ring members and 1 to 3 heteroatoms, each independently being N or O; and each heteroaryl independently is 5-6 ring members and 1-4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently being 0-3 R ４ａ is substituted with a group, Each R ４ａ became independent and C １－３ Alkyl, C １－３ Alkoxy, C ２－３ Alkoxyalkyl, halogen, C １－３ Haloalkyl, -CN, -S(O) ２ R ４ｂ , C ３－６ cycloalkyl, and heterocycloalkyl, where each heterocycloalkyl independently has 3 to 6 ring members and 1 to 2 heteroatoms, each independently being N, O, or S; Each R ４ｂ But, C １－３ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, which is alkyl.

26. R ４ is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, methoxymethyl, methoxyethyl, -(CH ２ CH ２ O) ２ CH ３ , C ３－６ Cycloalkyl, C １－２ Alkyl-C ３－６ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ aryl or heteroaryl; wherein each cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each heterocycloalkyl is azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, or morpholine; each heteroaryl is pyrrole, pyridine, pyrazole, imidazole, pyridazine, pyrimidine, pyrazine, isoxazole, oxazole, isothiazole, thiazole, or triazole; Each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently represents 0 to 2 R ４ａ is substituted with a group, Each R ４ａ are independently methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, n-propoxy, iso-propoxy, methoxymethyl, methoxyethyl, fluoro, chloro, bromo, -CH ２ F, -CHF ２ , -CF ３ , -CN, -S(O) ２ Me, -S(O) ２ 26. The compound according to any one of claims 1 to 25, which is Et, cyclopropyl, cyclobutyl, cyclopentyl, piperidine, tetrahydropyran, or morpholine, or a pharma- ceutically acceptable salt thereof.

27. R ４ is methyl, ethyl, isopropyl, isobutyl, t-butyl, methoxymethyl, methoxyethyl, -(CH ２ CH ２ O) ２ CH ３ , 【Chemistry 9-1】 【Chemistry 9-2】 27. The compound according to any one of claims 1 to 26, wherein:

28. R ４ Methyl, ethyl, isopropyl, isobutyl, methoxymethyl, methoxyethyl, CH ２ (CH ２ OCH ２ ) ２ H. 【Chemistry 10-1】 【Chemistry 10-2】 28. The compound according to any one of claims 1 to 27, wherein:

29. R ４ Methyl, isopropyl, t-butyl, methoxyethyl, 【Chemistry 11】 28. The compound according to any one of claims 1 to 27, wherein:

30. Each L ５ is independently absent or C １－６ is alkylene, Each R ５ became independent and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ２－６ Alkoxyalkyl, hydroxy, C １－６ Hydroxyalkyl, oxo, -OR ５ａ , -C(O)R ５ａ , -C(O)OR ５ａ , -OC(O)R ５ａ , -C(O)N(R ５ａ ) (R ５ｂ ), -N(R ５ａ ) C(O)R ５ｂ , -OC(O)N(R ５ａ ) (R ５ｂ ), -N(R ５ａ ) C(O)OR ５ｂ , -S(O) ２ R ５ａ , -S(O) ２ N (R ５ａ ) (R ５ｂ ), -N(R ５ａ ) S (O) ２ R ５ｂ , C ３－８ Cycloalkyl, heterocycloalkyl, C ６－１２ aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R ５ｃ is substituted with a group, Each R ５ａ and R ５ｂ are independently hydrogen, C １－６ Alkyl, C ３－８ Cycloalkyl, C １－６ Alkyl-C ３－８ Cycloalkyl, heterocycloalkyl, C １－６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C １－６ Alkyl-C ６－１２ Aryl, heteroaryl, or C １－６ alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R ５ｄ is substituted with a group, Alternatively, R ５ａ and R ５ｂ are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 12 ring members and 1 to 3 additional heteroatoms, each independently being N, O, or S, where said heterocycloalkyl has 0, 1, or 2 C １－６ substituted with an alkyl group, Each R ５ｃ became independent and C １－６ Alkyl, halogen, or C １－６ is haloalkyl, Each R ５ｄ became independent and C １－６ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl or halogen.

31. Each L ５ is independently absent or C １－２ is alkylene, Each R ５ became independent and C １－３ Alkyl, C ２－４ Alkynyl, C １－３ Alkoxy, C １－３ Hydroxyalkyl, oxo, -OR ５ａ , -C(O)N(R ５ａ ) (R ５ｂ ), -N(R ５ａ ) C(O)R ５ｂ , heterocycloalkyl, C ６－１２ aryl, or heteroaryl, where each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms, each of which is independently N, O, or S; each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each of which is independently N, O, or S; and each heterocycloalkyl, aryl, and heteroaryl independently has 0 to 4 R ５ｃ is substituted with a group, Each R ５ａ and R ５ｂ are independently hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C ６－１２ Aryl, C １－２ Alkyl-C ６－１２ aryl, or heteroaryl, where each heteroaryl independently has 5 to 10 ring members and 1 to 4 heteroatoms, each independently being N, O, or S; and each cycloalkyl, aryl, and heteroaryl independently has 0 to 4 R ５ｄ is substituted with a group, Alternatively, R ５ａ and R ５ｂ are combined with the atom to which they are attached to form a heterocycloalkyl having 3 to 6 ring members and one additional heteroatom that is N or O, where said heterocycloalkyl has 0, 1, or 2 C １－３ substituted with an alkyl group, Each R ５ｃ became independent and C １－３ Alkyl, halogen, or C １－３ is haloalkyl, Each R ５ｄ became independent and C １－３ 31. The compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl or halogen.

32. Each L ５ are independently absent or -CH ２ - and Each R ５ are independently methyl, -C≡CH, -C≡CCH ３ , -CH ２ C≡CCH ３ , methoxy, ethoxy, n-propoxy, iso-propoxy, -CH ２ OH, -CH ２ CH ２ OH, -CH ２ CH ２ CH ２ OH, oxo, -OR ５ａ , -C(O)N(R ５ａ ) (R ５ｂ ), -N(R ５ａ ) C(O)R ５ｂ , heterocycloalkyl, C ６－１２ aryl or heteroaryl; wherein each heterocycloalkyl is azetidine, pyrrolidine, piperidine, or morpholine; the aryl is phenyl; each heteroaryl is pyrrole, pyridine, pyrazole, imidazole, pyridazine, pyrimidine, pyrazine, isoxazole, oxazole, benzoxazole, isothiazole, thiazole, benzothiazole, triazole, oxadiazole, or thiadiazole; Each heterocycloalkyl, aryl, and heteroaryl independently represents 0 to 2 R ５ｃ is substituted with a group, Each R ５ａ and R ５ｂ are independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, C ３－６ Cycloalkyl, C ６－１２ Aryl, C １－２ Alkyl-C ６－１２ aryl or heteroaryl; wherein each cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each aryl is phenyl; each heteroaryl is pyrrole, pyridine, pyrazole, imidazole, pyridazine, pyrimidine, or pyrazine; Each cycloalkyl, aryl, and heteroaryl is selected from 0 to 2 R ５ｄ is substituted with a group, Alternatively, R ５ａ and R ５ｂ taken together with the atom to which they are attached form a heterocycloalkyl which is azetidine, pyrrolidine, or piperidine; wherein the heterocycloalkyl is selected from the group consisting of 0, 1, or 2 C １－３ substituted with an alkyl group, Each R ５ｃ are independently methyl, ethyl, n-propyl, iso-propyl, fluoro, chloro, -CH ２ F, -CHF ２ , -CF ３ , or -CH ２ CF ３ and Each R ５ｄ 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, wherein is independently methyl, ethyl, n-propyl, iso-propyl, fluoro, chloro, or bromo.

33. Each R ５ -L ５ The - group is methyl, -C≡CCH ３ , methoxy, -CH ２ OH, oxo, 【Chemistry 12】 33. The compound according to any one of claims 1 to 32, wherein:

34. Each R ５ -L ５ The - group is methyl, -CH ２ O.H. 【Chemistry 13】 34. The compound according to any one of claims 1 to 33, wherein:

35. Each R ５ -L ５ The - group is methoxy, -C≡CCH ３ , oxo, 【Chemistry 14】 34. The compound according to any one of claims 1 to 33, wherein:

36. Each R ６ became independent and C １－６ alkoxy, hydroxy, or halogen; 36. The compound of any one of claims 1 to 35, wherein subscript m is 0 or 1, or a pharma- ceutically acceptable salt thereof.

37. Each R ６ are independently -OMe, -OEt, -OPr, -OiPr, hydroxy, F, Cl, or Br; 37. The compound of any one of claims 1 to 36, wherein subscript m is 0 or 1, or a pharma- ceutically acceptable salt thereof.

38. Each R ６ is independently -OMe, -OEt, hydroxy, or F; 38. The compound of any one of claims 1 to 37, wherein subscript m is 0 or 1, or a pharma- ceutically acceptable salt thereof.

39. 39. The compound of any one of claims 1 to 38, wherein subscript m is 0; or a pharma- ceutically acceptable salt thereof.

40. R １ but, 【Chemistry 15】 and Each A １ , A ２ , and A ４ is ═CH—, A ３ is ═CH— or ═C(Me)—, Ring A is C ３ Cycloalkyl or C ５ is cycloalkyl, L ２ is absent, -C(O)-, -C(O)O-, -S(O) ２ - or -S(O) ２ N (R ３ ) - and R ３ is hydrogen or methyl; R ４ iso-propyl, iso-butyl, t-butyl, methoxymethyl, methoxyethyl, CH ２ (CH ２ OCH ２ ) ２ H. 【Chemistry 16-1】 【Chemistry 16-2】 and Each R ５ -L ５ The - group is methyl, -C≡CCH ３ , methoxy, -CH ２ OH, oxo, 【Chemistry 17】 and Each R ６ is independently -OMe, -OEt, hydroxy, or F; the subscript m is 0 or 1; 40. The compound of any one of claims 1 to 39, wherein the subscript n is 1, or a pharma- ceutically acceptable salt thereof.

41. R ４ Methyl, ethyl, isopropyl, isobutyl, methoxymethyl, methoxyethyl, CH ２ (CH ２ OCH ２ ) ２ H. 【Chemistry 18-1】 【Chemistry 18-2】 and Each R ５ -L ５ The - group is methyl, -CH ２ O.H. 【Chemistry 19】 41. The compound according to any one of claims 1 to 40, wherein:

42. R ４ Methyl, isopropyl, t-butyl, methoxyethyl, 【Chemistry 20】 and Each R ５ -L ５ The - group is methoxy, -C≡CCH ３ , oxo, 【Chemistry 21】 41. The compound according to any one of claims 1 to 40, wherein:

43. Formula Id-1 or Formula Id-2: 【Chemistry 22】 39. The compound of any one of claims 1 to 38, having the structure:

44. R ４ But, C ６－１２ aryl or heteroaryl having 5-6 ring members and 1-4 heteroatoms each independently being N, O, or S, where the aryl and heteroaryl are independently selected from 0-3 R ４ａ is substituted with a group, Each R ４ａ became independent and C １－３ Alkyl, C １－３ Alkoxy, halogen, C １－３ Haloalkyl, -CN, -S(O) ２ R ４ｂ , C ３－６ cycloalkyl, and heterocycloalkyl, where each heterocycloalkyl independently has 5 to 6 ring members and 1 to 2 heteroatoms, each independently being N, O, or S; Each R ４ｂ But, C １－３ 44. The compound of any one of claims 1 to 43, or a pharma- ceutically acceptable salt thereof, which is alkyl.

45. R ４ But 0 to 2 R ４ａ phenyl, pyridine, pyridazine, pyrimidine, or pyrazine substituted with a group; Each R ４ａ are independently methyl, isopropyl, methoxy, fluoro, -CHF ２ , -CF ３ , -CN, -S(O) ２ 45. The compound of any one of claims 1 to 44, wherein R is Me, cyclopropyl, or morpholine, or a pharma- ceutically acceptable salt thereof.

46. R ４ 0 to 1 R ４ａ phenyl or pyridine, each substituted with a group; R ４ａ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 45, wherein:

47. R ４ but, 【Chemistry 23】 46. ​​The compound according to any one of claims 1 to 45, wherein:

48. 41. The compound of any one of claims 1 to 40, which is a compound of Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, or Table 1G, or a pharma- ceutically acceptable salt thereof.

49. 49. The compound of any one of claims 1 to 41 or 48, which is a compound of Table 1A or Table 1B, or a pharma- ceutically acceptable salt thereof.

50. 49. The compound of any one of claims 1 to 40, 42, or 48, which is a compound of Table 1C, Table 1D, Table 1E, Table 1F, or Table 1G, or a pharma- ceutically acceptable salt thereof. 【Request 51】 【Chemical 24-1】 【Chemistry 24-2】 49. The compound of any one of claims 1 to 40, 42, or 48, having the structure:

52. 【Chemical 25】 49. The compound of any one of claims 1 to 40, 42, or 48, having the structure:

53. 【Catalogue 26】 49. The compound of any one of claims 1 to 40, 42, or 48, having the structure:

54. 【Catalogue 27】 49. The compound of any one of claims 1 to 40, 42, or 48, having the structure:

55. 【Catalogue 28】 49. The compound of any one of claims 1 to 40, 42, or 48, having the structure:

56. 【Catalogue 29】 49. The compound of any one of claims 1 to 40, 42, or 48, having the structure:

57. 【Chemical 30】 49. The compound of any one of claims 1 to 40, 42, or 48, having the structure:

58. 【Chemical 31】 49. The compound of any one of claims 1 to 40, 42, or 48, having the structure:

59. 【Chemical 32】 49. The compound of any one of claims 1 to 40, 42, or 48, having the structure:

60. 60. A pharmaceutical composition comprising a compound according to any one of claims 1 to 59, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

61. 61. A method of treating a disorder or condition by modulating the glucocorticoid receptor, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 59 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 60, thereby treating said disorder or condition.

62. 61. A method for treating a disorder or condition by antagonizing the glucocorticoid receptor, comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 59 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 60.

63. 63. The method of claim 61 or 62, wherein the disorder or condition is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), antipsychotic-induced weight gain, cancer, Cushing's disease, Cushing's syndrome, psychotic major depression, nonalcoholic steatohepatitis, and obesity.

64. A compound according to any one of claims 1 to 59 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 60, for use in a method for treating a disorder or condition by modulating the glucocorticoid receptor.

65. A compound according to any one of claims 1 to 59, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 60, for use in a method for treating a disorder or condition by antagonizing the glucocorticoid receptor.

66. 61. Use of a compound according to any one of claims 1 to 59 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 60, in the manufacture of a medicament for treating a disorder or condition by modulating the glucocorticoid receptor.

67. 61. Use of a compound according to any one of claims 1 to 59 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 60, in the manufacture of a medicament for treating a disorder or condition by antagonizing the glucocorticoid receptor.

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