Quaternary indazole glucocorticoid receptor antagonists

Abstract

The present disclosure provides compounds of Formula I or II. The compounds of Formula I or II can be used in pharmaceutical formulations and can be used to modulate the glucocorticoid receptor.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 042,188, filed June 22, 2020, the entirety of which is incorporated herein for all purposes. [Background technology]

[0002] 2. Background of the Invention 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), which shows both circadian rhythmic changes and elevations in response to stress and food. Cortisol levels respond within minutes to many physical and psychological stresses, including trauma, surgery, exercise, anxiety, and depression. Cortisol is a steroid that acts by binding to the glucocorticoid receptor (GR) within cells. 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 actions 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 substances can block the physiological effects of GR agonist binding. These antagonists include compositions that bind to the GR, thereby blocking the ability of agonists to effectively bind to and / or activate the 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 has a dissociation constant (Kd) of 10 -9 M binds to GR with high affinity (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 for the GR, and the MR is normally considered fully occupied under normal physiological conditions. Under stress conditions, cortisol concentrations increase and the GR becomes occupied. The MR also binds aldosterone, and aldosterone and cortisol have similar affinities for the MR. However, glucocorticoids circulate at levels approximately 100 times higher than mineralocorticoids. An enzyme (11-β hydroxysteroid dehydrogenase 1) is present in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids.

[0005] Steroids can exhibit both the intended therapeutic effect and negative side effects when administered to a subject in need thereof. What is needed in the art are new compositions 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] or a pharma- ceutical acceptable salt thereof, R 1 is a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms each being N, O, or S, phenyl, or a heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each being N, O, or S, each independently consisting of 1 to 5 R 1a is substituted with a group; Each R 1a are independently hydrogen, C 1-6 Alkyl, C 1-6 Deuterated 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 8 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 3-8 membered heterocycloalkyl having 1-3 heteroatoms, each independently N, O, or S; A 1 , A 2 , A 3 , and A 4 are each 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, C1-6 haloalkoxy, hydroxy, or -CN; Ring J is a 3-10 membered heterocycloalkyl having 1-3 heteroatoms which are each independently N, O, or S, where at least one heteroatom is N, and wherein ... 3a and R 3b optionally substituted with a group; Each R 3a are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3a1 , -C(O)OR 3a1 , -C(O)N(R 3a1 )(R 3a2 ), -OH, oxo, 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 alkenyl and alkynyl is C 6-12 optionally substituted with aryl or heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each of which is independently N, O, or S, and where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each of which is independently N, O, or S; Each R 3a1 and R 3a2 are independently hydrogen or C 1-6 is alkyl; Alternatively, two Rs attached to the same atom 3a The groups, together with the atoms to which they are attached, form C 3-6 Can form a cycloalkyl; Alternatively, two Rs attached to different atoms 3a The groups, together with the atoms to which they are attached, form C 3-10 cycloalkyl, or 3-10 membered heterocycloalkyl having 1-4 heteroatoms, each independently N, O, or S, each of which can be 1-4 R 3a3 is substituted with a group; Each R 3a3 are independently hydrogen or C 1-6 is alkyl; Each R 3b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3b1 , -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, C 2-6 Alkynyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, C 2-6 Alkenyl-C 6-12 Aryl, C 2-6 Alkynyl-C 6-12 Aryl, C 1-6 Alkyl-OC 6-12 Aryl, C 1-6 Alkoxyalkyl-C 6-12 Aryl, -C(O)-C 6-12 Aryl, heteroaryl, or C 1-6alkyl-heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each independently N, O, or S, where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each independently N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 is alkyl; Or, R 3b1 and R 3b2 together with the atom to which they are attached form a 3-6 membered heterocycloalkyl having 1-2 additional heteroatoms, each independently N, O, or S; Each R 3b3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, or C 1-6 haloalkoxy; Or, R 3b is an R on an adjacent ring atom. 3a and each of which, together with the atom to which it is attached, is C substituted with 0 to 4 halogens. 3-6 Forming a cycloalkyl; R 4 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -CN, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12aryl, or a 5-10 membered heteroaryl having 1-5 heteroatoms each independently being N, O, or S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-5 R 4a is substituted with a group; Each R 4a is hydrogen, C 1-6 Alkyl, C 1-6 Deuterated 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 , -C(O)N(R 4b )(R 4c ), -S(O) 2 R 4b , -S(O) 2 N(R 4b )(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, -OC 6-12 Aryl, Heteroaryl, C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms that are each independently N, O, or S, where each heteroaryl independently has 5 to 8 ring members and 1 to 4 heteroatoms that are each independently N, O, or S, and where each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is selected from the group consisting of C 1-6 optionally substituted with alkoxy; Each R 4b and R4c is hydrogen or C 1-6 is alkyl; L 1 is absent or -N(R 5a )-and; L 2 does not exist, and C 1-6 Alkylene, -C(O)-, -C(O)-C 1-6 Alkylene-, C(O)-C 1-6 Alkylene -O-, -C(O)O-, -C(O)N(R 5b )-, -S(O) 2 - or -S(O) 2 N(R 5b )--and R 5a and R 5b are each independently hydrogen, C 1-6 Alkyl or C 2-6 is an alkoxyalkyl; Here, L 2 If does not exist, R 3b is not hydrogen, and Here, A 1 , A 2 , A 3 , and A 4 are -CH-, and ring J is [ka] and L 1 is -NH-, and L 2 is -C(O)-, -C(O)O-, or -S(O) 2 - If, then each R 3a is H].

[0007] In another embodiment, the present invention provides a compound of formula I: [ka] or a pharma- ceutical acceptable salt thereof, R 1 are each independently hydrogen, C 1-6 Alkoxy, halogen, -OH, and -C(O)N(R1b )(R 1c ) 1 to 5 R 1a phenyl or pyridyl substituted with a group; Each R 1b and R 1c are independently hydrogen, C 1-6 alkyl, or 3-8 membered heterocycloalkyl having 1-3 heteroatoms, each independently N, O, or S; A 1 , A 2 , A 3 , and A 4 are each 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, or -CN; Ring J is a 3-10 membered heterocycloalkyl having 1-3 heteroatoms, each independently N, O, or S, where at least one heteroatom is N, and wherein ... 3a and R 3b optionally substituted with a group; Each R 3a is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3a1 , -C(O)OR 3a1 , -C(O)N(R 3a1 )(R 3a2 ), Oxo, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each alkenyl and alkynyl is C 6-12 optionally substituted with aryl or heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each of which is independently N, O, or S, and where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each of which is independently N, O, or S; Each R 3a1 and R 3a2 are independently hydrogen or C 1-6 is alkyl; Alternatively, two Rs attached to the same atom 3a The groups, together with the atoms to which they are attached, form C 3-6 Can form a cycloalkyl; Alternatively, two Rs attached to different atoms 3a The groups, together with the atoms to which they are attached, form C 3-10 cycloalkyl, or 3-10 membered heterocycloalkyl having 1-4 heteroatoms, each independently N, O, or S, each of which can be 1-4 R 3a3 is substituted with a group; Each R 3a3 are independently hydrogen or C 1-6 is alkyl; Each R 3b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3b1 , -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each independently N, O, or S, where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each independently N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 is alkyl; Or, R 3b1 and R 3b2 together with the atom to which they are attached form a 3-6 membered heterocycloalkyl having 1-2 additional heteroatoms, each independently N, O, or S; Each R 3b3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, or C 1-6 haloalkoxy; Or, R 3b is an R on an adjacent ring atom. 3a and each of which, together with the atom to which it is attached, is C substituted with 0 to 4 halogens. 3-6 Forming a cycloalkyl; R 4 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12aryl, or a 5-10 membered heteroaryl having 1-5 heteroatoms each independently being N, O, or S, wherein the heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-5 R 4a is substituted with a group; Each R 4a is hydrogen, 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, oxo, -C(O)R 4b , -C(O)OR 4b , -C(O)N(R 4b )(R 4c ), -S(O) 2 R 4b , -S(O) 2 N(R 4b )(R 4c ), C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl or -OC 6-12 aryl, where each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms which are each independently N, O, or S, and where each aryl is C 1-6 optionally substituted with alkoxy; Each R 4b and R 4c is hydrogen or C 1-6 is alkyl; L 1 is absent or -N(R 5a )-and; L 2 does not exist, -C(O)-, -C(O)-C 1-6 Alkylene-, C(O)-C 1-6Alkylene -O-, -C(O)O-, -C(O)N(R 5b )-, -S(O) 2 - or -S(O) 2 N(R 5b )--and R 5a and R 5b are each independently hydrogen, C 1-6 Alkyl or C 2-6 is an alkoxyalkyl.

[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, the method 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, the method 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 for 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] Detailed Description of the Invention I. Overview The present invention provides compounds of formula I 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 a disorder or condition by modulating, stimulating, 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 one of ordinary skill in the art to which this invention belongs. Furthermore, 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 not only aspects with one element but also aspects with two or more elements. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a "cell" includes a plurality of such cells, a reference to an "agent" includes a 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 group 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 1-6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl may 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" refers to an alkyl group having the indicated number of carbon atoms (i.e., C 1-6 means 1 to 6 carbons), a straight or branched, saturated, aliphatic group, i.e., a divalent hydrocarbon group, that links at least two other groups. The two moieties attached to the alkylene can be attached 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 C 2 , C 2-3 , C2-4 , 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 Alkenyl 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 6Examples 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 has been replaced with deuterium. With respect to the alkyl group, a deuteroalkyl group is a C 1-6 Exemplary C can have any suitable number of carbon atoms, such as 1-4 The deuterated alkyl group is not particularly limited, but may be, for example, -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 etc.

[0023] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment (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, isopropoxy, 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 group having an alkyl component and an alkoxy component, where the alkyl component links the alkoxy component to a point of attachment. The alkyl component is as defined above, except that it is at least a divalent alkylene to link the alkoxy component to a point of attachment. The alkyl component can have any number of carbons, e.g., C 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 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6 In some cases, the alkyl component may be absent. The alkoxy component 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, where at least one of the hydrogen atoms is replaced with a hydroxy group. With respect to the alkyl group, the hydroxyalkyl or alkylhydroxy group 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 (when hydroxy is in the 1- or 2-position), hydroxypropyl (when hydroxy is in the 1-, 2-, or 3-position), hydroxybutyl (when hydroxy is 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, the haloalkyl group is 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 group 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 an alkyl group, a haloalkoxy group is a C 1-6 The alkoxy group can 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 persubstituted, such as perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

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

[0030] "Alkylamine" refers to an alkyl group, as defined herein, having one or more amino groups. The amino groups can be primary, secondary, or tertiary. The alkylamines can be further substituted with hydroxy groups to form aminohydroxy groups. Alkylamines useful in the present invention include, but are not limited to, ethylamine, propylamine, iso-propylamine, ethylenediamine, and ethanolamine. The amino group can link the alkylamine to the point of attachment to the remainder of the compound, be in the omega position of the alkyl group, or link at least two carbon atoms of the alkyl group together. One of ordinary skill in the art will appreciate that other alkylamines are useful in the present invention.

[0031] "Heteroalkyl" refers to an alkyl group of any suitable length having 1-3 heteroatoms, such as N, O, and S. Heteroalkyl groups have the indicated number of carbon atoms with at least one non-terminal carbon replaced with a heteroatom. Additional heteroatoms can also be useful, including but not limited to B, Al, Si, and P. Heteroatoms also include, but are not limited to, -S(O)- and -S(O) 2 -, etc. For example, heteroalkyls can include ethers, thioethers, and alkylamines. Heteroalkyl groups do not include peroxides (-OO-) or other consecutively linked heteroatoms. The heteroatom portion of a heteroalkyl can replace a hydrogen on an alkyl group to form a hydroxy, thio, or amino group. Alternatively, the heteroatom portion can be the linking atom or inserted between two carbon atoms.

[0032] "Oxo" refers to the carbonyl group =O.

[0033] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic, or bridged polycyclic ring system containing 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, e.g., C 3-6 , C 4-6 , C 5-6 , C3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12 Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. The cycloalkyl group may also be partially unsaturated, having one or more double or triple bonds within the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. When the cycloalkyl is a 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.

[0034] "Alkyl-cycloalkyl" refers to a group having an alkyl component and a cycloalkyl component, where the alkyl component connects the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that it is at least divalent alkylene to connect to the alkoxy component and the point of attachment. In some cases, the alkyl component can be absent. The alkyl component can be any number of carbons, e.g., C 1-6 , C 1-2 , C 1-3 , C1-4 , C 1-5 , 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 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.

[0035] "Alkenyl-cycloalkyl" refers to a group having an alkenyl component and a cycloalkyl component, where the alkenyl component links the cycloalkyl component to a point of attachment. The alkenyl component is as defined above, except that it is at least divalent alkenylene to link the cycloalkyl component to the point of attachment. The alkenyl component can be any number of carbons, e.g., C 2-6 , 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 cycloalkyl moiety is as defined herein. Exemplary alkenylene-cycloalkyl groups include, but are not limited to, ethenylene-cyclopropyl, ethenylene-cyclobutyl, ethenylene-cyclopentyl, and ethenylene-cyclohexyl.

[0036] "Alkynyl-cycloalkyl" refers to a group having an alkynyl component and a cycloalkyl component, where the alkynyl component links the cycloalkyl component to a point of attachment. The alkynyl component is as defined above, except that the alkynyl component is at least divalent alkynylene to link the cycloalkyl component to the point of attachment. The alkynyl component can be any number of carbons, e.g., C 2-6 , 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 cycloalkyl moiety is as defined herein. Exemplary alkynylene-cycloalkyl groups include, but are not limited to, ethynyl-cyclopropyl, propynyl-cyclopropyl, ethynyl-cyclobutyl, ethynyl-cyclopentyl, and ethynyl-cyclohexyl.

[0037] "Heterocycloalkyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 5 heteroatoms of N, O, and S. Heteroatoms also include, for example, but not limited to, -S(O)- and -S(O) 2 Heterocycloalkyl groups can contain any number of ring atoms, for example, 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. Heterocycloalkyl groups can contain any suitable number of heteroatoms, such as 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, etc. Heterocycloalkyl groups can be 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 3-12Heterocycloalkyl groups can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, diazepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), 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, including but not limited to diazabicycloheptane, diazabicyclooctane, diazaspirooctane, or diazaspirononane. Heterocycloalkyl groups can also be unsubstituted or substituted. For example, heterocycloalkyl groups can be, in particular, C 1-6 It can be substituted with alkyl or oxo (=O). Heterocycloalkyl groups can also contain double or triple bonds, such as, but not limited to, dihydropyridine or 1,2,3,6-tetrahydropyridine.

[0038] The heterocycloalkyl group can be attached 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. In particular, tetrahydrofuran may be 1- or 2-tetrahydrofuran, oxazolidine may be 2-, 3-, 4-, or 5-oxazolidine, isoxazolidine may be 2-, 3-, 4-, or 5-isoxazolidine, thiazolidine may be 2-, 3-, 4-, or 5-thiazolidine, isothiazolidine may be 2-, 3-, 4-, or 5-isothiazolidine, and morpholine may be 2-, 3-, or 4-morpholine.

[0039] When a heterocycloalkyl contains 3 to 8 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, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. Heterocycloalkyls can also form rings with 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.

[0040] "Alkyl-heterocycloalkyl" refers to a group 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 it is at least a divalent alkylene to link the heterocycloalkyl component to the point of attachment. The alkyl component can have any number of carbons, such as 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 may be substituted or unsubstituted.

[0041] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups 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 or fused to form bicyclic or tricyclic groups, or joined by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl, which has a methylene linking group. Some aryl groups have 6 to 12 ring members, for example, phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, for example, phenyl or naphthyl. Some other aryl groups have 6 ring members, for example, phenyl. Aryl groups can be substituted or unsubstituted.

[0042] "Alkylaryl" refers to a group having an alkyl component and an aryl component, where the alkyl component links the aryl component to a point of attachment. The alkyl component is as defined above, except that it is at least divalent alkylene to link the aryl component to the point of attachment. The alkyl component can have any number of carbons, e.g., 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 aryl component 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.

[0043] "Alkenylaryl" refers to a group having both an alkenyl and an aryl component, where the alkenyl component links the aryl component to a point of attachment. The alkenyl component is as defined above, except that it is at least divalent alkenylene to link the aryl component and the point of attachment. The alkenyl component can be any number of carbons, e.g., C 2-6 , 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. The alkenyl-aryl group may be substituted or unsubstituted.

[0044] "Alkynyl-aryl" refers to a group having both an alkynyl and an aryl component, where the alkynyl component links the aryl component to a point of attachment. The alkynyl component is as defined above, except that it is at least divalent to link to the aryl component and to the point of attachment. The alkynyl component can be any number of carbons, e.g., C 2-6 , 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. The alkynyl-aryl group may be substituted or unsubstituted.

[0045] "Alkoxyalkyl-aryl" refers to a group having an alkoxyalkyl moiety and an aryl moiety, where the alkoxyalkyl moiety links the aryl moiety to a point of attachment. The alkoxyalkyl moiety is as defined above, except that it is at least divalent to link the aryl moiety to the point of attachment. The alkoxyalkyl moiety can have any number of carbons, e.g., C 2-6 , 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. The alkoxyalkyl-aryl group may be substituted or unsubstituted.

[0046] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring system containing 5 to 16 ring atoms, where 1 to 5 of the ring atoms are heteroatoms such as N, O, or S. Heteroatoms also include, for example, but are not limited to, -S(O)- and -S(O) 2-. Heteroaryl groups can contain any number of carbons, for example, 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 can be included in the heteroaryl group, such as 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-, 1,2,4-, and 1,3,5-isomers), 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.

[0047] 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, furan includes 2- and 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-indole, isoindoles include 1- and 2-isoindole, 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.

[0048] 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-, 1,2,4-, and 1,3,5-isomers), 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 8 ring members and 1 to 3 ring atoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), 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.

[0049] "Alkyl-heteroaryl" refers to a group having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to a point of attachment. The alkyl component is as defined above, except that it is at least divalent alkylene to link the heteroaryl component and the point of attachment. The alkyl component can have any number of carbons, e.g., C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C2-4 , 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. The alkyl-heteroaryl group may be substituted or unsubstituted.

[0050] "Pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to and absorption by a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, surfactants, coating agents, sweeteners, flavoring agents, and coloring agents. One of ordinary skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0051] "Treate", "treating", and "treatment" refer to an indication of success in treating or ameliorating an injury, condition, or state, and include any objective or subjective parameter, such as relief; remission; reduction in symptoms or making the injury, condition, or state more tolerable to the patient; slowing the rate of degeneration or decline; reducing the debilitating end point of degeneration; improving the physical or mental well-being of the patient. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of medical examinations, neuropsychiatric testing, and / or psychiatric evaluations.

[0052] "Administration" 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.

[0053] "Therapeutically effective amount" refers to the dosage that produces the therapeutic effect that it is administered. The exact dosage 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.

[0054] "Glucocorticoid receptor" ("GR") refers to one of 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.

[0055] 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, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292).

[0056] "Mineralocorticoid receptor" (MR) refers to the type I glucocorticoid receptor (GRI), which is activated by aldosterone in humans.

[0057] "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 or both. For example, GRM acting as an agonist, such as dexamethasone, increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (a human liver hepatoma 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 A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0058] "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 can be GR. Thus, GR antagonists can be identified by measuring the ability of a compound to inhibit the action of dexamethasone. TAT activity can be measured as outlined in A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. Inhibitors have an IC of less than 10 micromolar. 50 (half maximal 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.

[0059] "Modulate" and "modulating" are used according to their plain ordinary meaning and refer to the act of changing or altering one or more properties. "Modulation" refers to the process of changing or altering one or more properties. For example, when applied to the action 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.

[0060] "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 the target of the molecule.

[0061] "Antagonize" and "antagonizing" refer to inhibiting the binding of an agonist at a receptor molecule or inhibiting the signal generated by the receptor-agonist. Receptor antagonists inhibit or suppress agonist-mediated responses, such as gene expression.

[0062] "Antagonist" refers to a substance that can detectably reduce the expression or activity of a given gene or protein. An antagonist 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 the antagonist. In some embodiments, inhibition is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more, of the expression or activity in the absence of the antagonist.

[0063] "Inhibit," "inhibit," and "inhibitor" refer to a compound or method that prevents a particular action or function.

[0064] "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, obesity, hypertension, depression, anxiety, and Cushing's syndrome. In some embodiments, the disorder or condition includes non-alcoholic liver disease and / or non-alcoholic steatohepatitis. In some embodiments, the disorder or condition includes an addictive disorder. In some embodiments, the disorder or condition includes cancer.

[0065] "Pharmaceutical product" refers to a composition or substance used in the treatment of a disease or condition.

[0066] "Subject" refers to an 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, bovines, rats, mice, dogs, monkeys, goats, sheep, cows, deer, horses, and other non-mammals. In some embodiments, the patient is a human.

[0067] III.Compound In some embodiments, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt thereof: [ka] [In the formula, R 1 is a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms each being N, O, or S, phenyl, or a heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each being N, O, or S, each independently consisting of 1 to 5 R 1a is substituted with a group; Each R 1a are independently hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6Alkoxyalkyl, 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 8 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 3-8 membered heterocycloalkyl having 1-3 heteroatoms, each independently N, O, or S; A 1 , A 2 , A 3 , and A 4 are each 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, or -CN; Ring J is a 3-10 membered heterocycloalkyl having 1-3 heteroatoms, each independently N, O, or S, where at least one heteroatom is N, and wherein ... 3a and R 3b optionally substituted with a group; Each R 3a are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3a1 , -C(O)OR 3a1 , -C(O)N(R 3a1 )(R3a2 ), -OH, oxo, 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 alkenyl and alkynyl is C 6-12 optionally substituted with aryl or heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each of which is independently N, O, or S, and where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each of which is independently N, O, or S; Each R 3a1 and R 3a2 are independently hydrogen or C 1-6 is alkyl; Alternatively, two Rs attached to the same atom 3a The groups, together with the atoms to which they are attached, form C 3-6 Can form a cycloalkyl; Alternatively, two Rs attached to different atoms 3a The groups, together with the atoms to which they are attached, form C 3-10 cycloalkyl, or 3-10 membered heterocycloalkyl having 1-4 heteroatoms, each independently N, O, or S, each of which can be 1-4 R 3a3 is substituted with a group; Each R 3a3 are independently hydrogen or C 1-6 is alkyl; Each R 3b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R3b1 , -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, C 2-6 Alkynyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, C 2-6 Alkenyl-C 6-12 Aryl, C 2-6 Alkynyl-C 6-12 Aryl, C 1-6 Alkyl-OC 6-12 Aryl, C 1-6 Alkoxyalkyl-C 6-12 Aryl, -C(O)-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each independently N, O, or S, where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each independently N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 is alkyl; Or, R 3b1 and R 3b2 together with the atom to which they are attached form a 3-6 membered heterocycloalkyl having 1-2 additional heteroatoms, each independently N, O, or S; Each R 3b3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6Hydroxyalkyl, halogen, C 1-6 Haloalkyl, or C 1-6 haloalkoxy; Or, R 3b is an R on an adjacent ring atom. 3a and each of which, together with the atom to which it is attached, is C substituted with 0 to 4 halogens. 3-6 Forming a cycloalkyl; R 4 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -CN, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12 aryl, or a 5-10 membered heteroaryl having 1-5 heteroatoms each independently being N, O, or S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-5 R 4a is substituted with a group; Each R 4a is hydrogen, C 1-6 Alkyl, C 1-6 Deuterated 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 , -C(O)N(R 4b )(R 4c ), -S(O) 2 R 4b , -S(O) 2 N(R 4b )(R 4c ), 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, -OC 6-12 Aryl, Heteroaryl, C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms that are each independently N, O, or S, where each heteroaryl independently has 5 to 8 ring members and 1 to 4 heteroatoms that are each independently N, O, or S, and where each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is selected from the group consisting of C 1-6 optionally substituted with alkoxy; Each R 4b and R 4c is hydrogen or C 1-6 is alkyl; L 1 is absent or -N(R 5a )-and; L 2 does not exist, and C 1-6 Alkylene, -C(O)-, -C(O)-C 1-6 Alkylene-, C(O)-C 1-6 Alkylene -O-, -C(O)O-, -C(O)N(R 5b )-, -S(O) 2 - or -S(O) 2 N(R 5b )--and R 5a and R 5b are each independently hydrogen, C 1-6 Alkyl or C 2-6 is an alkoxyalkyl; Here, L 2 If does not exist, R 3b is not hydrogen, and Here, A 1 , A 2 , A 3 , and A 4 are -CH-, and ring J is [ka] and L 1 is -NH-, and L 2 is -C(O)-, -C(O)O-, or -S(O) 2 - If, then each R 3a is H].

[0068] In some embodiments, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt thereof: [ka] [In the formula, R 1 are each independently hydrogen, C 1-6 Alkoxy, halogen, -OH, and -C(O)N(R 1b )(R 1c ) 1 to 5 R 1a phenyl or pyridyl substituted with a group; Each R 1b and R 1c are independently hydrogen, C 1-6 alkyl, or 3-8 membered heterocycloalkyl having 1-3 heteroatoms, each independently N, O, or S; A 1 , A 2 , A 3 , and A 4 are each 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, or -CN; Ring J is a 3-10 membered heterocycloalkyl having 1-3 heteroatoms, each independently N, O, or S, where at least one heteroatom is N, and wherein ... 3a and R 3boptionally substituted with a group; Each R 3a is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3a1 , -C(O)OR 3a1 , -C(O)N(R 3a1 )(R 3a2 ), Oxo, 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 alkenyl and alkynyl is C 6-12 optionally substituted with aryl or heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each of which is independently N, O, or S, and where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each of which is independently N, O, or S; Each R 3a1 and R 3a2 are independently hydrogen or C 1-6 is alkyl; Alternatively, two Rs attached to the same atom 3a The groups, together with the atoms to which they are attached, form C 3-6 Can form a cycloalkyl; Alternatively, two Rs attached to different atoms 3a The groups, together with the atoms to which they are attached, form C 3-10 cycloalkyl, or 3-10 membered heterocycloalkyl having 1-4 heteroatoms, each independently N, O, or S, each of which can be 1-4 R 3a3 is substituted with a group; Each R 3a3 are independently hydrogen or C 1-6 is alkyl; Each R 3b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3b1 , -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), 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 has 3-8 ring members and 1-3 heteroatoms, each independently N, O, or S, where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each independently N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 is alkyl; Or, R 3b1 and R 3b2 together with the atom to which they are attached form a 3-6 membered heterocycloalkyl having 1-2 additional heteroatoms, each independently N, O, or S; Each R 3b3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6Hydroxyalkyl, halogen, C 1-6 Haloalkyl, or C 1-6 haloalkoxy; Or, R 3b is an R on an adjacent ring atom. 3a and each of which, together with the atom to which it is attached, is C substituted with 0 to 4 halogens. 3-6 Forming a cycloalkyl; R 4 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12 aryl, or a 5-10 membered heteroaryl having 1-5 heteroatoms each independently being N, O, or S, wherein the heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-5 R 4a is substituted with a group; Each R 4a is hydrogen, 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, oxo, -C(O)R 4b , -C(O)OR 4b , -C(O)N(R 4b )(R 4c ), -S(O) 2 R 4b , -S(O) 2 N(R 4b )(R 4c ), C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl or -OC6-12 aryl, where each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms which are each independently N, O, or S, and where each aryl is C 1-6 optionally substituted with alkoxy; Each R 4b and R 4c is hydrogen or C 1-6 is alkyl; L 1 is absent or -N(R 5a )-and; L 2 does not exist, -C(O)-, -C(O)-C 1-6 Alkylene-, C(O)-C 1-6 Alkylene -O-, -C(O)O-, -C(O)N(R 5b )-, -S(O) 2 - or -S(O) 2 N(R 5b )--and R 5a and R 5b are each independently hydrogen, C 1-6 Alkyl or C 2-6 is an alkoxyalkyl.

[0069] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, V, VI, or VII, or a pharma- ceutically acceptable salt thereof, is 1 are independently hydrogen, C 1-6 Alkoxy, halogen, -OH, and -C(O)N(R 1b )(R 1c ) 1 to 5 R 1a phenyl or pyridyl, each independently substituted with a group, and each R 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.

[0070] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, V, VI, or VII, or a pharma- ceutically acceptable salt thereof, is 1 are independently hydrogen, C 1-6 Alkoxy, halogen, or -C(O)N(R 1b )(R 1c ) 1 to 5 R 1a and each R 1b and R 1c are compounds in which R can be independently hydrogen or a 4-6 membered heterocycloalkyl having 1-3 rings, each independently being N, O, or S. In some embodiments, the compound of Formula I or II, or a pharma- ceutical acceptable salt thereof, is a compound of Formula I or II, wherein R 1 In some embodiments, the compound of formula I or II, or a pharma- ceutical acceptable salt thereof, is a compound of formula I or II, wherein R 1 In some embodiments, the compound of formula I or II, or a pharma- ceutical acceptable salt thereof, is a compound of formula I or II, wherein R 1 is 4-fluoro-phenyl.

[0071] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVg, V, VI, or VII, or a pharma- ceutically acceptable salt thereof, is 1 but, [ka] It is a compound wherein

[0072] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVg, V, VI, or VII, or a pharma- ceutically acceptable salt thereof, is 1 but, [ka] It is a compound wherein

[0073] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, is 1 , A 2 , A 3 , and A 4 However, each is 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 Compounds that are haloalkoxy, hydroxy, or -CN.

[0074] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, is 1 , A 2 , A 3 , and A 4 Each of these is independently =CR 2 In some embodiments, the compound of Formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, is a compound of Formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, wherein A 1 , A 2 , A 3 , and A 4 Each of these is =CR 2 In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, is a compound having the formula 1 , A 2 , A 3 , and A 4 In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, wherein1 can be =N-, A 2 , A 3 , and A 4 Each of these is =CR 2 In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, is a compound having the formula: 1 , A 3 , and A 4 Each of these is =CR 2 - may be A 2 In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutically acceptable salt thereof, wherein A 1 , A 2 , and A 4 Each of these is =CR 2 - may be A 3 In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, is a compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, wherein A is a substituted or unsubstituted aryl group; 1 , A 2 , and A 3 GA=CR 2 A 4 is a compound in which =N- may be present.

[0075] In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVg, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, is 2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or C 1-6In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVg, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVg, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, wherein at least one R 2 But, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or C 1-6 In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, or IIc-2, or a pharma- ceutically acceptable salt thereof, is a compound having a formula: 2 are independently hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogen, or C 1-3 In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVg, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, is a compound having the formula: 2 are independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, n-propoxy, iso-propoxy, F, Cl, Br, -OCH 2 F, -OCHF 2 , or -OCF 3 In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVg, V, VI, or VII, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVg, V, VI, or VII, or a pharma- ceutically acceptable salt thereof, 2 are independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, n-propoxy, iso-propoxy, F, Cl, Br, -OCH 2 F, -OCHF 2 , -OCF 3 or -CN.

[0076] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, is 1 , A 2 , A 3 , and A 4 However, each is independently =CR 2 - or =N-; and each R 2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or C 1-6 In some embodiments, the compound of formula I or II or a pharma- ceutical acceptable salt thereof is a compound having a structure represented by the formula: A 1 , A 2 , A 3 , and A 4 Each of the -CR 2- It is a compound wherein

[0077] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, is 1 is =CH- or =N; A 2 and A 4 are each independently =CH-, =C(Me)-, or =N-; A 3 are =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, =C(F)-, =C(Cl)-, =C(OCHF 2 In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutically acceptable salt thereof, is a compound wherein A is -, or =N-, or =N-. 1 , A 2 and A 4 are =CH- and A 3 is =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, =C(F)-, =C(Cl)-, or =C(OCHF 2In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutically acceptable salt thereof, is a compound having the formula: 1 is ═CH— or ═N—; A 2 and A 4 are each independently =CH-, =C(Me)-, or =N-; and A 3 is =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, =C(Cl)-, =C(OCHF 2 )-, or =N-.

[0078] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutical acceptable salt thereof, is 1 is ═CH— or ═N—; A 2 and A 4 are =CH- and A 3 In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII, wherein A is a phenyl group, 1 , A 2 , and A 4 are =CH- and A 3 is =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, or =C(F)-.

[0079] In some embodiments, the compound of formula I or II, or a pharma- ceutical acceptable salt thereof, is Ring J is a 3-10 membered heterocycloalkyl having 1-3 heteroatoms which are each independently N, O, or S, where at least one heteroatom is N, and wherein ... 3a and R 3b optionally substituted with a group; Each R 3aBut hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3a1 , -C(O)OR 3a1 , -C(O)N(R 3a1 )(R 3a2 ), Oxo, 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 alkenyl and alkynyl is C 6-12 optionally substituted with aryl or heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each of which is independently N, O, or S, and where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each of which is independently N, O, or S; Each R 3a1 and R 3a2 are independently hydrogen or C 1-6 is alkyl; Alternatively, two Rs attached to the same atom 3a The groups, together with the atoms to which they are attached, form C 3-6 Can form a cycloalkyl; Alternatively, two Rs attached to different atoms 3a The groups, together with the atoms to which they are attached, form C 3-10 cycloalkyl, or 3-10 membered heterocycloalkyl having 1-4 heteroatoms, each independently N, O, or S, each of which can be 1-4 R 3a3 is substituted with a group; Each R 3a3are independently hydrogen or C 1-6 is alkyl; Each R 3b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3b1 , -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), 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 has 3-8 ring members and 1-3 heteroatoms, each independently N, O, or S, where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each independently N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 is alkyl; Or, R 3b1 and R 3b2 together with the atom to which they are attached form a 3-6 membered heterocycloalkyl having 1-2 additional heteroatoms, each independently N, O, or S; Each R 3b3 But hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6Haloalkyl, or C 1-6 haloalkoxy; Or, R 3b R on the adjacent ring atom 3a and each of which, together with the atom to which it is attached, is C substituted with 0 to 4 halogens. 3-6 It is a compound that forms a cycloalkyl.

[0080] In some embodiments, the compound of Formula I or II, or a pharma- ceutical acceptable salt thereof, is a C 1 -C 2 -C ... 3-8 heterocycloalkyl, where ring J is optionally selected from 1 to 13 R 3a and R 3b In some embodiments, the compound of formula I or II or a pharma- ceutically acceptable salt thereof is a compound in which ring J is a C 1 -C 2 -containing nitrogen ring atom. 5-8 Heterocycloalkyl, ring J may be one of 13 R 3a and R 3b In some embodiments, the compound of formula I or II or a pharma- ceutically acceptable salt thereof is a compound in which ring J can be aziridine, azetidine, pyrrolidine, imidazolidine, piperidine, 1,2,3,6-tetrahydropyridine, piperazine, azepane, diazepane, azocane, diazabicycloheptane, diazabicyclooctane, diazaspiroctane, or diazaspirononane, and ring J can be 1 to 13 R 3a and R 3b In some embodiments, the compound of formula I or II or a pharma- ceutically acceptable salt thereof is a compound in which ring J can be pyrrolidine, imidazolidine, piperidine, 1,2,3,6-tetrahydropyridine, piperazine, azepane, diazepane, azocane, diazabicycloheptane, diazabicyclooctane, diazaspiroctane, or diazaspirononane, and ring J can be 1 to 13 R 3a and R 3b The compound may be optionally substituted with a group.

[0081] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound in which ring J has the structure: [ka] [In the formula, L 3a and L 3b are -C(R 3a3 )(R 3a3 )- and each R 3a3 are independently hydrogen or C 1-6 alkyl; and the subscripts r and s are each independently 0, 1, or 2, such that the sum of r and s is 2.

[0082] In some embodiments, the compound of Formula I or II, or a pharma- ceutical acceptable salt thereof, comprises each R 3a But hydrogen, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)OR 3a1 , Oxo, C 6-12 Aryl or C 1-6 Alkyl-C 6-12 aryl; or two R 3a The groups, together with the atoms to which they are attached, form C 3-6 can form a cycloalkyl; R 3a1 is hydrogen or C 1-6 R is alkyl; 3b But hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), C 1-6 Alkyl-C 6-12 Aryl, C 1-6alkyl-heteroaryl, where each heteroaryl has 5-10 ring members and 1-5 heteroatoms that are each independently N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl; or R 3b1 and R 3b2 together with the atom to which they are attached form a 3- to 6-membered heterocycloalkyl having 1-2 additional heteroatoms which are each independently N, O, or S; 3b3 But hydrogen, C 1-6 Alkyl, halogen, or C 1-6 haloalkyl; and / or R 3b R on the adjacent ring atom 3a and each of which, together with the atom to which it is attached, is C substituted with 0 to 4 halogens. 3-6 It is a compound that forms a cycloalkyl.

[0083] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is a compound in which ring J has the structure: [ka] [where, X 1 and X 2 are each independently -CR 3b - or -N-, where X 1 and X 2 at least one of is -N-; and the subscripts p and q are each independently 0, 1, or 2.

[0084] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is a compound of the formula, wherein the compound of formula I is a compound of formula II: [ka] [where, X 1and X 2 are each independently -CR 3b - or -N-, where X 1 and X 2 at least one of is -N-; and the subscripts p and q are each independently 0, 1, or 2.

[0085] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is a compound of the formula, wherein the compound of formula I is a compound of formula II: [ka] [where, X 1 and X 2 are each independently -CR 3b - or -N-, where X 1 and X 2 at least one of is -N-; and the subscripts p and q are each independently 0, 1, or 2, and 1 , A 2 , A 3 , and A 4 are -CH- and X 1 is N and X 2 is -CH-, the sum of the subscripts p and q is 1, and L 1 is -NH-, and L 2 is -C(O)-, -C(O)O-, or -S(O) 2 - If, then each R 3a is H].

[0086] In some embodiments, the compound of formula I or II, or a pharma- ceutically acceptable salt thereof, is 1 -CR 3b - and X 2 In some embodiments, the compound of formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound in which X can be -N-. In some embodiments, the compound of formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound in which X can be -N-. 1 can be -N-, and X 2 -CR3b In some embodiments, the compound of formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound that can be represented by the formula I or II, or a pharma- ceutically acceptable salt thereof, X 1 and X 2 is a compound which is a compound which can be -N-.

[0087] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound in which ring J has the structure: [ka] [In the formula, L 3a and L 3b are -C(R 3a3 )(R 3a3 )- and each R 3a3 are independently hydrogen or C 1-6 alkyl; and the subscripts r and s are each independently 0, 1, or 2, such that the sum of r and s is 2.

[0088] In some embodiments, the compound of or a pharma- ceutically acceptable salt thereof has the structure: [ka] [In the formula, X 2 -CR 3b -or -N-; and the subscripts p, q, r, r1, s, and s1 are each independently 0, 1, or 2, such that the sum of r and s is 2 or 3, and the sum of r1 and s1 is 2 or 3; Here, A 1 , A 2 , A 3 , and A 4 are -CH- and X 2 is -CH-, the sum of the subscripts p and q is 1, and L 1 is -NH-, and L 2 is -C(O)-, -C(O)O-, or -S(O)2 - If, then each R 3a is H].

[0089] In some embodiments, the present invention provides a compound of formula III, formula IV, formula V, formula VI, or formula VII, or a pharma- ceutically acceptable salt thereof: [ka] [In the formula, R 1 is a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms each being N, O, or S, phenyl, or a heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each being N, O, or S, each independently consisting of 1 to 5 R 1a is substituted with a group; Each R 1a are independently hydrogen, C 1-6 Alkyl, C 1-6 Deuterated 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 8 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 3-8 membered heterocycloalkyl having 1-3 heteroatoms, each independently N, O, or S; A 1 , A 2 , A 3 , and A 4 are each independently =CR 2 - or =N-; Each R 2 are independently hydrogen, C1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 haloalkoxy, hydroxy, or -CN; Each R 3a are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3a1 , -C(O)OR 3a1 , -C(O)N(R 3a1 )(R 3a2 ), -OH, oxo, 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 alkenyl and alkynyl is C 6-12 optionally substituted with aryl or heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each of which is independently N, O, or S, and where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each of which is independently N, O, or S; Each R 3a1 and R 3a2 are independently hydrogen or C 1-6 is alkyl; Alternatively, two Rs attached to the same atom 3a The groups, together with the atoms to which they are attached, form C 3-6 Can form a cycloalkyl; Alternatively, two Rs attached to different atoms 3aThe groups, together with the atoms to which they are attached, form C 3-10 cycloalkyl, or 3-10 membered heterocycloalkyl having 1-4 heteroatoms, each independently N, O, or S, each of which can be 1-4 R 3a3 is substituted with a group; Each R 3a3 are independently hydrogen or C 1-6 is alkyl; Each R 3b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3b1 , -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, C 2-6 Alkynyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, C 2-6 Alkenyl-C 6-12 Aryl, C 2-6 Alkynyl-C 6-12 Aryl, C 1-6 Alkyl-OC 6-12 Aryl, C 1-6 Alkoxyalkyl-C 6-12 Aryl, -C(O)-C 6-12 Aryl, heteroaryl, or C 1-6alkyl-heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each independently N, O, or S, where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each independently N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 is alkyl; Or, R 3b1 and R 3b2 together with the atom to which they are attached form a 3-6 membered heterocycloalkyl having 1-2 additional heteroatoms, each independently N, O, or S; Each R 3b3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, or C 1-6 haloalkoxy; Or, R 3b is an R on an adjacent ring atom. 3a and each of which, together with the atom to which it is attached, is C substituted with 0 to 4 halogens. 3-6 Forming a cycloalkyl; X 2 CR 3b -or -N-; the subscripts p, q, r, r1, s, and s1 are each independently 0, 1, or 2, such that the sum of r and s is 2 or 3, and the sum of r1 and s1 is 2 or 3; R 4 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -CN, C 3-8cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12 aryl, or a 5-10 membered heteroaryl having 1-5 heteroatoms each independently being N, O, or S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-5 R 4a is substituted with a group; Each R 4a is hydrogen, C 1-6 Alkyl, C 1-6 Deuterated 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 , -C(O)N(R 4b )(R 4c ), -S(O) 2 R 4b , -S(O) 2 N(R 4b )(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, -OC 6-12 Aryl, Heteroaryl, C 1-6alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms that are each independently N, O, or S, where each heteroaryl independently has 5 to 8 ring members and 1 to 4 heteroatoms that are each independently N, O, or S, and where each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is selected from the group consisting of C 1-6 optionally substituted with alkoxy; Each R 4b and R 4c is hydrogen or C 1-6 is alkyl; L 1 is absent or -N(R 5a )-and; L 2 does not exist, and C 1-6 Alkylene, -C(O)-, -C(O)-C 1-6 Alkylene-, C(O)-C 1-6 Alkylene -O-, -C(O)O-, -C(O)N(R 5b )-, -S(O) 2 - or -S(O) 2 N(R 5b )--and R 5a and R 5b are each independently hydrogen, C 1-6 Alkyl or C 2-6 is an alkoxyalkyl; Here, L 2 If does not exist, R 3b is not hydrogen, and Here, A 1 , A 2 , A 3 , and A 4 are -CH- and X 2 is -CH-, the sum of the subscripts p and q is 1, and L 1 is -NH-, and L 2 is -C(O)-, -C(O)O-, or -S(O) 2 - If, then each R 3a is H].

[0090] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, has the structure: [ka] [ka] [In the formula, X 2 HA-CR 3b -or -N-; and The subscripts p, q, r, r1, s, and s1 are each independently 0, 1, or 2, such that the sum of r and s is 2 or 3, and the sum of r1 and s1 is 2 or 3.

[0091] In some embodiments, the present invention provides a compound of formula IIIa, IIIb, IV, V, VI, or VII, or a pharma- ceutically acceptable salt thereof: [ka] [ka] [In the formula, R 1 is a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms each being N, O, or S, phenyl, or a heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each being N, O, or S, each independently consisting of 1 to 5 R 1a is substituted with a group; Each R 1a are independently hydrogen, C 1-6 Alkyl, C 1-6 Deuterated 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 ), C3-10 cycloalkyl or heterocycloalkyl having 3 to 8 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 3-8 membered heterocycloalkyl having 1-3 heteroatoms, each independently N, O, or S; A 1 , A 2 , A 3 , and A 4 are each 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, or -CN; Each R 3a are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3a1 , -C(O)OR 3a1 , -C(O)N(R 3a1 )(R 3a2 ), -OH, oxo, 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 alkenyl and alkynyl is C 6-12optionally substituted with aryl or heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each of which is independently N, O, or S, and where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each of which is independently N, O, or S; Each R 3a1 and R 3a2 are independently hydrogen or C 1-6 is alkyl; Alternatively, two Rs attached to the same atom 3a The groups, together with the atoms to which they are attached, form C 3-6 Can form a cycloalkyl; Alternatively, two Rs attached to different atoms 3a The groups, together with the atoms to which they are attached, form C 3-10 cycloalkyl, or 3-10 membered heterocycloalkyl having 1-4 heteroatoms, each independently N, O, or S, each of which can be 1-4 R 3a3 is substituted with a group; Each R 3a3 are independently hydrogen or C 1-6 is alkyl; Each R 3b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3b1 , -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, C 2-6 Alkynyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C6-12 Aryl, C 2-6 Alkenyl-C 6-12 Aryl, C 2-6 Alkynyl-C 6-12 Aryl, C 1-6 Alkyl-OC 6-12 Aryl, C 1-6 Alkoxyalkyl-C 6-12 Aryl, -C(O)-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each independently N, O, or S, where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each independently N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 is alkyl; Or, R 3b1 and R 3b2 together with the atom to which they are attached form a 3-6 membered heterocycloalkyl having 1-2 additional heteroatoms, each independently N, O, or S; Each R 3b3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, or C 1-6 haloalkoxy; Or, R 3b is an R on an adjacent ring atom. 3a and each of which, together with the atom to which it is attached, is C substituted with 0 to 4 halogens. 3-6 Forming a cycloalkyl; X 2 CR 3b -or -N-; the subscripts p, q, r, r1, s, and s1 are each independently 0, 1, or 2, such that the sum of r and s is 2 or 3, and the sum of r1 and s1 is 2 or 3; R 4 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -CN, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12 aryl, or a 5-10 membered heteroaryl having 1-5 heteroatoms each independently being N, O, or S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-5 R 4a is substituted with a group; Each R 4a is hydrogen, C 1-6 Alkyl, C 1-6 Deuterated 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 , -C(O)N(R 4b )(R 4c ), -S(O) 2 R 4b , -S(O) 2 N(R 4b )(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, -OC 6-12Aryl, Heteroaryl, C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms that are each independently N, O, or S, where each heteroaryl independently has 5 to 8 ring members and 1 to 4 heteroatoms that are each independently N, O, or S, and where each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is selected from the group consisting of C 1-6 optionally substituted with alkoxy; Each R 4b and R 4c is hydrogen or C 1-6 is alkyl; L 1 is absent or -N(R 5a )-and; L 2 does not exist, and C 1-6 Alkylene, -C(O)-, -C(O)-C 1-6 Alkylene-, C(O)-C 1-6 Alkylene -O-, -C(O)O-, -C(O)N(R 5b )-, -S(O) 2 - or -S(O) 2 N(R 5b )--and R 5a and R 5b are each independently hydrogen, C 1-6 Alkyl or C 2-6 is an alkoxyalkyl; Here, L 2 If does not exist, R 3b is not hydrogen].

[0092] In some embodiments, the compound of formula I or II, or a pharma- ceutically acceptable salt thereof, is 3a and L 3b Each independently is -CH 2 -, -CH(Me)-, or C(Me) 2In some embodiments, the compound of formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound of formula I or II, or a pharma- ceutically acceptable salt thereof, wherein L 3a and L 3b are CH 2 - is a compound that may be a compound.

[0093] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, IVc, or V, or a pharma- ceutically acceptable salt thereof, is 3a But hydrogen, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)OR 3a1 , C 6-12 Aryl or C 1-6 Alkyl-C 6-12 Aryl; R 3a1 is hydrogen or C 1-6 R is alkyl; 3b But hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), C 1-6 Alkyl-C 6-12 Aryl, C 1-6 alkyl-heteroaryl, where each heteroaryl has 5-10 ring members and 1-5 heteroatoms that are each independently N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl; or R 3b1 and R 3b2together with the atom to which they are attached form a 3-6 membered heterocycloalkyl having 1-2 additional heteroatoms which are each independently N, O, or S; and each R 3b3 But hydrogen, C 1-6 Alkyl, halogen, or C 1-6 haloalkyl; or R 3b R on the adjacent ring atom 3a and each of which, together with the atom to which it is attached, is C substituted with 0 to 4 halogens. 3-6 It is a compound that forms a cycloalkyl.

[0094] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound in which ring J has the structure: [ka]

[0095] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, IVc, or V, or a pharma- ceutically acceptable salt thereof, is 3a But hydrogen, C 1-6 Alkyl, C 2-3 Alkoxyalkyl, C 1-3 Hydroxyalkyl, -C(O)OR 3a1 , Oxo, C 6-12 Aryl or C 1-2 Alkyl-C 6-12 aryl; or two R 3a The groups, together with the atoms to which they are attached, form C 3-4 can form a cycloalkyl; R 3a1 is hydrogen or C 1-3 alkyl; and R 3b In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, IVc, or V, or a pharma- ceutically acceptable salt thereof, is a compound wherein each R 3aare independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, -CH 2 OMe, -CH 2 OEt, -CH 2 OPr, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, oxo, -C(O)OMe, -C(O)OEt, -C(O)O n Pr, phenyl, or benzyl; or two R 3a In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, IVc, or V, or a pharma- ceutically acceptable salt thereof, is a compound in which each R 3a is hydrogen, methyl, iso-butyl, -CH 2 OMe, -CH 2 OH, oxo, -C(O)OMe, phenyl, or benzyl; or two R 3a The groups, together with the atoms to which they are attached, form C 3-4 can form a cycloalkyl; and R 3b is a compound in which

[0096] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound in which ring J has the structure: [ka] [In the formula, each R 3a is hydrogen, methyl, iso-butyl, -CH 2 OMe, -CH 2 OH, oxo, -C(O)OMe, phenyl, or benzyl.

[0097] In some embodiments, the compound of Formula I, II, III, IIIa, IIIb, or V, or a pharma- ceutically acceptable salt thereof, is 3a is hydrogen or methyl; and R 3b is a compound in which

[0098] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound in which ring J has the structure: [ka]

[0099] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound in which ring J has the structure: [ka]

[0100] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound in which ring J has the structure: [ka]

[0101] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound in which ring J has the structure: [ka]

[0102] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVg, or a pharma- ceutically acceptable salt thereof, is Each R 3a is hydrogen; R3b But, C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), C 2-6 Alkynyl-C 3-6 Cycloalkyl, C 1-6 Alkyl-C 6-12 Aryl, C 2-6 Alkenyl-C 6-12 Aryl, C 2-6 Alkynyl-C 6-12 Aryl, C 1-6 Alkyl-OC 6-12 Aryl, C 1-6 Alkoxyalkyl-C 6-12 Aryl, -C(O)-C 6-12 Aryl or C 1-6 alkyl-heteroaryl, where each heteroaryl contains 5-10 ring members and 1-5 heteroatoms, each independently N, O, or S, and where each aryl and heteroaryl contains 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 is alkyl; Or, R 3b1 and R 3b2 together with the atom to which they are attached form a 3-6 membered heterocycloalkyl having 1-2 additional heteroatoms, each independently N, O, or S; and Each R 3b3 But hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, halogen, or C 1-6 is haloalkyl; Or, R 3b is an R on an adjacent ring atom. 3a and each of which, together with the atom to which it is attached, is C substituted with 1 to 4 halogens. 3-6Forms a cycloalkyl.

[0103] In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVg, or a pharma- ceutically acceptable salt thereof, is 3a is hydrogen; R 3b But, C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), C 1-6 Alkyl-C 6-12 Aryl, C 1-6 alkyl-heteroaryl, where each heteroaryl has 5-10 ring members and 1-5 heteroatoms each independently being N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl; or R 3b1 and R 3b2 together with the atom to which they are attached form a 3-6 membered heterocycloalkyl having 1-2 additional heteroatoms which are each independently N, O, or S; and each R 3b3 But hydrogen, C 1-6 Alkyl, halogen, or C 1-6 haloalkyl; or R 3b R on the adjacent ring atom 3a and each of which, together with the atom to which it is attached, is C substituted with 1 to 4 halogens. 3-6 It is a compound that forms a cycloalkyl.

[0104] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVg, or a pharma- ceutically acceptable salt thereof, is Each R 3a is hydrogen; R 3b But, C 1-3 Alkyl, C 2-3 Alkynyl, C 2-3 Alkoxyalkyl, C 2-3 Alkynyl-C 3-6 Cycloalkyl, C 1-3 Alkyl-C 6-12 Aryl, C 2-3 Alkenyl-C 6-12 Aryl, C 2-3 Alkynyl-C 6-12 Aryl, C 1-3 Alkyl-OC 6-12 Aryl, C 1-3 Alkoxyalkyl-C 6-12 Aryl, -C(O)-C 6-12 Aryl or C 1-3 alkyl-heteroaryl, where each heteroaryl has 5-10 ring members and 1-3 heteroatoms each independently being N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; and Each R 3b3 But hydrogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, halogen, or C 1-3 is haloalkyl; Or, R 3b R on the adjacent ring atom 3a and each of them, together with the atom to which it is attached, is C substituted with 1 to 2 halogens. 3-4 It is a compound that forms a cycloalkyl.

[0105] In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVg, or a pharma- ceutically acceptable salt thereof, is 3a is hydrogen; R 3b But, C 1-3 Alkyl, benzyl, or C 1-2 alkyl-heteroaryl, where each heteroaryl has 5-10 ring members and 1-3 heteroatoms that are each independently N or S, and where each aryl and heteroaryl has 1-3 R 3b3 groups; and each R 3b3 But hydrogen, C 1-3 Alkyl, halogen, or C 1-3 haloalkyl; or R 3b R on the adjacent ring atom 3a and each of them, together with the atom to which it is attached, is C substituted with 1 to 2 halogens. 3-4 It is a compound that forms a cycloalkyl.

[0106] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVg, or a pharma- ceutically acceptable salt thereof, is 3b Methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt, [ka] It is a compound wherein

[0107] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVg, or a pharma- ceutically acceptable salt thereof, is3b Methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt, [ka] It is a compound wherein

[0108] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVg, or a pharma- ceutically acceptable salt thereof, is 3b But methyl, [ka] It is a compound wherein

[0109] In some embodiments, the compound of formula I, II, III, IIIa, IV, IVa, IVb, IVg, or V, or a pharma- ceutically acceptable salt thereof, is 3a is hydrogen, methyl, iso-butyl, oxo, -CH 2 OMe, -CH 2 OH, -C(O)OMe, phenyl, or benzyl; R 3b Methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt, [ka] It is a compound wherein

[0110] In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IV, IVa, IVb, IVg, or V, or a pharma- ceutical acceptable salt thereof, is 3b Methyl, ethyl, -CH 2 C≡CH, -CH2 OMe, -CH 2 OH, -C(O)OEt, [ka] It is a compound wherein

[0111] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutical acceptable salt thereof, is 4 But, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12 aryl, or a 5-10 membered heteroaryl having 1-5 heteroatoms each independently being N, O, or S, wherein the heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-5 R 4a groups; each R 4a But hydrogen, 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, oxo, -C(O)R 4b , -C(O)OR 4b , -C(O)N(R 4b )(R 4c ), -S(O) 2 R 4b , -S(O) 2 N(R 4b )(R 4c ), C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl or -OC 6-12 aryl, where each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; and where each aryl is C 1-6 and each R 4b and R 4c is hydrogen or C 1-6 It is a compound that is alkyl.

[0112] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutical acceptable salt thereof, is 4 But, C 1-6 Alkyl, -CN, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12 aryl, or a 5-10 membered heteroaryl having 1-5 heteroatoms each independently being N, O, or S, wherein the heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-5 R 4a groups; and each R 4a But hydrogen, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12 Aryl or -OC 6-12 aryl, where each aryl is C 1-6The compound is optionally substituted with alkoxy.

[0113] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutical acceptable salt thereof, is 4 But, C 1-4 Alkyl, -CN, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl with one heteroatom N or O, C 6-12 aryl, or a 5-10 membered heteroaryl having 1-4 heteroatoms each independently being N, O, or S, wherein the heterocycloalkyl, aryl, and heteroaryl each independently are each independently selected from 1-2 R 4a groups; and each R 4a But hydrogen, C 1-4 Alkyl, C 2-4 Alkoxyalkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, C 1-2 Alkyl-C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl having one heteroatom N, O, or S, or C 6-12 aryl, where each aryl is C 1-3 The compound is optionally substituted with alkoxy.

[0114] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is R 4 But, C 1-3 Alkyl, C 1-3 Haloalkyl, -CN, C 3-6cycloalkyl, 4-6 membered heterocycloalkyl with one heteroatom each being N or O, C 6-12 aryl, or a 5-10 membered heteroaryl having 1-4 heteroatoms each independently being N, O, or S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-2 R 4a is substituted with a group; and Each R 4a But hydrogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 2-3 Alkoxyalkyl, C 1-3 Hydroxyalkyl, halogen, C 1-3 Haloalkyl, -CN, -OH, oxo, -S(O) 2 R 4b , -S(O) 2 N(R 4b )(R 4c ), C 3-6 Cycloalkyl, C 1-2 Alkyl-C 3-6 Cycloalkyl, C 6-12 Aryl or -OC 6-12 aryl, where each aryl is C 1-6 The compound is optionally substituted with alkoxy.

[0115] In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, or IIc-2, or a pharma- ceutically acceptable salt thereof, is 4a But hydrogen, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12 Aryl or -OC6-12 aryl, where each aryl is C 1-6 In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, or IIc-2, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, or IIc-2, or a pharma- ceutically acceptable salt thereof, wherein each R 4a But hydrogen, C 1-4 Alkyl, C 2-4 Alkoxyalkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, C 1-2 Alkyl-C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl having one heteroatom N, O, or S, or C 6-12 aryl, where each aryl is optionally C 1-3 In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, or IIc-2, or a pharma- ceutically acceptable salt thereof, is a compound wherein each R is substituted with alkoxy. 4a is hydrogen, methyl, n-propyl, iso-propyl, iso-butyl, -OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 OH, F, -CF 3 , -CH 2 CF 3 , cyclopentyl, -CH 2 -cyclopropyl, tetrahydrofuranyl, or 2-methoxyphenyl.

[0116] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is 4 Methyl, ethyl, n-propyl, iso-propyl, t-butyl, -CN, [ka] It is a compound wherein

[0117] In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, or IIc-2, or a pharma- ceutically acceptable salt thereof, is 4a But hydrogen, C 1-4 Alkyl, C 2-4 Alkoxyalkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, C 1-2 Alkyl-C 3-5 cycloalkyl, or a 4-6 membered heterocycloalkyl having one heteroatom N, O, or S. In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, or IIc-2, or a pharma- ceutical acceptable salt thereof, is a compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, or IIc-2, or a pharma- ceutical acceptable salt thereof, wherein each R 4a is hydrogen, methyl, n-propyl, iso-propyl, iso-butyl, -CH 2 CH 2 OCH 3 , F, -CF 3 , -CH 2 CF 3 , cyclopentyl, -CH 2 -cyclopropyl, or tetrahydrofuranyl.

[0118] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is 4 Methyl, ethyl, n-propyl, iso-propyl, t-butyl, [ka] It is a compound wherein

[0119] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutical acceptable salt thereof, is 4 But, C 1-3 Alkyl, -CN, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl having one heteroatom each being N or O, or 5-10 membered heteroaryl having one to four heteroatoms each being independently N, O, or S, wherein the heterocycloalkyl, aryl, and heteroaryl each independently have one to two R 4a groups; and each R 4a Aruri, Hydrogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-2 Alkyl-C 3-6 Cycloalkyl, or C 6-12 aryl, where each aryl is C 1-6 The compound is optionally substituted with alkoxy.

[0120] In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is 4a But hydrogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-2 Alkyl-C-6 cycloalkyl, or C 6-12 aryl, where each aryl is C 1-6In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is a compound optionally substituted with alkoxy, 4a is hydrogen, methyl, n-propyl, -OCH 3 , -CH 2 OH, -CH 2 -cyclopropyl, or 2-methoxyphenyl.

[0121] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is R 4 Methyl, ethyl, -CF 2 CH 3 , -CN, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl, pyrimidine-dione, phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyridin-2-one, pyridazinyl, pyrimidinyl, indazolyl, pyrazolo-pyrimidine, oxazolyl, isoxazolyl, oxadiazolyl, benzoisoxazolyl, thiophenyl, benzothiophenyl, or thiazolyl; and Each R 4a is hydrogen, methyl, ethyl, n-propyl, iso-butyl, -CD 3 , methoxy, -CH 2 CH 2 OCH 3 , Hydroxymethyl, F, Cl, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CN, -OH, oxo, -S(O) 2 Me, -S(O) 2 Compounds that are -NHMe, cyclobutyl, cyclopropylmethyl, 2-methoxyphenyl, or -OPh.

[0122] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutical acceptable salt thereof, is 4 is methyl, -CN, cyclopropyl, piperidinyl, tetrahydropyranyl, phenyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolo-pyrimidine, oxazolyl, isoxazolyl, oxadiazolyl, benzoisoxazolyl, thiophenyl, benzothiophenyl, or thiazolyl; and each R 4a is hydrogen, methyl, n-propyl, methoxy, hydroxymethyl, cyclopropylmethyl, or 2-methoxyphenyl.

[0123] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutical acceptable salt thereof, is 4 Methyl, ethyl, -CF 2 CH 3 , -CN, [ka] [ka] It is a compound wherein

[0124] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutical acceptable salt thereof, is 4 Methyl, -CN, [ka] It is a compound wherein

[0125] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutical acceptable salt thereof, is 4 But methyl, [ka] It is a compound wherein

[0126] In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1, IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is 1 is not present or -N(R 5a )- and;L 2 However, it does not exist, and -C(O)- and -C(O)-C 1-6 Alkylene-, C(O)-C 1-6 Alkylene -O-, -C(O)O-, -C(O)N(R 5b )-, -S(O) 2 - or -S(O) 2 N(R 5b )-; and R 5a and R 5b are independently hydrogen, C 1-6 Alkyl or C 2-6 The compound is an alkoxyalkyl.

[0127] In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is 1In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, wherein L 1 In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound wherein L 1 In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, wherein L 1 In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, wherein L 1 In some embodiments, the compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, wherein L 2 does not exist, -C(O)-, -C(O)O-, -C(O)NR 5b -, -S(O) 2 - or -S(O) 2 -NR 5b In some embodiments, the compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, wherein L 2 However, it does not exist, and -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)(CH 2) 3 O-, -C(O)O-, -C(O)NH-, -S(O) 2 -, -S(O) 2 -NH- or -S(O) 2 In some embodiments, the compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, wherein L 2 But -S(O) 2 -, -S(O) 2 -NH- or S(O) 2 The compound is -N(Me)-.

[0128] In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is 1 and L 2 does not exist, -CH 2 -, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)CH 2 O-, -C(O)(CH 2 ) 3 O-, -C(O)O-, -C(O)NH-, -S(O) 2 -, -NH-S(O) 2 -, -N(Me)S(O) 2 -, -N(CH 2 CH 2 OCH 3 )S(O) 2 -, -S(O) 2 -NH- or -S(O) 2 In some embodiments, the compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, wherein L 1 and L 2 does not exist, -C(O)-, -C(O)CH 2-, -C(O)CH 2 CH 2 -, -C(O)(CH 2 ) 3 O-, -C(O)O-, -C(O)NH-, -S(O) 2 -, -NH-S(O) 2 -, -N(Me)S(O) 2 -, -N(CH 2 CH 2 OCH 3 )S(O) 2 -, -S(O) 2 -NH- or -S(O) 2 In some embodiments, the compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, wherein L 1 and L 2 are both -C(O)-, -C(O)O-, -C(O)NH-, -S(O) 2 -, -NH-S(O) 2 -, -N(Me)S(O) 2 -,-N(CH 2 CH 2 OCH 3 )S(O) 2 -,-S(O) 2 -NH- or -S(O) 2 In some embodiments, the compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, wherein L 1 and L 2 does not exist, -CH 2 -, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)CH 2 O-, -C(O)(CH 2 ) 3 O-, -S(O) 2 -, -NH-S(O) 2 - or -N(Me)S(O) 2In some embodiments, the compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, wherein L 1 and L 2 does not exist, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)(CH 2 ) 3 O-, -S(O) 2 -, -NH-S(O) 2 - or -N(Me)S(O) 2 - is a compound.

[0129] In some embodiments, the compound of formula I, II, or IIa-1, or a pharma- ceutically acceptable salt thereof, is Ring J has the structure: [ka] having L 1 is not present; and, L 2 But -C(O)-, -C(O)-C 1-6 Alkylene-, C(O)-C 1-6 Alkylene-O-, -C(O)O-, or -S(O) 2 In some embodiments, the compound of formula I, II, or IIa-1, or a pharma- ceutical acceptable salt thereof, is a compound wherein L 1 and L 2 Both are -C(O)- and -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)(CH 2 ) 3 O- or -S(O) 2 - is a compound.

[0130] In some embodiments, the compound of formula I, II, or IIa-2, or a pharma- ceutically acceptable salt thereof, is Ring J has the structure: [ka] and L 1 -N(R 5a )- and;L 2 But -C(O)-, -C(O)-C 1-6 Alkylene-, C(O)-C 1-6 Alkylene-O- or -S(O) 2 - and R 5a is hydrogen or C 1-6 In some embodiments, the compound of formula I, II, or IIa-2, or a pharma- ceutical acceptable salt thereof, is a compound having the formula: 1 and L 2 Both are -NH-S(O) 2 -or-N(Me)S(O) 2 It is a compound wherein

[0131] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound of Formula IIa-1 or IIa-2: [ka] [In the formula, each R 2 , R 3b , L 1 , L 2 , and R 4 is as defined herein].

[0132] In some embodiments, the compound of Formula I, II, IIa-1, or IIa-2, or a pharma- ceutically acceptable salt thereof, is a compound of Formula IIb-1 or IIb-2: [ka] [In the formula, each R 2 , R 3b , L 1 , and R 4a is as defined herein].

[0133] In some embodiments, the compound of Formula I, II, IIa-1, IIa-2, IIb-1, or IIb-2, or a pharma- ceutically acceptable salt thereof, is a compound of Formula IIc-1 or IIc-2: [ka] [In the formula, each R 2 , R 3b , R 4a , and R 5a is as defined herein].

[0134] In some embodiments, the compound of formula I or II, or a pharma- ceutical acceptable salt thereof, is R 1 are independently hydrogen, C 1-6 Alkoxy, halogen, or -C(O)N(R 1b )(R 1c ) 1 to 5 R 1a groups, where each R 1b and R 1c is independently hydrogen or a 4-6 membered heterocycloalkyl having 1-3 heteroatoms which are each independently N, O, or S; A 1 , A 2 , A 3 , and A 4 However, each is independently =CR 2 - or =N-; Each R 2 are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or C 1-6 haloalkoxy; Ring J has the following structure: [ka] having; Each R 3a But hydrogen, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)OR 3a1, C 6-12 Aryl or C 1-6 Alkyl-C 6-12 is aryl; R 3a1 is hydrogen or C 1-6 is alkyl; R 3b But hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), C 1-6 Alkyl-C 6-12 Aryl, C 1-6 alkyl-heteroaryl, where each heteroaryl has 5-10 ring members and 1-5 heteroatoms that are each independently N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 is alkyl; Or, R 3b1 and R 3b2 together with the atom to which they are attached form a 3-6 membered heterocycloalkyl having 1-2 additional heteroatoms, each independently N, O, or S; Each R 3b3 But hydrogen, C 1-6 Alkyl, halogen, or C 1-6 is haloalkyl; Or, R 3b R on the adjacent ring atom 3a and each of which, together with the atom to which it is attached, is C substituted with 0 to 4 halogens. 3-6 Forming a cycloalkyl; L 3a and L 3b are -C(R 3a3 )(R 3a3 )-and; Each R 3a3are independently hydrogen or C 1-6 is alkyl; R 4 But, C 1-6 Alkyl, -CN, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12 aryl, or a 5-10 membered heteroaryl having 1-5 heteroatoms each independently being N, O, or S, wherein the heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-5 R 4a is substituted with a group; Each R 4a But hydrogen, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12 Aryl or -OC 6-12 aryl, where each aryl is C 1-6 optionally substituted with alkoxy; L 1 is not present or -N(R 5a )-and; L 2 However, it does not exist, and -C(O)- and -C(O)-C 1-6 Alkylene-, C(O)-C 1-6 Alkylene -O-, -C(O)O-, -C(O)N(R 5b )-, -S(O) 2 - or -S(O) 2 N(R 5b )-and; R 5a and R 5b are independently hydrogen, C 1-6 Alkyl or C 2-6and the subscripts r and s are each independently 0, 1, or 2, such that the sum of r and s is 2.

[0135] In some embodiments, the compound of formula I or II, or a pharma- ceutical acceptable salt thereof, is R 1 but [ka] and; A 1 is =CH- or =N-; A 2 and A 4 are each independently =CH-, =C(Me)-, or =N-; A 3 is =CH-, =C(Me)-, =C(Et)-, =C(iPr)-, =C(OMe)-, =C(F)-, =C(Cl)-, =C(OCHF 2 )-, ═C(CN)-, or ═N-; Ring J, [ka] and; Each R 3a is hydrogen, methyl, iso-butyl, -OH, oxo, -CH 2 OMe, -CH 2 OH, -C(O)OMe, phenyl, or benzyl; R 3b Methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt, [ka] and; L 1 and L 2 does not exist, -CH 2 -, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH2 -, -C(O)CH 2 O-, -C(O)(CH 2 ) 3 O-, -C(O)O-, -C(O)NH-, -S(O) 2 -, -NH-S(O) 2 -, -N(Me)S(O) 2 -, -N(CH 2 CH 2 OCH 3 )S(O) 2 -, -S(O) 2 -NH- or -S(O) 2 -N(Me)-; and R 4 Methyl, ethyl, n-propyl, iso-propyl, t-butyl, -CF 2 CH 3 , -CN, [ka] [ka] It is a compound wherein

[0136] In some embodiments, the compound of formula I or II, or a pharma- ceutical acceptable salt thereof, is R 1 but [ka] and; A 1 is =CH- or =N-; A 2 and A 4 are each independently =CH-, =C(Me)-, or =N-; A 3 are =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, =C(F)-, =C(Cl)-, =C(OCHF 2 )- or =N-; Ring J, [ka] and; Each R 3a is hydrogen, methyl, iso-butyl, oxo, -CH 2 OMe, -CH 2 OH, -C(O)OMe, phenyl, or benzyl; R 3b Methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt, [ka] and; L 1 and L 2 does not exist, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)(CH 2 ) 3 O-, -C(O)O-, -C(O)NH-, -S(O) 2 -, -NH-S(O) 2 -, -N(Me)S(O) 2 -, -N(CH 2 CH 2 OCH 3 )S(O) 2 -, -S(O) 2 -NH- or -S(O) 2 -N(Me)-; and R 4 Methyl, ethyl, n-propyl, iso-propyl, t-butyl, -CN, [ka] It is a compound wherein

[0137] In some embodiments, the compound of formula I or II, or a pharma- ceutical acceptable salt thereof, is R 1 but, [ka] and; A1 is =CH- or =N-; A 2 and A 4 are each independently =CH-, =C(Me)-, or =N-; A 3 is =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, =C(Cl)-, =C(OCHF 2 )- or =N-; Ring J, [ka] and; Each R 3a is hydrogen, methyl, iso-butyl, -CH 2 OMe, -CH 2 OH, oxo, -C(O)OMe, phenyl, or benzyl; L 1 and L 2 However, together with C(O)-, -C(O)O-, -C(O)NH-, -S(O) 2 -, -NH-S(O) 2 -, -N(Me)S(O) 2 -, -N(CH 2 CH 2 OCH 3 )S(O) 2 -, -S(O) 2 -NH- or -S(O) 2 -N(Me)-; and R 4 Methyl, ethyl, n-propyl, iso-propyl, t-butyl, [ka] It is a compound wherein

[0138] In some embodiments, the compound of formula I or II, or a pharma- ceutical acceptable salt thereof, is R 1 but, [ka] and; A1 is =CH- or =N-; A 2 and A 4 are =CH-, respectively; A 3 is =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, or =C(F)-; Ring J has the structure: [ka] having R 3b Methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt, [ka] and; L 1 and L 2 does not exist, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)(CH 2 ) 3 O-, -S(O) 2 -, -NH-S(O) 2 - or -N(Me)S(O) 2 - and R 4 Methyl, -CN, [ka] It is a compound wherein

[0139] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is a compound in which ring J has the structure: [ka]

[0140] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is a compound in which ring J has the structure: [ka]

[0141] In some embodiments, the compound of Formula I, II, or IV, or a pharma- ceutically acceptable salt thereof, is a compound having the following structure: [ka]

[0142] In some embodiments, the present invention provides a compound of formula IVa: [ka] or a pharma- ceutical acceptable salt thereof, R 1 is a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms each being N, O, or S, phenyl, or a heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each being N, O, or S, each independently consisting of 1 to 5 R 1a is substituted with a group; Each R 1a are independently hydrogen, C 1-6 Alkyl, C 1-6 Deuterated 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 8 ring members and 1 to 4 heteroatoms, each of which is N, O, or S; Each R 1b and R1c are independently hydrogen, C 1-6 alkyl, or 3-8 membered heterocycloalkyl having 1-3 heteroatoms, each independently N, O, or S; A 1 , A 2 , A 3 , and A 4 are each 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, or -CN; Each R 3a are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3a1 , -C(O)OR 3a1 , -C(O)N(R 3a1 )(R 3a2 ), -OH, oxo, 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 alkenyl and alkynyl is C 6-12optionally substituted with aryl or heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each of which is independently N, O, or S, and where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each of which is independently N, O, or S; Each R 3a1 and R 3a2 are independently hydrogen or C 1-6 is alkyl; Alternatively, two Rs attached to the same atom 3a The groups, together with the atoms to which they are attached, form C 3-6 Can form a cycloalkyl; Alternatively, two Rs attached to different atoms 3a The groups, together with the atoms to which they are attached, are C 3-10 can form a cycloalkyl or a 3-10 membered heterocycloalkyl having 1-4 heteroatoms, each independently being N, O, or S, each of which can be 1-4 R 3a3 is substituted with a group; Each R 3a3 are independently hydrogen or C 1-6 is alkyl; Each R 3b is independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, -C(O)R 3b1 , -C(O)OR 3b1 , -C(O)N(R 3b1 )(R 3b2 ), C 3-8 Cycloalkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, C 2-6 Alkynyl-C 3-8 Cycloalkyl, heterocycloalkyl, C 1-6 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl-C6-12 Aryl, C 2-6 Alkenyl-C 6-12 Aryl, C 2-6 Alkynyl-C 6-12 Aryl, C 1-6 Alkyl-OC 6-12 Aryl, C 1-6 Alkoxyalkyl-C 6-12 Aryl, -C(O)-C 6-12 Aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, where each heterocycloalkyl has 3-8 ring members and 1-3 heteroatoms, each independently N, O, or S, where each heteroaryl has 5-10 ring members and 1-5 heteroatoms, each independently N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 is substituted with a group; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 is alkyl; Or, R 3b1 and R 3b2 together with the atom to which they are attached form a 3-6 membered heterocycloalkyl having 1-2 additional heteroatoms, each independently N, O, or S; Each R 3b3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, or C 1-6 haloalkoxy; R 4 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -CN, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12aryl, or a 5-10 membered heteroaryl having 1-5 heteroatoms each independently being N, O, or S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-5 R 4a is substituted with a group; Each R 4a is hydrogen, C 1-6 Alkyl, C 1-6 Deuterated 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 , -C(O)N(R 4b )(R 4c ), -S(O) 2 R 4b , -S(O) 2 N(R 4b )(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, -OC 6-12 Aryl, Heteroaryl, C 1-6 alkyl-heteroaryl, where each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms that are each independently N, O, or S, where each heteroaryl independently has 5 to 8 ring members and 1 to 4 heteroatoms that are each independently N, O, or S, and where each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is selected from the group consisting of C 1-6 optionally substituted with alkoxy; Each R 4b and R4c is hydrogen or C 1-6 is alkyl; L 1 is absent or -N(R 5a )-and; L 2 does not exist, and C 1-6 Alkylene, -C(O)-, -C(O)-C 1-6 Alkylene-, C(O)-C 1-6 Alkylene -O-, -C(O)O-, -C(O)N(R 5b )-, -S(O) 2 - or -S(O) 2 N(R 5b )--and R 5a and R 5b are each independently hydrogen, C 1-6 Alkyl or C 2-6 is an alkoxyalkyl.

[0143] In some embodiments, the compound of formula I, II, III, IIIa, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is 1 is a heterocycloalkyl having 5-6 ring members and 1-2 heteroatoms each being N, phenyl, or a heteroaryl having 5-6 ring members and 1-2 heteroatoms each being N or S, each of which is represented by 1-3 R 1a groups; and each R 1a are independently hydrogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, halogen, C 1-3 Haloalkyl, oxo, -CN, C 3-6 In some embodiments, the compound of formula I, II, III, IIIa, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is a compound having a structure of formula I, II, III, IIIa, IV, or IVa, wherein R 1is piperidine, pyridin-2-one, phenyl, pyridine, pyrazole, or thiazole, each of which is represented by 1 to 3 R 1a groups; and each R 1a is hydrogen, methyl, ethyl, iso-propyl, -CD 3 , methoxy, -CH 2 OH, F, Cl, -CHF 2 , -CF 3 , oxo, -CN, cyclopropyl, or oxetane.

[0144] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is 1 but, [ka] It is a compound wherein

[0145] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is 1 but, [ka] It is a compound wherein

[0146] In some embodiments, the compound of Formula I, II, III, IIIa, IIIb, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is a compound having the following structure: [ka]

[0147] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, or IVb, or a pharma- ceutically acceptable salt thereof, is 1 , A 2 , A 3 , and A 4However, each is independently =CR 2 - or =N-; and each R 2 are independently hydrogen, C 1-4 Alkyl, C 1-4 In some embodiments, the compound of formula I, II, IIa-1, IIb-1, IIc-1, III, III, IIIa, IIIb, IV, IVa, or IVb, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, IIa-1, IIb-1, IIc-1, III, III, IIIa, IIIb, IV, IVa, or IVb, or a pharma- ceutically acceptable salt thereof, wherein each R 2 is independently hydrogen, methyl, ethyl, iso-propyl, methoxy, F, Cl, or -CN. In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, or IVb, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, III, IIIa, IIIb, IV, IVa, or IVb, or a pharma- ceutically acceptable salt thereof, 1 , A 2 , A 3 , and A 4 are each independently CH-, =C(Me)-, =C(Et)-, =C(iPr)-, =C(OMe)-, =C(F)-, =C(Cl)-, =C(CN)-, or =N-. In some embodiments, the compound of Formula I, II, III, IIIa, IIIb, IV, IVa, or IVb, or a pharma- ceutically acceptable salt thereof, is a compound of Formula I, II, III, IIIa, IIIb, IV, IVa, or IVb, or a pharma- ceutically acceptable salt thereof, 1 is =CH- or =N-; A 2 and A 4 are each =CH-; and A 3 In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, or IVb, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, II, III, IIIa, IIIb, IV, IVa, or IVb, wherein A is a phenyl group, R ... 1 , A 2 , and A 4 are each =CH-; and A 3 is a compound where =C(Me)-.

[0148] In some embodiments, the compound of Formula I, II, III, IIIa, IV, IVa, or IVb, or a pharma- ceutically acceptable salt thereof, is a compound having the following structure: [ka]

[0149] In some embodiments, the compound of Formula I, II, III, IIIa, IV, IVa, IVb, or IVc, or a pharma- ceutically acceptable salt thereof, is 3a In some embodiments, the compound of Formula I, II, III, IIIa, IV, IVa, IVb, or IVc, or a pharma- ceutically acceptable salt thereof, is a compound wherein each R 3a is a compound in which

[0150] In some embodiments, the compound of Formula I, II, IIa-1, III, IIIa, IV, IVa, IVb, or IVc, or a pharma- ceutically acceptable salt thereof, is a compound having the following structure: [ka]

[0151] In some embodiments, the compound of formula I, II, IIa-1, IIb-1, IIc-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, or IVd, or a pharma- ceutically acceptable salt thereof, is 3b But, C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkoxyalkyl, C 2-6 Alkynyl-C 3-6 Cycloalkyl, C 1-6 Alkyl-C 6-12 Aryl, C 2-6 Alkenyl-C 6-12 Aryl, C 2-6 Alkynyl-C 6-12 Aryl, C 1-6 Alkyl-OC 6-12Aryl, C 1-6 Alkoxyalkyl-C 6-12 Aryl, -C(O)-C 6-12 Aryl or C 1-6 alkyl-heteroaryl, where each heteroaryl has 5-10 ring members and 1-3 heteroatoms, each independently N, O, or S; and each aryl and heteroaryl has 1-3 R 3b3 groups; and each R 3b3 But hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, halogen, or C 1-6 A compound that is a haloalkyl.

[0152] In some embodiments, the compound of formula I, II, IIa-1, IIb-1, IIc-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, or IVd, or a pharma- ceutically acceptable salt thereof, is 3b But, C 1-3 Alkyl, C 2-3 Alkynyl, C 2-3 Alkoxyalkyl, C 2-3 Alkynyl-C 3-6 Cycloalkyl, C 1-3 Alkyl-C 6-12 Aryl, C 2-3 Alkenyl-C 6-12 Aryl, C 2-3 Alkynyl-C 6-12 Aryl, C 1-3 Alkyl-OC 6-12 Aryl, C 1-3 Alkoxyalkyl-C 6-12 Aryl, -C(O)-C 6-12 Aryl or C 1-3 alkyl-heteroaryl, where each heteroaryl has 5-10 ring members and 1-3 heteroatoms each independently being N, O, or S, and where each aryl and heteroaryl has 1-3 R 3b3 groups; and each R 3b3 But hydrogen, C 1-3 Alkyl, C 1-3Hydroxyalkyl, halogen, or C 1-3 A compound that is a haloalkyl.

[0153] In some embodiments, the compound of formula I, II, IIa-1, IIb-1, IIc-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, or IVd, or a pharma- ceutically acceptable salt thereof, is 3b3 is hydrogen, methyl, -CH 2 OH, F, -CHF 2 , or -CF 3 In some embodiments, the compound of formula I, II, IIa-1, IIb-1, IIc-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, or IVd, or a pharma- ceutically acceptable salt thereof, is a compound wherein R 3b Ethyl, -CH 2 C≡CH, -CH 2 OMe, [ka] It is a compound wherein

[0154] In some embodiments, the compound of formula I, II, IIa-1, IIb-1, IIc-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, or IVd, or a pharma- ceutically acceptable salt thereof, is 3b but, [ka] It is a compound wherein

[0155] In some embodiments, the compound of Formula I, II, IIa-1, III, IIIa, IV, IVa, IVb, IVc, or IVd, or a pharma- ceutically acceptable salt thereof, is a compound having the following structure: [ka]

[0156] In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is 1 is not present; and L 2 But it doesn't exist, C 1-4 Alkylene, -C(O)-, -C(O)-C 1-4 Alkylene-, C(O)-C 1-4 Alkylene-O- or -S(O) 2 In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound wherein L 1 is not present; and L 2 But it doesn't exist, -CH 2 -, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)CH 2 O-, -C(O)(CH 2 ) 3 O- or S(O) 2 In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound wherein L 2 But -CH 2 -, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)CH 2 O-, -C(O)(CH 2 ) 3 O- or S(O) 2 In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound wherein L 2 is -C(O)- or S(O) 2 - is a compound.

[0157] In some embodiments, the compound of Formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharma- ceutically acceptable salt thereof, is a compound having the following structure: [ka]

[0158] In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is 4 But, C 1-6 Alkyl, C 1-6 Haloalkyl, -CN, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C 6-12 aryl, or a 5-10 membered heteroaryl having 1-5 heteroatoms each independently being N, O, or S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-5 R 4a groups; each R 4a But hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, halogen, C 1-6 Haloalkyl, -CN, -OH, oxo, -S(O) 2 R 4b , -S(O) 2 N(R 4b )(R 4c ), C 3-6 Cycloalkyl, C 6-12 Aryl or -OC 6-12 aryl, where each aryl is C 1-6 and each R 4b and R 4c is hydrogen or C1-6 It is a compound that is alkyl.

[0159] In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is 4 But, C 1-3 Alkyl, C 1-3 Haloalkyl, -CN, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl with one heteroatom each being N or O, C 6-12 aryl, or a 5-10 membered heteroaryl having 1-4 heteroatoms each independently being N, O, or S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-2 R 4a groups; each R 4a But hydrogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 2-3 Alkoxyalkyl, C 1-3 Hydroxyalkyl, halogen, C 1-3 Haloalkyl, -CN, -OH, oxo, -S(O) 2 R 4b , -S(O) 2 N(R 4b )(R 4c ), C 3-6 Cycloalkyl, C 6-12 Aryl or -OC 6-12 aryl, where each aryl is C 1-3 and each R 4b and R 4c is hydrogen or C 1-3 It is a compound that is alkyl.

[0160] In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is4 Methyl, ethyl, -CF 2 CH 3 , -CN, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl, pyrimidine-dione, phenyl, pyridinyl, pyridin-2-one, quinolinyl, pyrazolyl, imidazolyl, pyridazinyl, pyrimidinyl, indazolyl, triazolyl, pyrazolopyrimidine, tetrazolyl, oxazolyl, isoxazolyl, benzoisoxazolyl, oxadiazolyl, thiophenyl, benzothiophenyl, or thiazolyl; and each R 4a is hydrogen, methyl, ethyl, n-propyl, iso-butyl, -CD 3 , methoxy, -CH 2 CH 2 OCH 3 , Hydroxymethyl, F, Cl, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CN, -OH, oxo, -S(O) 2 Me, -S(O) 2 Compounds that are -NHMe, cyclobutyl, 2-methoxyphenyl, or -OPh.

[0161] In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is 4 Methyl, -CF 2 CH 3 , -CN, [ka] [ka] It is a compound wherein

[0162] In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is 4 but, [ka] It is a compound wherein

[0163] In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is 4 but, [ka] It is a compound wherein

[0164] In some embodiments, the compound of formula I, II, IV, or IVa, or a pharma- ceutical acceptable salt thereof, is represented by the formula: [ka] It is a compound having the formula:

[0165] In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharma- ceutically acceptable salt thereof, is 4 but, [ka] It is a compound wherein

[0166] In some embodiments, the compound of formula I, II, IV, or IVa, or a pharma- ceutical acceptable salt thereof, is 1 but, [ka] and; A 1 is =CH- or =N-; A 2 and A 4 are =CH-, respectively; A3 is =CH-, =C(Me)-, =C(Et)-, =C(iPr)-, =C(OMe)-, =C(F)-, =C(Cl)-, or =C(CN)-; Ring J has the structure: [ka] having; Each R 3a is hydrogen, -OH, or oxo; R 3b Ethyl, -CH 2 C≡CH, -CH 2 OMe, [ka] and; L 1 and L 2 does not exist, -CH 2 -, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)CH 2 O-, -C(O)(CH 2 ) 3 O- or S(O) 2 - and R 4 Methyl, -CF 2 CH 3 ,-CN, [ka] [ka] It is a compound wherein

[0167] In some embodiments, the compound of formula I, II, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is R 1 but, [ka] and; A1 Wherein, =CH-; A 2 and A 4 are =CH-, respectively; A 3 is =CH-, =C(Me)-, =C(Et)-, =C(OMe)-, =C(Cl)-, or =C(CN)-; Ring J has the structure: [ka] having Each R 3a is hydrogen, -OH, or oxo; R 3b But -CH 2 OMe, [ka] and; L 1 and L 2 Both are CH 2 -, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)CH 2 O- or S(O) 2 - and R 4 Methyl, -CF 2 CH 3 , [ka] [ka] It is a compound wherein

[0168] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1A: [ka] [ka] [ka]

[0169] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1B: [ka] [ka] [ka]

[0170] In some embodiments, the compound of Formula I or II or a pharma- ceutically acceptable salt thereof is a compound of Table 1C: [ka] [ka] [ka]

[0171] In some embodiments, the compound of Formula I or II or a pharma- ceutically acceptable salt thereof is a compound of Table 1D: [ka] [ka] [ka]

[0172] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1E: [ka] [ka] [ka]

[0173] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1F: [ka]

[0174] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1G: [ka]

[0175] In some embodiments, the compound of Formula I or II or a pharma- ceutically acceptable salt thereof is a compound of Table 1H: [ka] [ka]

[0176] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound of Table II: [ka] [ka] [ka]

[0177] In some embodiments, the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1J: [ka] [ka] [ka]

[0178] In some embodiments, the compound of Formula I or II or a pharma- ceutically acceptable salt thereof is a compound of Table 1K: [ka]

[0179] In some embodiments, the compound of Formula I or II or a pharma- ceutically acceptable salt thereof is a compound of Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, Table 1I, Table IJ, or Table 1K. In some embodiments, the compound of Formula I or II 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 or II or a pharma- ceutically acceptable salt thereof is a compound of Table 1F, Table 1G, Table 1H, Table 1I, Table IJ, or Table 1K. In some embodiments, the compound of Formula I, II, IV, or IVa or a pharma- ceutically acceptable salt thereof is a compound of Table 1H, Table 1I, Table IJ, or Table 1K. In some embodiments, the compound of Formula I, II, IV, or IVa or a pharma- ceutically acceptable salt thereof is a compound of Table 1H. In some embodiments, the compound of Formula I, II, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1I. In some embodiments, the compound of Formula I, II, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is a compound of Table IJ. In some embodiments, the compound of Formula I, II, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is a compound of Table 1K.

[0180] In some embodiments, the compound of Formula I, II, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is a compound of Table 2A: [ka] [ka] [ka]

[0181] In some embodiments, the compound of Formula I, II, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is a compound of Table 2B: [ka] [ka] [ka]

[0182] In some embodiments, the compound of Formula I, II, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is a compound of Table 2C: [ka] [ka] [ka]

[0183] In some embodiments, the compound of Formula I, II, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is a compound of Table 2D: [ka] [ka] [ka]

[0184] In some embodiments, the compound of Formula I, II, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is a compound of Table 2E: [ka] [ka] [ka]

[0185] In some embodiments, the compound of Formula I, II, IV, or IVa, or a pharma- ceutically acceptable salt thereof, is a compound of Table 2F: [ka]

[0186] In some embodiments, the compound of Formula I, II, IV, or IVa or a pharma- ceutically acceptable salt thereof is a compound of Table 2A, Table 2B, Table 2C, Table 2D, Table 2E, or Table 2F. In some embodiments, the compound of Formula I, II, IV, or IVa or a pharma- ceutically acceptable salt thereof is a compound of Table 2A. In some embodiments, the compound of Formula I, II, IV, or IVa or a pharma- ceutically acceptable salt thereof is a compound of Table 2B. In some embodiments, the compound of Formula I, II, IV, or IVa or a pharma- ceutically acceptable salt thereof is a compound of Table 2C. In some embodiments, the compound of Formula I, II, IV, or IVa or a pharma- ceutically acceptable salt thereof is a compound of Table 2D. In some embodiments, the compound of Formula I, II, IV, or IVa or a pharma- ceutically acceptable salt thereof is a compound of Table 2E. In some embodiments, the compound of Formula I, II, IV, or IVa or a pharma- ceutically acceptable salt thereof is a compound of Table 2F.

[0187] In some embodiments, the compound of Formula I or II or a pharma- ceutically acceptable salt thereof is a compound of Table 1A, Table IB, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, Table 1I, Table IJ, Table 1K, Table 2A, Table 2B, Table 2C, Table 2D, Table 2E, or Table 2F. In some embodiments, the compound of Formula I or II or a pharma- ceutically acceptable salt thereof is a compound of Table 1F, Table 1G, Table 1H, Table 1I, Table IJ, Table 1K, Table 2A, Table 2B, Table 2C, Table 2D, Table 2E, or Table 2F. In some embodiments, the compound of Formula I or II or a pharma- ceutically acceptable salt thereof is a compound of Table 1H, Table 1I, Table IJ, Table 1K, Table 2A, Table 2B, Table 2C, Table 2D, Table 2E, or Table 2F.

[0188] The compounds of the present invention may exist as salts. The present invention includes such salts that 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, such as racemic mixtures, succinate, benzoate, and salts with amino acids such as glutamic acid. These salts can 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. When the compounds of the present invention include a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of acceptable acid addition salts include those 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, and 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 galactunonic acid. 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.

[0189] Other salts include the acid or base salts of the compounds used in the method of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid salts (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.). It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information regarding 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.

[0190] 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 a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a desired base, either neat or in a suitable inert solvent.Examples of pharma-ceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts.When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a desired acid, either neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids, and the like, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, etc. Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic or galactunolic acids (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific 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.

[0191] 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.

[0192] Certain compounds of the present invention can exist in unsolvated forms as well as 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 polycrystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0193] Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; enantiomers, racemates, diastereoisomers, tautomers, geometric isomers, stereoisomers, and individual isomers that can be defined with respect to absolute stereochemistry as (R)- or (S)- or (D)- or (L)- of amino acids are encompassed within the scope of the invention. Compounds of the invention do not include those known in the art to be too unstable to synthesize and / or isolate. The invention is meant to include compounds in racemic and optically pure form. Optically active (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0194] Isomers include compounds that have the same number and types of atoms, and therefore the same molecular weight, but different structural or spatial arrangements of the atoms.

[0195] Unless specifically stated otherwise, structures depicted herein are also meant to include all stereochemical forms of the structure (i.e., the R and S configurations of 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.

[0196] Unless otherwise stated, 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 radioactive or stable isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), Fluorine-18(18 F), Nitrogen-15( 15 N), oxygen-17( 17 O), oxygen-18( 18 O), Carbon-13( 13 C), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0197] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that easily undergo 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 a suitable enzyme or chemical reagent.

[0198] IV. Composition In some embodiments, the present invention provides a pharmaceutical composition comprising any one of the compounds of the present invention and a pharma- ceutically acceptable excipient.

[0199] The compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Oral formulations 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. Additionally, the compounds of the present invention can be administered transdermally. The compounds of formula I of the present invention can also be administered by ocular, intravaginal, and intrarectal routes, including suppositories, insufflation, 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). Accordingly, the present invention also provides pharmaceutical compositions comprising one or more pharma- ceutically acceptable carriers and / or excipients and either a compound of formula I or a pharma- ceutically acceptable salt of a compound of formula I.

[0200] For preparing pharmaceutical compositions from the compounds of the present invention, pharma- ceutically acceptable carriers can be either solid or liquid. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that can also function as diluents, flavoring agents, surfactants, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details of techniques for formulation and administration are fully described in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0201] 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.

[0202] The 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 "formulation" is intended to include a combination of the active compound with an encapsulating material as a carrier to provide a capsule, in which the active compound, with or without other excipients, is surrounded by a carrier, i.e., with a carrier. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0203] 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; gums including gum arabic and gum tragacanth; proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0204] Dragee cores are provided with suitable coatings such as concentrated sugar solutions, lacquer solutions, and suitable organic solvents or solvent mixtures, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide. Dyestuffs or pigments can be added to the tablets or dragee coatings for product identification 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 glycerol or sorbitol. Push-fit capsules can contain the compound of formula I mixed with fillers or binders such as lactose or starch, lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the compound of formula I can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol, with or without stabilizers.

[0205] 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, as by stirring, etc. The molten homogeneous mixture is then poured into suitable sized molds, allowed to cool and thus solidify.

[0206] 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 solution in aqueous polyethylene glycol solution.

[0207] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers and thickeners as necessary.Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as natural 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 fatty acids and partial esters derived from hexitols (e.g. polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with fatty acids and partial esters derived from 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.

[0208] Also included are solid preparations that are intended to be converted shortly before use into liquid 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.

[0209] Oil suspensions can be prepared by suspending the compound of formula I in vegetable oil, for example peanut oil, olive oil, sesame oil, or coconut oil, or mineral oil, such as liquid paraffin, or mixtures thereof. Oil suspensions can contain thickening agents, for example beeswax, hard paraffin, cetyl alcohol. Sweeteners, such as glycerol, sorbitol, or sucrose, can be added to provide a palatable oral preparation. These preparations can be preserved by adding an antioxidant, such as ascorbic acid. For examples of injectable oil vehicles, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical preparation of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be the above-mentioned vegetable oil or mineral oil, 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 the condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweetening and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, preservative, or coloring agent.

[0210] The compounds of formula I of the present invention can be delivered by topical and transdermal routes by formulation as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0211] The compound and composition of formula I of the present invention can also be delivered as microspheres for sustained release in the body.For example, microspheres can be administered via intradermal injection of drug-containing microspheres that slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable and injectable gel formulations (see, for example, Gao Pharm. Res. 12:857-863, 1995), or as microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. 49:669-674, 1997).

[0212] Pharmaceutical formulations of the compounds of formula I of the present invention can be provided as salts, which can be generated using 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 the corresponding aqueous solutions, or other protic solvents, in the corresponding free base form. In other cases, the preparations can be lyophilized powders in 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, pH range 4.5 to 5.5, which are mixed with a buffer prior to use.

[0213] Pharmaceutical formulations of the compounds of formula I of the present invention can be provided as salts, which can be formed using bases, i.e., alkali metal and alkaline earth metal salts such as sodium, lithium, potassium, calcium, magnesium, and ammonium salts such as ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts, and other cationic salts.

[0214] In some embodiments, the formulation of the compound of formula I of the present invention can be delivered by using liposomes that fuse with cell membrane or are endocytosed, i.e., by using ligands that bind to liposomes or directly bind to oligonucleotides that bind to cell surface membrane protein receptors that cause endocytosis.By using liposomes, the delivery of GR modulators can be focused to target cells in vivo, especially when the liposome surface carries ligands specific to target cells or is otherwise preferentially directed to specific organs.(See, for example, 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).

[0215] Pharmaceutical preparations are preferably in unit dosage form.In such form, the preparation is divided into unit doses containing appropriate amounts of active ingredients.The unit dosage form may be a packaged preparation, the package containing discrete amounts of preparations, such as packeted tablets, capsules, and powders in vials or ampoules.Also, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0216] The amount of active ingredient in a unit dose preparation may be varied or 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, according to the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, as required.

[0217] Dosage regimens also take into account pharmacokinetic parameters, such as rate of absorption, bioavailability, metabolism, clearance, 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; the latest Remington's, supra). State of the art allows the clinician to determine the dosing regimen for each individual patient, GR and / or MR modulator, and disease or condition being treated.

[0218] Single or multiple administrations of the formulation of the compound of formula I can be performed depending on the dosage and frequency required and tolerated by the patient. The formulation should provide a sufficient amount of the active substance to effectively treat the condition. Thus, in one embodiment, the pharmaceutical formulation for oral administration of the compound of formula I is a daily dose of about 0.5 to about 30 mg / kg body weight per day. In another embodiment, the dosage is about 1 mg to about 20 mg / kg body weight per patient per day. Smaller doses may be used, especially when the drug is administered to an anatomically isolated site such as the cerebrospinal fluid (CSF) space, as opposed to oral administration into the bloodstream, a body cavity, or the lumen of an organ. Substantially higher doses may be used for local administration. Actual methods of preparing formulations containing the compound of formula I for parenteral administration are known or apparent to those skilled in the art and are described in more detail in publications such as Remington, supra. See also Nieman, "Receptor Mediated Antisteroid Action," Agarwal, et al., eds., De Gruyter, New York (1987).

[0219] The compounds described herein can be used in combination with each other, with other active agents known to be useful in modulating the glucocorticoid receptor, or in combination with adjuvants that are not effective alone but may contribute to the effectiveness of the active agent.

[0220] 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 the 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 simultaneous 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 auxiliary agents can be linked or bound to each other.

[0221] Pharmaceutical compositions containing a compound of formula I of the invention can be formulated with one or more acceptable carriers, placed in an appropriate container, and labeled for treatment of an indicated condition. For administration of a compound of formula I, such labeling would include, for example, instructions concerning the amount, frequency, and method of administration.

[0222] In some embodiments, the compositions of the present invention are useful for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. Formulations for administration generally include 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, which is isotonic sodium chloride. In addition, sterile fixed oils can be conventionally used 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 also be used in the preparation of injectables. 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 necessary to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity 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 preparations can vary widely and is selected mainly based on the volume of body fluids, viscosity, body weight, etc., according to the particular mode of administration selected and the needs of the patient. For IV administration, the preparation can be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be prepared according to known techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0223] In some embodiments, the formulation of the composition of the present invention can be delivered by using liposomes that fuse with cell membranes or are endocytosed, i.e., by using ligands that are attached to liposomes or directly attached to oligonucleotides that bind to cell surface membrane protein receptors and cause endocytosis.The use of liposomes can focus the in vivo delivery of the composition of the present invention to target cells, especially when the surface liposomes carry ligands specific to target cells or are otherwise preferentially directed to specific organs.(See, for example, 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).

[0224] V. Methods and Use 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 a compound of the present invention or a pharmaceutical composition of the present invention, thereby treating the disorder or condition.

[0225] In exemplary embodiments, the GR modulator is an antagonist of GR activity (also referred to herein as a "glucocorticoid receptor antagonist"). A glucocorticoid receptor antagonist, as used herein, 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 an agonist.

[0226] 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 preferentially binds to GR rather than to another nuclear receptor (NR), thereby inhibiting any biological response associated with the binding of GR to an agonist. In some embodiments, the specific glucocorticoid receptor antagonist preferentially binds to GR rather than to mineralocorticoid receptor (MR), aldosterone receptor (AR), or progesterone receptor (PR). In an exemplary embodiment, the specific glucocorticoid receptor antagonist preferentially binds to GR rather than to mineralocorticoid receptor (MR). In another exemplary embodiment, the specific glucocorticoid receptor antagonist preferentially binds to GR rather than to progesterone receptor (PR). In another exemplary embodiment, the specific glucocorticoid receptor antagonist preferentially binds to GR rather than to aldosterone receptor (AR).

[0227] In some embodiments, the specific glucocorticoid receptor antagonist binds to GR with an association constant (Kd) that is at least 10 times lower than the Kd for any other NR. In some embodiments, the specific glucocorticoid receptor antagonist binds to GR with an association constant (Kd) that is at least 100 times lower than the Kd for any other NR. In some embodiments, the specific glucocorticoid receptor antagonist binds to GR with an association constant (Kd) that is at least 1000 times lower than the Kd for any other NR.

[0228] In some embodiments, the present invention provides a method for treating a disorder or condition by antagonizing the glucocorticoid receptor, the method comprising administering to a subject in need of such treatment an effective amount of any one of the compounds of the present invention or the pharmaceutical compositions of the present invention.

[0229] In some embodiments, the disorder or condition is selected from the group consisting of amyotrophic lateral sclerosis (ALS), obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, neurodegeneration, Alzheimer's disease, Parkinson's disease, Cushing's syndrome, Cushing's disease, cancer, liver disease, osteoporosis, muscle weakness, disorders due to excess cortisol associated with adrenal disease, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, fractures following surgery, GR-related metabolic disorders, severe psychotic depression, mild cognitive impairment, dementia, hyperglycemia, stress disorders, weight gain due to antipsychotics, delirium, cognitive impairment in depressed patients, postpartum psychosis, postpartum depression, and neurological disorders of prematurity.

[0230] In some embodiments, the method includes administering one or more second agents (e.g., therapeutic agents). In some embodiments, the method includes administering one or more second agents (e.g., therapeutic agents) in a therapeutically effective amount. In some embodiments, the second agent is an agent known to be useful for modulating the glucocorticoid receptor. In some embodiments, the second agent is for treating amyotrophic lateral sclerosis (ALS), obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, neurodegeneration, Alzheimer's disease, Parkinson's disease, Cushing's syndrome, Cushing's disease, cancer, liver disease, osteoporosis, muscle weakness, disorders due to excess cortisol associated with adrenal disease, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, bone fractures after surgery, GR-related metabolic disorders, severe psychotic depression, mild cognitive impairment, dementia, hyperglycemia, stress disorder, antipsychotic-induced weight gain, delirium, cognitive impairment in depressed patients, postpartum psychosis, postpartum depression, and neurological disorders in premature infants.In some embodiments, the second agent is for treating severe psychotic depression, stress disorder, or antipsychotic-induced weight gain. In some embodiments, the second agent is an agent for treating non-alcoholic fatty liver disease and / or non-alcoholic steatohepatitis.In some embodiments, the second agent is an agent for treating addiction disorder.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.

[0231] In some embodiments, the compounds of the present invention or any one of the pharmaceutical compositions of the present invention can be used in a method of treating a disorder or condition by modulating the glucocorticoid receptor.

[0232] In some embodiments, the compounds of the present invention or any one of the pharmaceutical compositions of the present invention can be used in a method of treating a disorder or condition by antagonizing the glucocorticoid receptor.

[0233] In some embodiments, any one of the compounds of the present invention or the pharmaceutical compositions of the present invention can be used for the manufacture of a medicament for treating a disorder or condition by modulating the glucocorticoid receptor.

[0234] In some embodiments, any one of the compounds of the present invention or the pharmaceutical compositions of the present invention can be used in the manufacture of a medicament for treating a disorder or condition by antagonizing the glucocorticoid receptor.

[0235] VI. Working Examples General Procedure All starting materials and solvents were obtained from commercial sources or prepared according to literature citations. All reactions were stirred unless otherwise stated. Organic solutions were usually dried over anhydrous magnesium sulfate. Hydrogenations were carried out in a Thales H-cube flow reactor under the conditions described or under pressure in a gas autoclave (bomb).

[0236] Column chromatography was performed on pre-packed silica (230-400 mesh, 40-63 μm) cartridges using the amounts 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. It was then washed with 1% NH 3 The desired material was eluted by washing with .

[0237] Analysis method Reversed-phase high performance liquid chromatography. Method 1: Waters XSelect CSH UPLC C18, 1.7 μm (2.1x30 mm), 40 °C; flow rate 0.77 mL / min, H 2 Elute with a 3 min gradient of 0-MeCN (containing 0.1% v / v formic acid) and UV detection from 210 to 400 nm. Gradient information: 0–0.11 min, 95% H 2 Hold in HO-5% MeCN; 0.11–2.15 min, 95% HO 2O-5% MeCN to 5% H 2 Gradient to 2.15-2.49 min, 5% H 2 Hold in O-95% MeCN, 2.49–2.56 min, 5% H 2 O-95%MeCN to 95%H 2 Gradient to HO-5% MeCN; 2.56–3.00 min, 95% HO 2 Maintained in O-5% MeCN.

[0238] Method 2: Waters XSelect CSH C18, 2.5 μm (4.6 × 30 mm), 40 °C; flow rate 2.5–4.5 mL / min, H 2 Elute with a 4 min gradient of 0-MeCN (containing 0.1% v / v formic acid) with UV detection at 254 and 215 nm. Gradient information: 0–3.00 min, 95% H 2 O-5% MeCN to 5% H 2 Gradient to 20H2O-95% MeCN; 3.00–3.01 min, 5% H 2 H-95% MeCN was used as the hold time and the flow rate was increased to 4.5 mL / min; 3.01–3.50 min, 5% H 2 Hold in O-95% MeCN; 3.50–3.60 min, 95% H 2 The mixture was then returned to 20H2O-5% MeCN and the flow rate was reduced to 3.50 mL / min; 3.60–3.90 min, 95% H2O-5% MeCN, and the flow rate was reduced to 3.50 mL / min; 2 Hold in HO-5% MeCN; 3.90–4.00 min, 95% HO 2 The flow rate was reduced to 2.5 mL / min, maintaining at O-5% MeCN.

[0239] Method 3: Waters XBridge BEH C18, 1.7 μm (2.1 × 30 mm), 40 °C; flow rate 2.5–4.5 mL / min, H 2 Elute with a 4 min gradient of 0-MeCN (containing 10 mM ammonium bicarbonate) with UV detection at 254 nm. Gradient information: 0–0.11 min, 95% H 2 Hold in HO-5% MeCN; 0.11–2.15 min, 95% HO 2 O-5% MeCN to 5% H 2 Gradient to 2.15-2.49 min, 5% H 2 Hold in O-95% MeCN; 2.49–2.56 min, 5% H2 O-95%MeCN to 95%H 2 Gradient to HO-5% MeCN; 2.56–3.00 min, 95% HO 2 Maintained in O-5% MeCN.

[0240] Method 4: Waters XSelect BEH C18, 1.7 μm (2.1 × 30 mm), 40 °C; flow rate 0.77 mL / min, H 2 Elute with a 3 min gradient of 0-MeCN (containing 10 mM ammonium bicarbonate) with UV detection from 210 to 400 nm. Gradient information: 0–0.11 min, 95% H 2 Hold in HO-5% MeCN; 0.11–2.15 min, 95% HO 2 O-5% MeCN to 5% H 2 Gradient to 2.15-2.49 min, 5% H 2 Hold in O-95% MeCN; 2.49–2.56 min, 5% H 2 O-95%MeCN to 95%H 2 Gradient to HO-5% MeCN; 2.56–3.00 min, 95% HO 2 Maintained in O-5% MeCN.

[0241] Method 5: Waters XSelect CSH UPLC C18, 1.7 μm (2.1 × 30 mm), 40 °C; flow rate 0.77 mL / min, H 2 Elute with a 10 min gradient of 0-MeCN (containing 0.1% v / v formic acid) and use UV detection from 210 to 400 nm. Gradient information: 0–9.52 min, 95% H 2 O-5% MeCN to 5% H 2 Gradient to 20H-95% MeCN; 9.52–9.93 min, 5% H 2 Hold in O-95% MeCN; 9.93–10.00 min, 5% H 2 O-95%MeCN to 95%H 2 Gradient to HO-5% MeCN; 10.00–10.20 min, 95% HO 2 Maintained in O-5% MeCN.

[0242] Method 6: Waters HClass; binary solvent pump, SM-FTN, CMA, PDA: 210-400 nm, QDa: ACQ-QDa ESI; Column: Waters CSH C18, 30 × 2.1 mm, 1.7 μm, Temperature: 40 °C, Flow rate: 0.77 mL / min, Gradient: t0 = 2% B, t2.5 min = 100% B, t3.0 min = 100% B, Eluent A: 0.1% formic acid in water, Eluent B: acetonitrile.

[0243] Method 7: Waters HClass; Quaternary solvent pump, SM-FTN, CMA, PDA: 210-400 nm, QDa: ACQ-QDa ESI; Column: Waters CSH C18, 30×2.1 mm, 1.7 μm, Temperature: 40° C., Flow rate: 0.77 mL / min, Gradient: t0=2% B, t2.5 min=100% B, t3.0 min=100% B, Eluent A: 0.1% formic acid in water, Eluent B: acetonitrile.

[0244] 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: t0=2% B, t2.5 min=100% B, t3.0 min=100% B, Eluent A: 0.1% NH3 in water, Eluent B: acetonitrile.

[0245] NMR spectra were recorded using a Bruker 400MHz Avance Neo spectrometer equipped with a Bruker 5mm iProbe or a Bruker 500MHz Avance III HD spectrometer equipped with a Bruker 5mm Smart Probe™. Unless otherwise stated, spectra were measured at 298K and referenced to the solvent resonance. Chemical shifts are reported in parts per million. Data were acquired using Bruker TopSpin software and processed using MestreNova software.

[0246] All chemical names were generated using ChemDraw. Intermediates Intermediate A: 4-bromo-N-(4-fluorophenyl)-5-methyl-2-nitroaniline [ka]

[0247] N,N-Diisopropylethylamine (1.642 ml, 9.40 mmol) was added to a solution of 4-fluoroaniline (0.810 ml, 8.55 mmol) and 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (2 g, 8.55 mmol) in acetonitrile (10 mL) and the reaction mixture was heated to 90 °C overnight. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-20% EtOAc / isohexane) to give 4-bromo-N-(4-fluorophenyl)-5-methyl-2-nitroaniline (Intermediate A) (2.6 g, 5.68 mmol, 66.4% yield) as an orange oil that solidified on standing: δH (CDCl 3 , 500 MHz) 9.34 (s, 1H), 8.40 (s, 1H), 7.28-7.23 (m, 2H), 7.16 (t, 8.5, 2H), 6.91 (s, 1H), 2.33 (s, 3H). Intermediate B: 4-bromo-N1-(4-fluorophenyl)-5-methylbenzene-1,2-diamine [ka]

[0248] Iron (2.070 g, 37.1 mmol) was added followed by aqueous HCl (2M, 7.41 ml, 14.82 mmol) to a solution of 4-bromo-N-(4-fluorophenyl)-5-methyl-2-nitroaniline (Intermediate A) (2.41 g, 7.41 mmol) in ethanol (5 mL) and acetic acid (21 mL) and stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were washed with saturated NaHCO 3 aqueous solution (100 mL), filtered through Celite and washed with EtOAc (50 mL). The filtrate was concentrated in vacuo to give 4-bromo-N1-(4-fluorophenyl)-5-methylbenzene-1,2-diamine (Intermediate B) (2.23 g, 6.80 mmol, 92% yield) as a brown solid; δH (CDCl 3 , 500 MHz) 7.04 (s, 1H), 6.97 - 6.92 (m, 3H), 6.73 (dd, J 8.9, 4.5, 2H), 2.27 (s, 3H). No exchangeable protons were observed. Intermediate C: 5-bromo-1-(4-fluorophenyl)-6-methyl-1H-benzo[d][1,2,3]triazole [ka]

[0249] 37% HCl (6.12 ml, 74.5 mmol) was added to a stirred 0° C. suspension of 4-bromo-N1-(4-fluorophenyl)-5-methylbenzene-1,2-diamine (Intermediate B) (2.2 g, 7.45 mmol) in water (13 mL). After 5 min, a solution of sodium nitrite (0.599 g, 8.68 mmol) in water (13 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was basified by addition of 2 M NaOH (aq) and the resulting precipitate was collected by filtration and purified by chromatography on silica gel (80 g cartridge, 0-20% EtOAc / isohexane) to give 5-bromo-1-(4-fluorophenyl)-6-methyl-1H-benzo[d][1,2,3]triazole (Intermediate C) (502 mg, 1.607 mmol, 21.56% yield) as a brown solid; δH (CDCl 3 , 500 MHz) 8.38 (s, 1H), 7.75 (dd, J 8.9, 4.6, 2H), 7.58 (s, 1H), 7.35 (dd, J 9.0, 8.0, 2H), 2.61 (s, 3H). Example 1: (R)-1-(4-fluorophenyl)-5-(2-methyl-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperazin-1-yl)-1H-indazole Intermediate D: 5-bromo-1-(4-fluorophenyl)-1H-indazole [ka]

[0250] Pyridine (0.877 ml, 10.84 mmol) was added to a solution of 5-bromo-1H-indazole (1.068 g, 5.42 mmol), (4-fluorophenyl)boronic acid (1.517 g, 10.84 mmol), and copper(II) acetate (1.477 g, 8.13 mmol) in dichloromethane (75 mL) and stirred overnight exposed to air through a perforated septum. The reaction was filtered through a pad of Celite, which was washed with dichloromethane (30 mL) and concentrated under vacuum. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-10% EtOAc / isohexane) to give 5-bromo-1-(4-fluorophenyl)-1H-indazole (Intermediate D) (610 mg, 2.074 mmol, 38.3% yield) as a white solid; R t 1.76 min (Method 1); m / z 291.63 and 293.46 (M+H) + (ES + ). Intermediate E: (R)-4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpiperazine-1-carboxylate tert-butyl [ka]

[0251] A solution of 5-bromo-1-(4-fluorophenyl)-1H-indazole (Intermediate D) (1.0 g, 3.44 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (688 mg, 3.44 mmol), and sodium tert-butoxide (528 mg, 5.50 mmol) in 1,4-dioxane (10 mL) was degassed by bubbling nitrogen through for 5 min. Chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (69 mg, 0.172 mmol) was then added and the solution was degassed for an additional 5 min. The solution was then heated to 80 °C and stirred overnight. The reaction mixture was cooled to room temperature and partitioned between EtOAc (50 mL) and water (80 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organics were washed with MgSO 4The crude product was purified by chromatography on silica gel (40 g cartridge, 0-30% EtOAc / isohexane) to give (R)-tert-butyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpiperazine-1-carboxylate (Intermediate E) (800 mg, 1.929 mmol, 56.2% yield) as a white solid; R t 1.72 minutes (method 1); m / z 411.85 (M+H) + (ES + ). Example 1: (R)-1-(4-fluorophenyl)-5-(2-methyl-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperazin-1-yl)-1H-indazole [ka]

[0252] HCl (4M in 1,4-dioxane) (886 μl, 3.54 mmol) was added to a solution of (R)-tert-butyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpiperazine-1-carboxylate (Intermediate E) (97 mg, 0.236 mmol) in 1,4-dioxane (1 ml) and the reaction was stirred at room temperature for 3 h then concentrated to dryness.

[0253] A solution of 1-methyl-1H-pyrazole-4-sulfonyl chloride (64.0 mg, 0.354 mmol) in dichloromethane (1 ml) was added to a solution of (R)-1-(4-fluorophenyl)-5-(2-methylpiperazin-1-yl)-1H-indazole and pyridine (96 μl, 1.182 mmol) in dichloromethane (2 ml) and the mixture was stirred at room temperature overnight. Water (10 mL) and dichloromethane (10 mL) were added, the layers were separated and the organic layer was washed with water (10 mL) and diluted with MgSO 4The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to give (R)-1-(4-fluorophenyl)-5-(2-methyl-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperazin-1-yl)-1H-indazole (Example 1) (70 mg, 0.152 mmol, 64.5% yield) as a colorless solid; R t 1.49 minutes (method 1); m / z 455.11 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) 8.38 (s, 1H), 8.22 (d, J 0.9, 1H), 7.83 (d, J 0.7, 1H), 7.78 (dd, J 9.0, 4.8, 2H), 7.73 - 7.67 (m, 1H), 7.41 (t, J 8.8, 2H), 7.29 (m, 2H), 3.94 (s, 3H), 3.90 (dt, J 7.3, 4.1, 1H), 3.31 - 3.26 (m, 1H), 3.24 - 3.15 (m, 2H), 3.04 (dd, J 11.0, 4.7, 1H), 2.88 (dd, J 11.1, 3.3, 1H), 2.73 (ddd, J 11.2, 8.2, 3.7, 1H), 0.95 (d, J 6.4, 3H). Example 2: (R)-(4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone [ka]

[0254] HCl (4M in 1,4-dioxane) (685 μl, 2.74 mmol) was added to a solution of (R)-tert-butyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpiperazine-1-carboxylate (Intermediate E) (75 mg, 0.183 mmol) in 1,4-dioxane (1 ml) and the reaction was stirred at room temperature for 3 h then concentrated to dryness.

[0255] A solution of benzoyl chloride (31.6 μl, 0.274 mmol) in dichloromethane (1 ml) was added to a solution of (R)-1-(4-fluorophenyl)-5-(2-methylpiperazin-1-yl)-1H-indazole and pyridine (73.9 μl, 0.914 mmol) in dichloromethane (2 ml) and the mixture was stirred at room temperature overnight. Water (10 mL) and dichloromethane (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 (R)-(4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone (Example 2) (62 mg, 0.147 mmol, 80% yield) as a dark yellow solid; R t 1.55 minutes (method 1); m / z 415.19 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) 8.22 (d, J 0.9, 1H), 7.79 (dd, J 9.0, 4.8, 2H), 7.72 (d, J 9.1, 1H), 7.51 - 7.43 (m, 5H), 7.41 (dd, J 9.8, 7.8, 2H), 7.33 (s, 1H), 7.28 (d, J 2.2, 1H), 4.26 (br. s, 0.5H), 4.07 - 3.91 (m, 1H), 3.83 (br. s, 0.5H), 3.59 (s, 1.5H), 3.44 - 3.34 (m, 1.5H), 3.23 (br. s, 0.5H), 3.11 (br. s, 1.5H), 0.93 (br.s, 1.5H), 0.80 (br. s, 1.5H). The compound exists as a 1:1 mixture of conformers / rotamers. Example 3: 1-(4-fluorophenyl)-5-(7-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,7-diazaspiro[2.5]octan-4-yl)-1H-indazole Intermediate F: tert-butyl 7-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,7-diazaspiro[2.5]octane-4-carboxylate [ka]

[0256] A solution of 1-propyl-1H-pyrazole-4-sulfonyl chloride (211 μl, 1.413 mmol) in dichloromethane (1 ml) was added to a solution of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.942 mmol) and pyridine (381 μl, 4.71 mmol) in dichloromethane (10 ml) and the mixture was stirred at room temperature overnight. Water (10 ml) and dichloromethane (10 ml) were added and the layers were separated. The organic layer was washed with water (10 mL) and diluted with MgSO 4 The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc / isohexane) to give tert-butyl 7-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (Intermediate F) (301 mg, 0.775 mmol, 82% yield) as a white powder; δH (CDCl 3 , 500 MHz) 7.74 (s, 1H), 7.72 (d, J 0.7, 1H), 4.14 (t, J 7.0, 2H), 3.65 (t, J 5.0, 2H), 2.99 (s, 2H), 2.83 (s, 2H), 1.94 (h, J 7.3, 2H), 1.41 (s, 9H), 1.05 (m, 2H), 0.94 (t, J 7.4, 3H), 0.93 - 0.89 (m, 2H). Example 3: 1-(4-fluorophenyl)-5-(7-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,7-diazaspiro[2.5]octan-4-yl)-1H-indazole [ka]

[0257] HCl (4M in 1,4-dioxane) (1288 μl, 5.15 mmol) was added to a solution of tert-butyl 7-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (Intermediate F) (132 mg, 0.344 mmol) in 1,4-dioxane (1 ml) and the reaction was stirred at room temperature for 3 h then concentrated to dryness.

[0258] 5-Bromo-1-(4-fluorophenyl)-1H-indazole (Intermediate D) (100 mg, 0.344 mmol), sodium tert-butoxide (52.8 mg, 0.550 mmol), and 1,4-dioxane (1 mL) were added and the solution was degassed by bubbling nitrogen through for 5 min. Chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (6.86 mg, 0.017 mmol) was added and the solution was degassed for an additional 5 min, heated to 80 °C, and stirred overnight. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate (15 mL) and water (20 mL), the layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 15 mL). 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 1-(4-fluorophenyl)-5-(7-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,7-diazaspiro[2.5]octan-4-yl)-1H-indazole (Example 3) (15 mg, 0.029 mmol, 8.39% yield) as a light brown solid; R t 1.67 min (method 1); m / z 495.73 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) 8.30 (d, J 0.8, 1H), 8.13 (d, J 0.9, 1H), 7.76 - 7.72 (m, 3H), 7.62 (dt, J 9.3, 0.9, 1H), 7.40 (t, J 8.8, 2H), 7.28 (d, J 2.2, 1H), 7.22 (dd, J 9.2, 2.3, 1H), 4.03 (t, J 6.8, 2H), 3.78 (br. s, 2H), 2.92 (s, 2H), 2.54 - 2.52 (obs. m, 2H), 1.63 (h, J 7.2, 2H), 0.89 - 0.79 (m, 4H), 0.49 (t, J 7.3, 3H). Example 4: (S)—N-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-yl)-1-propyl-1H-pyrazole-4-sulfonamide Intermediate G: (S)-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-yl)carbamate tert-butyl [ka]

[0259] 5-Bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (prepared by the method of Intermediate D) (800 mg, 2.62 mmol), (S)-tert-butyl pyrrolidin-3-ylcarbamate (977 mg, 5.24 mmol), RuPhosG3 precatalyst (219 mg, 0.262 mmol), and cesium carbonate (2.56 g, 7.87 mmol) were evacuated and backfilled with nitrogen (×3). 1,4-Dioxane (15 mL) was added and the resulting pale green suspension was heated at 80° C. for 3 days. The reaction mixture was quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were combined and passed through a hydrophobic frit. The solvent was removed under reduced pressure to give a dark yellow residue. The crude product was purified by chromatography on silica gel (liquid loading with DCM, 120 g cartridge, 0-50% EtOAc / isohexane) to afford (S)-tert-butyl (1-(1-(4-fluorophenyl)-6)-methyl-1H-indazol-5-yl)pyrrolidin-3-yl)carbamate (Intermediate G) (976 mg, 2.347 mmol, 90% yield) as an off-white solid; R t 1.76 min (method 1); m / z 411.4 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) 8.17 (d, J 0.9, 1H), 7.80 - 7.75 (m, 2H), 7.60 (s, 1H), 7.44 - 7.37 (m, 2H), 7.30 (s, 1H), 7.17 (br d, J 7.1, 1H), 4.11 (obs. br. d, J 6.3, 1H), 3.31 - 3.25 (m, 1H), 3.20 - 3.08 (m, 2H), 2.95 (dd, J 9.4, 5.4, 1H), 2.41 (d, J 0.9, 3H), 2.24 - 2.13 (m, 1H), 1.85 - 1.75 (m, 1H), 1.40 (s, 9H). (S)-N-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-yl)-1-propyl-1H-pyrazole-4-sulfonamide [ka]

[0260] To a solution of (S)-tert-butyl (1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-yl)carbamate (Intermediate G) (500 mg, 1.218 mmol) in dichloromethane (10 mL) was added HCl (3.5 M in 1,4-dioxane) (3480 μl, 12.18 mmol). The resulting cloudy solution was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the resulting solid was triturated with tert-butyl methyl ether (5 mL), filtered, rinsed with tert-butyl methyl ether (2×5 mL) and dried in vacuo to give (S)-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-amine hydrochloride as a white solid, which was used without further purification.

[0261] To a solution of (S)-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-amine hydrochloride (160 mg, 0.461 mmol) in dichloromethane (4 mL) was added pyridine (187 μl, 2.307 mmol) and 1-propyl-1H-pyrazole-4-sulfonyl chloride (193 mg, 0.923 mmol). The resulting white suspension was stirred at room temperature for 4 days. The reaction mixture was diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were combined and passed through a hydrophobic frit. The solvent was removed under reduced pressure and the crude product was purified by chromatography on silica gel (liquid loading, 40 g cartridge, 0-50% EtOAc / isohexane) to give (S)—N-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-yl)-1-propyl-1H-pyrazole-4-sulfonamide (Example 4) (58 mg, 0.118 mmol, 25.6% yield) as a yellow solid; R t 1.60 minutes (method 1); m / z 483.4 (M+H) +(ES + ); δH (DMSO-d6, 500 MHz) 8.31 (s, 1H), 8.17 (d, J = 0.9 Hz, 1H), 7.78 (dd, J= 9.01, 4.8 Hz, 2H), 7.60 (s, 1H), 7.41 (app. t, J = 8.8 Hz, 2H), 7.30 (s, 1H), 4.12 (t, J = 6.9 Hz, 2H), 3.85 (q, J = 6.7 Hz, 1H), 3.17 - 3.05 (m, 3H), 2.95 (dd, J = 9.5, 5.5 Hz, 1H), 2.37 - 2.32 (m, 3H), 2.13 (d, J = 6.5 Hz, 1H), 1.78 (ddd, J = 12.1, 9.6, 6.2 Hz, 4H), 0.79 (t, J = 7.4 Hz, 3H). Example 5: (S)—N-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-yl)-N-methyl-1-propyl-1H-pyrazole-4-sulfonamide [ka]

[0262] To a solution of (S)-N-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-yl)-1-propyl-1H-pyrazole-4-sulfonamide (Example 4) (48 mg, 0.099 mmol) in dimethylformamide (3 mL) at 0° C. was added sodium hydride (60% in mineral oil) (4.77 mg, 0.119 mmol) in one portion. The resulting yellow solution was stirred at 0° C. for 30 minutes and methyl iodide (12.44 μl, 0.199 mmol) was added. The resulting white solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated bicarbonate solution (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were combined and passed through a hydrophobic frit. The solvent was removed under reduced pressure and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc / isohexane) to give (S)-N-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-yl)-N-methyl-1-propyl-1H-pyrazole-4-sulfonamide (Example 5) (42 mg, 0.084 mmol, 84% yield) as a yellow solid; R t 1.76 min (method 1); m / z 497.4 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) 8.44 (d, J 0.7, 1H), 8.18 (d, J 0.9, 1H), 7.88 (d, J 0.7, 1H), 7.77 (dd, J 9.0, 4.8, 2H), 7.60 (s, 1H), 7.41 (app. t, J 8.8, 2H), 7.34 (s, 1H), 4.66 - 4.55 (m, 1H), 4.13 (t, J 6.8, 2H), 3.13 (td, J 8.5, 3.3, 1H), 2.91 (m, 3H), 2.80 (s, 3H), 2.34 (s, 3H), 2.16 - 2.05 (m, 1H), 1.85 - 1.73 (m, 3H), 0.78 (t, J 7.4, 3H). Example 6: 1-(4-fluorophenyl)-6-methyl-5-(1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole Intermediate H: tert-butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate [ka]

[0263] 5-Bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (prepared using the method described for Intermediate D) (0.262 g, 0.859 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.4 g, 1.294 mmol), potassium carbonate (0.4 g, 2.89 mmol), and Pd(dppf)Cl2.DCM (0.140 g, 0.172 mmol) were suspended in a mixture of 1,4-dioxane (5 mL) and water (1 mL). The vial was evacuated and backfilled with nitrogen three times, then heated to reflux for 16 h. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), filtered through Celite, then absorbed directly onto silica gel and purified by silica gel chromatography (24 g cartridge, 0-100% EtOAc / isohexane) to afford tert-butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate H) (329 mg, 0.783 mmol, 91% yield) as a pale yellow tar; R t 1.99 minutes (method 1); m / z 408.7 (M+H) + (ES + ). Intermediate I: tert-butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)piperidine-1-carboxylate [ka]

[0264] tert-Butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate H) (329 mg, 0.783 mmol) was dissolved in a mixture of ethanol / tetrahydrofuran (5:1, 6 mL) and palladium on activated carbon (type 39, 10% loading, 50% w / w water) (150 mg, 0.070 mmol) was added. The mixture was stirred under 5 bar hydrogen pressure for 4 h. The mixture was filtered through Celite and eluted with ethanol (3×5 mL) and ethyl acetate (3×5 mL). After concentration of the filtrate, tert-butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)piperidine-1-carboxylate (Intermediate I) (281 mg, 0.672 mmol, 86% yield) was isolated as a pale yellow solid foam; R t 1.97 minutes (method 1); m / z 410.3 (M+H) + (ES + ). Example 6: 1-(4-fluorophenyl)-6-methyl-5-(1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole [ka]

[0265] tert-Butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)piperidine-1-carboxylate (Intermediate I) (0.05 g, 0.122 mmol) was dissolved in HCl (4M in 1,4-dioxane) (2 mL, 8.00 mmol) and stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was suspended in dichloromethane (2 mL). Pyridine (50 μl, 0.618 mmol) and methanesulfonyl chloride (20 μl, 0.258 mmol) were added and the mixture was warmed to 35° C. (bath temperature) for 3 days. The mixture was allowed to warm to room temperature and then quenched with 1M HCl (aq) (1 mL). The organic phase was separated by passing through a hydrophobic frit and then concentrated in vacuo. 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-(1-(methylsulfonyl)piperidin-4-yl-1H-indazole (Example 6) (36 mg, 0.092 mmol, 76% yield) as a colorless solid; R t 1.74 min (method 1); m / z 482.3 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) 8.43 (s, 1H), 8.24 (s, 1H), 7.85 (s, 1H), 7.78 (dd, J 8.9, 4.9, 2H), 7.70 (s, 1H), 7.60 (s, 1H), 7.42 (app. t, J 8.6, 2H), 4.17 (t, J 6.9, 2H), 3.75 (d, J 11.3, 2H), 2.79 (tt, J 11.9, 3.5, 1H), 2.42 (s, 3H), 2.42 - 2.35 (m, 2H), 1.91 - 1.81 (m, 4H), 1.81 - 1.70 (m, 2H), 0.84 (t, J 7.4, 3H). Example 7: 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-4-(methylsulfonyl)piperazin-2-one Intermediate J: tert-butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-oxopiperazine-1-carboxylate [ka]

[0266] 5-Bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (prepared using the method described for Intermediate D) (0.25 g, 0.819 mmol), tert-butyl 3-oxopiperazine-1-carboxylate (0.246 g, 1.229 mmol), copper iodide (0.031 g, 0.164 mmol), and potassium carbonate (0.340 g, 2.458 mmol) were suspended in 1,4-dioxane (3 mL) under nitrogen. The mixture was evacuated and backfilled with nitrogen three times. trans-N1,N2-dimethylcyclohexane-1,2-diamine (0.039 ml, 0.246 mmol) was added and the mixture was heated to reflux overnight. The mixture was cooled to room temperature, filtered through a plug of Celite, and the solvent was removed under vacuum. The crude product was purified by silica gel chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to give tert-butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-oxopiperazine-1-carboxylate (Intermediate J) (0.05 g, 0.110 mmol, 13.37% yield) as a yellow solid; R t 1.53 minutes (method 1); m / z 425.3 (M+H) + (ES + ). Example 7: 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-4-(methylsulfonyl)piperazin-2-one [ka]

[0267] tert-Butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-oxopiperazine-1-carboxylate (Intermediate J) (0.025 g, 0.059 mmol) was dissolved in HCl (4 M in 1,4-dioxane) (3 mL) and stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was suspended in dichloromethane (3 mL). Methanesulfonyl chloride (10 μl, 0.129 mmol) was added, followed by triethylamine (0.04 ml, 0.287 mmol). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in dimethylsulfoxide (2 mL). The mixture was filtered and then directly purified by preparative HPLC (Method A, 20-50% MeCN in water). After concentration of the product-containing fractions (Genevac), 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-4-(methylsulfonyl)piperazin-2-one (Example 7) (10 mg, 0.025 mmol, 42.2% yield) was isolated as a colorless oil; R t 1.21 min (method 1); m / z 403.1 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) 8.34 (d, J 0.9, 1H), 7.87 - 7.77 (m, 3H), 7.73 (s, 1H), 7.45 (app. t, J 8.8, 2H), 4.04 (d, J 16.7, 1H), 3.97 (d, J 16.8, 1H), 3.88 - 3.78 (m, 1H), 3.73 - 3.65 (m, 1H), 3.63 - 3.51 (m, 2H), 3.10 (s, 3H), 2.30 (s, 3H). Example 8: 1-(4-fluorophenyl)-5-((2R)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole Intermediate K: (2R)-tert-butyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-hydroxy-2-methylpiperidine-1-carboxylate [ka]

[0268] A solution of 5-bromo-1-(4-fluorophenyl)-1H-indazole (Intermediate D) (291 mg, 1,000 mmol) in tetrahydrofuran (3 mL) was cooled to −78° C. and treated with n-butyllithium (2.5 M in isohexane) (600 μl, 1,500 mmol). A solution of (R)-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (250 mg, 1.172 mmol) in tetrahydrofuran (3 mL) was added immediately and the mixture was stirred at −78° C. for 30 min. The mixture was quenched at low temperature with saturated aqueous ammonium chloride (1 mL) followed by water (3 mL). Ethyl acetate (10 mL) was added. The organic phase was separated and washed with brine (2 mL) and then with MgSO. 4 The crude product was purified by chromatography on silica gel (24 g cartridge, 0-70% EtOAc / isohexane over 20 min) to give (2R)-tert-butyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-hydroxy-2-methylpiperidine-1-carboxylate (Intermediate K) (103 mg, 0.232 mmol, 23.24% yield) as a clear, colorless glass; t 0.74 min (method 1); m / z 426.7 (M+H) + (ES + ). Intermediate L: (R)-1-(4-fluorophenyl)-5-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole hydrochloride and (R)-1-(4-fluorophenyl)-5-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole hydrochloride [ka]

[0269] (2R)-tert-butyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-hydroxy-2-methylpiperidine-1-carboxylate (Intermediate K) (100 mg, 0.226 mmol) was dissolved in HCl (4M in 1,4-dioxane) (3 mL, 12.00 mmol) and stirred at room temperature for 15 min. The yellow oily suspension was concentrated in vacuo to give a 1:1 mixture of (R)-1-(4-fluorophenyl)-5-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole hydrochloride and (R)-1-(4-fluorophenyl)-5-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole hydrochloride (Intermediate L) (87 mg, 100%), which was used without further purification; R t 0.39 and 0.44 min (Method 1); m / z 308.2 (M+H) + (ES + ). Intermediate M: (R)-1-(4-fluorophenyl)-5-(6-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole and (R)-1-(4-fluorophenyl)-5-(2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [ka]

[0270] A 1:1 mixture of (R)-1-(4-fluorophenyl)-5-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole hydrochloride and (R)-1-(4-fluorophenyl)-5-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole hydrochloride (Intermediate L) (87 mg, 0.226 mmol) was suspended in dichloromethane (3 mL). 1-Propyl-1H-pyrazole-4-sulfonyl chloride (70.7 mg, 0.339 mmol) was added followed by triethylamine (0.1 ml, 0.717 mmol). The mixture was heated to reflux for 1 h. Dichloromethane (10 mL) and water (5 mL) were added. The organic phase was separated, dried by passing through a hydrophobic frit and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give a 1:1 mixture of (R)-1-(4-fluorophenyl)-5-(6-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole and (R)-1-(4-fluorophenyl)-5-(2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole (Intermediate M) (53 mg, 0.103 mmol, 45.5% yield) as a clear, colorless oil; R t 0.75 min (method 1); m / z 480.3 (M+H) + (ES + ). Example 8: 1-(4-fluorophenyl)-5-((2R)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole [ka]

[0271] A 1:1 mixture of (R)-1-(4-fluorophenyl)-5-(2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole (intermediate M) (25 mg, 0.048 mmol) and (R)-1-(4-fluorophenyl)-5-(6-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole (25 mg, 0.048 mmol) was dissolved in ethanol (2 mL) and tetrahydrofuran (1 mL). Palladium on activated carbon (type 39, 10% Pd, 50 wt% water) (10 mg, 4.70 μmol) was added and the mixture was stirred under 5 bar hydrogen pressure for 4 h. The mixture was filtered through Celite and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give (R)-1-(4-fluorophenyl)-5-(2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole (Example 8) (43 mg, 0.089 mmol, 92% yield) as a 1.4:1 mixture of diastereoisomers; R t 1.74 and 1.76 min (Method 1). m / z 482.3 (M+H) + (ES + ). Example 9: 1-(4-fluorophenyl)-5-((2R,4R)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole, and Example 10: 1-(4-fluorophenyl)-5-((2R)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole [ka]

[0272] (R)-1-(4-fluorophenyl)-5-(2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole (Example 8) (32 mg, 0.066 mmol) as a 1.4:1 mixture of diastereoisomers was dissolved in ethanol at 20 mg / mL without the need for sonication or heating and then separated by chiral SFC using a Chiralpak® IA, column (1x25 cm, 5 μm particle size), 25% ethanol at 40°C, 120 bar, flow rate 15 mL / min, on a Waters prep 15 with UV detection by DAD from 210-400 nm. The combined fractions were then concentrated in vacuo to give 1-(4-fluorophenyl)-5-((2R,4R)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole (Example 9) (10.5 mg, 0.022 mmol) as a colorless glass; R t 1.77 min (method 1); m / z 482.3 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) 8.47 (s, 1H), 8.30 (d, J 0.9, 1H), 7.89 (d, J 0.8, 1H), 7.79 (dd, J 9.0, 4.8, 2H), 7.73 (d, J 8.8, 1H), 7.67 (s, 1H), 7.46 - 7.39 (m, 2H), 7.38 (dd, J 8.9, 1.7, 1H), 4.18 (t, J 6.9, 2H), 3.90 (dt, J 12.2, 4.2, 1H), 2.84 - 2.63 (m, 3H), 2.01 - 1.91 (m, 1H), 1.89 - 1.80 (m, 3H), 1.80 - 1.71 (m, 1H), 1.70 - 1.59 (m, 1H), 1.37 (d, J 6.3, 3H), 0.83 (t, J 7.4, 3H); and 1-(4-fluorophenyl)-5-((2R,4S)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole (Example 10) (15.1 mg, 0.031 mmol); R t 1.74 min (Method 1) was obtained as a colorless glass; m / z 482.3 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) 8.43 (s, 1H), 8.29 (d, J 0.9, 1H), 7.87 (d, J 0.7, 1H), 7.79 (dd, J 9.0, 4.8, 2H), 7.72 (d, J 8.8, 1H), 7.62 (s, 1H), 7.43 (app. t, J 8.8, 2H), 7.33 (dd, J 8.9, 1.7, 1H), 4.35 - 4.26 (m, 1H), 4.15 (t, J 6.8, 2H), 3.81 - 3.70 (m, 1H), 3.20 - 3.02 (m, 2H), 1.88 - 1.70 (m, 4H), 1.70 - 1.63 (m, 1H), 1.53 (qd, J 12.7, 4.6, 1H), 1.18 (d, J 6.9, 3H), 0.80 (t, J 7.4, 3H). Example 11: (R)-1-(4-fluorophenyl)-6-methyl-5-(2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole [ka]

[0273] A mixture of (R)-1-(4-fluorophenyl)-6-methyl-5-(6-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole (41 mg, 0.128 mmol) and (R)-1-(4-fluorophenyl)-6-methyl-5-(2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole, prepared in a similar manner as described for intermediate M, was dissolved in MeOH at 50 mg / mL without the need for sonication or heating, filtered, and then analyzed by LUX at 40 °C and 120 bar in a Waters prep 15 with UV detection by DAD from 210 to 400 nm. Separation was performed by chiral SFC using 35% MeOH on a C4 column (1×25 cm, 5 μm particle size) at a flow rate of 15 mL / min. The combined fractions were then concentrated under vacuum to give (R)-1-(4-fluorophenyl)-6-methyl-5-(2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole (Example 11) (10.5 mg, 0.021 mmol) as a colorless tar; R t 1.80 minutes (method 1); m / z 494.3 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) 8.45 (s, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.78 (dd, J 9.0, 4.8, 1H), 7.62 - 7.56 (m, 1H), 7.42 (app. t, J 8.8, 1H), 7.33 (s, 1H), 5.60 - 5.55 (m, 1H), 4.32 (p, J 6.6, 1H), 4.24 - 4.11 (m, 4H), 3.78 - 3.68 (m, 1H), 2.27 (s, 3H), 1.94 (br. d, J 17.1 1H), 1.82 (h, J 7.2, 2H), 1.16 (d, J 6.8, 3H), 0.80 (t, J 7.4, 3H). The other regioisomers were not cleanly separated. Example 12: 1-(4-fluorophenyl)-6-methyl-5-((2R,4R)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole, and Example 13: 1-(4-fluorophenyl)-6-methyl-5-((2R,4S)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole [ka]

[0274] A mixture of 1-(4-fluorophenyl)-6-methyl-5-((2R,4R)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole and 1-(4-fluorophenyl)-6-methyl-5-((2R,4S)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)(sulfonyl)piperidin-4-yl)-1H-indazole (22 mg, 0.045 mmol), prepared in a manner similar to that described in Example 7, was dissolved in MeOH at 50 mg / mL without the need for sonication or heating, filtered, and then purified using a Waters prep kit with UV detection by DAD from 210 to 400 nm. The mixture was separated by chiral SFC using a Chiralpak® IA column (1×25 cm, 5 μm particle size) at 40° C., 120 bar, 25% ethanol at a flow rate of 15 mL / min. The combined fractions were then concentrated under vacuum to give 1-(4-fluorophenyl)-6-methyl-5-((2R,4R)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole (Example 12) (10.2 mg, 0.020 mmol) as a colorless glass; R t 1.80 minutes (method 1); m / z 496.3 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) 8.47 (s, 1H), 8.23 ​​(s, 1H), 7.91 (s, 1H), 7.81 - 7.72 (m, 2H), 7.68 (s, 1H), 7.58 (s, 1H), 7.45 - 7.30 (m, 2H), 4.17 (t, J = 6.8 Hz, 2H), 3.92 - 3.84 (m, 1H), 2.97 - 2.69 (m, 3H), 2.35 (s, 3H), 2.01 - 1.88 (m, 1H), 1.88 - 1.72 (m, 3H), 1.72 - 1.58 (m, 2H), 1.38 (d, J = 6.3 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H); and 1-(4-fluorophenyl)-6-methyl-5-((2R,4S)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole (10.1 mg, 0.020 mmol) (Example 13) was obtained as a colorless glass; R t 1.79 min (method 1); m / z 496.4 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) 8.44 (s, 1H), 8.21 (s, 1H), 7.88 (s, 1H), 7.78 (dd, J 9.0, 4.8, 2H), 7.61 (s, 1H), 7.51 (s, 1H), 7.42 (t, J 8.8, 2H), 4.36 - 4.25 (m, 1H), 4.16 (t, J = 6.8 Hz, 2H), 3.84 - 3.72 (m, 1H), 3.24 - 3.10 (m, 2H), 2.46 (s, 3H), 1.83 (h, J 7.2, 2H), 1.77 - 1.55 (m, 4H), 1.22 (d, J 6.9, 3H), 0.81 (t, J 7.4, 3H). Example 14: (S)-(1-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)sulfonyl)-4-(1-(4-fluorophenyl)-1H-indazol-5-yl)piperazin-2-yl)methanol [ka]

[0275] To a solution of (S)-5-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)sulfonyl)piperazin-1-yl)-1-(4-fluorophenyl)-1H-indazole (135 mg, 0.180 mmol) in tetrahydrofuran (2 mL) at 0° C., prepared in a similar manner as described in Example 3, was added tetrabutylammonium fluoride (1M in THF) (360 μl, 0.360 mmol) dropwise. The resulting pale yellow solution was stirred at 0° C. for 1 h. The reaction mixture was quenched with sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were combined, washed with brine (1×5 mL) and passed through a hydrophobic frit. The solvent was removed under reduced pressure to give a residue. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to give (S)-(1-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)sulfonyl)-4-(1-(4-fluorophenyl)-1H-indazol-5-yl)piperazin-2-yl)methanol (Example 14) (80 mg, 0.155 mmol, 86% yield) as a sticky colorless gum; R t 1.49 min (method 1); m / z 511.5 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) 8.44 (s, 1H), 8.20 (d, J 0.9, 1H), 7.88 (s, 1H), 7.77 (app. dd, J 9.0, 4.8, 2H), 7.70 (d, J 9.2, 1H), 7.41 (t, J 8.8, 2H), 7.25 (dd, J 9.3, 2.3, 1H), 7.18 (d, J 2.2, 1H), 5.02 (obs. br. t, J 5.5, 1H), 4.02 (d, J 7.2, 2H), 3.95 - 3.90 (m, 1H), 3.79 (td, J 9.9, 5.6, 1H), 3.70 (dd, J 12.5, 8.8, 2H), 3.52 - 3.46 (m, 1H), 3.43 (br. d, J 11.8, 1H), 3.31 - 3.26 (obs. m, 1H), 2.63 - 2.56 (m, 2H), 1.25 (m, 1H), 0.53 - 0.47 (m, 2H), 0.39 - 0.33 (m, 2H). Example 15: (S)-5-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)sulfonyl)-3-(methoxymethyl)piperazin-1-yl)-1-(4-fluorophenyl)-1H-indazole [ka]

[0276] To a solution of (S)-(1-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)sulfonyl)-4-(1-(4-fluorophenyl)-1H-indazol-5-yl)piperazin-2-yl)methanol (Example 14) (60 mg, 0.118 mmol) in tetrahydrofuran (2 mL) at 0° C. was added sodium hydride (60% in mineral oil) (7.05 mg, 0.176 mmol) in one portion. The resulting white suspension was stirred at 0° C. for 30 minutes. Methyl iodide (9.55 μl, 0.153 mmol) was added and the resulting solution was stirred at room temperature for 15 hours. The reaction mixture was quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were combined, washed with brine (5 mL), passed through a hydrophobic frit and the solvent removed under reduced pressure to give a yellow residue. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give (S)-5-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl))sulfonyl)-3-(methoxymethyl)piperazin-1-yl)-1-(4-fluorophenyl)-1H-indazole (Example 15) (20 mg, 0.037 mmol, 31.9% yield) as a sticky colorless oil; R t 1.69 min (method 1); m / z 525.4 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) 8.44 (d, J = 0.7 Hz, 1H), 8.20 (d, J = 0.9 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.77 (dd, J = 9.0, 4.8 Hz, 2H), 7.71 (d, J = 9.1 Hz, 1H), 7.41 (t, J = 8.8 Hz, 2H), 7.20 (dd, J = 9.2, 2.3 Hz, 1H), 7.17 (d, J = 2.2 Hz, 1H), 4.16 - 4.11 (m, 1H), 4.02 (d, J = 7.2Hz, 2H), 3.75 - 3.66 (m, 2H), 3.58 (br. d, J = 12.3 Hz, 1H), 3.48 (dd, J = 9.6, 6.0 Hz, 1H), 3.45 (br. d, J = 12.1 Hz, 1H), 3.33 (m, 1H, H 2 O signal), 3.28 (s, 3H), 2.67 (dd, J = 12.3, 3.7 Hz, 1H), 2.60 (td, J = 11.7, 3.5 Hz, 1H), 1.25 (m, 1H), 0.53 - 0.47 (m, 2H), 0.38 - 0.34 (m, 2H). Example 16: 5-(3-benzyl-1-(methylsulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole Intermediate N: 1-(4-fluorophenyl)-6-methyl-5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole [ka]

[0277] 5-Bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (prepared using the method described for Intermediate D) (1.00 g, 3.27 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.30 g, 5.12 mmol), potassium acetate (1.40 g, 14.27 mmol), and Pd(dppf)Cl 2 DCM (250 mg, 0.31 mmol) was suspended in 1,4-dioxane (15 mL). The mixture was evacuated and backfilled with nitrogen (three times) and heated at 80° C. for 16 h. The mixture was cooled to room temperature and then filtered through Celite, eluting with ethyl acetate (50 mL). The filtrate was washed with water (2×50 mL) and brine (50 mL) and then with Na 2 SO 4 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 N) (1.060 g, 2.4 mmol, 73%) as a pale yellow crystalline solid; R t 2.06 min (method 1); m / z 353.4 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) δ 8.35 (s, 1H), 8.22 (s, 1H), 7.88 - 7.74 (m, 2H), 7.59 - 7.57 (m, 1H), 7.51 - 7.38 (m, 2H), 2.62 (s, 3H), 1.33 (s, 12H). Intermediate O: 1-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidine-2,5-dione [ka]

[0278] 1-(4-Fluorophenyl)-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate N) (1.060 g, 2.4 mmol), N-benzylmaleimide (0.50 g, 2.67 mmol), and hydroxy(cyclooctadiene)rhodium dimer (55 mg, 0.12 mmol) were suspended in a mixture of 1,4-dioxane (9 mL) and water (1 mL). Triethylamine (0.37 g, 3.6 mmol) was added and the mixture was evacuated and backfilled with nitrogen (3x). The dark brown mixture was heated to 50° C. overnight. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-50% EtOAc / isohexane) to give 1-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidine-2,5-dione (Intermediate O) (1.05 g, 2.0 mmol, 84%) as a pale yellow oil; R t 1.68 min (method 1); m / z 414.5 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) δ 8.26 (s, 1H), 7.83 - 7.75 (m, 2H), 7.67 (s, 1H), 7.63 (s, 1H), 7.47 - 7.40 (m, 2H), 7.40 - 7.23 (m, 5H), 4.68 (s, 2H), 4.60 (dd, J = 9.5, 5.1 Hz, 1H), 3.36 (dd, J = 18.2, 9.5 Hz, 1H), 2.81 (dd, J = 18.2, 5.2 Hz, 1H), 2.44 (s, 3H). Intermediate P: 1,3-dibenzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidine-2,5-dione [ka]

[0279] To a solution of 1-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidine-2,5-dione (Intermediate O) (454 mg, 1.10 mmol) in tetrahydrofuran (8 mL) at 0° C. was added sodium hydride (66 mg, 60 wt %, 1.65 mmol). The resulting dark purple solution was stirred at 0° C. for 30 minutes at which point benzyl bromide (376 mg, 2.20 mmol) was added and the resulting purple solution was stirred at room temperature for 2 hours. The reaction mixture was quenched at 0° C. by the addition of a saturated solution of sodium bicarbonate (30 mL) and extracted with ethyl acetate (3×25 mL). The organic layers were combined, washed with brine (10 mL) and passed through a hydrophobic frit. The solvent was removed to give a colorless oil and the crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc / isohexane) to give 1,3-dibenzyl-3-(1-(4-fluorophenyl))-6-methyl-1H-indazol-5-yl)pyrrolidine-2,5-dione (Intermediate P) (135 mg, 0.25 mmol, 23%) as a white solid; R t 1.99 minutes (method 1); m / z 504.5 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) δ 8.35 (d, J = 0.9 Hz, 1H), 8.11 (s, 1H), 7.83 - 7.77 (m, 2H), 7.68 (s, 1H), 7.47 - 7.39 (m, 2H), 7.31 - 7.20 (m, 8H), 7.15 - 7.11 (m, 2H), 4.33 (d, J = 14.4 Hz, 1H), 4.25 (d, J = 14.4 Hz, 1H), 3.62 (d, J = 12.7 Hz, 1H), 3.40 (d, J = 12.7 Hz, 1H), 3.22 (d, J = 18.9 Hz, 1H), 3.05 (d, J = 18.9 Hz, 1H), 2.21 (s, 3H). Intermediate Q: 5-(1,3-dibenzylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole [ka]

[0280] To a solution of 1,3-dibenzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidine-2,5-dione (Intermediate P) (135 mg, 0.26 mmol) in tetrahydrofuran (2 mL) was added lithium aluminum hydride (2M in THF) (29 mg, 0.4 mL, 0.77 mmol) dropwise. The mixture was heated to 60° C. for 2 h. After cooling to room temperature, the mixture was diluted with tetrahydrofuran (5 mL) and then carefully quenched with water (0.2 mL) followed by the addition of 2M aqueous sodium hydroxide solution (0.2 mL) and then water (0.4 mL). Na 2 SO 4 was added and the mixture was filtered. After concentration of the filtrate, 5-(1,3-dibenzylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Intermediate Q) (125 mg, 0.26 mmol, 102%) was isolated as a colorless oil; R t 1.23 minutes (method 1); m / z 476.5 (M+H) + (ES + ); The product was used in the next step without further purification. Intermediate R: 5-(3-benzylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole [ka]

[0281] 5-(1,3-dibenzylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Intermediate Q) (130.0 mg, 0.25 mmol) was dissolved in ethyl acetate (5 mL). 10% Pd / C (Type 39) (26 mg, 0.25 mmol) was added and the mixture was stirred at 50° C. under 5 bar hydrogen pressure overnight. The mixture was filtered through Celite, eluting with ethyl acetate (3×5 mL) and methanol (3×5 mL). The combined filtrate was concentrated under vacuum to give 5-(3-benzylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Intermediate R) (100 mg, 0.21 mmol, 86%) as a colorless oil; R t 1.34 min (method 4); m / z 386.5 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz). The crude product was used in the next step without further purification. Example 16: 5-(3-benzyl-1-(methylsulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole [ka]

[0282] To a solution of 5-(3-benzylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Intermediate R) (30 mg, 0.63 mmol) in dichloromethane (2 mL) was added methanesulfonyl chloride (14 mg, 0.13 mmol) and triethylamine (32 mg, 0.32 mmol). The resulting yellow solution was stirred at room temperature for 18 hours. The reaction was quenched by the addition of a saturated solution of sodium bicarbonate (10 mL) and extracted with dichloromethane (3×10 mL). The organic layers were combined and passed through a hydrophobic frit. The solvent was removed under reduced pressure to give a black residue. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to give 5-(3-benzyl-1-(methylsulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Example 16) (5.0 mg, 11 μmol, 17%) as a white solid; R t 1.75 minutes (method 1); m / z 464.1 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) δ 8.16 (s, 1H), 7.82 (dd, J = 8.8, 4.8 Hz, 2H), 7.66 (s, 1H), 7.43 (t, J = 8.7 Hz, 2H), 7.13 - 7.07 (m, 2H), 7.05 (t, J = 7.3 Hz, 2H), 6.59 (d, J = 7.4 Hz, 2H), 3.95 (br. d, J = 9.4 Hz, 1H), 3.63 (br. q, J = 9.0, 8.5 Hz, 1H), 3.50 (br. t, J = 9.5 Hz, 1H), 3.44 (d, J = 9.4 Hz, 1H), 3.14 (br. d, J = 13.6 Hz, 1H), 3.02 (s, 3H) overlapping with 3.00 (m, 1H), 2.50 (m, 1H, hidden in DMSO signal), (2) 2.47 (s, 3H), 2.21 (q, J = 10.6 Hz, 1H). Example 17: (S)-5-(3-benzyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole Example 18: (R)-5-(3-benzyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole [ka]

[0283] The racemic product was dissolved at 50 mg / mL in 1:1 dichloromethane:methanol by sonication and heating, then filtered, then separated by chiral SFC using a Chiralpak® IC (Daicel Ltd.) column (1 x 25 cm, 5 μm particle size) at 40 °C, 120 bar, flow rate 15 mL / min in a Waters prep 15 with UV detection by DAD at 210-400 nm, 50% ethanol with 0.1% ammonia. Clean fractions were pooled, rinsed with ethanol, and evaporated to dryness using a rotary evaporator. The residue was redissolved in ethanol, transferred to a final vial, and evaporated at 40 °C under a stream of nitrogen. The sample was then further dried in a vacuum oven at 40° C. / 5 mbar over the weekend to give (S)-5-(3-benzyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Example 17) (23 mg, 39 μmol, 27%) as a white solid; R t 1.89 min (method 1); m / z 558.8 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) δ 8.53 (s, 1H), 8.13 (s, 1H), 7.97 (s, 1H), 7.84 - 7.77 (m, 2H), 7.63 (s, 1H), 7.43 (t, J = 8.7 Hz, 2H), 7.11 - 7.00 (m, 4H), 6.48 (d, J = 7.4 Hz, 2H), 4.07 (t, J = 6.8 Hz, 2H), 3.90 (d, J = 9.8 Hz, 1H), 3.54 (dd, J = 16.2, 8.4 Hz, 1H), 3.36 (t, J = 10.2 Hz, 1H), 3.21 (d, J = 9.7 Hz, 1H), 2.97 (d, J = 13.4 Hz, 1H), 2.65 (d, J = 10.5 Hz, 1H), 2.44 (s, 3H), 2.37 (s, 1H), 1.98 (q, J = 10.1 Hz, 1H), 1.71 (h, J = 7.1 Hz, 2H), 0.67 (t, J = 7.4 Hz, 3H), and (R)-5-(3-benzyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Example 18) (25 mg, 43 μmol, 29%) was obtained as a white solid; R t 1.88 min (method 1); m / z 558.4 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) δ 8.53 (s, 1H), 8.13 (s, 1H), 7.97 (s, 1H), 7.83 - 7.76 (m, 2H), 7.63 (s, 1H), 7.43 (t, J = 8.8 Hz, 2H), 7.11 - 7.00 (m, 4H), 6.48 (d, J = 7.4 Hz, 2H), 4.07 (t, J = 6.8 Hz, 2H), 3.90 (d, J = 9.7 Hz, 1H), 3.60 - 3.49 (m, 1H), 3.36 (t, J = 10.5 Hz, 1H), 3.21 (br. d, J = 9.7 Hz, 1H), 2.97 (d, J = 13.4 Hz, 1H), 2.65 (br. d, J = 11.5 Hz, 1H), 2.44 (s, 3H), 2.37 (m, 1H), 1.98 (q, J = 10.3 Hz, 1H), 1.71 (h, J = 7.2 Hz, 2H), 0.67 (t, J = 7.4 Hz, 3H). Example 19: (3-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone [ka]

[0284] To a solution of 5-(3-benzylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Intermediate R) (30 mg, 78 μmol) and triethylamine (39 mg, 54 μL, 0.39 mmol) in dichloromethane (2 mL) was added 1-methyl-1H-pyrazole-4-carbonyl chloride (23 mg, 0.16 mmol). The resulting yellow solution was stirred for 16 h. The reaction mixture was quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted with dichloromethane (3×10 mL). The organic layers were combined and passed through a hydrophobic frit. The solvent was removed under reduced pressure to give a yellow residue. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) and silica gel (12 g cartridge, 0-10% MeOH / DCM) to give (3-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone (Example 19) (12 mg, 24 μmol, 31%) as a white solid; R t 1.60 minutes (method 1); m / z 494.5 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz, 363K) δ 8.16 - 8.12 (m, 2H), 7.84 - 7.79 (m, 3H), 7.62 (s, 1H), 7.43 - 7.37 (m, 2H), 7.27 (s, 1H), 7.10 (t, J = 7.3 Hz, 1H), 7.04 (t, J = 7.4 Hz, 2H), 6.63 (br. s, 2H), 4.38 (br. d, J = 11.0 Hz, 1H), 3.91 (s, 3H), 3.81 - 3.65 (m, 2H), 3.08 - 3.02 (m, 2H), 2.62 - 2.55 (m, 1H), 2.53 (s, 4H), 2.35 - 2.25 (m, 1H). Example 20: 5-(3-benzyl-1-methylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole [ka]

[0285] To a solution of 5-(3-benzylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Intermediate R) (20 mg, 0.052 mmol) in dichloromethane (2 mL) was added a 37% solution of formaldehyde (8.4 mg, 0.10 mmol) in water (1 mL). The resulting solution was stirred at room temperature for 1 h before sodium triacetoxyborohydride (33 mg, 0.16 mmol) was added. The resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition of 10 mL of water and extracted with dichloromethane (3 x 20 mL). The organic layers were combined and passed through a hydrophobic frit. The solvent was removed under reduced pressure to give a colourless oil. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH / DCM) to give 5-(3-benzyl-1-methylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Example 20) (10 mg, 24 μmol, 47%) as a white solid; R t 1.69 min (method 4); m / z 400.5 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) δ 8.11 (d, J = 0.9 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.64 (s, 1H), 7.46 - 7.39 (m, 2H), 7.07 - 6.99 (m, 3H), 6.98 (s, 1H), 6.54 - 6.49 (m, 2H), 3.19 (d, J = 4.4 Hz, 1H), 3.17 (s, 1H), 3.12 - 3.06 (m, 2H), 2.53 (s, 3H), 2.45 (d, J = 8.9 Hz, 1H), 2.36 - 2.31 (m, 2.38 (s, 3H), (3) 2.30 - 2.23 (m, 1H), 2.20 - 2.13 (m, 1H). Example 21: (4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)(pyrrolidin-1-yl)methanone Intermediate S: 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)piperidine-1,4-dicarboxylate 1-(tert-butyl) 4-methyl [ka]

[0286] To a solution of dicyclohexylamine (0.6 ml, 3.02 mmol) in toluene (5 mL) cooled to 0° C. was added n-BuLi (2.5 M in hexanes) (1.1 ml, 2.75 mmol). The mixture was stirred at room temperature for 15 min, then 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (0.685 ml, 2.79 mmol) was added. After stirring for an additional 10 min, Pd-162 (33 mg, 0.082 mmol) and a solution of 5-bromo-1-(4-fluorophenyl)-1H-indazole (Intermediate D) (0.5 g, 1.718 mmol) in toluene (5 mL) were added. The mixture was heated to 100° C. for 20 min. The mixture was absorbed directly onto silica gel and purified by silica gel chromatography (40 g cartridge, 0-50% EtOAc / isohexane) to afford 1-tert-butyl 4-ethyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)piperidine-1,4-dicarboxylate (Intermediate S) (691 mg, 1.404 mmol, 82% yield) as a pale yellow glass that slowly crystallized on standing; R t 1.95 minutes (method 1); m / z 468.4 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) δ 8.37 (s, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.83 - 7.76 (m, 3H), 7.52 (dd, J = 9.0, 1.8 Hz, 1H), 7.46 - 7.40 (m, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.90 - 3.79 (m, 2H), 3.11 - 2.86 (m, 2H), 2.50 - 2.45 (m, 2H), 1.90 - 1.80 (m, 2H), 1.40 (s, 9H), 1.12 (t, J = 7.1 Hz, 3H). Example 21: Ethyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate [ka]

[0287] 1-tert-Butyl 4-ethyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)piperidine-1,4-dicarboxylate (Intermediate S) (480 mg, 1.027 mmol) was dissolved in HCl (4M in dioxane) (5 mL, 20.00 mmol) and stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (5 mL). 1-Propyl-1H-pyrazole-4-sulfonyl chloride (257 mg, 1.232 mmol) was added as a solution in dichloromethane (1 mL) followed by triethylamine (400 μl, 2.87 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (10 mL) and washed with 1 M aqueous HCl (2×5 mL) and brine (5 mL), then dried through a hydrophobic frit and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-60% EtOAc / isohexane) to afford ethyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate (Example 21) (354 mg, 0.636 mmol, 62% yield) as a pale yellow solid foam; R t 1.72 minutes (method 1); m / z 540.3 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) δ 8.41 (s, 1H), 8.36 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.80 - 7.73 (m, 3H), 7.51 - 7.46 (m, 1H), 7.46 - 7.39 (m, 2H), 4.12 (t, J = 6.7 Hz, 2H), 3.98 (q, J = 7.0 Hz, 2H), 3.53 - 3.43 (m, 2H), 2.62 (d, J = 13.4 Hz, 2H), 2.41 (t, J = 11.5 Hz, 2H), 2.12 - 2.03 (m, 2H), 1.75 (h, J = 7.2 Hz, 2H), 0.98 (t, J = 7.0 Hz, 3H), 0.69 (t, J = 7.4 Hz, 3H). Example 22: (4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)(pyrrolidin-1-yl)methanone Intermediate T: 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylic acid [ka]

[0288] Ethyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate (prepared using the same method as in Example 21) (0.1 g, 0.181 mmol) was dissolved in a mixture of tetrahydrofuran and methanol (3:1, 4 mL). A solution of lithium hydroxide (0.022 g, 0.903 mmol) in water (0.5 mL) was added and the mixture was heated to 50° C. overnight. The mixture was concentrated in vacuo and then suspended in a mixture of ethanol (5 mL) and 2 M aqueous sodium hydroxide solution (5 mL). The mixture was heated to reflux for 3 days. The mixture was cooled to room temperature and the ethanol was removed in vacuo. The mixture was acidified with 1 M hydrochloric acid. The resulting solid formed was isolated and dried in vacuum at 50° C. overnight to give 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylic acid (Intermediate T) (184 mg, 0.315 mmol, 174% yield) as a colorless solid; R t 0.66 min (method 1); m / z 526.3 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) δ 12.68 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.81 - 7.76 (m, 2H), 7.59 (s, 1H), 7.45 - 7.39 (m, 2H), 4.14 (t, J = 6.8 Hz, 2H), 3.45 - 3.37 (m, 2H), 2.82 - 2.75 (m, 2H), 2.49 - 2.46 (m, 2H), 2.44 (s, 3H), 2.12 - 2.04 (m, 2H), 1.78 (h, J = 7.2 Hz, 2H), 0.75 (t, J = 7.4 Hz, 3H). Example 22: (4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)(pyrrolidin-1-yl)methanone [ka]

[0289] To a stirred solution of 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylic acid (Intermediate T) (40 mg, 0.076 mmol) in tetrahydrofuran (2 mL) was added HATU (50 mg, 0.131 mmol) and N,N-diisopropylethylamine (50 μl, 0.286 mmol). After stirring at room temperature for 15 min, pyrrolidine (10 μl, 0.122 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (10 mL). The organic phase was washed with 1 M hydrochloric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL), then sodium bicarbonate (10 mL). 2 SO 4The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give (4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)(pyrrolidin-1-yl)methanone (Example 22) (17.3 mg, 0.029 mmol, 43% yield) as an amorphous colorless solid; R t 1.63 minutes (method 1); m / z 579.3 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) δ 8.39 (s, 1H), 8.29 (s, 1H), 7.94 (s, 1H), 7.83 - 7.76 (m, 3H), 7.62 (s, 1H), 7.45 - 7.37 (m, 2H), 4.15 (t, J = 6.8 Hz, 2H), 3.39 (s, 2H), 3.25 (t, J = 6.9 Hz, 2H), 2.95 (br s, 2H), 2.49 - 2.42 (m, 4H), 2.32 (s, 3H), 2.03 (br s, 2H), 1.79 (h, J = 7.1 Hz, 2H), 1.58 - 1.42 (m, 4H), 0.76 (t, J = 7.4 Hz, 3H). Example 23: 1-(4-fluorophenyl)-5-(4-(methoxymethyl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole Intermediate U: (4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol [ka]

[0290] To a stirred solution of ethyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate (prepared using the same method as in Example 21) (150 mg, 0.278 mmol) in tetrahydrofuran (3 mL) was added lithium aluminum hydride (2 M in THF) (0.3 mL, 0.60 mmol) slowly over 5 min. The mixture was stirred at room temperature for 2 h. Water (0.05 mL) was added, followed by 2 M aqueous sodium hydroxide (0.05 mL) and additional water (0.15 mL). The mixture was stirred until gas evolution ceased, then Na 2 SO 4 The mixture was dried at 40° C. and filtered through Celite eluting with tetrahydrofuran (3×5 mL). The filtrate was concentrated in vacuo. The residue was dissolved in a minimum amount of dichloromethane and then isohexane (5 mL) was added to give a cloudy suspension. The solvent was removed in vacuo to give (4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol (Intermediate U) (130 mg, 0.259 mmol, 93% yield) as a colorless amorphous solid; R t 1.37 minutes (method 1); m / z 498.4 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) δ 8.27 (s, 1H), 8.22 (s, 1H), 7.80 - 7.72 (m, 3H), 7.69 (d, J = 9.0 Hz, 1H), 7.67 (s, 1H), 7.48 - 7.39 (m, 3H), 4.69 (t, J = 5.5 Hz, 1H), 3.98 (t, J = 6.7 Hz, 2H), 3.35 - 3.28 (m, 4H), 2.39 - 2.27 (m, 4H), 2.03 - 1.93 (m, 2H), 1.53 (h, J = 7.2 Hz, 2H), 0.32 (t, J = 7.4 Hz, 3H). Example 24: 1-(4-fluorophenyl)-5-(4-(methoxymethyl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole [ka]

[0291] To a stirred solution of (4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol (Intermediate U) (25 mg, 0.049 mmol) and methyl iodide (25 μl, 0.400 mmol) in tetrahydrofuran (1 mL) was added sodium tert-butoxide (2M in THF) (40 μl, 0.080 mmol). The yellow mixture was stirred at room temperature for 1 h then partitioned between dichloromethane (5 mL) and water (2 mL). The organic phase was separated, washed with brine (1 mL), dried by passing through a hydrophobic frit then concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-60% EtOAc / isohexane) to afford 1-(4-fluorophenyl)-5-(4-(methoxymethyl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-6-methyl-1H-indazole (Example 24) (17.8 mg, 0.033 mmol, 67.9% yield) as an amorphous colorless solid; R t 1.67 min (method 1); m / z 526.3 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) δ 8.25 (s, 1H), 8.20 (d, J = 0.9 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.69 (d, J = 5.2 Hz, 2H), 7.56 (s, 1H), 7.45 - 7.39 (m, 2H), 3.98 (t, J = 6.7 Hz, 2H), 3.46 (s, 2H), 3.26 - 3.20 (m, 2H), 3.11 (s, 3H), 2.59 (s, 3H), 2.58 - 2.52 (m, 4H), 2.07 - 1.98 (m, 2H), 1.54 (h, J = 7.2 Hz, 2H), 0.38 (t, J = 7.4 Hz, 3H). Example 25: 5-(4-benzyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1-(4-fluorophenyl)-1H-indazole Intermediate V: 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbaldehyde [ka]

[0292] Dess-Martin periodic acid (236 mg, 0.56 mmol) was added to a 0° C. solution of (4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol (Intermediate U) (237 mg, 0.46 mmol) in dichloromethane (3 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was diluted with dichloromethane (10 mL) and 2M Na 2 S 2 O 3 (20 mL), followed by saturated sodium carbonate (20 mL). The organic layer was washed with MgSO 4Drying at 40° C., filtering and concentrating in vacuo afforded 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbaldehyde (Intermediate V) (277 mg, 0.46 mmol, 99%) as a white solid which was used in the next step without further purification; R t 0.73 min (method 1); m / z 510.35 (M+H) + (ES + ). Intermediate W: (4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)(phenyl)methanol [ka]

[0293] Phenylmagnesium chloride (2M in THF) (0.14 mL, 0.27 mmol) was added to a 0° C. solution of 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbaldehyde (Intermediate V) (75 mg, 0.14 mmol) in tetrahydrofuran (1 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (10 mL) and the layers separated. The aqueous phase was extracted with dichloromethane (3×10 mL) and the combined organic layers were washed with MgSO 4 The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to give (4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)(phenyl)methanol (Intermediate W) (53 mg, 87 μmol, 63%) as a white powder; R t 1.68 min (method 1); m / z 588.80 (M+H) + (ES + ). Example 25: 5-(4-benzyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1-(4-fluorophenyl)-1H-indazole [ka]

[0294] Boron trifluoride etherate (68 mg, 0.48 mmol) was added to a solution of (4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)(phenyl)methanol (Intermediate W) (28 mg, 0.48 mmol) and triethylsilane (76 μL, 0.48 mmol) in dichloromethane (1 mL) and stirred at 80 °C for 4 h. The reaction was quenched with water (10 mL) and the layers separated. The aqueous phase was extracted with dichloromethane (3 × 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 5-(4-benzyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Example 25) (2.00 mg, 0.33 mmol, 4%) as a white solid; R t 1.97 min (method 1); m / z 572.50 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) δ 8.35 (d, J 0.8, 1H), 8.24 (d, J 0.9, 1H), 8.02 (s, 1H), 7.77 (d, J 0.7, 1H), 7.77 - 7.74 (m, 2H), 7.55 (s, 1H), 7.42 - 7.37 (m, 2H), 7.35 - 7.31 (m, 2H), 7.25 (t, J 7.6, 2H), 7.15 - 7.11 (m, 1H), 4.15 (t, J 7.0, 2H), 3.89 (d, J 11.0, 1H), 3.58 - 3.48 (m, 2H), 2.45 (s, 3H), 2.36 - 2.26 (m, 1H), 2.25 - 2.11 (m, 2H), 1.83 (h, J 7.2, 2H), 1.75- 1.68 (m, 1H), 1.42 - 1.35 (m, 1H), 1.35 - 1.15 (m, 2H), 0.84 (t, J 7.4, 3H). Example 26: 1-(4-fluorophenyl)-6-methyl-5-(3-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole Intermediate X: 1-(4-fluorophenyl)-6-methyl-5-(3-methylpyridin-4-yl)-1H-indazole [ka]

[0295] 5-Bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (prepared using the method described in Intermediate D) (0.5 g, 1.64 mmol), (3-methylpyridin-4-yl)boronic acid (0.25 g, 1.83 mmol), and Pd(dppf)Cl in dioxane (5 mL). 2To a suspension of DCM (0.1 g, 0.122 mmol) was added a solution of potassium carbonate (0.75 g, 5.43 mmol) in water (2 mL). The mixture was evacuated and backfilled with nitrogen (3 times) and heated at 90 °C for 3 h. The mixture was cooled to room temperature and diluted with ethyl acetate (10 mL). The organic phase was separated and absorbed directly onto silica gel. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to give 1-(4-fluorophenyl)-6-methyl-5-(3-methylpyridin-4-yl)-1H-indazole (Intermediate X) (324 mg, 0.99 mmol, 60% yield) as a light brown semi-solid; R t 1.03 min (method 1); m / z 3018.3 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) δ 8.56 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.34 (s, 1H), 7.87 - 7.82 (m, 2H), 7.78 (s, 1H), 7.62 (s, 1H), 7.49 - 7.43 (m, 2H), 7.18 (d, J = 4.9 Hz, 1H), 2.14 (s, 3H), 2.04 (s, 3H). Intermediate Y: 1-(4-fluorophenyl)-6-methyl-5-(3-methylpiperidin-4-yl)-1H-indazole [ka]

[0296] 1-(4-Fluorophenyl)-6-methyl-5-(3-methylpyridin-4-yl)-1H-indazole (Intermediate X) (100 mg, 0.315 mmol) was dissolved in acetic acid (2 mL). Platinum(IV) oxide (50 mg, 0.220 mmol) was added and the mixture was stirred at 50° C. under 5 bar hydrogen pressure for 16 h. The mixture was filtered through a short plug of Celite eluting with methanol (5×10 mL). The filtrate was treated with SCX (3 g) and stirred for 15 min. The SCX was washed with methanol (100 mL) and then the product was eluted with 0.7 M ammonia in methanol (5×10 mL). The combined fractions were concentrated in vacuo to give 1-(4-fluorophenyl)-6-methyl-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-indazole (Intermediate Y) (92 mg, 0.284 mmol, 90% yield) as a yellow oil, which was carried on crude to the final step. Example 26: 1-(4-fluorophenyl)-6-methyl-5-(3-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole [ka]

[0297] 1-(4-Fluorophenyl)-6-methyl-5-(3-methylpiperidin-4-yl)-1H-indazole (Intermediate Y) (92 mg, 0.284 mmol) was dissolved in dichloromethane (3 mL). 1-Propyl-1H-pyrazole-4-sulfonyl chloride (89 mg, 0.427 mmol) was added as a solution in dichloromethane (1 mL) followed by triethylamine (100 μl, 0.717 mmol). The mixture was stirred at room temperature for 3 h and then directly purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to give 1-(4-fluorophenyl)-6-methyl-5-((3R,4R)-3-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole (Example 26) (31 mg, 0.059 mmol, 21% yield) as a colorless solid; R t 1.81 min (method 1); m / z 496.4 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) δ 8.40 (s, 1H), 8.26 (s, 1H), 7.83 (s, 1H), 7.82 - 7.75 (m, 2H), 7.61 (s, 1H), 7.57 (s, 1H), 7.45 - 7.38 (m, 2H), 4.17 (t, J = 6.9 Hz, 2H), 3.82 - 3.76 (m, 1H), 3.53 - 3.48 (m, 1H), 3.08 - 3.01 (m, 1H), 2.58 - 2.53 (m, 1H), 2.43 (s, 3H), 2.41 - 2.33 (m, 2H), 2.16 - 2.08 (m, 1H), 1.84 (h, J = 7.2 Hz, 2H), 1.64 - 1.58 (m, 1H), 0.84 (t, J = 7.4 Hz, 3H), 0.78 (d, J = 7.0 Hz, 3H). Example 27: 5-(7,7-difluoro-3-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-3-azabicyclo[4.1.0]heptan-6-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole Intermediate Z: tert-butyl 7,7-difluoro-6-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate [ka]

[0298] tert-Butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate H) (50 mg, 0.123 mmol) and sodium iodide (10 mg, 0.067 mmol) were suspended in tetrahydrofuran (3 mL) and stirred at room temperature. Trimethyl(trifluoromethyl)silane (50 μl, 0.338 mmol) was added and the mixture was heated to 60° C. overnight. Further trimethyl(trifluoromethyl)silane (50 μl, 0.338 mmol) was added and the mixture was heated for a further 24 hours. The mixture was cooled to room temperature, absorbed onto silica gel, and purified by silica gel chromatography (12 g cartridge, 0-50% EtOAc / isohexane) to afford tert-butyl 7,7-difluoro-6-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (Intermediate Z) (42 mg, 0.083 mmol, 67% yield) as a pale yellow oil; R t 1.99 minutes (method 1); m / z 458.4 (M+H) + (ES + ); NMR is rotamer so this was used directly in the next step. Example 27: 5-(7,7-difluoro-3-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-3-azabicyclo[4.1.0]heptan-6-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole [ka]

[0299] Step A: tert-Butyl 7,7-difluoro-6-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (Intermediate Z) (40 mg, 0.087 mmol) was dissolved in HCl (4M in dioxane) (3 mL, 12.00 mmol) and stirred at room temperature for 1 h. The solvent was removed under vacuum and the oily residue was triturated with diethyl ether (3 mL) to give 5-(7,7-difluoro-3-azabicyclo[4.1.0]heptane-6-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole, HCl (32 mg, 0.081 mmol, 93% yield) as a colorless solid.

[0300] Step B: 5-(7,7-difluoro-3-azabicyclo[4.1.0]heptan-6-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole, HCl (15 mg, 0.038 mmol) was suspended in dichloromethane (2 mL). 1-Propyl-1H-pyrazole-4-sulfonyl chloride (12 mg, 0.058 mmol) was added followed by triethylamine (20 μl, 0.143 mmol). The mixture was stirred at room temperature for 1 h and then directly purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to give 5-(7,7-difluoro-3-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-3-azabicyclo[4.1.0]heptan-6-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Example 27) (17 mg, 0.030 mmol, 80% yield) as a colorless solid foam; R t 1.78 min (method 1); m / z 530.4 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) δ 8.48 (s, 1H), 8.24 (s, 1H), 7.91 (s, 1H), 7.81 - 7.75 (m, 2H), 7.65 (s, 1H), 7.57 (s, 1H), 7.47 - 7.39 (m, 2H), 4.18 (t, J = 6.9 Hz, 2H), 3.61 - 3.54 (m, 1H), 3.45 - 3.37 (m, 1H), 3.18 - 3.10 (m, 1H), 2.71 - 2.63 (m, 1H), 2.44 (s, 3H), 2.35 - 2.25 (m, 1H), 1.96 - 1.87 (m, 1H), 1.87 - 1.78 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H), one proton obscured due to residual DMSO. Example 28: 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-methylpyrrolidine-3-sulfonamide [ka]

[0301] Evacuate a vial containing RuPhosG3 precatalyst (13.70 mg, 0.016 mmol), N-methylpyrrolidine-3-sulfonamide hydrochloride (65.8 mg, 0.328 mmol), 5-bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (prepared using the method described for Intermediate D) (50 mg, 0.164 mmol) in 1,4-dioxane (2 mL) and add N 2(x3). A 1M solution of LiHMDS (655 μl, 0.655 mmol) in tetrahydrofuran (1 mL) was added and the resulting orange solution was stirred at room temperature for 18 h. The reaction mixture was quenched with a saturated solution of sodium bicarbonate (5 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined and passed through a hydrophobic frit. The solvent was removed under reduced pressure to give a black oil. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to give 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-methylpyrrolidine-3-sulfonamide (Example 28) (32 mg, 0.078 mmol, 48% yield) as a pale yellow solid; R t 1.46 minutes (method 1); m / z 389.3 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) δ 8.20 (d, J = 0.9 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.63 (s, 1H), 7.45 - 7.39 (m, 3H), 7.09 (q, J = 4.8 Hz, 1H), 4.02 (tt, J = 9.2, 5.7 Hz, 1H), 3.40 - 3.33 (m, 2H), 3.18 (t, J = 6.6 Hz, 2H), 2.65 (d, J = 4.9 Hz, 3H), 2.44 (d, J = 0.9 Hz, 3H), 2.34 - 2.18 (m, 2H). Example 29: 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-methyl-N-(1-propyl-1H-pyrazol-4-yl)pyrrolidine-3-sulfonamide Intermediate AA: tert-butyl 3-(N-(1-propyl-1H-pyrazol-4-yl)sulfamoyl)pyrrolidine-1-carboxylate [ka]

[0302] To a solution of tert-butyl 3-(chlorosulfonyl)pyrrolidine-1-carboxylate (200 mg, 0.741 mmol) and triethylamine (517 μl, 3.71 mmol) in dichloromethane (4 mL) was added 1-propyl-1H-pyrazol-4-amine (186 mg, 1.48 mmol). The resulting yellow solution was stirred at room temperature for 18 hours. The reaction was quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted with dichloromethane (3×10 mL). The organic layers were combined and passed through a hydrophobic frit. The solvent was removed in vacuo to give a dark oil. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to give tert-butyl 3-(N-(1-propyl-1H-pyrazol-4-yl)sulfamoyl)pyrrolidine-1-carboxylate (Intermediate AA) (115 mg, 0.305 mmol, 41% yield) as a light purple oil; R t 1.19 minutes (method 1); m / z 381.4 (M+H) + (ES + ); δH (DMSO-d6, 500 MHz) δ 9.39 (s, 1H), 7.67 (s, 1H), 7.30 (s, 1H), 3.99 (t, J = 7.0 Hz, 2H), 3.80 (d, J = 26.6 Hz, 1H), 3.53 (d, J = 7.5 Hz, 2H), 3.40 (dt, J = 10.3, 7.2 Hz, 1H), 2.18 (q, J = 7.8, 7.4 Hz, 3H), 1.75 (h, J = 7.2 Hz, 2H), 1.40 (s, 9H), 0.81 (t, J = 7.4 Hz, 3H). Example 29: 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(1-propyl-1H-pyrazol-4-yl)pyrrolidine-3-sulfonamide [ka]

[0303] Compound was prepared by a method similar to that described for Example 29; Rt 1.57 min (method 1); m / z 483.4 (M+H)+ (ES+). δH (DMSO-d6, 500 MHz) δ 9.30 (s, 1H), 8.20 (d, J = 0.9 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.70 (s, 1H), 7.63 (s, 1H), 7.44 - 7.37 (m, 3H), 7.33 (d, J = 0.7 Hz, 1H), 3.99 (t, J = 7.0 Hz, 2H), 3.90 (tt, J = 8.8, 6.0 Hz, 1H), 3.42 (dd, J = 10.3, 5.6 Hz, 1H), 3.29 (dd, J = 10.3, 8.5 Hz, 1H), 3.18 (t, J = 6.6 Hz, 2H), 2.41 (br s, 3H), 2.27 (m, 2H), 1.74 (h, J = 7.3 Hz, 2H), 0.79 (t, J = 7.4 Hz, 3H). Example 30: 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-methyl-N-(1-propyl-1H-pyrazol-4-yl)pyrrolidine-3-sulfonamide [ka]

[0304] To a solution of 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(1-propyl-1H-pyrazol-4-yl)pyrrolidine-3-sulfonamide (30 mg, 0.062 mmol) in dimethylformamide (2 mL) at 0° C. was added sodium hydride (2.98 mg, 0.075 mmol) in one portion. The resulting yellow solution was stirred at 0° C. for 30 min and methyl iodide (7.77 μl, 0.124 mmol) was added. The resulting white solution was stirred at room temperature for 2 h. The reaction mixture was quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were combined and passed through a hydrophobic frit. The solvent was removed under reduced pressure to give a pale yellow residue. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to give 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-methyl-N-(1-propyl-1H-pyrazol-4-yl)pyrrolidine-3-sulfonamide (Example 30) (10 mg, 0.020 mmol, 32% yield) as a pale yellow solid; Rt 1.70 min (Method 1); m / z 497.4 (M+H)+ (ES+). δH (DMSO-d6, 500 MHz) δ 8.18 (d, J = 0.9 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.62 (s, 1H), 7.54 (d, J = 0.8 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.38 (s, 1H), 4.18 - 4.08 (m, 1H), 4.01 (t, J = 6.9 Hz, 2H), 3.30 (m, 1H, overlapped with water signal), 3.24 (s, 3H), 3.23 - 3.14 (m, 2H), 3.10 (m, 1H), 2.37 (d, J = 0.9 Hz, 3H), 2.31 (m, 1H), 2.18 (dq, J = 13.6, 6.9 Hz, 1H), 1.75 (h, J = 7.2 Hz, 2H), 0.79 (t, J = 7.4 Hz, 3H). Example 31: 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-phenylpiperidine-1-carboxamide [ka]

[0305] 1-(4-Fluorophenyl)-6-methyl-5-(piperidin-4-yl)-1H-indazole, HCl (deprotection of intermediate I) (30 mg, 0.087 mmol) was suspended in dichloromethane (2 mL). Triethylamine (50 μl, 0.359 mmol) was added, followed by phenyl isocyanate (20 μl, 0.183 mmol). The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in DMSO (2 mL) and then purified by preparative HPLC (Waters, acidic (0.1% formic acid), acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 35-65% MeCN in 0.1% aqueous formic acid) to give 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-phenylpiperidine-1-carboxamide (Example 31) (9.8 mg, 0.022 mmol, 26% yield) as a colorless solid; Rt 1.71 min (Method 1); m / z 429.5 (M+H)+ (ES+). δH (DMSO-d6, 500 MHz) δ 8.54 (s, 1H), 8.23 ​​(s, 1H), 7.81-7.77 (m, 2H), 7.71 (s, 1H), 7.63 (s, 1H), 7.53 - 7.48 (m, 2H), 7.46 - 7.40 (m, 2H), 7.27 - 7.21 (m, 2H), 6.94 (t, J = 7.3 Hz, 1H), 4.37 - 4.28 (m, 2H), 3.09 - 3.00 (m, 1H), 3.00 - 2.91 (m, 2H), 2.52 (s, 3H), 1.86 - 1.79 (m, 2H), 1.69 - 1.57 (m, 2H). Example 32: 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-isopropylpiperidine-1-carboxamide [ka]

[0306] The compound was prepared by a method similar to that described for Example 31; Rt 1.59 min (method 1); m / z 395.4 (M+H)+ (ES+). δH (DMSO-d6, 500 MHz) δ 8.23 ​​(s, 1H), 7.82 - 7.74 (m, 2H), 7.66 (s, 1H), 7.61 (s, 1H), 7.45 - 7.39 (m, 2H), 6.17 (d, J = 7.6 Hz, 1H), 4.19 - 4.15 (m, 2H), 3.85 - 3.73 (m, 1H), 3.00 - 2.90 (m, 1H), 2.82 - 2.71 (m, 2H), 2.49 (s, 3H), 1.77 - 1.70 (m, 2H), 1.59 - 1.47 (m, 2H), 1.09 (d, J = 6.6 Hz, 6H). Example 33: 1-(4-fluorophenyl)-6-methyl-5-(4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-1-yl)-1H-indazole Intermediate AB: tert-butyl 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine-1-carboxylate [ka]

[0307] To a solution of 1-methyl-1H-pyrazole-4-sulfonyl chloride (1.66 g, 9.19 mmol) in tetrahydrofuran (25 mL) at 0° C. was added hydrazine hydrate (1.3 ml, 26.1 mmol). The mixture was allowed to warm to room temperature over 1 h. The mixture was diluted with dichloromethane (50 mL) and water (10 mL). The aqueous solution was washed with 10% methanol in dichloromethane (3×20 mL). The combined organics were dried through a hydrophobic frit and then concentrated in vacuo to give 1-methyl-1H-pyrazole-4-sulfonohydrazide (668 mg, 3.79 mmol, 41% yield) as a colourless solid. The solid was dissolved in ethanol (10 mL). Potassium acetate (4.51 g, 46.0 mmol) and tert-butyl 4-bromopiperidine-1-carboxylate (2.43 g, 9.19 mmol) were added and the mixture was heated to reflux for 3 days. The mixture was cooled to room temperature and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to give tert-butyl 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine-1-carboxylate (Intermediate AB) (78 mg, 0.189 mmol, 2% yield) as a clear, colorless oil; UPLC analysis was inconclusive due to very little colored material. δH (DMSO-d6, 500 MHz) δ 8.38 (s, 1H), 7.83 (s, 1H), 4.09 - 3.95 (m, 2H), 3.91 (s, 3H), 3.32 - 3.27 (m, 1H), 2.73 (s, 2H), 1.95 - 1.88 (m, 2H), 1.38 (s, 9H), 1.35 - 1.24 (m, 2H). Intermediate AC: 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine [ka]

[0308] To a solution of tert-butyl 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine-1-carboxylate (Intermediate AB) (40 mg, 0.097 mmol) in dichloromethane (1 mL) was added HCl (4M in dioxane) (1 mL, 4.00 mmol) in one portion and the mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum and the resulting solid was dried under vacuum at 40° C. for 1 h to give 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine.HCl (Intermediate AC), which was used in the next step without further purification. Example 33: 1-(4-fluorophenyl)-6-methyl-5-(4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-1-yl)-1H-indazole [ka]

[0309] A stirred suspension of 5-bromo-1-(4-fluorophenyl)-1H-indazole (prepared using the method described for Intermediate D) (27 mg, 0.093 mmol), 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine, HCl (Intermediate AC) (26 mg, 0.098 mmol), sodium tert-butoxide (25 mg, 0.260 mmol), and Pd-162 (5 mg, 0.013 mmol) in dioxane (2 mL) was evacuated and backfilled with nitrogen (3×) and heated at 90° C. for 16 h. The mixture was cooled to room temperature and then directly absorbed onto silica gel. The crude product was purified by silica gel chromatography (12 g cartridge, 0-100% EtOAc / isohexane) to afford 1-(4-fluorophenyl)-5-(4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-1-yl)-1H-indazole (Example 33) (5 mg, 0.001 mmol, 12% yield) as a pale yellow foam; R t 1.31 min (method 1); m / z 440.4 (M+H) + (ES +); δH (DMSO-d6, 500 MHz) δ 8.42 (s, 1H), 8.20 (s, 1H), 7.86 (s, 1H), 7.80 - 7.74 (m, 2H), 7.68 (d, J = 9.2 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.30 (dd, J = 9.2, 2.3 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 3.93 (s, 3H), 3.77 - 3.70 (m, 2H), 2.75 - 2.68 (m, 2H), 2.07 - 2.01 (m, 2H), 1.72 - 1.61 (m, 2H), one proton is unclear due to residual water in the DMSO solvent. Examples 34 to 96 [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] Examples 97 to 103 [Table 2-1] [Table 2-2] Example 104: (R)-1-(4-fluorophenyl)-5-(3-methyl-4-(propylsulfonyl)piperazin-1-yl)-1H-indazole [ka]

[0310] The compound was prepared by a method similar to that described for Example 3; t 1.71 min (method 1); m / z 417.43 (M+H) + (ES + ). Examples 105 to 133 [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] Examples 134 to 146 [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] Examples 147 to 189 [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] [Table 5-10] [Table 5-11] [Table 5-12] [Table 5-13] Examples 190 to 208 [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] Example 209: 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-4-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperazin-2-one [ka]

[0311] The compound was prepared by a method similar to that described for Example 7; t 1.44 minutes (method 1); m / z 497.3 (M+H) + (ES + ). Examples 210 to 228 [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] Examples 229 to 235 [Table 8-1] [Table 8-2] Example 236: 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-(6-methoxypyridin-3-yl)-6-methyl-1H-indazole Intermediate AD: 6-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole [ka]

[0312] To a solution of 5-bromo-6-methyl-1H-indazole (25.00 g, 118.4 mmol) and dihydropyran (19.93 g, 21.5 mL, 236.9 mmol) in chloroform (400 mL) was added p-toluenesulfonic acid monohydrate (2.253 g, 1.817 mL, 11.84 mmol). The brown suspension was stirred at room temperature for 48 h. The reaction mixture was washed with sodium bicarbonate (2×200 mL), the organic layer was dried using anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 5-bromo-6-methyl-1-(tetrahydro-2H-pyran)-2-yl)-1H-indazole (39 g, 0.12 mol, 97%) as a brown oil. A solution of 5-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (39 g, 87.3 wt%, 0.12 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (35 g, 0.14 mol), and potassium acetate (51 g, 0.52 mol) in 1,4-dioxane (250 mL) was diluted with N 2 The PdCl2(dppf)-CH2Cl2 adduct (4.7 g, 5.8 mmol) was added and the solution was sparged with N 2 The reaction mixture was sparged with EtOAc (500 mL) and 1:1 brine / H2O for 15 min, heated to 80 °C and stirred for 3.5 h. The reaction mixture was cooled to room temperature overnight and diluted with EtOAc (500 mL) and 1:1 brine / H2O. 2 The mixture was partitioned between 250 mL of HO, the layers were separated, and the aqueous layer was extracted with EtOAc (300 mL). The combined organics were washed with sodium bicarbonate solution (2×250 mL) and MgSO. 4 Drying at 40° C., filtration and concentration in vacuo afforded 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (45 g, 0.11 mol, 94%) (Intermediate AD) as a dark brown oil which was used crude in the next step. Intermediate AE: 1-benzyl-3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyrrolidine-2,5-dione [ka]

[0313] To a solution of 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate AD) (45 g, 82.5 wt%, 0.11 mol), 1-benzyl-1H-pyrrole-2,5-dione (24 g, 0.13 mol), and triethylamine (16 g, 23 mL, 0.16 mol) in 1,4-dioxane (300 mL) and water (33.3 mL) was added N 2 Hydroxy(cyclooctadiene)rhodium(I) dimer (1.5 g, 3.3 mmol) was added and the solution was sparged with N 2 The mixture was sparged with EtOAc (300 mL) for 5 min, heated at 80 °C and stirred for 1 h. The reaction was cooled and concentrated to a small volume (approximately 150 mL). The reaction mixture was partitioned between EtOAc (300 mL) and water (150 mL), the layers were separated and the organic layer was washed with half-saturated brine (100 mL). The organics were washed with MgSO 4 The crude product was purified by chromatography on silica gel (330 g cartridge, 0-65% EtOAc / isohexane) to give 1-benzyl-3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyrrolidine-2,5-dione (Intermediate AE) (32 g, 78 mmol, 72%) as a sticky tan gum; R t 1.93 min (Method 7); m / z 404.3 (M+H)+ (ES+). δH (400 MHz, DMSO-d 6) δ 7.97 (s, 1H), 7.57 (s, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.40 - 7.20 (m, 5H), 5.83 - 5.72 (m, 1H), 4.66 (s, 2H), 4.55 (m, 1H), 3.87 (m, 1H), 3.77 - 3.67 (m, 1H), 3.40 - 3.32 (m, 1H), 2.77 (ddd, J = 18.2, 5.1, 2.7 Hz, 1H), 2.41 (m, 4H), 1.99 (m, 1H), 1.93 (m, 1H), 1.80 - 1.65 (m, 1H), 1.61 - 1.5 (m, 2H). Intermediate AF: 1,3-dibenzyl-3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyrrolidine-2,5-dione [ka]

[0314] To a solution of 1-benzyl-3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyrrolidine-2,5-dione (Intermediate AE) (6.10 g, 74 wt%, 11.2 mmol) in THF (55.0 mL) was added N 2 The mixture was sparged with water for 10 min. Sodium hydride (685 mg, 60 wt%, 17.1 mmol) was added in one portion and the resulting solution was stirred at 0 °C for 30 min. (Bromomethyl)benzene (3.83 g, 2.66 mL, 22.4 mmol) was added and the reaction mixture was warmed to 20 °C and stirred for 23 h. The reaction mixture was quenched with water (40 mL) and the aqueous phase was extracted with EtOAc (3 x 60 mL). The combined organic phase was diluted with MgSO 4It was dried over low heat, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-50% EtOAc / isohexane) to give 1,3-dibenzyl-3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyrrolidine-2,5-dione (Intermediate AF) (5.47 g, 9.42 mmol, 55.7%) as a white solid; δH (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.97 (s, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.30 - 7.17 (m, 8H), 7.15 - 7.08 (m, 2H), 5.77 (dd, J = 10.1, 2.9 Hz, 1H), 4.32 (dd, J = 14.4, 4.0 Hz, 1H), 4.23 (dd, J = 14.4, 5.2 Hz, 1H), 3.90 - 3.83 (m, 1H), 3.76 - 3.67 (m, 1H), 3.57 (dd, J = 12.7, 5.4 Hz, 1H), 3.37 (d, J = 12.7 Hz, 1H), 3.18 (d, J = 18.8 Hz, 1H), 3.03 (d, J = 18.8 Hz, 1H), 2.46 - 2.34 (m, 1H), 2.19 (d, J = 5.3 Hz, 3H), 2.09 - 1.99 (m, 1H), 1.98 - 1.89 (m, 1H), 1.80 - 1.65 (m, 2H). Intermediate AG: 5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ka]

[0315] In a three-neck round-bottom flask equipped with a bubbler, a solution of 1,3-dibenzyl-3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5)-yl)pyrrolidine-2,5-dione (Intermediate AF) (6.40 g, 85 wt%, 11.0 mmol) in 1,4-dioxane (44.0 mL) was added with N2 The reaction mixture was sparged with water for 10 min and then cooled to 0° C. DIBAL-H (1 molar in hexanes) (11.7 g, 82.0 mL, 1 mole, 82.0 mmol) was added and the resulting solution was then warmed to 20° C. and stirred for 18 h. The reaction was cooled to 0° C. and water (3.3 mL), 2M NaOH (3.3 mL), and water (8.2 mL) were added very slowly in sequence. The reaction mixture was warmed to room temperature and MgSO 4 (excess) was added and the reaction mixture was then stirred for 15 min. The slurry was filtered, washed with EtOAc (2×50 mL) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-50% EtOAc / isohexane) to give 5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate AG) (3.96 g, 7.99 mmol, 72.5%) as a pale yellow foam; δH (400 MHz, DMSO-d6) δ 7.84 - 7.79 (m, 1H), 7.50 (s, 1H), 7.46 - 7.42 (m, 2H), 7.42 - 7.36 (m, 2H), 7.34 - 7.26 (m, 1H), 7.00 - 6.92 (m, 1H), 6.87 (td, J = 7.5, 3.5 Hz, 2H), 6.75 (d, J = 7.3 Hz, 1H), 6.41 - 6.33 (m, 2H), 5.80 - 5.71 (m, 1H), 3.95 - 3.83 (m, 1H), 3.79 - 3.69 (m, 2H), 3.61 - 3.53 (m, 1H), 3.22 - 3.01 (m, 4H), 2.55 - 2.51 (m, 3H), 2.42 - 2.31 (m, 4H), 2.20 - 2.09 (m, 1H), 2.07 - 1.99 (m, 1H), 1.97 - 1.87 (m, 1H), 1.80 - 1.67 (m, 1H), 1.62 - 1.53 (m, 2H). Intermediate AH: 5-(3-benzylpyrrolidin-3-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ka]

[0316] 10% Palladium on activated carbon (1.06 g, 4 wt%, 400 μmol) in EtOH (2.0 mL) was added to a solution of 5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate AG) (3.96 g, 94 wt%, 7.99 mmol) in EtOH (15.0 mL). The reaction mixture was stirred for 2 h. 2 (5 bar) at 20° C. for 23 h. The reaction mixture was filtered through a glass microfiber filter, washed with EtOH (3×25 mL) and concentrated in vacuo to give 5-(3-benzylpyrrolidin-3-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate AH) (3.04 g, 7.3 mmol, 91%) as a light brown oil; t 1.29 min (method 7); m / z 376.3 (M+H)+ (ES+). Intermediate AI: 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazole [ka]

[0317] To a suspension of 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (prepared using a method similar to that described in Example 16) (1.17 g, 92 wt%, 2.07 mmol) in ethanol (15.0 mL) was added HCl (4 M in dioxane) (2.2 g, 15 mL, 4 mol, 60 mmol). The reaction mixture was stirred at 20° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (30 mL) and saturated NaHCO 3The layers were separated and the aqueous phase was then extracted with dichloromethane (2×10 mL). The combined organic phase was washed with MgSO 4 The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% (3:1 EtOAc / EtOH) / isohexane) to give 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazole (1.20 g, 2.4 mmol, 60%) (Intermediate AI) as a pale yellow solid; R t 1.78 min (Method 7); m / z 437.2 (M+H)+ (ES+). δH (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.35 (s, 1H), 7.82 (d, J = 1.2 Hz, 1H), 7.29 (s, 1H), 7.10 - 7.04 (m, 1H), 7.03 - 6.97 (m, 2H), 6.92 (s, 1H), 6.50 - 6.43 (m, 2H), 4.16 (s, 3H), 3.94 (d, J = 9.6 Hz, 1H), 3.68 - 3.59 (m, 1H), 3.53 - 3.45 (m, 1H), 3.34 (d, J = 9.8 Hz, 1H), 2.98 (d, J = 13.4 Hz, 1H), 2.71 (d, J = 13.4 Hz, 1H), 2.44 - 2.34 (m, 4H), 2.11 - 2.00 (m, 1H). Example 236: 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-(6-methoxypyridin-3-yl)-6-methyl-1H-indazole [ka]

[0318] Pyridine (130 mg, 0.13 mL, 1.65 mmol) was added to a solution of 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazole (360 mg, 825 μmol) (Intermediate AI), (6-methoxypyridin-3-yl)boronic acid (252 mg, 1.65 mmol), and copper(II) acetate (150 mg, 825 μmol) in dichloromethane (10 mL) and stirred overnight in an open vessel. The reaction was adsorbed onto silica and purified by silica gel chromatography (24 g cartridge, 0-80% EtOAc / isohexane) to afford 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-(6-methoxypyridin-3-yl)-6-methyl-1H-indazole (26 mg, 47 μmol, 5.7%) (Example 236) as a white solid; R t 1.75 min (Method 6); m / z 544.4 (M+H)+ (ES+). δH (DMSO-d6, 500 MHz) δ 8.59 - 8.57 (m, 1H), 8.34 (s, 1H), 8.15 (d, J 0.9, 1H), 8.09 (dd, J 8.8, 2.8, 1H), 7.58 (s, 1H), 7.12 - 7.02 (m, 5H), 6.54 - 6.51 (m, 2H), 4.16 (s, 3H), 3.97 (d, J 9.8, 1H), 3.94 (s, 3H), 3.68 - 3.61 (m, 1H), 3.54 - 3.47 (m, 1H), 3.41 - 3.36 (m, 1H), 3.02 (d, J 13.4, 1H), 2.75 (d, J 13.5, 1H), 2.45 - 2.38 (m, 4H), 2.12 - 2.03 (m, 1H). Example 237: 5-(5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazol-1-yl)-1,3-dimethylpyridin-2(1H)-one [ka]

[0319] To a solution of 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazole (52.0 mg, 94 wt%, 112 μmol), (1R,2R)-cyclohexane-1,2-diamine (14.3 mg, 15.0 μL, 125 μmol) (Intermediate AI), 5-bromo-1,3-dimethylpyridin-2(1H)-one (51.0 mg, 252 μmol), and potassium phosphate (64.0 mg, 302 μmol) in DMF (2.00 mL) was added N 2 After sparging with H O for 5 min, copper(I) iodide (12.0 mg, 63.0 μmol) was added. The reaction mixture was sparged with N 2 was sparged for 5 min, and the reaction mixture was then heated at 120 °C for 21 h. The reaction mixture was cooled to room temperature, diluted with 5% LiCl (aq) solution (10 mL) and extracted with EtOAc (4 x 5 mL). The combined organic phase was washed with 1:1 brine (aq) / water (2 x 10 mL) and MgSO 4 The crude product was purified by preparative HPLC (Waters, acidic (0.1% formic acid in water), acidic, Waters XSelect CSH, C18, ODB prep column, 30-60% MeCN in water) to give 5-(5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazol-1-yl)-1,3-dimethylpyridin-2(1H)-one (Example 237) (32.3 mg, 56.8 μmol, 50.7%) as a tan solid; R t1.97 min (Method 6); m / z 558.3 ​​(M+H)+ (ES+). δH (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.09 - 8.04 (m, 2H), 7.66 (dd, J = 2.9, 1.3 Hz, 1H), 7.48 (s, 1H), 7.12 - 6.99 (m, 4H), 6.54 - 6.47 (m, 2H), 4.17 (s, 3H), 3.97 (d, J = 9.7 Hz, 1H), 3.70 - 3.60 (m, 1H), 3.56 (s, 3H), 3.53 - 3.46 (m, 1H), 3.36 (d, J = 9.8 Hz, 1H), 3.01 (d, J = 13.4 Hz, 1H), 2.73 (d, J = 13.5 Hz, 1H), 2.45 - 2.37 (m, 4H), 2.13 - 2.01 (m, 4H). Examples 238-243

Table 9-1

Table 9-2

Table 10-1

Table 10-2

Table 10-3

Table 10-4

Table 10-5

Table 10-6

Table 10-7

[0320] To a solution of 5-bromo-6-methyl-1H-indazole (25.00 g, 118.4 mmol) in dichloromethane (500 mL) was added tetrabutylammonium bromide (381.9 mg, 1.184 mmol) and 50% wt / wt potassium hydroxide (30 g, 20 mL, 1 mole, 20 mmol), followed by SEM-Cl (21.72 g, 23.1 mL, 130.3 mmol) over 5 min. The reaction was then stirred overnight at room temperature. The reaction was partitioned into water (200 mL), the phases separated and the aqueous phase further extracted with dichloromethane (2×100 mL), then the organics washed with brine (100 mL) before being washed with MgSO 4 The mixture was dried at rt and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (330 g cartridge, 0-50% EtOAc / isohexane) to give 5-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (Intermediate AJ) (29.2 g, 85.6 mmol, 72.2%, 100% pure) as a yellow oil; R t 1.75 min (method 6); m / z 341.1 / 343.0 (M+H)+ (ES+). δH (500 MHz, DMSO-d 6) δ 8.06 (br. s, 2H), 7.77 - 7.75 (m, 1H), 5.71 (s, 2H), 3.53 - 3.43 (m, 2H), 2.48 (s, 3H), 0.81 - 0.74 (m, 2H), -0.11 (s, 9H). Intermediate AK: 5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole [ka]

[0321] The compound was prepared in a similar manner as described for Example 16 to give 5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (Intermediate AK); R t 1.23 min (method 6); m / z 512.2 (M+H)+ (ES+). δH (400 MHz, DMSO-d6) δ 7.84 (d, J = 0.9 Hz, 1H), 7.51 (s, 1H), 7.47 - 7.35 (m, 4H), 7.33 - 7.26 (m, 1H), 6.99 - 6.90 (m, 1H), 6.83 (t, J = 7.5 Hz, 2H), 6.74 (s, 1H), 6.38 - 6.24 (m, 2H), 5.67 (s, 2H), 3.75 (d, J = 12.8 Hz, 1H), 3.60 - 3.53 (m, 1H), 3.49 (t, J = 7.9 Hz, 2H), 3.25 - 3.13 (m, 2H), 3.10 (d, J = 8.8 Hz, 1H), 3.03 (d, J = 12.9 Hz, 1H), 2.52 (s, 3H), 2.41 - 2.29 (m, 3H), 2.17 (ddd, J = 12.2, 9.4, 5.7 Hz, 1H), 0.79 (td, J = 7.7, 2.6 Hz, 2H), -0.11 (s, 9H). Intermediate AL: 5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1H-indazole [ka]

[0322] To a solution of 5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (Intermediate AK) (5.00 g, 9.77 mmol) in 1,4-dioxane (22 mL) was added HCl (4 M in 1,4-dioxane) (5.34 g, 36.6 mL, 4 mol, 147 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under vacuum. The resulting purple residue was redissolved in dichloromethane (60 mL) and treated with ethane-1,2-diamine (5.8 g, 6.5 mL, 97 mmol), turning the solution orange. The reaction mixture was stirred at room temperature for 90 min and then quenched with water (40 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic extracts were washed with MgSO 4 The crude product was purified by chromatography on silica gel (80 g cartridge, 0-50% EtOAc / heptane) to give 5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1H-indazole (Intermediate AL) (3.03 g, 7.5 mmol, 77%) as a white solid; R t0.62 min (method 7); m / z 382.2 (M+H)+ (ES+). δH (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.77 (s, 1H), 7.48 - 7.37 (m, 4H), 7.33 - 7.27 (m, 2H), 6.99 - 6.91 (m, 1H), 6.85 (t, J = 7.6 Hz, 2H), 6.73 (s, 1H), 6.44 - 6.23 (m, 2H), 3.75 (d, J = 12.8 Hz, 1H), 3.57 (d, J = 12.8 Hz, 1H), 3.20 - 2.98 (m, 4H), 2.49 (obs s, 3H), 2.41 - 2.30 (m, 3H), 2.22 - 2.09 (m, 1H). Intermediate AM: 5-(5-(3-benzylpyrrolidin-3-yl)-6-methyl-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one [ka]

[0323] To a solution of 5-(5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one (2.15 g, 4.40 mmol) (prepared using a method similar to that of Example 237) in dichloroethane (30 mL) was added 1-chloroethyl carbonochloridate (1.26 g, 949 μL, 8.80 mmol) and the reaction mixture was stirred at 80° C. for 3 days. The reaction mixture was concentrated under vacuum and the residue was redissolved in MeOH (30 mL). The reaction mixture was stirred at 60° C. for 2 h, then cooled to room temperature and concentrated onto silica gel. The crude product was purified by silica gel chromatography (24 g cartridge, 0-10% (0.7 M ammonia / MeOH) / DCM) to give 5-(5-(3-benzylpyrrolidin-3-yl)-6-methyl-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one (Intermediate AM) (571 mg, 1.2 mmol, 28%) as a tan solid; R t1.08 min (Method 6); m / z 399.2 (M+H)+ (ES+). δH (400 MHz, DMSO-d6) δ 8.21 (d, J = 3.0 Hz, 1H), 8.09 (d, J = 0.9 Hz, 1H), 7.76 (dd, J = 9.6, 3.0 Hz, 1H), 7.52 (s, 1H), 7.16 - 6.96 (m, 4H), 6.67 - 6.52 (m, 3H), 3.68 (d, J = 11.2 Hz, 1H), 3.55 (s, 3H), 3.35 (m, 4H), 3.17 (d, J = 11.2 Hz, 1H), 3.07 (d, J = 13.6 Hz, 1H), 2.99 (d, J = 13.5 Hz, 1H), 2.45 (s, 3H), 2.10 (q, J = 10.0 Hz, 1H). Example 275: 5-(5-(3-benzyl-1-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one [ka]

[0324] The compound was prepared using intermediate AM in a similar manner as described for Example 16 to give 5-(5-(3-benzyl-1-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one (Example 275). t1.78 points (Method 6); m / z 544.0 (M+H)+ (ES+). δH (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.21 (d, J = 2.9 Hz, 1H), 8.08 (d, J = 0.9 Hz, 1H), 7.75 (dd, J = 9.6, 3.0 Hz, 1H), 7.49 (s, 1H), 7.12 - 7.07 (m, 1H), 7.06 - 6.99 (m, 3H), 6.56 (d, J = 9.6 Hz, 1H), 6.54 - 6.49 (m, 2H), 4.06 (s, 3H), 3.99 (d, J = 9.6 Hz, 1H), 3.74 - 3.64 (m, 1H), 3.54 (s, 4H), 3.38 (d, J = 9.6 Hz, 1H), 3.01 (d, J = 13.4 Hz, 1H), 2.77 (d, J = 13.2 Hz, 1H), 2.41 (m, 4H), 2.00 (q, J = 9.9 Hz, 1H). Example 276-325

Table 11-1

Table 11-2

Table 11-3

Table 11-4

Table 11-5

Table 11-6

Table 11-7

Table 11-8

Table 11-9

[0325] A vial containing 6-chloro-5-(1,3-dibenzylpyrrolidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (prepared using a method similar to that described in Example 275) (300 mg, 90 wt%, 507 μmol), cesium carbonate (496 mg, 1.52 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (156 mg, 1.01 mmol), and Pd-161 (46.9 mg, 101 μmol) was evacuated under vacuum and charged with N 2The mixture was recharged with (×3). 1,4-dioxane (5 mL) was added and the resulting solution was heated at 90° C. for 18 h. The reaction mixture was cooled to room temperature and then added NaHCO 3 (20 mL) and extracted with EtOAc (3×20 mL). The combined organics were washed with brine (10 mL) and 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 (24 g cartridge, 0-50% EtOAc / isohexane) to give 5-(1,3-dibenzylpyrrolidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinyl-1H-indazole (Intermediate AN) (300 mg, 462 μmol, 91.0%) as a sticky yellow oil: R t 1.35 min (method 6); m / z 524.6 (M+H)+ (ES+). Intermediate AO: 5-(3-benzylpyrrolidin-3-yl)-6-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole [ka]

[0326] To a solution of 5-(1,3-dibenzylpyrrolidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinyl-1H-indazole (300 mg, 573 μmol) in EtOAc (6 mL) was added 10% palladium on activated carbon (type 39) (61.0 mg, 10 wt%, 57.3 μmol) and the reaction mixture was stirred under 5 bar of hydrogen for 3 days. Further palladium on activated carbon (type 39) (3.05 mg, 28.6 μmol) was added and the reaction mixture was heated at 50° C. under 5 bar of hydrogen for 18 h. The reaction mixture was filtered through a Whatman GF / F filter pad and rinsed with EtOH (3×1 mL). The combined filtrates were concentrated in vacuo to give 5-(3-benzylpyrrolidin-3-yl)-6-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (Intermediate AO) (215 mg, 0.30 mmol, 53%) as an orange oil which was used directly in the next step; R t 0.55 min (method 6); m / z 436.5 (M+H)+ (ES+). Intermediate AP: 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole [ka]

[0327] The compound was prepared by a method similar to that described for Example 16 to give 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (Intermediate AP); R t 1.93 min (method 6); m / z 581.5 (M+H)+ (ES+). Intermediate AQ: 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-ethyl-1H-indazole [ka]

[0328] The compound was prepared by a method similar to that described for Example 275 to give 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-ethyl-1H-indazole (Intermediate AQ); R t 1.45 min (method 6); m / z 451.5 (M+H)+ (ES+). Example 333: 5-(5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-ethyl-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one [ka]

[0329] The compound was prepared by a method similar to that described for Example 237 to give 5-(5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-ethyl-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one (Example 333); R t 1.44 min (method 6); m / z 558.1 (M+H)+ (ES+). δH (500 MHz, DMSO-d 6) δ 8.31 (s, 1H), 8.21 (d, J = 2.9 Hz, 1H), 8.08 (d, J = 0.9 Hz, 1H), 7.77 (dd, J = 9.6, 3.0 Hz, 1H), 7.51 (s, 1H), 7.11 - 7.00 (m, 4H), 6.58 (d, J = 9.6 Hz, 1H), 6.55 - 6.51 (m, 2H), 4.13 (s, 3H), 3.92 (d, J = 9.8 Hz, 1H), 3.61 (q, J = 8.4 Hz, 1H), 3.55 (s, 3H), 3.46 (t, J = 9.2 Hz, 1H), 3.43 - 3.36 (m, 1H), 3.04 (d, J = 13.5 Hz, 1H), 2.87 - 2.74 (m, 3H), (3) 2.43 - 2.33 (m, 1H), 2.14 - 2.04 (m, 1H), 1.29 (t, J = 7.3 Hz, 3H). Example 334: 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-1H-indazole-6-carbonitrile Intermediate AR: 5-(1,3-dibenzylpyrrolidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbonitrile [ka]

[0330] A vial containing sodium carbonate (155 mg, 1.47 mmol), palladium diacetate (21.9 mg, 97.7 μmol), tetrapotassium iron(II) cyanide trihydrate (413 mg, 977 μmol), 2-(2-(dicyclohexylphosphanyl)phenyl)-1-methyl-1H-indole (78.9 mg, 195 μmol), and 6-chloro-5-(1,3-dibenzylpyrrolidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (520 mg, 977 μmol) (prepared using a method similar to that described for Example 275) was evacuated under vacuum and backfilled with nitrogen (×3). 1,4-Dioxane (4 mL) and water (4 mL) were added and the solution was degassed with nitrogen for 10 min and heated in a microwave at 130° C. for 12 h. The reaction mixture was diluted with NaHCO 3 (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were passed through a hydrophobic frit and the solvent removed under reduced pressure to give a pale yellow residue. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% (0.7 M ammonia / MeOH) / DCM) to give 5-(1,3-dibenzylpyrrolidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbonitrile (430 mg, 587 μmol, 60.1%, 74.4% purity) as a sticky yellow oil; R t 1.28 min (method 6); m / z 523.2 (M+H)+ (ES+). Intermediate AS: 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1H-indazole-6-carbonitrile [ka]

[0331] The compound was prepared in a similar manner to that described in Example 275 to give 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1H-indazole-6-carbonitrile (Intermediate AR); R t 1.45 min (method 6); m / z 451.5 (M+H)+ (ES+). Example 334: 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-1H-indazole-6-carbonitrile [ka]

[0332] The compound was prepared in a similar manner as described for Example 16 to give 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-1H-indazole-6-carbonitrile (Example 334); R t 1.65 min (Method 8); m / z 542.2 (M+H)+ (ES+). δH (400 MHz, methanol-d 4 ) δ 8.29 (s, 1H), 8.24 (d, J = 1.0 Hz, 1H), 8.04 (s, 1H), 7.86 - 7.79 (m, 2H), 7.45 - 7.36 (m, 3H), 7.14 - 7.04 (m, 3H), 6.71 - 6.65 (m, 2H), 4.19 - 4.10 (m, 1H), 4.08 (s, 3H), 3.84 (d, J = 10.4 Hz, 1H), 3.76 (dt, J = 10.1, 7.4 Hz, 1H), 3.64 - 3.53 (m, 1H), 3.39 (d, J = 13.8 Hz, 1H), 3.11 (d, J = 13.8 Hz, 1H), 2.68 - 2.58 (m, 1H), 2.46 - 2.35 (m, 1H). Example 335: 5-(5-(3-benzyl-4-methyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one Intermediate AT: 1,3-dibenzyl-4-methyl-3-(6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)pyrrolidine-2,5-dione [ka]

[0333] To a solution of 1,3-dibenzyl-3-(6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)pyrrolidine-2,5-dione (4.12 g, 87 wt%, 6.64 mmol) (prepared using methods similar to those described in Example 16 and Example 275) in THF (60 mL) at 0° C., lithium diiso-propylamide (2M in THF) (1.1 g, 5.0 mL, 2.0 moles, 10 mmol) was added and the resulting solution was stirred at this temperature for 30 minutes. Iodomethane (1.89 g, 827 μL, 13.3 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was purified with saturated NaHCO 3 It was quenched with aqueous solution (50 mL) and 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 product was purified by chromatography on silica gel (220 g cartridge, 0-40% EtOAc / isohexane) to give 1,3-dibenzyl-4-methyl-3-(6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)pyrrolidine-2,5-dione (Intermediate AT) (3.02 g, 4.6 mmol, 70%) as a sticky yellow oil that solidified to a yellow solid on standing overnight; R t 2.61 min (method 7); m / z 542.2 (M+H)+ (ES+). Example 335: 5-(5-(3-benzyl-4-methyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one [ka]

[0334] The compound was prepared by a method similar to that described for Example 275 to give 5-(5-(3-benzyl-4-methyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one (Example 335) (59.75 mg, 0.10 mmol, 67%) as a yellow solid; R t 1.76 min (Method 7); m / z 558.2 (M+H)+ (ES+). δH (400 MHz, DMSO-d 6 ) δ 8.29 (s, 1H), 8.10 (d, J = 2.9 Hz, 1H), 8.01 (d, J = 1.0 Hz, 1H), 7.72 (dd, J = 9.6, 3.0 Hz, 1H), 7.48 (s, 1H), 7.09 - 7.04 (m, 1H), 7.01 (dd, J = 8.1, 6.4 Hz, 2H), 6.85 (s, 1H), 6.55 (d, J = 9.6 Hz, 1H), 6.52 - 6.49 (m, 2H), 4.24 (s, 3H), 4.00 (dd, J = 10.3, 6.3 Hz, 1H), 3.77 (d, J = 9.4 Hz, 1H), 3.56 (s, 3H), 3.48 (d, J = 9.1 Hz, 1H), 3.28 (d, J = 10.2 Hz, 1H), 3.14 (d, J = 13.5 Hz, 1H), 2.98 - 2.91 (m, 1H), 2.55 (s, 3H), 0.53 (d, J = 7.0 Hz, 3H) - one CH is obscured by water. Example 336: 1,3-dibenzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-hydroxypyrrolidin-2-one [ka]

[0335] To a solution of 1,3-dibenzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidine-2,5-dione (Intermediate O) (0.105 g, 209 μmol) in dioxane (3 mL) was added DIBAL-H (29.7 mg, 209 μL, 1 mole, 209 μmol) in hexanes and the reaction was stirred at room temperature overnight. The reaction was cooled to room temperature with NaHCO 3 (10 mL), extracted with EtOAc (2 x 10 mL) and the organics washed with MgSO 4 The mixture was dried at 40° C. and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to give 5-(1,3-dibenzylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Example xx) as a yellow solid (Example 336) (52 mg, 0.21 mmol, 48%); t 1.76 min (method 7); m / z 558.2 (M+H)+ (ES+). Example 337: 1,3-dibenzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-2-one [ka]

[0336] To a solution of 1,3-dibenzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-hydroxypyrrolidin-2-one (0.052 g, 0.10 mmol) (Example 336) in TFA (1 mL) was added triethylsilane (0.12 g, 0.16 mL, 1.0 mmol) and the reaction was stirred at room temperature for 1 h. The reaction was cooled to room temperature with NaHCO3 (10 mL), then EtOAc (2×10 mL) was added, the organics were combined, and then MgSO 4 The mixture was dried at 40° C. and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give 1,3-dibenzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-2-one (0.016 g, 32 μmol, 31%) (Example 337) as a pale yellow solid; R t 3.00 min (method 2); m / z 490.0 (M+H)+ (ES+). δH (500 MHz, DMSO-d 6 ) δ 8.32 (s, 1H), 8.02 (s, 1H), 7.94 - 7.74 (m, 2H), 7.68 (s, 1H), 7.43 (t, J = 8.8 Hz, 2H), 7.37 - 7.20 (m, 8H), 7.18 - 6.97 (m, 2H), 4.49 (d, J = 14.5 Hz, 1H), 4.03 (d, J = 14.5 Hz, 1H), 3.45 - 3.28 (m, 2H), 3.2 (s, 3H), 2.99 - 2.81 (m, 1H), 2.34 - 2.14 (m, 3H). Example 338: 3-benzyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-(methylsulfonyl)pyrrolidin-2-one Intermediate AU: 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-(4-methoxybenzyl)pyrrolidine-2,5-dione [ka]

[0337] To a solution of 1-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.672 g, 87 wt%, 1.73 mmol) (prepared using a method similar to that described in Example 16) in dioxane (10 mL) and water (1 mL) that had been degassed with nitrogen for 10 min, 1-(4-methoxybenzyl)-1H-pyrrole-2,5-dione (413 mg, 1.90 mmol), triethylamine (262 mg, 361 μL, 2.59 mmol), and hydroxy(cyclooctadiene)rhodium(I) dimer (39.4 mg, 86.4 μmol) were added and then heated to 80° C. overnight. The reaction was cooled and partitioned between EtOAc (2×20 mL) and water (20 mL), then the organics were washed with MgSO 4 The mixture was dried at 40° C. and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / isohexane) to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-(4-methoxybenzyl)pyrrolidine-2,5-dione (Intermediate AU) (0.651 g, 1.5 mmol, 87%) as a yellow solid; t 2.49 min (method 2); m / z 429.8 (M+H)+ (ES+). Intermediate AV: 3-benzyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-one [ka]

[0338] To a solution of 3-benzyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (0.131 g, 259 μmol) (prepared using a method similar to that described in Example 337) in MeCN (3 mL) was added ceric ammonium nitrate (284 mg, 518 μmol) and the reaction was stirred at room temperature overnight. Additional ceric ammonium nitrate (142 mg, 259 μmol) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with EtOAc (2×20 mL) and NaHCO3 (20 mL) and partition the organics between MgSO 4 The mixture was dried at 40° C. and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to give 3-benzyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-one (intermediate AV) (0.028 g, 70 μmol, 27%) as a yellow solid; t 2.40 min (method 2); m / z 385.8 (M+H)+ (ES+). δH (500 MHz, DMSO-d 6 ) δ 8.34 (d, J = 0.8 Hz, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.84 - 7.70 (m, 5H), 7.47 - 7.39 (m, 2H), 7.23 - 7.13 (m, 3H), 7.12 - 7.04 (m, 2H), 3.18 - 3.07 (m, 2H), 3.01 - 2.92 (m, 1H), 2.88 (t, J = 8.0 Hz, 1H), 2.43 (ddd, J = 10.1, 6.8, 3.4 Hz, 1H), 2.32 (dt, J = 13.1, 8.1 Hz, 1H). Example 338: 3-benzyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-(methylsulfonyl)pyrrolidin-2-one [ka]

[0339] To a solution of 3-benzyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-one (0.027 g, 70 μmol) in DMF (3 mL) at 0° C., sodium hydride (5.1 mg, 60 wt%, 0.13 mmol) was added and the reaction was stirred for 10 min, after which methanesulfonyl chloride (15 mg, 10 μL, 0.13 mmol) was added and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was again cooled to 0° C., sodium hydride (10 mg, 0.42 mmol) was added, the reaction mixture was stirred for 10 min, then methanesulfonyl chloride (24 mg, 16 μL, 0.21 mmol) was added and the reaction was left overnight. Also. NaHCO 3 The reaction was quenched by slow addition of EtOAc (10 mL) and then EtOAc (15 mL), the aqueous was re-extracted with EtOAc (15 mL), and the organics were then combined and washed with brine (15 mL) and then MgSO 4 The mixture was dried at 40° C. and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to give 3-benzyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-(methylsulfonyl)pyrrolidin-2-one (0.005 g, 0.01 mmol, 20%, 98%) (Example 338) as a pale yellow solid; R t 2.64 min (method 2); m / z 463.8 (M+H)+ (ES+). δH (500 MHz, DMSO-d 6 ) δ 8.36 (d, J = 0.9 Hz, 1H), 7.90 - 7.86 (m, 1H), 7.85 - 7.78 (m, 3H), 7.67 (dd, J = 9.0, 1.9 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.21 - 7.16 (m, 3H), 7.01 - 6.95 (m, 2H), 3.60 - 3.50 (m, 2H), 3.28 (s, 3H), 3.25 (s, 2H), 2.57 (ddd, J = 13.2, 6.7, 4.4 Hz, 1H), 2.49 - 2.40 (m, 1H). Example 339: 3-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-(methylsulfonyl)pyrrolidin-2-one [ka]

[0340] The compound was prepared in a similar manner as described for Example 338 to give 3-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-(methylsulfonyl)pyrrolidin-2-one (Example 339); R t 1.70 min (method 1); m / z 478.3 (M+H) + (ES + ). δH (500 MHz, chloroform-d) δ 8.15 (d, J = 0.9 Hz, 1H), 7.97 (s, 1H), 7.70 - 7.64 (m, 2H), 7.55 (q, J = 0.9 Hz, 1H), 7.38 - 7.31 (m, 5H), 7.27 - 7.22 (m, 2H), 3.65 - 3.56 (m, 2H), 3.47 (d, J = 13.1 Hz, 1H), 3.13 (s, 3H), 2.96 - 2.90 (m, 1H), 2.61 (d, J = 0.8 Hz, 3H), 2.56 - 2.51 (m, 2H). Example 340: 1-(4-fluorophenyl)-5-(3-(methoxymethyl)-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazole Intermediate AW: tert-butyl 3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyrrolidine-1-carboxylate [ka]

[0341] To a microwave vial containing nickel chloride, dimethoxyethane adduct (230 mg, 1.05 mmol) was added DMA (7 mL). The blue solution was subjected to vacuum / nitrogen cycles (x3) and stirred at room temperature for 5 min. Meanwhile, to a solution of bis(pinacolato)diborane (1.66 g, 6.55 mmol) and 5-bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (Intermediate D) (2.50 g, 8.19 mmol) in THF (15 mL) and dimethylacetamide (2 mL) was added tert-butyl 3-methylenepyrrolidine-1-carboxylate (600 mg, 594 μL, 3.27 mmol), sodium t-butoxide (2M THF...

Claims

1. Compound of formula IVa: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, R １ are 5-6 membered heterocycloalkyl having 1-2 heteroatoms each being N, phenyl, or 5-6 membered heteroaryl having 1-2 heteroatoms each being N or S, each having 1-3 R １ａ is substituted with a group, Each R １ａ are independently hydrogen, C １－３ Alkyl, C １－３ Deuterated alkyl, C １－３ Alkoxy, C １－３ Hydroxyalkyl, halogen, C １－３ Haloalkyl, oxo, -CN, C ３－６ cycloalkyl or 3-5 membered heterocycloalkyl having 1-2 heteroatoms, each of which is N or O; A １ , A ２ , A ３ , and A ４ are each 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, or -CN; Each R ３ａ is independently hydrogen, —OH, or oxo; Each R ３ｂ is C1-6 alkyl, C ２－６ Alkynyl, C2-6 alkoxyalkyl, C ２－６ Alkynyl-C ３－６ Cycloalkyl, C １－６ Alkyl-C ６－１２ Aryl, C ２－６ Alkenyl-C ６－１２ Aryl, C ２－６ Alkynyl-C ６－１２ Aryl, C １－６ Alkyl-O-C ６－１２ Aryl, C １－６ Alkoxyalkyl-C ６－１２ Aryl, —C(O)—C ６－１２ Aryl, or C １－６ alkyl-heteroaryl, where each heteroaryl is a 5-10 membered heteroaryl having 1-3 heteroatoms each independently being N, O, or S, and where each aryl and heteroaryl is selected from 1-3 R ３ｂ３ is substituted with a group; Each R ３ｂ３ is hydrogen, C １－６ Alkyl, C １－６ Hydroxyalkyl, halogen, C １－６ haloalkyl; R ４ is C １－６ Alkyl, C １－６ Haloalkyl, -CN, C ３－８ cycloalkyl, 3-8 membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O, or S; C ６－１２ aryl, or 5-10 membered heteroaryl having 1-5 heteroatoms each independently being N, O, or S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently being 1-5 R ４ａ is substituted with a group; Each R ４ａ is hydrogen, C １－６ Alkyl, C １－６ Deuterated alkyl, C ２－６ Alkoxyalkyl, C １－６ Hydroxyalkyl, halogen, C １－６ Haloalkyl, -CN, -OH, oxo, -S(O) ２ R ４ｂ , -S(O) ２ N (R ４ｂ ) (R ４ｃ ), C ３－６ Cycloalkyl, C ６－１２ Aryl, or —O—C ６－１２ aryl, where each aryl is C １－６ optionally substituted with alkoxy; Each R ４ｂ and R ４ｃ is hydrogen or C １－６ is alkyl; L １ does not exist, and L ２ does not exist, -CH ２ -, -C(O)-, -C(O)CH ２ --, --C(O)CH ２ CH ２ --, --C(O)CH ２ O-, -C(O)(CH ２ ) ３ O- or -S(O) ２ -is.

2. 2. A compound according to claim 1 or a pharma- ceutically acceptable salt thereof, wherein R １ is piperidine, pyridin-2-one, phenyl, pyridine, pyrazole, or thiazole, each of which is 1 to 3 R １ａ is substituted with a group; and Each R １ａ is hydrogen, methyl, ethyl, isopropyl, -CD ３ , methoxy, -CH ２ OH, F, Cl, -CHF ２ , -CF ３ , oxo, -CN, cyclopropyl, or oxetane, or a pharma- ceutically acceptable salt thereof.

3. 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein R １ but, 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

4. structure: 【Chemistry 3】 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, having the formula:

5. A １ , A ２ , A ３ , and A ４ However, each independently = CR ２ - or =N-; and Each R ２ are independently hydrogen, C １－４ Alkyl, C １－４ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, which is alkoxy, halogen, or -CN.

6. A １ , A ２ , A ３ , and A ４ are each independently =CH-, =C(Me)-, =C(Et)-, =C(iPr)-, =C(OMe)-, =C(F)-, =C(Cl)-, =C(CN)-, or =N-, or a pharma- ceutically acceptable salt thereof.

7. structure: 【Chemistry 4】 The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, having the formula:

8. structure: 【Chemistry 5】 The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, having the formula:

9. A compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein R ３ｂ But, C １－３ Alkyl, C ２－３ Alkynyl, C ２－３ Alkoxyalkyl, C ２－３ Alkynyl-C ３－６ Cycloalkyl, C １－３ Alkyl-C ６－１２ Aryl, C ２－３ Alkenyl-C ６－１２ Aryl, C ２－３ Alkynyl-C ６－１２ Aryl, C １－３ Alkyl-O-C ６－１２ Aryl, C １－３ Alkoxyalkyl-C ６－１２ Aryl, —C(O)—C ６－１２ Aryl, or C １－３ alkyl-heteroaryl, where each heteroaryl is a 5-10 membered heteroaryl having 1-3 heteroatoms each independently being N, O, or S, and where each aryl and heteroaryl is selected from 1-3 R ３ｂ３ is substituted with a group; and Each R ３ｂ３ is hydrogen, C １－３ Alkyl, C １－３ Hydroxyalkyl, halogen, or C １－３ The compound or a pharma- ceutically acceptable salt thereof, wherein: R is H;

10. R ３ｂ３ is hydrogen, methyl, -CH ２ OH, F, -CHF ２ , or -CF ３ 10. The compound according to any one of claims 1 to 9, wherein:

11. A compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein R ３ｂ Ethyl, -CH ２ C≡CH, -CH ２ O Me, 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

12. structure: 【Chemistry 7】 12. The compound according to any one of claims 1 to 11, having the formula: or a pharma- ceutically acceptable salt thereof.

13. L ２ is -C(O)- or S(O) ２ 13. The compound according to any one of claims 1 to 12, wherein R is - or a pharma- ceutically acceptable salt thereof.

14. structure: 【Chemistry 8】 14. The compound according to any one of claims 1 to 13, having the formula: or a pharma- ceutically acceptable salt thereof.

15. A compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein R ４ But, C １－３ Alkyl, C １－３ Haloalkyl, -CN, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl with one heteroatom each being N or O, C ６－１２ aryl, or 5-10 membered heteroaryl having 1-4 heteroatoms each independently being N, O, or S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently are each independently 1-2 R ４ａ is substituted with a group; Each R ４ａ is hydrogen, C １－３ Alkyl, C １－３ Deuterated alkyl, C １－３ Alkoxy, C ２－３ Alkoxyalkyl, C １－３ Hydroxyalkyl, halogen, C １－３ Haloalkyl, -CN, -OH, oxo, -S(O) ２ R ４ｂ , -S(O) ２ N (R ４ｂ ) (R ４ｃ ), C ３－６ Cycloalkyl, C ６－１２ Aryl, or —O—C ６－１２ aryl, where each aryl is C １－３ optionally substituted with alkoxy; and Each R ４ｂ and R ４ｃ is hydrogen or C １－３ or a pharma- ceutically acceptable salt thereof.

16. 16. A compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, wherein R ４ Methyl, ethyl, -CF ２ CH ３ , -CN, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl, pyrimidine-dione, phenyl, pyridinyl, pyridin-2-one, quinolinyl, pyrazolyl, imidazolyl, pyridazinyl, pyrimidinyl, indazolyl, triazolyl, pyrazolo-pyrimidine, tetrazolyl, oxazolyl, isoxazolyl, benzoisoxazolyl, oxadiazolyl, thiophenyl, benzothiophenyl, or thiazolyl; and Each R ４ａ is hydrogen, methyl, ethyl, n-propyl, iso-butyl, -CD ３ , methoxy, -CH ２ CH ２ OCH ３ , hydroxymethyl, F, Cl, -CHF ２ , -CF ３ , -CH ２ CF ３ , -CN, -OH, oxo, -S(O) ２ Me, -S(O) ２ The compound or a pharma- ceutically acceptable salt thereof, wherein: R is -NHMe, cyclobutyl, 2-methoxyphenyl, or -OPh.

17. 17. A compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein R ４ Methyl, -CF ２ CH ３ , -CN, 【Chemistry 9-1】 【Chemistry 9-2】 or a pharma- ceutically acceptable salt thereof.

18. 18. A compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein R １ but, 【Chemistry 10】 and A １ is ═CH— or ═N—; A ２ and A ４ are each ═CH—; A ３ is ═CH—, ═C(Me)—, ═C(Et)—, ═C(iPr)—, ═C(OMe)—, ═C(F)—, ═C(Cl)—, or ═C(CN)—; Each R ３ａ is hydrogen, —OH, or oxo; R ３ｂ Ethyl, -CH ２ C≡CH, -CH ２ O Me, 【Chemistry 11】 and L １ and L ２ Both are -CH ２ -, -C(O)-, -C(O)CH ２ --, --C(O)CH ２ CH ２ --, --C(O)CH ２ O-, -C(O)(CH ２ ) ３ O- or S(O) ２ - and R ４ Methyl, -CF ２ CH ３ , -CN, 【Chemistry 12-1】 【Chemistry 12-2】 or a pharma- ceutically acceptable salt thereof.

19. A compound selected from the following: 【Chemical A1】 【Chemical A2】 【Chemical A3】 【Chemical A4】 【Chemical A5】 【Chemical A6】 【Chemical A7】 【Chemical A8】 【Chemical A9】 【Chemical A10】 【Chemical A11】 【Chemical A12】 【Chemical A13】 【Chemical A14】 【Chemical A15】 【Chemical A16】 【Chemical A17】 【Chemical A18】 【Chemical A19】 【Chemical A20】 【Chemical A21】 【Chemical A22】 【Chemical A23】 【Chemical A24】 2. The compound of claim 1, wherein:

20. structure: 【Chemistry 13】 20. The compound according to any one of claims 1 to 19, having the formula:

21. structure: 【Chemistry 14】 20. The compound according to any one of claims 1 to 19, having the formula:

22. structure: 【Chemistry 15】 20. The compound according to any one of claims 1 to 19, having the formula:

23. structure: 【Chemistry 16】 20. The compound according to any one of claims 1 to 19, having the formula:

24. structure: 【Chemistry 17】 20. The compound according to any one of claims 1 to 19, having the formula:

25. structure: 【Chemistry 18】

26. 26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

27. A pharmaceutical composition for treating a disorder or condition by modulating the glucocorticoid receptor, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 25 or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26, thereby treating the disorder or condition.

28. A pharmaceutical composition for treating a disorder or condition by antagonizing the glucocorticoid receptor, comprising an effective amount of a compound according to any one of claims 1 to 25 or a pharma- ceutical acceptable salt thereof, or the pharmaceutical composition according to claim 26, for administering to a subject in need of such treatment.

29. 29. The pharmaceutical composition of claim 27 or 28, wherein the disorder or condition is selected from the group consisting of amyotrophic lateral sclerosis (ALS), obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, neurodegeneration, Alzheimer's disease, Parkinson's disease, Cushing's syndrome, cancer, liver disease, osteoporosis, muscle weakness, disorders due to excess cortisol associated with adrenal gland disease, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, fractures after surgery, GR-related metabolic disorders, severe psychotic depression, mild cognitive impairment, dementia, hyperglycemia, stress disorders, weight gain due to antipsychotics, delirium, cognitive impairment in depressed patients, postpartum psychosis, postpartum depression, and neurological disorders of premature infants.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, for use in treating a disorder or condition by modulating the glucocorticoid receptor.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharma- ceutical composition according to claim 26, for use in treating a disorder or condition by antagonizing the glucocorticoid receptor, or a pharma- ceutical composition according to claim 27.

32. 27. Use of a compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, in the manufacture of a medicament for treating a disorder or condition by modulating the glucocorticoid receptor.

33. Use of a compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, in the manufacture of a medicament for treating a disorder or condition by antagonizing the glucocorticoid receptor.

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