Quaternary indole glucocorticoid receptor antagonist

Abstract

The present invention provides compounds of formula I or II. The compounds of formula I or II can be used in pharmaceutical preparations and can be used to modulate the glucocorticoid receptor.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 042,188, filed Jun. 22, 2020, which is incorporated herein by reference in its entirety for all purposes. Background of the invention

[0004] 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 (adrenocorticotropic hormone) and exhibit circadian rhythm variations and elevated responses 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 intracellular glucocorticoid receptor (GR). In humans, the glucocorticoid receptor exists in two forms: one is the ligand - binding GR - α consisting of 777 amino acids; the other is the GR - β isoform lacking 50 carboxy - terminal residues. Since these residues include the ligand - binding domain, GR - β cannot bind the natural ligand and is constitutively localized in the nucleus.

[0005] The biological actions of cortisol, including those mediated by cortisol, can be modulated at the GR level by receptor modulators such as agonists, partial agonists, and antagonists. Several different classes of drugs are capable of blocking the physiological actions of GR agonists. These antagonists include compositions that block the ability of agonists to bind effectively and / or activate GR by binding to GR. One known GR antagonist, mifepristone, has been found to be an effective human antiglucocorticoid agent (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to GR with high affinity, with a dissociation constant (Kd) of 10 -9 M (Cadepond (1997) Annu. Rev. Med. 48:129).

[0006] Cortisol (and corticosterone) also binds to the mineralocorticoid receptor MR. Cortisol has a higher affinity for MR than for GR, and under normal physiological conditions, MR is generally considered to be fully occupied. Under stress conditions, cortisol concentrations increase and GR is occupied. MR also binds aldosterone, and aldosterone and cortisol have similar affinities for MR. However, the circulating levels of glucocorticoids are approximately 100 - fold higher than those of mineralocorticoids. There is an enzyme (11 - hydroxysteroid dehydrogenase 1) present in mineralocorticoid target tissues to prevent over - stimulation by glucocorticoids.

[0007] When administered to a subject in need, steroids can provide both the desired therapeutic effect and have negative side effects. What is needed in the art are new compositions and methods for selectively modulating GR. The present invention unexpectedly meets these and other needs. SUMMARY OF THE INVENTION

[0009] In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0010]

[0011] Wherein

[0012] R 1 is a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms each independently being N, O, or S, phenyl, or a heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O, or S, each group independently being substituted with 1 to 5 R 1a groups;

[0013] Each R 1a is 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 a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms each independently being N, O, or S;

[0014] Each R 1b and R 1c are independently hydrogen, C 1-6 alkyl or a 3 - 8 membered heterocycloalkyl having 1 - 3 heteroatoms each independently being N, O, or S;

[0015] A 1 、A 2 、A 3 and A 4 are each independently =CR 2 - or =N-;

[0016] Each R 2 is 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;

[0017] Ring J is a 3- to 10-membered heteroalkyl group having 1 to 3 heteroatoms independently selected from N, O or S, at least one of which is N, and wherein Ring J is optionally substituted with 1 to 13 R 3a and R 3b groups;

[0018] Each R 3a is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkoxy, 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, heteroalkyl, C 1-6 alkyl-heteroalkyl, C 6-12 aryl, C 1-6 alkyl-C 6-12 aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, wherein each alkenyl and alkynyl is optionally substituted with C 6-12 aryl or heteroaryl, wherein each heteroalkyl has 3 to 8 ring members and 1 to 3 heteroatoms each independently selected from N, O or S, and wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently selected from N, O or S;

[0019] R 3a1 and R 3a2 are each independently hydrogen or C 1-6 alkyl;

[0020] Alternatively, two R 3a groups attached to the same atom may combine with the atom to which they are attached to form a C 3-6 cycloalkyl;

[0021] Alternatively, two R 3a groups attached to different atoms may combine with the atoms to which they are attached to form a C3-10 cycloalkyl or a 3- to 10-membered heteroalkyl having 1 to 4 heteroatoms each independently selected from N, O or S, each group being substituted with 1 to 4 R 3a3 groups;

[0022] Each R3a3 Independently hydrogen or C 1-6 alkyl;

[0023] Each R 3b is 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-O-C 6-12 aryl, C 1-6 alkoxyalkyl-C 6-12 aryl, -C(O)-C 6-12 aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, wherein each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms independently selected from N, O, or S, wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms independently selected from N, O, or S,, and wherein each aryl and heteroaryl is substituted with 1 to 3 R 3b3 groups;

[0024] R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl;

[0025] Alternatively, R 3b1 and R 3b2 bond to the atoms to which they are attached to form a 3- to 6-membered heterocycloalkyl having 1 to 2 additional heteroatoms independently selected from N, O, or S;

[0026] Each R 3b3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C2-6 alkoxyalkyl, C 1-6 hydroxyalkyl, halogen, C 1-6 haloalkyl, or C 1-6 haloalkoxy;

[0027] Alternatively, R 3b combines with R 3a on an adjacent ring atom and the atoms to which they are respectively attached to form a C 3-6 cycloalkyl which is substituted with 0 - 4 halogens;

[0028] R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -CN, C 3-8 cycloalkyl, a 3 - to 8 - membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O or S, C 6-12 aryl or a 5 - to 10 - membered heteroaryl having 1 to 5 heteroatoms each being N, O or S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently substituted with 1 to 5 R 4a groups;

[0029] 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, -O - C 6-12 aryl, heteroaryl, C 1-6Alkyl - heteroaryl, wherein each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each heteroaryl independently has 5 to 8 ring members and 1 to 4 heteroatoms each independently being N, O or S, and wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with C 1-6 alkoxy;

[0030] R 4b and R 4c are each independently hydrogen or C 1-6 alkyl;

[0031] L 1 is absent or is - N(R 5a );

[0032] L 2 is absent, or is 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

[0033] R 5a and R 5b are each independently hydrogen, C 1-6 alkyl or C 2-6 alkoxyalkyl;

[0034] wherein, when L 2 is absent, then R 3b is not hydrogen, and

[0035] wherein, when A 1 , A 2 , A 3 and A 4 are each - CH -, ring J is

[0036]

[0037] L 1 is - NH -, L 2 is - C(O)-, - C(O)O - or - S(O) 2 - and each R 3a is H.

[0038] In another embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0039]

[0040] wherein

[0041] R 1 is phenyl or pyridyl, each independently substituted with 1 to 5 R 1a groups, each independently being hydrogen, C 1-6 alkoxy, halogen, -OH, and -C(O)N(R 1b )(R 1c );

[0042] Each R 1b and R 1c is independently hydrogen, C 1-6 alkyl, or a 3- to 8-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O, or S;

[0043] A 1 、A 2 、A 3 and A 4 are each independently =CR 2 - or =N-;

[0044] Each R 2 is 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;

[0045] Ring J is a 3- to 10-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O, or S, wherein at least one heteroatom is N, and wherein Ring J is optionally substituted with 1 to 13 R 3a and R 3b groups;

[0046] Each R 3a is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkoxy, 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, C6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 Alkyl-heteroaryl, wherein each alkenyl and alkynyl is optionally substituted with C 6-12 Aryl or heteroaryl, wherein each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O, or S, and wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O, or S;

[0047] R 3a1 and R 3a2 are each independently hydrogen or C 1-6 alkyl;

[0048] Alternatively, two R 3a groups attached to the same atom can combine with the atom to which they are attached to form a C 3-6 cycloalkyl;

[0049] Or, two R 3a groups attached to different atoms can combine with the atoms to which they are attached to form a C3-10 cycloalkyl or a 3-10 membered heterocycloalkyl having 1-4 heteroatoms each independently being N, O, or S, each group being substituted with 1-4 R 3a3 groups;

[0050] Each R 3a3 is independently hydrogen or C 1-6 alkyl;

[0051] Each R 3b is 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 1-6An alkyl - heteroaryl, wherein each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O or S, and wherein each aryl and heteroaryl is substituted by 1 to 3 R 3b3 groups;

[0052] R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl;

[0053] Alternatively, R 3b1 and R 3b2 combine with the atoms to which they are attached to form a 3 - to 6 - membered heterocycloalkyl having 1 to 2 additional heteroatoms each independently being N, O or S;

[0054] 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;

[0055] Alternatively, R 3b combines with R 3a on adjacent ring atoms and the atoms to which they are attached to form a C 3-6 cycloalkyl substituted by 0 - 4 halogens;

[0056] R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, - CN, C 3-8 cycloalkyl, a 3 - to 8 - membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O or S, C 6-12 aryl, or a 5 - to 10 - membered heteroaryl having 1 - 5 heteroatoms each independently being N, O or S, wherein the heterocycloalkyl, aryl and heteroaryl are each independently substituted by 1 - 5 R 4a groups;

[0057] Each R 4a is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkoxy, C 1-6 hydroxyalkyl, halogen, C 1-6 haloalkyl, C 1-6Halogenated alkoxy, -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 -O-C 6-12 aryl, wherein each heterocycloalkyl independently has 3-8 ring members and 1-3 heteroatoms each independently being N, O or S, and wherein each aryl is optionally substituted with C 1-6 alkoxy;

[0058] R 4b and R 4c are each independently hydrogen or C 1-6 alkyl;

[0059] L 1 is absent or is -N(R 5a );

[0060] L 2 is absent, or is -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

[0061] R 5a and R 5b are each independently hydrogen, C 1-6 alkyl or C 2-6 alkoxyalkyl.

[0062] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0063] In another embodiment, the present invention provides a method of treating a disease or disorder 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 so as to treat the disease or disorder.

[0064] In another embodiment, 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 a compound or pharmaceutical composition of the present invention.

[0065] In another embodiment, the present invention provides a compound or pharmaceutical composition for use in a method of treating a disease or condition by modulating the glucocorticoid receptor.

[0066] In another embodiment, the present invention provides a compound or pharmaceutical composition for use in a method of treating a disease or condition by antagonizing the glucocorticoid receptor.

[0067] 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.

[0068] 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.

[0069] Detailed Description of the Invention

[0070] Overview

[0071] The present invention provides compounds of formula I capable of modulating and / or antagonizing the glucocorticoid receptor and thereby providing beneficial therapeutic effects. The present invention also provides methods for treating diseases and conditions by modulating the glucocorticoid receptor or by 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 the glucocorticoid receptor, stimulating the glucocorticoid receptor or antagonizing the glucocorticoid receptor.

[0072] Definitions

[0073] Unless otherwise specifically stated, 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. In addition, any methods or materials similar or equivalent to those described herein can be used in the practice of the present invention. For the purposes of the present invention, the following terms are defined.

[0074] As used herein, "a", "an" or "the" includes aspects having not only one member but also aspects having more than one member. For example, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, reference to "a reagent" includes reference to one or more reagents known to those skilled in the art, and so on.

[0075] "Alkyl" refers to a straight-chain or branched-chain saturated aliphatic group having the indicated number of carbon atoms. An alkyl can include any number of carbons, such as C 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, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. An alkyl can also refer to an alkyl having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. An alkyl can be substituted or unsubstituted.

[0076] "Alkylene" refers to a straight-chain or branched-chain saturated aliphatic group having the indicated number of carbon atoms (i.e., C 1-6 represents 1 to 6 carbons), and is connected to at least two other groups, i.e., a divalent hydrocarbon group. The two moieties connected to the alkylene can be connected to the same atom or different atoms of the alkylene. For example, a straight-chain alkylene can be a divalent group of (CH 2 ) n , where n is 1, 2, 3, 4, 5, or 6. Representative C 1-4 alkylene includes, but is not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, and sec-butylene.

[0077] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon having at least 2 carbon atoms and at least one double bond. An alkenyl can include any number of carbons, such as 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 , C4-6 , C 5 , C 5-6 and C 6 . The alkenyl group 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-hexatriene. The alkenyl group can be substituted or unsubstituted.

[0078] "Alkynyl" refers to a straight-chain or branched-chain hydrocarbon having at least 2 carbon atoms and at least one triple bond. The alkynyl group can include any number of carbons, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 and C 6 . Examples of alkynyl groups include but are not limited to ethynyl, propynyl, 1-butynyl, 2-butynyl, butadienyl, 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. The alkynyl group can be substituted or unsubstituted.

[0079] "Deuterated alkyl" refers to an alkyl group as defined above, in which at least one hydrogen atom is replaced by deuterium. Like the alkyl group, the deuterated alkyl group can have any suitable number of carbon atoms, such as C 1-6 . Exemplary C 1-4 deuterated alkyl groups include but are not limited to -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 , -CH 2 CHD2 , -CH 2 CD 3 etc.

[0080] "Alkoxy" refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. Like alkyl groups, alkoxy groups can have any suitable number of carbon atoms, such as C 1-6 . Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc. Alkoxy groups can be further substituted with various substituents as described therein. Alkoxy groups can be either substituted or unsubstituted.

[0081] "Alkoxyalkyl" refers to a group having an alkyl component and an alkoxy component, where the alkyl component connects the alkoxy component to the point of attachment. The alkyl component is defined as above, except that the alkyl component is at least a divalent alkylene group to connect to the alkoxy component and the point of attachment. The alkyl component can include any number of carbons, such as 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 defined as above. Examples of alkyl-alkoxy include, but are not limited to, 2-ethoxy-ethyl and methoxymethyl.

[0082] "Hydroxyalkyl" or "alkyl hydroxy" refers to an alkyl group as defined above, where at least one of the hydrogen atoms is replaced by a hydroxyl group. Like alkyl groups, hydroxyalkyl or alkyl hydroxy can have any suitable number of carbon atoms, such as C 1-6 . Exemplary C 1-4 hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (where the hydroxyl group is in the 1 or 2 position), hydroxypropyl (where the hydroxyl group is in the 1, 2 or 3 position), hydroxybutyl (where the hydroxyl group is in the 1, 2, 3 or 4 position), 1,2-dihydroxyethyl, etc.

[0083] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0084] "Halogenated alkyl" refers to an alkyl group as defined above, where some or all of the hydrogen atoms are replaced by halogen atoms. Like alkyl groups, halogenated alkyl groups can have any suitable number of carbon atoms, e.g., C 1-6 . For example, halogenated alkyl groups include trifluoromethyl, fluoromethyl, etc. In some cases, the term "perfluoro" can be used to define a compound or group where all hydrogens are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0085] "Halogenated alkoxy" refers to an alkoxy group where some or all of the hydrogen atoms are replaced by halogen atoms. For alkyl groups, halogenated alkoxy groups can have any suitable number of carbon atoms, e.g., C 1-6 . The alkoxy group can be substituted by 1, 2, 3 or more halogen atoms. When all hydrogens are replaced by halogen (e.g., fluorine), the compound is, for example, perfluorinated. Halogenated alkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, etc.

[0086] "Amino" refers to the -N(R) 2 group, where the R group can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, etc. The R groups can be the same or different. The amino group can be primary (each R is hydrogen), secondary (one R is hydrogen) or tertiary amino (each R is not hydrogen).

[0087] "Alkylamine" refers to an alkyl group having one or more amino groups as defined herein. The amino group can be primary, secondary or tertiary amino. The alkylamine can be further substituted by a hydroxyl group to form amino-hydroxy. Alkylamines useful in the present invention include, but are not limited to, ethylamine, propylamine, isopropylamine, ethylenediamine and ethanolamine. The amino group can connect the alkylamine to the rest of the compound at the connection point, located at the ω position of the alkyl group, or connect at least two carbon atoms of the alkyl group together. Those skilled in the art will understand that other alkylamines are useful in the present invention.

[0088] "Heteroalkyl" refers to an alkyl group of any suitable length having 1 to 3 heteroatoms (e.g., N, O and S). The heteroalkyl group has the indicated number of carbon atoms, where at least one non-terminal carbon is replaced by a heteroatom. Other heteroatoms can also be useful, including but not limited to B, Al, Si and P. The heteroatoms can also be oxidized, e.g., but not limited to -S(O)- and -S(O) 2 -. For example, heteroalkyl groups can include ethers, thioethers and alkylamines. Heteroalkyl groups do not include peroxides (-O-) or other continuously linked heteroatoms. The heteroatom moiety of the heteroalkyl group can replace the hydrogen of the alkyl group to form hydroxyl, thio or amino. Alternatively, the heteroatom moiety can be the connecting atom, or inserted between two carbon atoms.

[0089] "Oxo" refers to a carbonyl group, =O.

[0090] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly that contains from 3 to 12 ring atoms or the indicated number of atoms. The cycloalkyl can include any number of carbons, such as C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 and C 3-12 . 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, decalin, and adamantane. The cycloalkyl can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyls 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 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When the cycloalkyl is a saturated monocyclic C 3-6 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl can be substituted or unsubstituted.

[0091] "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 the alkyl component is at least a divalent alkylene to connect to the cycloalkyl component and to the point of attachment. In some cases, the alkyl component may be absent. The alkyl component can include any number of carbons, such as C 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6The cycloalkyl component is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0092] "Alkenyl-cycloalkyl" refers to a group having an alkenyl component and a cycloalkyl component, wherein the alkenyl component connects the cycloalkyl component to the point of attachment. The alkenyl component is as defined above, except that the alkenyl component is at least a divalent alkenylene group to connect to the cycloalkyl component and to the point of attachment. The alkenyl component may include any number of carbon atoms, such as 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 component is as defined herein. Exemplary alkenyl-cycloalkyl groups include, but are not limited to, vinyl-cyclopropyl, vinyl-cyclobutyl, vinyl-cyclopentyl, and vinyl-cyclohexyl.

[0093] "Alkynyl-cycloalkyl" refers to a group having an alkynyl component and a cycloalkyl component, wherein the alkynyl component connects the cycloalkyl component to the point of attachment. The alkynyl component is as defined above, except that the alkynyl component is at least a divalent alkynylene radical to the cycloalkyl component and to the point of attachment. The alkynyl component may include any number of carbon atoms, such as 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 component is as defined herein. Exemplary alkynyl-cycloalkyl groups include, but are not limited to, ethynyl-cyclopropyl, propynyl-cyclopropyl, ethynyl-cyclobutyl, ethynyl-cyclopentyl, and ethynyl-cyclohexyl.

[0094] "Heterocycloalkyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 5 heteroatoms of N, O and S. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O) 2-. The heterocycloalkyl group can include any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl group, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. The heterocycloalkyl group can include any number of carbons, such as C 3-6 、C 4-6 、C 5-6 、C 3-8 、C 4-8 、C 5-8 、C 6-8 、C 3-9 、C 3-10 、C 3-11 and C 3-12 。 The heterocycloalkyl group can include, such as aziridine, azetidine, pyrrolidine, piperidine, azetidine, diazetidine, azodiazetidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), ethylene oxide, oxirane, tetrahydrofuran, oxane (tetrahydropyran), ethylene oxide, thiolane, thiolane (tetrahydrothiophene), thiolane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl group can also be fused with an aromatic or non-aromatic ring system to form members including, but not limited to, indole. The heterocycloalkyl group can also form a spiro structure, such as, but not limited to, diazabicycloheptane, diazabicyclooctane, diazabicyclooctane, or diazaspiroalkanone. The heterocycloalkyl group can be unsubstituted or substituted. For example, the heterocycloalkyl group can be substituted with C 1-6 alkyl or oxo (=O), etc. The heterocycloalkyl group can also include double bonds or triple bonds, such as, but not limited to, dihydropyridine or 1,2,3,6-tetrahydropyridine.

[0095] The heterocycloalkyl group can be attached at 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, piperazine can be 1-, 2-, 3-, or 4-piperazine, tetrahydrofuran can be 1- or 2-tetrahydrofuran, oxazolidine can be 2-, 3-, 4-, or 5-oxazolidine, isoxazolidine can be 2-, 3-, 4-, or 5-isoxazolidine, thiazolidine can be 2-, 3-, 4-, or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4-, or 5-isothiazolidine, morpholine can be 2-, 3-, or 4-morpholine.

[0096] When the heterocycloalkyl group includes 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxolane, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. The heterocycloalkyl group can also form a ring having 5 to 6 ring members and 1 to 2 heteroatoms, and representative members thereof include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0097] "Alkylheterocycloalkyl" refers to a group having an alkyl component and a heterocycloalkyl component, wherein the alkyl component connects the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene group to connect to the heterocycloalkyl component and to the point of attachment. The alkyl component can include 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 component is as defined above. The alkyl-heterocycloalkyl can be substituted or unsubstituted.

[0098] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. The aryl can include any suitable number of ring atoms, such as 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. The aryl can be monocyclic, fused to form a bicyclic or tricyclic group, or linked by a bond to form a biaryl. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl having a methylene linking group. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. The aryl can be substituted or unsubstituted.

[0099] "Alkylaryl" refers to a group having an alkyl component and an aryl component, wherein the alkyl component connects the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene to connect to the aryl component and the point of attachment. The alkyl component can include 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 aryl component is as defined above. Examples of alkylaryl include but are not limited to benzyl and ethylbenzene. Alkyl-aryl can be substituted or unsubstituted.

[0100] "Alkenylaryl" refers to a group having an alkenyl component and an aryl component, wherein the alkenyl component connects the aryl component to the point of attachment. The alkenyl component is as defined above, except that the alkenyl component is at least a divalent alkenylene to connect to the aryl component and the point of attachment. The alkenyl component can include any number of carbons, such as 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 component is as defined above. Alkenyl-aryl can be substituted or unsubstituted.

[0101] "Alkynylaryl" refers to a group having an alkynyl component and an aryl component, wherein the alkynyl component connects the aryl component to the point of attachment. The alkynyl component is as defined above, except that the alkynyl component is at least a divalent alkynylene to connect to the aryl component and the point of attachment. The alkynyl component can include any number of carbons, such as 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 4-6and C 5-6 The aryl component is as defined above. The alkynyl-aryl can be substituted or unsubstituted.

[0102] "Alkoxyalkylaryl" refers to a group having an alkoxyalkyl component and an aryl component, wherein the alkoxyalkyl component connects the aryl component to the point of attachment. The alkoxyalkyl component is as defined above, except that the alkoxyalkyl component is at least divalent to connect the aryl component and the point of attachment. The alkoxyalkyl component can include any number of carbons, such as 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 component is as defined above. The alkoxyalkyl-aryl can be substituted or unsubstituted.

[0103] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, wherein 1 to 5 ring atoms are heteroatoms such as N, O or S, and the heteroatoms can also be oxidized, such as but not limited to -S(O)- and -S(O)-. The heteroaryl can include any number of ring atoms, for example, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11 or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl, such as 1, 2, 3, 4 or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. The heteroaryl can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. The heteroaryl 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. The heteroaryl can also be fused with an aromatic ring system (such as a benzene ring) to form members, including but not limited to benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryls include heteroaryl rings connected by a bond, such as bipyridine. The heteroaryl can be substituted or unsubstituted.

[0104] The heteroaryl can be attached at 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 3-furan, thiazole includes 2-, 4-, and 5-thiazole, isothiazole includes 3-, 4-, and 5-isothiazole, oxazole includes 2-, 4-, and 5-oxazole, isoxazole includes 3-, 4-, and 5-isoxazole, indole includes 1-, 2-, and 3-indole, isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3-, and 4-quinoline, isoquinoline includes 1-, 3-, and 4-isoquinoline, quinazoline includes 2- and 4-quinazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene, benzofuran includes 2- and 3-benzofuran.

[0105] Some heteroaryls include those having 5 to 10 ring members and 1 to 3 ring atoms (including 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 heteroaryls include groups having 5 to 8 ring members and 1 to 3 heteroatoms, 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. Still other heteroaryls 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. Yet other heteroaryls include those having 5 to 6 ring members and 1 to 2 ring atoms (including N, O, or S), such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0106] "Alkylheteroaryl" refers to a group having an alkyl moiety and a heteroaryl moiety, wherein the alkyl moiety attaches the heteroaryl moiety to the point of attachment. The alkyl moiety is as defined above, except that the alkyl moiety is at least a divalent alkylene to attach to the heteroaryl moiety and to the point of attachment. The alkyl moiety can include any number of carbons, such as C 0-6 、C1-2 , 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 heteroaryl component is as defined herein. The alkyl-heteroaryl may be substituted or unsubstituted.

[0107] "Pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject and is absorbed by the subject. Medicinal excipients that can be used in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, surfactants, coatings, sweeteners, flavoring agents, and coloring agents. Those skilled in the art will recognize that other pharmaceutical excipients can be used in the present invention.

[0108] "Treat", "treating", and "treatment" refer to any sign of success in treating or ameliorating an injury, pathology, or condition, including any objective or subjective parameter, such as alleviation; remission; reduction in symptoms or making the patient more tolerant of the injury, pathology, or condition; slowing the rate of degeneration or decline; making the ultimate point of degeneration less debilitating; improving the physical or mental health of the patient. Treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0109] "Administer" 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 slow-release device (e.g., a microosmotic pump) into a subject.

[0110] "Therapeutically effective amount" refers to a dose that produces the therapeutic effect for which it is administered. The exact dose will depend on the purpose of the treatment and will be determined by those skilled in the art using known techniques (e.g., see 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 ed., 2003, Gennaro, ed. Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective dose will generally be lower than the conventional therapeutically effective dose for non-sensitized cells.

[0111] The "glucocorticoid receptor" ("GR") refers to one of the intracellular receptor families that specifically bind cortisol and / or cortisol analogs such as dexamethasone (see, e.g., Turner and Muller, J. Mol. Endocrinol., Oct. 1, 2005, 35:283-292). The glucocorticoid receptor is also referred to as the cortisol receptor. The term includes GR isoforms, recombinant GRs, and mutant GRs.

[0112] The cortisol receptor is the glucocorticoid receptor (GR) that specifically binds cortisol and / or cortisol analogs such as dexamethasone, particularly type II GR (see, e.g., Turner and Muller, J. Mol. Endocrinol., Oct. 1, 2005, 35:283-292).

[0113] The "mineralocorticoid receptor" (MR) refers to type I glucocorticoid receptor (GRI), which is activated by aldosterone in humans.

[0114] A "glucocorticoid receptor modulator" (GRM) refers to any compound that modulates any biological response associated with the binding of a glucocorticoid receptor to an agonist. As used herein, with respect to GRM, the glucocorticoid receptor can be GR, or both. For example, a GRM that acts as an agonist (e.g., dexamethasone) increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (a human hepatoma cell line; ECACC, UK). A GRM that acts as an antagonist, such as mifepristone, inhibits the increase in tyrosine aminotransferase (TAT) activity induced by an agonist in HepG2 cells. The activity of TAT can be measured as described in the literature of A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0115] A "glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits any biological response associated with the binding of a glucocorticoid receptor to an agonist. As used herein, with respect to GRA, the glucocorticoid receptor can be GR. Thus, a GR antagonist can be identified by measuring the ability of the compound to inhibit the action of dexamethasone. The activity of TAT can be measured as described in the literature of A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. An inhibitor is a compound with an IC 50 (half-maximal inhibitory concentration) less than 10 micromoles. See Example 1 of U.S. Patent 8,685,973, the entire content of which is incorporated herein by reference in its entirety.

[0116] "Modulation" and "regulation" are used according to their ordinary meanings and refer to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, when applied to the action of a modulator on a target protein, regulation refers to changing by increasing or decreasing the nature or function of the target molecule or the amount of the target molecule.

[0117] "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 a molecule.

[0118] "Antagonize" and "counteract" refer to inhibiting the binding of an agonist to a receptor molecule or inhibiting the signal generated by a receptor-agonist. A receptor antagonist inhibits or suppresses an agonist-mediated response, such as gene expression.

[0119] "Antagonist" refers to a substance that can detectably reduce the expression or activity of a given gene or protein. Compared to a control in the absence of an antagonist, the antagonist can inhibit expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or less. In some embodiments, the 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 an antagonist.

[0120] "Inhibitory effect", "inhibit" and "inhibitor" refer to a compound that prohibits a specific action or function or a method that prohibits a specific action or function.

[0121] "Condition" or "disease" refers to the state of being 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 the condition or disease include, but are not limited to, obesity, hypertension, depression, anxiety, and Cushing's syndrome. In some embodiments, the condition or disease includes non-alcoholic liver disease and / or non-alcoholic steatohepatitis. In some embodiments, the condition or disease includes addictive disorders. In some embodiments, the condition or disease includes cancer.

[0122] "Drug" refers to a composition or substance used to treat a disease or condition.

[0123] "Subject" refers to a living organism that has or is susceptible to a disease or condition that can be treated by administering a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, horses, and other non-mammals. In some embodiments, the patient is a human.

[0124] Compound

[0125] In some embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0126]

[0127] wherein

[0128] R 1 is a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms each independently being N, O, or S, phenyl, or a heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O, or S, each group independently being substituted by 1 to 5 R 1a groups;

[0129] Each R 1a is 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 a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms independently being N, O, or S;

[0130] Each R 1b and R 1c are independently hydrogen, C 1-6 alkyl or a 3- to 8-membered heterocycloalkyl having 1 - 3 heteroatoms independently being N, O, or S;

[0131] A 1 、A 2 、A 3 and A 4 are each independently =CR 2 - or =N-;

[0132] Each R 2 is 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;

[0133] Ring J is a 3- to 10-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O, or S, wherein at least one heteroatom is N, and wherein ring J is optionally substituted by 1 to 13 R 3a and R 3b groups;

[0134] Each R 3a is 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 optionally substituted by C 6-12 aryl or heteroaryl, where each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms independently selected from N, O, or S, and where each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms independently selected from N, O, or S;

[0135] R 3a1 and R 3a2 are each independently hydrogen or C 1-6 alkyl;

[0136] Alternatively, two R 3a groups attached to the same atom can combine with the atom to which they are attached to form C 3-6 cycloalkyl;

[0137] Alternatively, two R 3a groups attached to different atoms can combine with the atoms to which they are attached to form a C3-10 cycloalkyl or a 3-10 membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, or S, each substituted by 1 to 4 R 3a3 groups;

[0138] Each R 3a3 is independently hydrogen or C 1-6 alkyl;

[0139] Each R 3b is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkoxyalkyl, C1-6 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-O-C 6-12 Aryl, C 1-6 Alkoxyalkyl-C 6-12 Aryl, -C(O)-C 6-12 Aryl, Heteroaryl, or C 1-6 Alkyl-Heteroaryl, wherein each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms independently selected from N, O, or S, wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms independently selected from N, O, or S, and wherein each aryl and heteroaryl is substituted with 1 to 3 R 3b3 groups;

[0140] R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl;

[0141] Alternatively, R 3b1 and R 3b2 combine with the atoms to which they are attached to form a 3- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S;

[0142] 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;

[0143] Alternatively, R 3b combines with R 3a on an adjacent ring atom and the atoms to which they are attached to form a C 3-6a cycloalkyl group;

[0144] R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -CN, C 3-8 cycloalkyl, a 3- to 8-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O or S, C 6-12 a phenyl group or a 5- to 10-membered heteroaryl having 1 to 5 heteroatoms each independently being N, O or S, wherein the cycloalkyl, heterocycloalkyl, phenyl group and heteroaryl are each independently substituted by 1 to 5 R 4a groups;

[0145] 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 phenyl group, C 1-6 alkyl-C 6-12 phenyl group, -O-C 6-12 phenyl group, heteroaryl, C 1-6 alkyl-heteroaryl, wherein each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms independently being N, O or S, wherein each heteroaryl independently has 5 to 8 ring members and 1 to 4 heteroatoms independently being N, O or S, and wherein each cycloalkyl, heterocycloalkyl, phenyl group and heteroaryl is optionally substituted by C 1-6 alkoxy;

[0146] R 4b and R 4cEach is hydrogen or C 1-6 alkyl;

[0147] L 1 is absent or is -N(R 5a )-;

[0148] L 2 is absent, or is 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

[0149] R 5a and R 5b are each independently hydrogen, C 1-6 alkyl or C 2-6 alkoxyalkyl;

[0150] wherein, when L 2 is absent, then R 3b is not hydrogen, and

[0151] wherein, when A 1 , A 2 , A 3 and A 4 are each -CH-, ring J is L 1 is -NH-, L 2 is -C(O)-, -C(O)O- or -S(O) 2 - and each R 3a is H.

[0152] In some embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0153]

[0154] wherein

[0155] R 1 is phenyl or pyridyl, each independently substituted by 1 to 5 R 1a groups, each independently being hydrogen, C 1-6 alkoxy, halogen, -OH and -C(O)N(R 1b )(R 1c );

[0156] Each R 1b and R 1cIndependently is hydrogen, C 1-6 alkyl or a 3- to 8-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O or S;

[0157] A 1 、A 2 、A 3 and A 4 are each independently =CR 2 - or =N-;

[0158] Each R 2 is 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;

[0159] Ring J is a 3- to 10-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O or S, wherein at least one heteroatom is N, and wherein Ring J is optionally substituted by 1 to 13 R 3a and R 3b groups;

[0160] Each R 3a is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkoxy, 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, wherein each alkenyl and alkynyl is optionally substituted by C 6-12 aryl or heteroaryl, wherein each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O or S, and wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O or S;

[0161] R 3a1 and R 3a2Each is independently hydrogen or C 1-6 alkyl;

[0162] Alternatively, two R groups attached to the same atom 3a may combine with the atom to which they are attached to form a C 3-6 cycloalkyl;

[0163] Alternatively, two R groups attached to different atoms 3a may combine with the atoms to which they are attached to form a C3-10 cycloalkyl or a 3-10 membered hetero cycloalkyl having 1-4 heteroatoms each independently selected from N, O or S, each being substituted by 1-4 R 3a3 groups;

[0164] Each R 3a3 is independently hydrogen or C 1-6 alkyl;

[0165] Each R 3b is 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, wherein each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms each independently selected from N, O or S, wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently selected from N, O or S, and wherein each aryl and heteroaryl is substituted by 1 to 3 R 3b3 groups;

[0166] R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl;

[0167] Alternatively, R 3b1 and R 3b2 combine with the atoms to which they are attached to form a 3 to 6 membered heterocycloalkyl having 1 to 2 additional heteroatoms each independently selected from N, O or S;

[0168] 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;

[0169] Alternatively, R 3b combines with R on adjacent ring atoms 3a and their respective attached atoms to form a C 3-6 cycloalkyl substituted with 0 - 4 halogens;

[0170] R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -CN, C 3-8 cycloalkyl, a 3 - 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently N, O or S, C 6-12 aryl, or a 5 - 10 membered heteroaryl having 1 to 5 heteroatoms each independently N, O or S, wherein the heterocycloalkyl, aryl and heteroaryl are each independently substituted with 1 - 5 R 4a groups;

[0171] Each R 4a is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkoxy, 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 -O - C 6-12An aryl group, wherein each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O, or S, and wherein each aryl group is optionally substituted by C 1-6 alkoxy;

[0172] R 4b and R 4c are each independently hydrogen or C 1-6 alkyl;

[0173] L 1 is absent or is -N(R 5a )-;

[0174] L 2 is absent, or is -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

[0175] R 5a and R 5b are each independently hydrogen, C 1-6 alkyl or C 2-6 alkoxyalkyl.

[0176] In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV, IVa, V, VI or VII or a pharmaceutically acceptable salt thereof is a compound wherein R 1 is phenyl or pyridyl, each independently substituted by 1 to 5 R 1a groups, each R 1a independently being hydrogen, C 1-6 alkoxy, halogen, -OH and -C(O)N(R 1b )(R 1c ), each R 1b and R 1c can independently be hydrogen, C 1-6 alkyl or a 3- to 8-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O or S.

[0177] In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV, IVa, V, VI or VII or a pharmaceutically acceptable salt thereof is a compound wherein R 1 is a phenyl group substituted by 1 to 5 R 1a groups, each R 1a independently being C 1-6An alkoxy group, a halogen, or -C(O)N(R 1b )(R 1c ), wherein each of R 1b and R 1c may independently be hydrogen or a 4- to 6-membered heterocycloalkyl group having 1 to 3 heteroatoms each independently being N, O, or S. In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein R 1 is a phenyl group substituted with a halogen. In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein R 1 is a phenyl group substituted with fluorine. In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein R 1 is 4-fluorophenyl.

[0178] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVg, V, VI, or VII or a pharmaceutically acceptable salt thereof is a compound wherein R 1 is as follows

[0179]

[0180] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVg, V, VI, or VII or a pharmaceutically acceptable salt thereof is a compound wherein R 1 is as follows

[0181]

[0182] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII or a pharmaceutically acceptable salt thereof is a compound wherein A 1 , A 2 , A 3 , and A 4 are each independently =CR 2 - or =N-; each R 2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkoxy, halogen, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, or -CN.

[0183] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, or VII or a pharmaceutically acceptable salt thereof is a compound wherein A 1, A 2 , A 3 and A 4 each independently can be a compound of =CR 2 -, or =N-. In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI or VII or a pharmaceutically acceptable salt thereof is one in which A 1 , A 2 , A 3 and A 4 each can be a compound of =CR 2 -. In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI or VII or a pharmaceutically acceptable salt thereof is one in which A 1 , A 2 , A 3 and A 4 each can be a compound of =N-. In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI or VII or a pharmaceutically acceptable salt thereof is one in which A 1 can be =N- and A 2 , A 3 and A 4 each can be a compound of =CR 2 -. In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI or VII or a pharmaceutically acceptable salt thereof is one in which A 1 , A 3 and A 4 each can be a compound of =CR 2 - and A 2 can be a compound of =N-. In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI or VII or a pharmaceutically acceptable salt thereof is one in which A 1 , A 2 , and A 4 each can be a compound of =CR 2 - and A 3 can be a compound of =N-. In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI or VII or a pharmaceutically acceptable salt thereof is one in which A 1 , A 2 , A 3 each can be a compound of =CR 2 , A 4 can be a compound of =N-.

[0184] In some embodiments, 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 pharmaceutically acceptable salt thereof is one in which each R 2 can independently be hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen or C 1-6 haloalkoxy. In some embodiments, 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 pharmaceutically acceptable salt thereof is one in which at least one R 2 is C 1-6 alkyl, C 1-6 alkoxy, halogen or C 1-6 haloalkoxy. In some embodiments, a compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1 or IIc-2 or a pharmaceutically acceptable salt thereof is one in which each R 2 is independently hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halogen, or C 1-3 haloalkoxy. In some embodiments, 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 pharmaceutically acceptable salt thereof is a compound in which R 2 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, F, Cl, Br, -OCH 2 F, -OCHF 2 or -OCF 3 . In some embodiments, 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 pharmaceutically acceptable salt thereof is a compound in which R 2 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, F, Cl, Br, -OCH 2 F, -OCHF 2 、-OCF3 or -CN.

[0185] In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI or VII or a pharmaceutically acceptable salt thereof is a compound wherein A 1 , A 2 , A 3 and A 4 are each independently =CR 2 - or =N-; and each R 2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen or C 1-6 haloalkoxy. In some embodiments, a compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein A 1 , A 2 , A 3 and A 4 are each -CR 2 -.

[0186] In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI or VII or a pharmaceutically acceptable salt thereof is a compound wherein 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(iPr)-, =C(OMe)-, =C(F)- =C(Cl)-, =C(OCHF 2 )- or =N-. In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI or VII or a pharmaceutically acceptable salt thereof is a compound wherein A 1 , A 2 and A 4 are each =CH-; A 3 is =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, =C(F)- =C(Cl)- or =C(OCHF 2 ). In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI or VII or a pharmaceutically acceptable salt thereof is a compound wherein A 1 is =CH- or =N-; A 2 and A 4Each is independently =CH-, =C(Me)- or =N-; A 3 is =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, =C(Cl)-, =C(OCHF 2 )- or =N-.

[0187] In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI or VII or a pharmaceutically acceptable salt thereof is a compound wherein A 1 is =CH- or =N-; A 2 and A 4 are each =CH-; A 3 is =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, or =C(F)-. In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI or VII or a pharmaceutically acceptable salt thereof is a compound wherein A 1 , A 2 and A 4 are each =CH-; A 3 is =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, or =C(F)-.

[0188] In some embodiments, a compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein

[0189] ring J is a 3- to 10-membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from N, O or S, wherein at least one heteroatom is N, and wherein ring J is optionally substituted with 1 to 13 R 3a and R 3b groups;

[0190] Each R 3a is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkoxy, 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, C6-12 Aryl, C 1-6 Alkyl-C 6-12 Aryl, heteroaryl, or C 1-6 Alkyl-heteroaryl, wherein each alkenyl and alkynyl is optionally substituted by C 6-12 Aryl or heteroaryl, wherein each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O, or S, and wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O, or S;

[0191] R 3a1 and R 3a2 are each independently hydrogen or C 1-6 alkyl;

[0192] Alternatively, two R 3a groups attached to the same atom may combine with the atom to which they are attached to form a C 3-6 cycloalkyl;

[0193] Alternatively, two R 3a groups attached to different atoms may combine with the atoms to which they are attached to form a C3-10 cycloalkyl or a 3-10 membered heterocycloalkyl having 1-4 heteroatoms each independently being N, O, or S, each being substituted by 1-4 R 3a3 groups;

[0194] Each R 3a3 is independently hydrogen or C 1-6 alkyl;

[0195] Each R 3b is 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 1-6Alkyl - heteroaryl, wherein each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O, or S, wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O, or S, and wherein each aryl and heteroaryl is substituted with 1 to 3 R 3b3 groups;

[0196] R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl;

[0197] Alternatively, R 3b1 and R 3b2 combine with the atoms to which they are attached to form a 3 - to 6 - membered heterocycloalkyl having 1 to 2 additional heteroatoms each independently being N, O, or S;

[0198] 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;

[0199] Alternatively, R 3b combines with R 3a on adjacent ring atoms and the atoms to which they are attached to form a C 3-6 cycloalkyl substituted with 0 - 4 halogens;

[0200] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein ring J can be a C 3-8 heterocycloalkyl having 1 to 3 nitrogen ring atoms, wherein ring J can optionally be substituted with 1 to 13 R 3a and R 3b groups. In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein ring J can be a C 5-8 heterocycloalkyl having 1 to 2 nitrogen ring atoms, wherein ring J can optionally be substituted with 1 to 13 R 3a and R 3b groups. In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein ring J can be aziridine, azetidine, pyrrolidine, imidazolidine, piperidine, 1,2,3,6 - tetrahydropyridine, piperazine, azepane, azepine, diazocane, or diazocine, wherein ring J can optionally be substituted with 1 to 13 R 3a and R 3bGroup substitution. In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound in which ring J can be pyrrolidine, imidazolidine, piperidine, 1,2,3,6 - tetrahydropyridine, piperazine, azetidine, diazepane, diazocane or diazocine, where ring J can be optionally substituted with 1 to 13 R 3a and R 3b groups.

[0201] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound in which ring J has the following structure:

[0202]

[0203] where L 3a and L 3b are each -C(R 3a3 )(R 3a3 )-; R 3a3 are each independently hydrogen or C 1-6 alkyl; the subscripts r and s are each independently 0, 1 or 2, such that the sum of r and s is 2.

[0204] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound in which each R 3a is 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 groups attached to the same atom can combine with the atom to which they are attached to form a C 3-6 cycloalkyl; R 3a1 is hydrogen or C 1-6 alkyl; R 3b is 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 to 10 ring members and 1 to 5 heteroatoms each independently being N, O or S, and where each aryl and heteroaryl is substituted with 1 to 3 R 3b3Group substitution; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl; or R 3b1 and R 3b2 combine with the atoms to which they are attached to form a 3- to 6-membered heteroalkyl ring having 1 to 2 additional heteroatoms each independently being N, O or S; each R 3b3 is hydrogen, C 1-6 alkyl, halogen or C 1-6 haloalkyl; or, R 3b combines with R 3a on an adjacent ring atom and the atoms to which they are attached to form a C 3-6 cycloalkyl substituted with 0-4 halogens.

[0205] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound in which ring J has the following structure:

[0206]

[0207] wherein X 1 and X 2 are each independently -CR 3b - or -N-, wherein at least one of X 1 and X 2 is -N-; and the subscripts p and q are each independently 0, 1 or 2.

[0208] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound in which the compound of formula I is a compound of formula II:

[0209]

[0210] wherein X 1 and X 2 are each independently -CR 3b - or -N-, wherein at least one of X 1 and X 2 is -N-; and the subscripts p and q are each independently 0, 1 or 2.

[0211] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound in which the compound of formula I is a compound of formula II:

[0212]

[0213] wherein X 1 and X 2 are each independently -CR 3b - or -N-, wherein at least one of X 1 and X 2at least one of which is -N-; and subscripts p and q are each independently 0, 1, or 2, and wherein when A 1 , A 2 , A 3 and A 4 are -CH-, respectively, X 1 is N, X 2 is -CH-, the sum of subscripts p and q is 1, L 1 is -NH-, L 2 is -C(O)-, -C(O)O-, or -S(O) 2 -, then each R 3a is H.

[0214] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein the compound of Formula I or II or a pharmaceutically acceptable salt thereof is one wherein X 1 can be -CR 3b - and X 2 can be -N-. In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is one wherein X 1 can be -N- and X 2 can be -CR 3b . In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is one wherein X 1 and X 2 can both be N.

[0215] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein ring J has the following structure:

[0216]

[0217]

[0218] wherein L 3a and L 3b are each -C(R 3a3 )(R 3a3 )-; R 3a3 are each independently hydrogen or C 1-6 alkyl; subscripts r and s are each independently 0, 1, or 2 such that the sum of r and s is 2.

[0219] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the following structure:

[0220]

[0221]

[0222] wherein

[0223] X 2 is -CR 3b - or -N-; and

[0224] the subscripts p, q, r, R 1 , 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,

[0225] wherein, when A 1 , A 2 , A 3 and A 4 are each -CH-, X 2 is -CH-, the sum of subscripts p and q is 1, L 1 is -NH-, L 2 is -C(O)-, -C(O)O- or -S(O) 2 - then each R 3a is H.

[0226] In some embodiments, the present invention provides a compound of formula III, formula IV, formula V, formula VI or formula VII or a pharmaceutically acceptable salt thereof:

[0227]

[0228]

[0229] wherein

[0230] R 1 is a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms each independently being N, O or S, phenyl, or a heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O or S, each independently substituted with 1 to 5 R 1a groups;

[0231] each R 1a is 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 a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms each independently being N, O or S;

[0232] Each R 1b and R 1c are independently hydrogen, C 1-6 alkyl, or a 3- to 8-membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from N, O, or S;

[0233] A 1 、A 2 、A 3 and A 4 are each independently =CR 2 - or =N-;

[0234] Each R 2 is 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;

[0235] Each R 3a is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkoxy, 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, wherein each alkenyl and alkynyl is optionally substituted by C 6-12 aryl or heteroaryl, wherein each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms each independently selected from N, O, or S, and wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently selected from N, O, or S;

[0236] R 3a1 and R 3a2 are each independently hydrogen or C 1-6 alkyl;

[0237] Alternatively, two R's attached to the same atom 3aThe groups can combine with the atoms to which they are attached to form a C 3-6 cycloalkyl group;

[0238] Alternatively, two R 3a groups attached to different atoms can combine with the atoms to which they are attached to form a C3-10 cycloalkyl group or a 3-10 membered heterocycloalkyl group having 1-4 heteroatoms each independently being N, O or S, each being substituted with 1-4 R 3a3 groups;

[0239] Each R 3a3 is independently hydrogen or C 1-6 alkyl;

[0240] Each R 3b is 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-o-c 6-12 aryl, C 1-6 alkoxyalkyl-C 6-12 aryl, -C(O)-C 6-12 aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, wherein each heterocycloalkyl group has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each heteroaryl group has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O or S, and wherein each aryl and heteroaryl group is substituted with 1 to 3 R 3b3 groups;

[0241] R 3b1 and R 3b2Each is independently hydrogen or C 1-6 alkyl;

[0242] Alternatively, R 3b1 and R 3b2 combine with the atoms to which they are attached to form a 3- to 6-membered heteroalkyl group having 1 to 2 additional heteroatoms each independently being N, O or S;

[0243] 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;

[0244] Alternatively, R 3b combines with R 3a on adjacent ring atoms and the atoms to which they are respectively attached to form a C 3-6 cycloalkyl group substituted with 0 - 4 halogens;

[0245] X 2 is -CR 3b - or -N-;

[0246] The subscripts p, q, r, R 1 , 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;

[0247] R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -CN, C 3-8 cycloalkyl, a 3- to 8-membered heteroalkyl group having 1 to 3 heteroatoms each independently being N, O or S, C 6-12 aryl or a 5- to 10-membered heteroaryl having 1 to 5 heteroatoms each independently being N, O or S, wherein the cycloalkyl, heteroalkyl, aryl and heteroaryl are each independently substituted with 1 to 5 R 4a groups;

[0248] 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, C1-6 Halogenated alkoxy, -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, -O-C 6-12 An aryl, heteroaryl, C 1-6 Alkyl-heteroaryl, wherein each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each heteroaryl independently has 5 to 8 ring members and 1 to 4 heteroatoms each independently being N, O or S, and wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted by C 1-6 Alkoxy;

[0249] R 4b And R 4c Are each independently hydrogen or C 1-6 Alkyl;

[0250] L 1 Is absent or is -N(R 5a )-;

[0251] L 2 Is absent, or is 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

[0252] R 5a And R 5b Are each independently hydrogen, C 1-6 Alkyl or C 2-6 Alkoxyalkyl;

[0253] Wherein, when L 2 Is absent, then R3b is not hydrogen, and

[0254] wherein, when A 1 、A 2 、A 3 and A 4 are each -CH-, X 2 is -CH-, the sum of subscripts p and q is 1, L 1 is -NH-, L 2 is -C(O)-, -C(O)O- or -S(O) 2 - then each R 3a is H.

[0255] In some embodiments, the compound or its pharmaceutically acceptable salt has the following structure:

[0256]

[0257]

[0258] wherein

[0259] X 2 is -CR 3b - or -N-; and

[0260] subscripts p, q, r, R 1 、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.

[0261] In some embodiments, the present invention provides a compound of formula IIIa, formula IIIb, formula IV, formula V, formula VI or formula VII or its pharmaceutically acceptable salt:

[0262]

[0263]

[0264] wherein

[0265] R 1 is a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms each independently being N, O or S, phenyl, or a heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O or S, each independently substituted with 1 to 5 R 1a groups;

[0266] each R 1a is independently hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C1-6 Hydroxyalkyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, -OH, oxo, -CN, -C(O)N(R 1b )(R 1c ),C 3-10 Cycloalkyl or heterocycloalkyl, each ring having 3 to 8 ring members and 1 to 4 heteroatoms each independently being N, O or S;

[0267] Each R 1b and R 1c independently is hydrogen, C 1-6 alkyl or 3- to 8-membered heterocycloalkyl having 1-3 heteroatoms each independently being N, O or S;

[0268] A 1 、A 2 、A 3 and A 4 each independently is =CR 2 - or =N-;

[0269] Each R 2 independently is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkoxyalkyl, halogen, C 1-6 halogenated alkyl, C 1-6 halogenated alkoxy, hydroxy or -CN;

[0270] Each R 3a independently is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkoxy, C 1-6 hydroxyalkyl, -C(O)R 3a1 ,-C(O)ORR 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, wherein each alkenyl and alkynyl is optionally substituted by C 6-12substituted with an aryl or heteroaryl, wherein each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O or S, and wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O or S;

[0271] R 3a1 and R 3a2 are each independently hydrogen or C 1-6 alkyl;

[0272] Alternatively, two R 3a groups attached to the same atom may combine with the atom to which they are attached to form a C 3-6 cycloalkyl;

[0273] Alternatively, two R 3a groups attached to different atoms may combine with the atoms to which they are attached to form a C3-10 cycloalkyl or a 3-10 membered heterocycloalkyl having 1-4 heteroatoms each independently being N, O or S, each being substituted with 1-4 R 3a3 groups;

[0274] Each R 3a3 is independently hydrogen or C 1-6 alkyl;

[0275] Each R 3b is 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-o-c 6-12 aryl, C 1-6 alkoxyalkyl-C 6-12aryl, -C(O)-C 6-12 aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, wherein each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O, or S, wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O, or S, and wherein each aryl and heteroaryl is substituted with 1 to 3 R 3b3 groups;

[0276] R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl;

[0277] Alternatively, R 3b1 and R 3b2 combine with the atoms to which they are attached to form a 3- to 6-membered heterocycloalkyl having 1 or 2 additional heteroatoms each independently being N, O, or S;

[0278] 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;

[0279] Alternatively, R 3b combines with R 3a on an adjacent ring atom and the atoms to which they are attached to form a C 3-6 cycloalkyl substituted with 0 - 4 halogens;

[0280] X 2 is -CR 3b - or -N-;

[0281] The subscripts p, q, r, R 1 , 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 R 1 and s1 is 2 or 3;

[0282] 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- to 8-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O, or S, C 6-12An aryl or a 5- to 10-membered heteroaryl having 1 to 5 heteroatoms each independently being N, O or S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently substituted with 1 to 5 R 4a groups;

[0283] 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, -O-c 6-12 aryl, heteroaryl, C 1-6 alkyl-heteroaryl, wherein each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each heteroaryl independently has 5 to 8 ring members and 1 to 4 heteroatoms each independently being N, O or S, and wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with C 1-6 alkoxy;

[0284] R 4b and R 4c are each independently hydrogen or C 1-6 alkyl;

[0285] L 1 is absent or is -N(R 5a );

[0286] L 2 is absent, or is C 1-6 alkylene, -C(O)-, -C(O)-C 1-6alkylene-, 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

[0287] R 5a and R 5b are each independently hydrogen, C 1-6 alkyl or C 2-6 alkoxyalkyl;

[0288] wherein when L 2 is absent, then R 3b is not hydrogen.

[0289] In some embodiments, a compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein the compound of formula I or II or a pharmaceutically acceptable salt thereof is L 3a and L 3b can each independently be -CH 2 -, -CH(Me)- or C(Me) 2 -. In some embodiments, a compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein the compound of formula I or II or a pharmaceutically acceptable salt thereof is L 3a and L 3b can each be CH 2 -.

[0290] In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, IVc or V or a pharmaceutically acceptable salt thereof is a compound wherein each R 3a is 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 alkyl; R 3b is 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 ), C1-6 alkyl-C 6-12 aryl, C 1-6 alkyl - heteroaryl, wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O or S, and wherein each aryl and heteroaryl is substituted with 1 to 3 R 3b3 groups; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl; or R 3b1 and R 3b2 combine with the atoms to which they are attached to form a 3 - to 6 - membered heterocycloalkyl having 1 to 2 additional heteroatoms each independently being N, O or S; each R 3b3 is hydrogen, C 1-6 alkyl, halogen or C 1-6 haloalkyl; or, R 3b combines with R 3a on adjacent ring atoms and the atoms to which they are attached to form a C 3-6 cycloalkyl substituted with 0 - 4 halogens.

[0291] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound in which ring J has the following structure:

[0292]

[0293]

[0294] In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, IVb, IVc or V or a pharmaceutically acceptable salt thereof is a compound in which each R 3a is 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 groups attached to the same atom can combine with the atoms to which they are attached to form C 3-4 cycloalkyl; R 3a1 is hydrogen or C 1-3 alkyl; R 3b is hydrogen. In some embodiments, the compound of formula I, II, IIIa, IIIb, IV, IVa, IVb, IVc or V or a pharmaceutically acceptable salt thereof is a compound in which each R 3aIndependently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 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 groups attached to the same atom may combine to form cyclopropyl, cyclobutyl or cyclopentyl. In some embodiments, a compound of formula I, II, IIIa, IIIb, IV, IVa, IVb, IVc or V or a pharmaceutically acceptable salt thereof is one wherein each R 3a is hydrogen, methyl, isobutyl, -CH 2 OMe, -CH 2 OH, oxo, -C(O)OMe, phenyl or benzyl; or, two R 3a groups attached to the same atom may combine with the atom to which they are attached to form a C 3-4 cycloalkyl; R 3b is hydrogen.

[0295] In some embodiments, a compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein ring J has the following structure:

[0296]

[0297] wherein each R 3a is hydrogen, methyl, isobutyl, -CH 2 OMe, -CH 2 OH, oxo, -C(O)OMe, phenyl or benzyl.

[0298] In some embodiments, a compound of formula I, II, III, IIIa, IIIb or V or a pharmaceutically acceptable salt thereof is a compound wherein each R 3a is hydrogen or methyl; and R 3b is hydrogen.

[0299] In some embodiments, a compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein ring J has the following structure:

[0300]

[0301] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound in which ring J has the following structure:

[0302] Or

[0303] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound in which ring J has the following structure:

[0304]

[0305] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound in which ring J has the following structure:

[0306]

[0307] 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 pharmaceutically acceptable salt thereof is a compound in which

[0308] each R 3a is hydrogen;

[0309] R 3b is 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-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 has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O or S, and where each aryl and heteroaryl is substituted with 1 to 3 R 3b3Group substitution;

[0310] R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl;

[0311] Alternatively, R 3b1 and R 3b2 combine with the atoms to which they are attached to form a 3- to 6-membered heteroalkyl ring having 1 to 2 additional heteroatoms each independently being N, O or S; and

[0312] each R 3b3 is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, halogen or C 1-6 haloalkyl;

[0313] Alternatively, R 3b combines with R 3a on an adjacent ring atom and the atoms to which they are respectively attached to form a C 3-6 cycloalkyl substituted by 1 - 4 halogens.

[0314] 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 pharmaceutically acceptable salt thereof is a compound wherein each R 3a is hydrogen; R 3b is 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, wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O or S, wherein each aryl and heteroaryl is substituted by 1 to 3 R 3b3 groups; R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl; or, R 3b1 and R 3b2 combine with the atoms to which they are attached to form a 3- to 6-membered heteroalkyl ring having 1 to 2 additional heteroatoms each independently being N, O or S; each R 3b3 is hydrogen, C 1-6 alkyl, halogen or C1-6 haloalkyl; or, R 3b together with the R on the adjacent ring atom 3a and the atoms to which each is attached, forms a C 3-6 cycloalkyl which is substituted with 1 to 4 halogens.

[0315] In some embodiments, a 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 pharmaceutically acceptable salt thereof is a compound wherein

[0316] each R 3a is hydrogen;

[0317] R 3b is 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, wherein each heteroaryl has 5 to 10 ring members and 1 to 3 heteroatoms independently selected from N, O or S, and wherein each aryl and heteroaryl is substituted with 1 to 3 R 3b3 groups; and

[0318] each R 3b3 is hydrogen, C 1-3 alkyl, C 1-3 hydroxyalkyl, halogen or C 1-3 haloalkyl;

[0319] or, R 3b together with the R on the adjacent ring atom 3a and the atoms to which each is attached, forms a C 3-4 cycloalkyl which is substituted with 1 to 2 halogens.

[0320] In some embodiments, a 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 pharmaceutically acceptable salt thereof, is a compound wherein each R 3a is hydrogen; R 3b is C 1-3 alkyl, benzyl or 1-2 alkyl - heteroaryl, wherein each heteroaryl has 5 to 10 ring members and 1 to 3 heteroatoms each independently being N or S, and wherein each aryl and heteroaryl is substituted with 1 to 3 R 3b3 groups; and each R 3b3 is hydrogen, C 1-3 alkyl, halogen or C 1-3 haloalkyl; or, R 3b combines with R 3a on an adjacent ring atom and the atoms to which they are each attached to form a C 3-4 cycloalkyl substituted with 1 - 2 halogens.

[0321] In some embodiments, a 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 pharmaceutically acceptable salt thereof, is a compound wherein R 3b is methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt,

[0322]

[0323] In some embodiments, a 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 pharmaceutically acceptable salt thereof, is a compound wherein R 3b is methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt,

[0324]

[0325] In some embodiments, a 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 pharmaceutically acceptable salt thereof, is a compound wherein R 3b is methyl,

[0326]

[0327] In some embodiments, a compound of formula I, II, III, IIIa, IV, IVa, IVb, IVg or V, or a pharmaceutically acceptable salt thereof, is a compound wherein each R 3a is hydrogen, methyl, isobutyl, oxo, -CH 2 OMe, -CH 2 OH, -C(O)OMe, phenyl or benzyl; R 3b is methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt,

[0328]

[0329] In some embodiments, a 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 pharmaceutically acceptable salt thereof, is a compound wherein R 3b is methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt,

[0330]

[0331] In some embodiments, a 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 pharmaceutically acceptable salt thereof, is a compound wherein R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -CN, C 3-8 cycloalkyl, a 3- to 8-membered heterocycloalkyl having 1-3 heteroatoms each independently selected from N, O or S, C 6-12An aryl group, or a 5- to 10-membered heteroaryl group having 1 to 5 heteroatoms each independently being N, O, or S, wherein the heterocycloalkyl group, the aryl group, and the heteroaryl group are each independently substituted with 1 to 5 R 4a groups; each R 4a is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkoxy, 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 -O-C 6-12 aryl, wherein each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O, or S, and wherein each aryl is optionally substituted with C 1-6 alkoxy; and each R 4b and R 4c is hydrogen or C 1-6 alkyl.

[0332] In some embodiments, a 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 pharmaceutically acceptable salt thereof, such a compound wherein R 4 is C 1-6 alkyl, -CN, C 3-8 cycloalkyl, a 3- to 8-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O, or S, C 6-12 aryl, or a 5- to 10-membered heteroaryl having 1 to 5 heteroatoms each independently being N, O, or S, wherein the heterocycloalkyl group, the aryl group, and the heteroaryl group are each independently substituted with 1 to 5 R 4a groups; and each R 4a is hydrogen, C 1-6Alkyl, 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- to 8-membered heterocycloalkyl having 1 to 3 heteroatoms each independently N, O or S, C 6-12 Aryl or -O-C 6-12 Aryl, wherein each aryl is optionally substituted by C 1-6 Alkoxy.

[0333] In some embodiments, a 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 pharmaceutically acceptable salt thereof, such a compound, wherein R 4 is C 1-4 Alkyl, -CN, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl having 1 heteroatom N or O, C 6-12 Aryl, or 5- to 10-membered heteroaryl having 1 to 4 heteroatoms each independently N, O or S, wherein the heterocycloalkyl, aryl and heteroaryl are each independently substituted by 1 to 2 R 4a groups; and each R 4a is 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- to 6-membered heterocycloalkyl having 1 heteroatom N, O or S, or C 6-12 Aryl, wherein each aryl is optionally substituted by C 1-3 Alkoxy.

[0334] In some embodiments, a 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 pharmaceutically acceptable salt thereof is such a compound, wherein

[0335] R 4 is C 1-3 Alkyl, C 1-3 Haloalkyl, -CN, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl having 1 heteroatom each independently N or O, C6-12 An aryl group, or a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms each independently being N, O, or S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently substituted with 1 to 2 R 4a groups; and

[0336] 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 1-2 alkyl-C 3-6 cycloalkyl, C 6-12 aryl or -O-C 6-12 aryl, wherein each aryl is optionally substituted with C 1-6 alkoxy.

[0337] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1 or IIc-2 or a pharmaceutically acceptable salt thereof is a compound in which each R 4a is for each R 4a is 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, a 3- to 8-membered heterocycloalkyl group having 1 to 3 heteroatoms each independently being N, O, or S, C 6-12 aryl or -O-C 6-12 aryl, wherein each aryl is optionally substituted with C 1-6 alkoxy. In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1 or IIc-2 or a pharmaceutically acceptable salt thereof is a compound in which each R 4a is hydrogen, C 1-4 alkyl, C 2-4 alkoxyalkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, C3-6 Cycloalkyl, C 1-2 Alkyl-C 3-5 Cycloalkyl, 4- to 6-membered heteroalkyl having 1 heteroatom N, O or S, or C 6-12 Aryl, wherein each aryl is optionally substituted with C 1-3 alkyl groups. In some embodiments, a compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1 or IIc-2 or a pharmaceutically acceptable salt thereof is a compound wherein each R 4a is hydrogen, methyl, n-propyl, isopropyl, isobutyl, -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.

[0338] In some embodiments, a compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe or IVf or a pharmaceutically acceptable salt thereof is a compound wherein R 4 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CN,

[0339]

[0340]

[0341] In some embodiments, a compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1 or IIc-2 or a pharmaceutically acceptable salt thereof is a compound wherein each R 4a is 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 4-6-membered heteroalkyl having 1 heteroatom N, O or S. In some embodiments, a compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1 or IIc-2 or a pharmaceutically acceptable salt thereof is a compound wherein each R 4a is hydrogen, methyl, n-propyl, isopropyl, isobutyl, -CH2 CH 2 OCH 3 、F、-CF 3 、-CH 2 CF 3 、 cyclopentyl, -CH 2 - cyclopropyl or tetrahydrofuranyl.

[0342] In some embodiments, a compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe or IVf or a pharmaceutically acceptable salt thereof is a compound wherein R 4 is methyl, ethyl, n-propyl, isopropyl, tert-butyl,

[0343] or

[0344] In some embodiments, a compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe or IVf or a pharmaceutically acceptable salt thereof is a compound wherein R 4 is C 1-3 alkyl, -CN, C 3-6 alkyl, a 4-6 membered heterocycloalkyl having 1 heteroatom each being N or O, C 6-12 aryl, or a 5-10 membered heteroaryl having 1 to 4 heteroatoms each independently being N, O or S, wherein the heterocycloalkyl, aryl and heteroaryl are each independently substituted by 1 to 2 R 4a groups; and each R 4a is 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, wherein each aryl is optionally substituted by C 1-6 alkoxy.

[0345] In some embodiments, a compound of formula I, II, IIa-1, IIa-2, IIb-1, IIb-2, IIc-1IIc-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe or IVf or a pharmaceutically acceptable salt thereof is a compound wherein each R 4a is hydrogen, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 3-6Cycloalkyl, C 1-2 Alkyl-C 3-6 Cycloalkyl, or 6-12 Aryl, wherein each aryl is optionally substituted by C 1-6 number of alkoxy groups. In some embodiments, a 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 pharmaceutically acceptable salt thereof is a compound wherein each R 4a is hydrogen, methyl, n-propyl, -OCH 3 , -CH 2 OH, -CH 2 -cyclopropyl or 2-methoxyphenyl.

[0346] In some embodiments, a 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 pharmaceutically acceptable salt thereof is a compound wherein

[0347] R 4 is methyl, ethyl, -CF 2 CH 3 , -CN, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl, pyrimidinedione, phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridyl-2-one, pyridazinyl, pyrimidinyl, indolyl, pyrazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, benzisoxazolyl, thienyl, benzothienyl or thiazolyl; and

[0348] each R 4a is hydrogen, methyl, ethyl, n-propyl, isobutyl, -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 NHMe, cyclobutyl, cyclopropylmethyl, 2-methoxyphenyl or -OPh.

[0349] In some embodiments, a 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 pharmaceutically acceptable salt thereof is a compound wherein R 4 is methyl, -CN, cyclopropyl, piperidinyl, tetrahydropyranyl, phenyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolylpyrimidine, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, thienyl or thiazolyl; and each R 4a is hydrogen, methyl, n-propyl, methoxy, hydroxymethyl, cyclopropylmethyl or 2-methoxyphenyl.

[0350] In some embodiments, a 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 pharmaceutically acceptable salt thereof is a compound wherein R 4 is methyl, ethyl, -CF 2 CH 3 , -CN,

[0351]

[0352]

[0353] In some embodiments, a 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 pharmaceutically acceptable salt thereof is a compound wherein R 4 is methyl, -CN,

[0354]

[0355] In some embodiments, a 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 pharmaceutically acceptable salt thereof is a compound wherein R 4 is methyl,

[0356] of the compound.

[0357] In some embodiments, a 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 pharmaceutically acceptable salt thereof, is a compound wherein L 1 is absent or is -N(R 5a )-; L 2 is absent, or is -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( r5b )-; and R 5a and R 5b are each independently hydrogen, C 1-6 alkyl, or C 2-6 alkoxyalkyl.

[0358] In some embodiments, 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 pharmaceutically acceptable salt thereof, is a compound wherein L 1 is absent, or is -NMe-, or -NH-. In some embodiments, 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 pharmaceutically acceptable salt thereof, is a compound wherein L 1 is absent. In some embodiments, 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 pharmaceutically acceptable salt thereof, is a compound wherein L 1 is -NMe- or -NH-. In some embodiments, 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 pharmaceutically acceptable salt thereof, is a compound wherein L 1 is -NMe-. In some embodiments, 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 pharmaceutically acceptable salt thereof, is a compound wherein L1 A compound of -NH-. 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 pharmaceutically acceptable salt thereof is one in which L 2 is absent, or is -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 pharmaceutically acceptable salt thereof is one in which L 2 is absent, or is -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 N(Me)-. 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 pharmaceutically acceptable salt thereof is one in which L 2 is -S(O) 2 -, -S(O) 2 -NH- or S(O) 2 N(Me)-.

[0359] 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 pharmaceutically acceptable salt thereof is one in which L 1 and L 2 together are absent, or 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-, -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)- compounds. In some embodiments, a compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd or IVe or a pharmaceutically acceptable salt thereof is one in which L 1 and L 2 together are absent, or are -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)- compounds. In some embodiments, a compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd or IVe or a pharmaceutically acceptable salt thereof is one in which L 1 and L 2 together are -C(O)-, -C(O)O-, -C(O)NH-, -S(O) 2 -, -NHS(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)- compounds. In some embodiments, a compound of formula I, II, IIa-1, IIa-2, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd or IVe or a pharmaceutically acceptable salt thereof is one in which L1 and L 2 are absent together, or 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-, -S(O) 2 -, -NH-S(O) 2 -, or -N(Me)S(O) 2 - of the compound. 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 pharmaceutically acceptable salt thereof is one wherein L 1 and L 2 are absent together, or are -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 - of the compound.

[0360] In some embodiments, the compound of formula I, II or IIa-1 or a pharmaceutically acceptable salt thereof is a compound wherein ring J has the following structure:

[0361]

[0362] L 1 is absent; L 2 is -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 pharmaceutically acceptable salt thereof is a compound wherein L 1 and L 2 together are -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)(CH 2 ) 3 O-, or -S(O) 2Compound of -.

[0363] In some embodiments, the compound of formula I, II or IIa-2 or a pharmaceutically acceptable salt thereof is a compound in which ring J has the following structure:

[0364] and

[0365] L 1 is -N(R 5a )-; L 2 is -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 alkyl. In some embodiments, the compound of formula I, II or IIa-2 or a pharmaceutically acceptable salt thereof is a compound in which L 1 and L 2 together are -NHS(O) 2 - or -N(Me)S(O) 2 -.

[0366] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound of formula IIa-1 or IIa-2:

[0367]

[0368] wherein each R 2 , R 3b , L 1 , L 2 and R 4 is as defined.

[0369] In some embodiments, the compound of formula I, II, IIa-1 or IIa-2 or a pharmaceutically acceptable salt thereof is a compound of formula IIb-1 or IIb-2:

[0370]

[0371] wherein each R 2 , R 3b , L 1 and R 4a is as defined.

[0372] In some embodiments, the compound of formula I, II, IIa-1, IIa-2, IIb-1 or IIb-2 or a pharmaceutically acceptable salt thereof is a compound of formula IIc-1 or IIc-2:

[0373]

[0374] where each R 2 、R 3b 、R 4a and R 5a is as defined therefor.

[0375] In some embodiments, a compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein

[0376] R 1 is phenyl substituted with 1 to 5 R 1a groups, each R 1a group independently being hydrogen, C 1-6 alkoxy, halogen or -C(O)N(R 1b )(R 1c ), where each R 1b and R 1c is independently hydrogen or a 4- to 6-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O or S;

[0377] A 1 、A 2 、A 3 and A 4 are each independently =CR 2 - or =N-;

[0378] Each R 2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen or C 1-6 haloalkoxy;

[0379] Ring J has the following structure:

[0380]

[0381]

[0382] Each R 3a is 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;

[0383] R 3a1 is hydrogen or C 1-6 alkyl;

[0384] R 3b is hydrogen, C1-6 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, wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O, or S, and wherein each aryl and heteroaryl is substituted with 1 to 3 R 3b3 groups;

[0385] R 3b1 and R 3b2 are each independently hydrogen or C 1-6 alkyl;

[0386] Alternatively, R 3b1 and R 3b2 combine with the atoms to which they are attached to form a 3 - to 6 - membered heteroalkyl, each heteroalkyl having 1 to 2 additional heteroatoms each independently being N, O, or S;

[0387] Each R 3b3 is hydrogen, C 1-6 alkyl, halogen, or C 1-6 haloalkyl;

[0388] Alternatively, R 3b combines with R 3a on an adjacent ring atom and the atoms to which they are respectively attached to form a C 3-6 cycloalkyl substituted with 0 - 4 halogens;

[0389] L 3a and L 3b are each -C(R 3a3 )(R 3a3 );

[0390] Each R 3a3 is independently hydrogen or C 1-6 alkyl;

[0391] R 4 is C 1-6 alkyl, -CN, C 3-8 cycloalkyl, a 3 - to 8 - membered heteroalkyl having 1 to 3 heteroatoms each independently being N, O, or S, C 6-12 aryl, or a 5 - to 10 - membered heteroaryl having 1 to 5 heteroatoms each independently being N, O, or S, wherein the heteroalkyl, aryl, and heteroaryl are each independently substituted with 1 to 5 R 4a groups;

[0392] Each R 4a is 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- to 8-membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from N, O or S, C 6-12 aryl or -O-C 6-12 aryl, where each aryl is optionally substituted with C 1-6 alkoxy;

[0393] L 1 is absent or is -N(R 5a )-;

[0394] L 2 is absent, or is -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 )-;

[0395] R 5a and R 5b are each independently hydrogen, C 1-6 alkyl or C 2-6 alkoxyalkyl; and

[0396] the subscripts r and s are each independently 0, 1 or 2 such that the sum of r and s is 2.

[0397] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein

[0398] R 1 is

[0399]

[0400] A 1 is =CH- or =N-;

[0401] A 2 and A 4 are each independently =CH-, =C(Me)- or =N-;

[0402] A 3is =CH-, =C(Me)-, =C(Et)-, =C(iPr)-, =C(OMe)-, =C(F)- =C(Cl)-, =C(OCHF 2 )-, =C(CN)- or =N-;

[0403] Ring J has the following structure:

[0404]

[0405] Each R 3a is hydrogen, methyl, isobutyl, -OH, oxo, -CH 2 OMe, -CH 2 OH, -C(O)OMe, phenyl or benzyl;

[0406] R 3b is methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt,

[0407]

[0408] L 1 and L 2 together do not exist, or 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-, -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

[0409] R 4 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CF 2 CH 3 -, -CN,

[0410]

[0411]

[0412] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein

[0413] R 1 is

[0414]

[0415] A 1 is =CH- or =N-;

[0416] A 2 and A 4 are each independently =CH-, =C(Me)- or =N-;

[0417] A 3 is =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, =C(F)- =C(Cl)-, =C(OCHF 2 )- or =N-;

[0418] Ring J has the following structure:

[0419]

[0420]

[0421] Each R 3a is hydrogen, methyl, isobutyl, oxo, -CH 2 OMe, -CH 2 OH, -C(O)OMe, phenyl or benzyl;

[0422] R 3b is methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt,

[0423]

[0424] L 1 and L 2 together are absent or are -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

[0425] R 4 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CN,

[0426]

[0427] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein

[0428] R 1 is

[0429]

[0430] A 1 is =CH- or =N-;

[0431] A 2 and A 4 are each independently =CH-, =C(Me)- or =N-;

[0432] A 3 is =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, =C(Cl)-, =C(OCHF 2 )- or =N-;

[0433] Ring J has the following structure:

[0434]

[0435] Each R 3a is hydrogen, methyl, isobutyl, -CH 2 OMe, -CH 2 OH, oxo, -C(O)OMe, phenyl or benzyl;

[0436] L 1 and L 2 together are -C(O)-, -C(O)O-, -C(O)NH-, -S(O) 2 -, -NHS(O) 2 -, -N(Me)S(O) 2 -, -N(CH 2 CH 2OCH 3 )S(O) 2 -,-S(O) 2 -NH- or S(O) 2 N(Me)-; and

[0437] R 4 is methyl, ethyl, n-propyl, isopropyl, tert-butyl,

[0438]

[0439]

[0440] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound wherein

[0441] R 1 is

[0442]

[0443] A 1 is =CH- or =N-;

[0444] A 2 and A 4 are each =CH-;

[0445] A 3 is =CH-, =C(Me)-, =C(iPr)-, =C(OMe)-, or =C(F)-;

[0446] Ring J has the following structure:

[0447]

[0448] R 3b is methyl, ethyl, -CH 2 C≡CH, -CH 2 OMe, -CH 2 OH, -C(O)OEt,

[0449]

[0450] L 1 and L 2 together are absent, or are -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

[0451] R 4 is methyl, -CN,

[0452]

[0453] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound in which ring J has the following structure:

[0454]

[0455] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound in which ring J has the following structure:

[0456]

[0457] In some embodiments, the compound of formula I, II or IV or a pharmaceutically acceptable salt thereof is a compound having the following structure:

[0458]

[0459] In some embodiments, the present invention provides a compound of formula IVa or a pharmaceutically acceptable salt thereof:

[0460]

[0461] wherein

[0462] R 1 is a heterocycloalkyl having 3 to 8 ring members and 1 to 4 heteroatoms each independently being N, O or S, phenyl, or a heteroaryl having 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O or S, each independently substituted by 1 to 5 R 1a groups;

[0463] Each R 1a is 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, each ring having 3 to 8 ring members and 1 to 4 heteroatoms each independently being N, O or S;

[0464] Each R 1b and R 1c are independently hydrogen, C 1-6 alkyl, or a 3- to 8-membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from N, O, or S;

[0465] A 1 、A 2 、A 3 and A 4 are each independently =CR 2 - or =N-;

[0466] Each R 2 is 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;

[0467] Each R 3a is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkoxy, 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, wherein each alkenyl and alkynyl is optionally substituted by C 6-12 aryl or heteroaryl, wherein each heterocycloalkyl has 3 to 8 ring members and 1 to 3 heteroatoms each independently selected from N, O, or S, and wherein each heteroaryl has 5 to 10 ring members and 1 to 5 heteroatoms each independently selected from N, O, or S;

[0468] R 3a1 and R 3a2 are each independently hydrogen or C 1-6 alkyl;

[0469] Alternatively, two R 3aThe groups can combine with the atoms to which they are attached to form a C 3-6 cycloalkyl group;

[0470] Alternatively, two R 3a groups attached to different atoms can combine with the atoms to which they are attached to form a C3-10 cycloalkyl group or a 3-10 membered heterocycloalkyl group having 1-4 heteroatoms each independently being N, O or S, each being substituted with 1-4 R 3a3 groups;

[0471] Each R 3a3 is independently hydrogen or C 1-6 alkyl;

[0472] Each R 3b is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkoxy, 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-O-C 6-12 aryl, C 1-6 alkoxyalkyl-C 6-12 aryl, -C(O)-C 6-12 aryl, heteroaryl, or C 1-6 alkyl-heteroaryl, wherein each heterocycloalkyl group has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each heteroaryl group has 5 to 10 ring members and 1 to 5 heteroatoms each independently being N, O or S, and wherein each aryl and heteroaryl group is substituted with 1 to 3 R 3b3 groups;

[0473] R 3b1 and R 3b2 are each independently hydrogen or C1-6 alkyl;

[0474] alternatively, R 3b1 and R 3b2 combine with the atoms to which they are attached to form a 3- to 6-membered heteroalkyl group having 1 to 2 additional heteroatoms each independently being N, O or S;

[0475] 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;

[0476] R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -CN, C 3-8 cycloalkyl, a 3- to 8-membered heteroalkyl group having 1 to 3 heteroatoms each independently being N, O or S, C 6-12 aryl or a 5- to 10-membered heteroaryl having 1 to 5 heteroatoms each independently being N, O or S, wherein the cycloalkyl, heteroalkyl, aryl and heteroaryl are each independently substituted by 1 to 5 R 4a groups;

[0477] 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, heteroalkyl, C 1-6Alkyl - heterocycloalkyl, C 6-12 Aryl, C 1-6 Alkyl - C 6-12 Aryl, -O - C 6-12 Aryl, heteroaryl, C 1-6 Alkyl - heteroaryl, wherein each heterocycloalkyl independently has 3 to 8 ring members and 1 to 3 heteroatoms each independently being N, O, or S, wherein each heteroaryl independently has 5 to 8 ring members and 1 to 4 heteroatoms each independently being N, O, or S, and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted by C 1-6 alkoxy;

[0478] R 4b and R 4c are each independently hydrogen or C 1-6 alkyl;

[0479] L 1 is absent or is -N(R 5a )-;

[0480] L 2 is absent, or is 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

[0481] R 5a and R 5b are each independently hydrogen, C 1-6 alkyl or C 2-6 alkoxyalkyl.

[0482] In some embodiments, the compound of formula I, II, III, IIIa, IV, or IVa, or a pharmaceutically acceptable salt thereof, is a compound wherein R 1 is a heterocycloalkyl having 5 to 6 ring members and 1 to 2 heteroatoms each being N, phenyl, or a heteroaryl having 5 to 6 ring members and 1 to 2 heteroatoms each being N or S, each being substituted by 1 to 3 R 1a groups; each R 1a is 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 3-6A cycloalkyl or a heterocycloalkyl having 3 - 5 ring members and 1 - 2 heteroatoms each being N or O. In some embodiments, a compound of formula I, II, III, IIIa, IV or IVa or a pharmaceutically acceptable salt thereof is a compound wherein R 1 is a compound of piperidine, pyridin - 2 - one, phenyl, pyridine, pyrazole or thiazole, each being substituted with 1 to 3 R 1a groups; 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.

[0483] In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV or IVa or a pharmaceutically acceptable salt thereof is a compound wherein R 1 is

[0484]

[0485] In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV or IVa or a pharmaceutically acceptable salt thereof is one wherein R 1 is

[0486] compound.

[0487] In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV or IVa or a pharmaceutically acceptable salt thereof is a compound having the following structure:

[0488]

[0489] In some embodiments, a compound of formula I, II, III, IIIa, IIIb, IV, IVa or IVb or a pharmaceutically acceptable salt thereof is a compound wherein A 1 , A 2 , A 3 and A 4 are each independently =CR 2 - or =N-; and each R 2 is independently hydrogen, C 1-4 alkyl, C 1-4An alkoxy group, a halogen, or -CN. In some embodiments, the compound of formula I, II, IIa-1, IIb-1, IIc-1, III, IIIa, IIIb, IV, IVa, or IVb or a pharmaceutically acceptable salt thereof is a compound in which each R 2 is independently hydrogen, methyl, ethyl, isopropyl, methoxy, F, Cl, or -CN. In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, or IVb or a pharmaceutically acceptable salt thereof is a compound in which 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-. In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, or IVb or a pharmaceutically acceptable salt thereof is a compound in which 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)-. In some embodiments, the compound of formula I, II, III, IIIa, IIIb, IV, IVa, or IVb or a pharmaceutically acceptable salt thereof is one in which A 1 , A 2 , and A 4 are each =CH-; and A 3 is =C(Me)-.

[0490] In some embodiments, the compound of formula I, II, III, IIIa, IV, IVa, or IVb or a pharmaceutically acceptable salt thereof is a compound having the following structure:

[0491]

[0492] In some embodiments, the compound of formula I, II, III, IIIa, IV, IVa, IVb, or IVc or a pharmaceutically acceptable salt thereof is a compound in which each R 3a is independently hydrogen, -OH, or oxo. In some embodiments, the compound of formula I, II, III, IIIa, IV, IVa, IVb, or IVc or a pharmaceutically acceptable salt thereof is a compound in which each R 3a is hydrogen.

[0493] In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IV, IVa, IVb or IVc, or a pharmaceutically acceptable salt thereof, is a compound having the following structure:

[0494]

[0495] 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 pharmaceutically acceptable salt thereof, is a compound wherein R 3b is 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-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, wherein each heteroaryl has 5 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, and wherein each aryl and heteroaryl is substituted with 1 to 3 R 3b3 groups; and each R 3b3 is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, halogen or C 1-6 haloalkyl.

[0496] 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 pharmaceutically acceptable salt thereof, is a compound wherein R 3b is 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-C6-12 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, wherein each heteroaryl has 5 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, and wherein each aryl and heteroaryl is substituted with 1 to 3 R 3b3 groups; and each R 3b3 is hydrogen, C 1-3 alkyl, C 1-3 hydroxyalkyl, halogen or C 1-3 haloalkyl.

[0497] In some embodiments, a compound of formula I, II, IIa-1, IIb-1, IIc-1, III, IIIa, IIIb, IV, IVa, IVb, IVc or IVd or a pharmaceutically acceptable salt thereof is one wherein R 3b3 is hydrogen, methyl, -CH 2 OH, F, -CHF 2 , or -CF 3 . In some embodiments, a compound of formula I, II, IIa-1, IIb-1, IIc-1, III, IIIa, IIIb, IV, IVa, IVb, IVc or IVd or a pharmaceutically acceptable salt thereof is one wherein R 3b is: ethyl, -CH 2 C≡CH, -CH 2 OMe,

[0498]

[0499] In some embodiments, a compound of formula I, II, IIa-1, III, IIIa, IV, IVa, IVb, IVc or IVd or a pharmaceutically acceptable salt thereof is one wherein R 3b is

[0500] .

[0501] In some embodiments, a compound of formula I, II, IIa-1, III, IIIa, IV, IVa, IVb, IVc or IVd or a pharmaceutically acceptable salt thereof is a compound having the following structure:

[0502]

[0503] In some embodiments, a compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharmaceutically acceptable salt thereof, is a compound in which L 1 is absent; and L 2 is absent or is 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, a compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharmaceutically acceptable salt thereof, is a compound in which L 1 is absent; and L 2 is absent or is -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 2 S(O)-. In some embodiments, a compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharmaceutically acceptable salt thereof, is one in which L 2 is -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, a compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, or IVe, or a pharmaceutically acceptable salt thereof, is one in which L 2 is -C(O)- or S(O) 2 -.

[0504] In some embodiments, a compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd or IVe, or a pharmaceutically acceptable salt thereof, is a compound having the following structure:

[0505]

[0506] In some embodiments, a compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe or IVf, or a pharmaceutically acceptable salt thereof, is a compound wherein R 4 is C 1-6 alkyl, C 1-6 haloalkyl, -CN, C 3-8 cycloalkyl, a 3- to 8-membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from N, O or S, C 6-12 aryl, or a 5- to 10-membered heteroaryl having 1 to 5 heteroatoms each independently selected from N, O or S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently substituted with 1 to 5 R 4a groups; each R 4a is hydrogen, C 1-6 alkyl, C 1-6 deuterioalkyl, 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 -O-C 6-12 aryl, wherein each aryl is optionally substituted with C 1-6 alkoxy; and each R 4b and R 4c are hydrogen or C 1-6 alkyl.

[0507] In some embodiments, a compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe or IVf, or a pharmaceutically acceptable salt thereof, is a compound wherein R 4 is C 1-3 alkyl, C 1-3 haloalkyl, -CN, C 3-6Cycloalkyl, 4- to 6-membered heterocycloalkyl having 1 heteroatom each independently being N or O, C 6-12 aryl, or 5- to 10-membered heteroaryl having 1 to 4 heteroatoms each independently being N, O or S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently substituted by 1 to 2 R 4a groups; each R 4a is hydrogen, C 1-3 alkyl, C 1-3 deuterioalkyl, 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, wherein each aryl is optionally substituted by C 1-3 alkoxy; and each R 4b and R 4c are hydrogen or C 1-3 alkyl.

[0508] In some embodiments, the compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe or IVf or a pharmaceutically acceptable salt thereof is a compound wherein R 4 is methyl, ethyl, -CF 2 CH 3 , -CN, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl, pyrimidinedione, phenyl, pyridyl, pyridin-2-one, quinolinyl, pyrazolyl, imidazolyl, pyridazinyl, pyrimidinyl, indolyl, triazolyl, pyrazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl each R 4a is hydrogen, methyl, ethyl, n-propyl, isobutyl, -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 NHMe, cyclobutyl, 2-methoxyphenyl or -OPh.

[0509] In some embodiments, a compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharmaceutically acceptable salt thereof, is a compound wherein R 4 is methyl, -CF 2 CH 3 , -CN,

[0510]

[0511]

[0512] In some embodiments, a compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharmaceutically acceptable salt thereof, is one wherein R 4 is

[0513] .

[0514] In some embodiments, a compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharmaceutically acceptable salt thereof, is one wherein R 4 is

[0515] .

[0516] In some embodiments, a compound of formula I, II, IV, or IVa, or a pharmaceutically acceptable salt thereof, is a compound having the following structure:

[0517]

[0518] In some embodiments, a compound of formula I, II, IIa-1, III, IIIa, IIIb, IV, IVa, IVb, IVc, IVd, IVe, or IVf, or a pharmaceutically acceptable salt thereof, is one wherein R 4 is

[0519] .

[0520] In some embodiments, a compound of formula I, II, IV, or IVa, or a pharmaceutically acceptable salt thereof, is a compound wherein

[0521] R 1 is

[0522]

[0523] A 1 is =CH- or =N-;

[0524] A 2 and A 4 are each =CH-;

[0525] A 3 is =CH-, =C(Me)-, =C(Et)-, =C(iPr)-, =C(OMe)-, =C(F)-, =C(Cl)-,

[0526] or =C(CN)-;

[0527] Ring J has the following structure:

[0528]

[0529] Each R 3a is hydrogen, -OH or oxo;

[0530] R 3b is ethyl, -CH 2 c≡CH, -CH 2 OMe,

[0531]

[0532] L 1 and L 2 are absent together or 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

[0533] R 4 is methyl, -CF 2 CH 3 , -CN,

[0534]

[0535]

[0536] In some embodiments, a compound of formula I, II, IV or IVa or a pharmaceutically acceptable salt thereof is a compound in which

[0537] R 1 is

[0538]

[0539] A 1 is =CH-;

[0540] A 2 and A 4 are each =CH-;

[0541] A 3 is =CH-, =C(Me)-, =C(Et)-, =C(OMe)-, =C(Cl)-, or =C(CN)-;

[0542] Ring J has the following structure:

[0543]

[0544] Each R 3a is hydrogen, -OH or oxo;

[0545] R 3b is -CH 2 OMe,

[0546]

[0547] L 1 and L 2 together are -CH2-, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -C(O)CH 2 O-, or S(O) 2 -; and

[0548] R 4 is methyl, -CF 2 CH 3 ,

[0549]

[0550]

[0551] In some embodiments, a compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound in Table 1A:

[0552]

[0553]

[0554]

[0555] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound in Table 1B:

[0556]

[0557]

[0558]

[0559] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound in Table 1C:

[0560]

[0561]

[0562]

[0563]

[0564] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound in Table 1D:

[0565]

[0566]

[0567]

[0568] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound in Table 1E:

[0569]

[0570]

[0571]

[0572] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound in Table 1F:

[0573]

[0574] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound in Table 1G:

[0575]

[0576] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound in Table 1H:

[0577]

[0578]

[0579]

[0580] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound in Table 1I:

[0581]

[0582]

[0583]

[0584]

[0585] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound in Table 1J:

[0586]

[0587]

[0588]

[0589]

[0590] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound in Table 1K:

[0591]

[0592] In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound in 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 pharmaceutically acceptable salt thereof is a compound in Table 1A, Table 1B, Table 1C, Table 1D or Table 1E. In some embodiments, the compound of Formula I or II or a pharmaceutically acceptable salt thereof is a compound in 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 pharmaceutically acceptable salt thereof is a compound in Table 1H, Table 1I, Table IJ or Table 1K. In some embodiments, the compound of Formula I, II, IV or IVa or a pharmaceutically acceptable salt thereof is a compound in Table 1H. In some embodiments, the compound of Formula I, II, IV or IVa or a pharmaceutically acceptable salt thereof is a compound in Table 1I. In some embodiments, the compound of Formula I, II, IV or IVa or a pharmaceutically acceptable salt thereof is a compound in Table IJ. In some embodiments, the compound of Formula I, II, IV or IVa or a pharmaceutically acceptable salt thereof is a compound in Table 1K.

[0593] In some embodiments, the compound of Formula I, II, IV or IVa or a pharmaceutically acceptable salt thereof is a compound in Table 2A:

[0594]

[0595]

[0596]

[0597] In some embodiments, the compound of Formula I, II, IV or IVa or a pharmaceutically acceptable salt thereof is a compound in Table 2B:

[0598]

[0599]

[0600]

[0601] Or

[0602] In some embodiments, the compound of Formula I, II, IV or IVa or a pharmaceutically acceptable salt thereof is a compound in Table 2C:

[0603]

[0604]

[0605] or

[0606] In some embodiments, the compound of formula I, II, IV or IVa, or a pharmaceutically acceptable salt thereof, is a compound in Table 2D:

[0607]

[0608]

[0609]

[0610] or

[0611] In some embodiments, the compound of formula I, II, IV or IVa, or a pharmaceutically acceptable salt thereof, is

[0612] a compound in Table 2E:

[0613]

[0614]

[0615]

[0616] In some embodiments, the compound of formula I, II, IV or IVa, or a pharmaceutically acceptable salt thereof, is a compound in Table 2F:

[0617]

[0618]

[0619] In some embodiments, the compound of formula I, II, IV or IVa, or a pharmaceutically acceptable salt thereof, is a compound in 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 pharmaceutically acceptable salt thereof, is a compound in Table 2A. In some embodiments, the compound of formula I, II, IV or IVa, or a pharmaceutically acceptable salt thereof, is a compound in Table 2B. In some embodiments, the compound of formula I, II, IV or IVa, or a pharmaceutically acceptable salt thereof, is a compound in Table 2C. In some embodiments, the compound of formula I, II, IV or IVa, or a pharmaceutically acceptable salt thereof, is a compound in Table 2D. In some embodiments, the compound of formula I, II, IV or IVa, or a pharmaceutically acceptable salt thereof, is a compound in Table 2E. In some embodiments, the compound of formula I, II, IV or IVa, or a pharmaceutically acceptable salt thereof, is a compound in Table 2F.

[0620] In some embodiments, the compound of formula I or II or a pharmaceutically acceptable salt thereof is a compound in Table 1A, Table 1B, 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 pharmaceutically acceptable salt thereof is a compound in 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 pharmaceutically acceptable salt thereof is a compound in Table 1H, Table 1I, Table IJ, Table 1K, Table 2A, Table 2B, Table 2C, Table 2D, Table 2E or Table 2F.

[0621] The compounds of the present invention may exist as salts. The present invention includes such salts, which may be pharmaceutically acceptable salts. Examples of suitable salt forms include hydrochloride, bromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate or mixtures thereof, including racemic mixtures), succinate, benzoate, and salts with amino acids such as glutamate. 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 contain relatively basic functional groups, the acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (pure or in a suitable inert solvent). Examples of acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydriodic acid or phosphorous acid, etc., and salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, glutaric acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginine, etc., and salts of organic acids such as glucuronic acid or galacturonic acid, etc. Certain specific compounds of the present invention contain both basic and acidic functional groups, which allow the compounds to be converted into base or acid addition salts.

[0622] Other salts include the acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are salts of inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference.

[0623] Pharmaceutically acceptable salts include salts of the active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts or the like. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, etc., and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginine, etc., and salts of organic acids such as glucuronic acid or galacturonic acid, etc. (see, e.g., Birch et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups, which allow the compounds to be converted into base or acid addition salts.

[0624] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs in certain physical properties from the various salt forms, such as solubility in polar solvents.

[0625] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to fall within the scope of the present invention.

[0626] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, which can be defined as (R)- or (S)- according to absolute stereochemistry or, as amino acids, (D)- or (L)-, and the individual isomers are included within the scope of the present invention. Compounds known in the art that are too unstable to be synthesized and / or isolated are not included in the compounds of the present invention. The object of the present invention is to include compounds in racemic and optically pure forms. The optically active (R)- and (S)-, or (D)- and (L)-isomers can be prepared with chiral synthons or chiral reagents, or resolved by conventional techniques.

[0627] Isomers include compounds that have the same number and kind of atoms and thus the same molecular weight, but differ in the structural arrangement or configuration of the atoms.

[0628] Unless otherwise specified, the structures described herein also mean to include all stereochemical forms of the structures; that is, the R and S configurations of each asymmetric center. Thus, the single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds of the present invention are within the scope of the present invention.

[0629] Unless otherwise specified, the compounds of the present invention may also contain unnatural proportions of atomic isotopes on one or more atoms that make up such compounds. For example, the compounds of the present invention may be labeled with 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 included within the scope of the present invention.

[0630] In addition to the salt forms, the present invention provides prodrug forms of the compounds. Prodrugs of the compounds described herein are those compounds that are readily chemically changed under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical means in an ex vivo environment. For example, a prodrug can be slowly converted to the compound of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0631] Composition

[0632] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of any one of the compounds of the present invention and a pharmaceutically acceptable excipient.

[0633] The compounds of the present invention can be prepared and administered in a variety of oral, parenteral, and topical dosage forms. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc., suitable for ingestion by a patient. The compounds of the present invention can also be administered by injection, i.e., intravenously, intramuscularly, intracavity, subcutaneously, intraduodenally, or intraperitoneally. In addition, the compounds described herein can be administered by inhalation, such as 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 intravitreal, intravaginal, and intrarectal routes, including suppositories, insufflators, powders, and aerosol formulations (e.g., steroid inhalers, see Lohrani, J. Clin. Pharmacol., 35:1187-1193, 1995; An, Allergy Asthma Immunol., 75:107-111, 1995). Accordingly, the present invention also provides pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and / or excipients and a pharmaceutically acceptable salt of a compound of formula I or a pharmaceutically acceptable salt of a compound of formula I.

[0634] For preparing pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier can be solid or liquid. Solid forms of the preparation include powders, tablets, pills, capsules, bougies, suppositories, and dispersible granules. The solid carrier can be one or more substances which may also serve as diluents, flavoring agents, surfactants, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details on formulation and administration techniques are well described in scientific and patent literature, e.g., see the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton PA ("Remington").

[0635] In powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties and the required additional excipients in suitable proportions and compacted into the desired shape and size.

[0636] 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, acacia, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, etc. The term "article" is intended to include preparations of the active compound with an encapsulating material as the carrier, thus providing a capsule in which the active ingredient, with or without other excipients, is surrounded by the carrier which is thus in association therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, capsules, and lozenges can be used as solid dosage forms suitable for oral administration.

[0637] Suitable solid excipients are carbohydrate or protein fillers, including but not limited to sugars, including lactose, sucrose, mannitol or sorbitol; starches from corn, wheat, rice, potato or other plants; celluloses such as methylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose; and gums, including gum arabic and tragacanth; and proteins such as gelatin and collagen. If desired, disintegrants or solubilizers may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts, such as sodium alginate.

[0638] The lozenge cores have suitable coatings, such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or sugar coatings for product identification or to characterize the amount of active compound (i.e., the dose). The pharmaceutical formulations of the present invention may also be used orally, for example, in push-fit capsules made of gelatin and soft-sealed capsules made of gelatin and coatings such as glycerol or sorbitol. The push-fit capsules may contain a compound of formula I mixed with a filler or binder such as lactose or starch, a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In the soft capsules, the compounds of formula I may be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol with or without a stabilizer.

[0639] To prepare suppositories, first melt a low melting point wax, such as a mixture of fatty acid glycerides or cocoa butter, and uniformly disperse the active ingredient therein by stirring. Then pour the molten homogeneous mixture into a conveniently sized mold and allow it to cool, thereby solidifying.

[0640] Formulations in liquid form include solutions, suspensions and emulsions, such as aqueous or water / propylene glycol solutions. For parenteral injection, the liquid formulations may be formulated in solutions in aqueous polyethylene glycol.

[0641] An aqueous solution suitable for oral administration can be prepared by dissolving the active ingredient in water and adding, as required, suitable colorants, flavorants, stabilizers, and thickening agents. An aqueous suspension suitable for oral administration can be prepared by dispersing the finely divided active ingredient in water, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, and acacia, and a dispersing or wetting agent, such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain fatty alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethyl or propyl p-hydroxybenzoate, one or more colorants, one or more flavorants, and one or more sweetening agents, such as sucrose, aspartame, or saccharin. The osmotic pressure of the formulation can be adjusted.

[0642] Also included are solid form formulations which are intended to be converted shortly before use into a liquid form formulation for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, these formulations may also contain colorants, flavorants, stabilizers, buffers, artificial and natural sweetening agents, dispersing agents, thickening agents, solubilizing agents, etc.

[0643] An oil suspension can be formulated by suspending a compound of formula I in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents can be added to provide a palatable oral formulation, such as glycerol, sorbitol, or sucrose. These formulations can be preserved by adding an antioxidant (e.g., ascorbic acid). As an example of an injectable oil carrier, see Mintun, Journal of Pharmacology and Experimental Therapeutics, 281:93-102, 1997. The pharmaceutical formulations of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil or a mineral oil as described above, or a mixture thereof. Suitable emulsifying agents include naturally occurring gums, such as acacia and tragacanth, naturally occurring phospholipids, such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydride, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening agents and flavorants, as in the formulation of syrups and elixirs. Such formulations may also contain anti-emulsants, preservatives, or colorants.

[0644] The compounds of formula I of the present invention can be delivered by transdermal and topical routes and formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols.

[0645] The compounds of formula I and the compositions of the present invention can also be delivered as microspheres for slow release in vivo. For example, the microspheres can be administered by intradermal injection of drug-containing microspheres, which are slowly released subcutaneously (see Rao, Journal of Biomaterials Science, Polymer Edition, 7:623-645, 1995); as biodegradable and injectable gel formulations (see, e.g., Gao, Pharmaceutical Research, 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Ayres, Journal of Medicine, 49:669-674, 1997). Both transdermal and intradermal routes can provide continuous delivery for several weeks or months.

[0646] The pharmaceutical formulations of the compounds of formula I of the present invention can be provided in salt form and can be formed with many acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, etc. The salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. In other cases, the formulation can be a lyophilized powder in the pH range of 4.5 to 5.5 in 1 mM - 50 mM histidine, 0.1% - 2% sucrose, 2% - 7% mannitol, which is combined with a buffer before use.

[0647] The pharmaceutical formulations of the compounds of formula I of the present invention can be provided as salts and can be formed with bases, i.e., cationic salts such as 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)methylammonium salts.

[0648] In some embodiments, the formulations of the compounds of formula I of the present invention can be delivered by using liposomes that fuse with cell membranes or are endocytosed, i.e., by using ligands attached to liposomes or directly attached to oligonucleotides that bind to surface membrane proteins of cells, resulting in endocytosis. By using liposomes, especially when ligands specific for target cells are carried on the surface of the liposomes or otherwise preferentially targeted to specific organs, the delivery of GR modulators can be focused on target cells in vivo. (See, e.g., Mohamed, Journal of Microencapsulation, 13:293-306, 1996; Current Opinion in Biotechnology, 6:698-708, 1995; Ostro, American Journal of Hospital Pharmacy, 46:1576-1587, 1989).

[0649] The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged preparation that contains discrete quantities of the preparation, such as tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be any of the appropriate number of these packaged forms.

[0650] The amount of the active ingredient in the unit dosage preparation can vary or be adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 1000 mg, and most typically from 10 mg to 500 mg, depending on the specific application and potency of the active ingredient. If desired, the composition can also contain other compatible therapeutic agents.

[0651] The dosage regimen also takes into account pharmacokinetic parameters well known in the art, i.e., absorption rate, bioavailability, metabolism, clearance, etc. (see, e.g., Hidalgo-Aragones (1996) Journal of Steroid Biochemistry, Molecular Biology, 58:611-617; Gronen (1996) Pharmazie, 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) Journal of Pharmaceutical Sciences, 84:1144-1146; Rohagi (1995) Pharmazie, 50:610-613; Brophy (1983) European Journal of Clinical Pharmacology, 24:103-108; the latest Remington, ibid.). The prior art allows clinicians to determine the dosage regimen for each individual patient, GR and / or MR modulator, and the disease or disorder being treated.

[0652] The single or multiple administrations of the preparation of the compound of formula I can be administered according to the dose and frequency required and tolerated by the patient. The preparation should provide a sufficient amount of the active agent to effectively treat the disease state. Thus, in one embodiment, the daily amount of the pharmaceutical preparation for oral administration of the compound of formula I is about 0.5 to about 30 mg / kg body weight / day. In another embodiment, the dose used is about 1 mg to about 20 mg per kilogram of body weight per patient per day. Lower doses can be used, especially when, as opposed to oral administration, the drug is administered to anatomically inaccessible sites (e.g., cerebrospinal fluid (CSF) space), into the bloodstream, into the lumen of a body cavity or organ. Significantly higher doses can be used for topical administration. The actual methods for preparing preparations comprising the compound of formula I for parenteral administration are known or obvious to those skilled in the art and are described in more detail in publications such as Remington. See also Nieman, in "Receptor-Mediated Anti-Steroid Action", edited by Agarwal et al., De Gruyter, New York (1987).

[0653] The compounds described herein can be used in combination with other active agents known to modulate the glucocorticoid receptor or with adjuvants that may not be effective alone but may contribute to the efficacy of the active agent.

[0654] In some embodiments, co - administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co - administration includes administering the two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co - administration can be achieved by co - formulating, i.e., preparing a single pharmaceutical composition comprising the two active agents. In some embodiments, the active agents can be formulated separately. In some embodiments, the active and / or adjuvant reagents can be linked or conjugated to each other.

[0655] After formulating a pharmaceutical composition comprising a compound of formula I of the present invention in one or more acceptable carriers, it can be placed in a suitable container and labeled for treating the indicated disorder. For the administration of a compound of formula I, such labeling will include, for example, instructions regarding the amount, frequency, and method of administration.

[0656] In some embodiments, the compositions of the present invention can be used for parenteral administration, such as intravenous (IV) administration or administration into the body cavity or lumen of an organ. The formulations for administration generally include a solution of the composition of the present invention dissolved in one or more pharmaceutically acceptable carriers. Acceptable carriers and solvents that can be used are water and Ringer's solution, isotonic sodium chloride. In addition, sterile non - volatile oils can generally be used as solvents or suspending media. For this purpose, any bland non - volatile oil can be used, including synthetic mono - or di - glycerides of fatty acids. 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 can contain pharmaceutically acceptable auxiliary substances as required for approximate physiological conditions, such as pH regulators and buffers, tonicity regulators, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. In these formulations, the concentration of the composition of the present invention can vary widely and will be mainly selected according to the fluid volume, viscosity, body weight, etc., depending on the particular mode of administration chosen and the needs of the patient. For IV administration, the formulation can be a sterile injectable formulation, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated using those suitable dispersing or wetting agents and suspending agents according to known techniques. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non - toxic parenterally acceptable diluent or solvent (e.g., a solution of 1,3 - butanediol).

[0657] In some embodiments, the formulations of the compositions of the invention can be delivered by using liposomes that fuse with cell membranes or are endocytosed, i.e., by using ligands attached to the liposomes or directly to the oligonucleotides that bind to surface membrane protein receptors of the cells, resulting in endocytosis. By using liposomes, particularly when carrying ligands specific for the target cells on the liposome surface or otherwise preferentially directed to a particular organ, the delivery of the compositions of the invention to the target cells can be concentrated in vivo. (See, e.g., Mohammed, Journal of Microencapsulation, 13:293-306, 1996; Current Opinion in Biotechnology, 6:698-708, 1995; Ostro, American Journal of Hospital Pharmacy 46:1576-1587, 1989).

[0658] Methods and Uses

[0659] In some embodiments, the invention provides a method of treating a disorder or condition by modulating the glucocorticoid receptor, the method comprising administering to a subject in need thereof a therapeutically effective amount of any one of the compounds of the invention or a pharmaceutical composition of the invention, thereby treating the disease or condition.

[0660] In one exemplary embodiment, 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 associated biological response of GR to agonist binding.

[0661] In some embodiments, the GR modulator is a specific glucocorticoid receptor antagonist. As used herein, a specific glucocorticoid receptor antagonist is a composition or compound that inhibits any biological response associated with the binding of GR to an agonist by preferentially binding to GR rather than to another nuclear receptor (NR). In some embodiments, the specific glucocorticoid receptor antagonist preferentially binds to GR rather than to a mineralocorticoid receptor (MR), an aldosterone receptor (AR), or a progesterone receptor (PR). In one exemplary embodiment, the specific glucocorticoid receptor antagonist preferentially binds to GR rather than to a mineralocorticoid receptor (MR). In another exemplary embodiment, the specific glucocorticoid receptor antagonist preferentially binds to GR rather than to a progesterone receptor (PR). In another exemplary embodiment, the specific glucocorticoid antagonist preferentially binds to GR rather than to an aldosterone receptor (AR).

[0662] In some embodiments, the association constant (Kd) of a specific glucocorticoid receptor antagonist binding to GR is at least 10-fold smaller than the Kd of binding to any other NR. In some embodiments, the association constant (Kd) of a specific glucocorticoid receptor antagonist binding to GR is at least 100-fold smaller than the Kd of binding to any other NR. In some embodiments, the association constant (Kd) of a specific glucocorticoid receptor antagonist binding to GR is at least 1000-fold smaller than the Kd of binding to any other NR.

[0663] In some embodiments, 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 any one of the compounds of the present invention or a pharmaceutical composition of the present invention.

[0664] In some embodiments, the disorder or condition is selected from 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 frailty, diseases caused by cortisol excess associated with adrenal diseases, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, post-surgical fractures, GR-related metabolic disorders, severe psychotic depression, mild cognitive impairment, dementia, hyperglycemia, stress disorders, antipsychotic-induced weight gain, delirium, cognitive impairment in patients with depression, postpartum psychosis, postpartum depression, and neurological diseases in premature infants.

[0665] 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 an agent 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 frailty, diseases caused by cortisol excess associated with adrenal diseases, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, post-surgical fractures, GR-related metabolic disorders, severe psychotic depression, mild cognitive impairment, dementia, hyperglycemia, stress disorders, antipsychotic-induced weight gain, delirium, cognitive impairment in patients with depression, postpartum psychosis, postpartum depression, and neurological diseases in premature infants. In some embodiments, the second agent is an agent for treating major psychotic depression, stress disorders, 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. 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.

[0666] In some embodiments, any one of the compounds of the invention or the pharmaceutical compositions of the invention can be used in a method for treating a disorder or condition by modulating the glucocorticoid receptor.

[0667] In some embodiments, any one of the compounds of the invention or the pharmaceutical compositions of the invention can be used in a method for treating a disorder or condition by antagonizing the glucocorticoid receptor.

[0668] In some embodiments, any compound of the invention or the pharmaceutical compositions of the invention can be used to prepare a medicament for treating a disorder or condition by modulating the glucocorticoid receptor.

[0669] In some embodiments, any compound of the invention or the pharmaceutical compositions of the invention can be used to prepare a medicament for treating a disorder or condition by antagonizing the glucocorticoid receptor. Examples

[0670] General Procedures

[0671] All starting materials and solvents were obtained from commercial sources or prepared according to literature citations. All reactions were stirred unless otherwise noted. Organic solutions were routinely dried over anhydrous magnesium sulfate. Hydrogenations were carried out on a ThalesNano H-Cube flow reactor under the indicated conditions or under the pressure of a gas autoclave (bomb).

[0672] Column chromatography was performed on a pre-packed silica (230 - 400 mesh, 40 - 63 μm) column using the indicated amounts. SCX was purchased from Chromatographic Specialties and treated with 1 M hydrochloric acid before use. Unless otherwise noted, the reaction mixture to be purified was first diluted with MeOH and acidified with a few drops of AcOH. The solution was loaded directly onto the SCX and washed with MeOH. The desired material was then eluted by washing with 1% NH 3 in MeOH.

[0673] Analytical Methods

[0674] Reverse-phase high-performance liquid chromatography. Method 1: Waters XSelect CSH UPLC C18 at 40 °C, 1.7 μm (2.1 x 30 mm); flow rate 0.77 mL.min -1 using a H 2 O-MeCN gradient elution containing 0.1% v / v formic acid for 3 minutes with UV detection at 210 and 400 nm. Gradient information: 0 - 0.11 minutes, held at 95% H 2 O - 5% MeCN, 0.11 - 2.15 minutes, rising from 95% H 2 O - 5% MeCN to 5% H 2 O - 95% MeCN; 2.15 - 2.49 minutes, held at 5% H 2 O - 95% MeCN, 2.49 - 2.56 minutes, rising from 5% H 2 O - 95% MeCN to 95% H 2 O - 5% MeCN; 2.56 - 3.00 minutes, held at 95% H 2 O - 5% MeCN.

[0675] Method 2: Waters XSelect CSH C18 at 40 °C, 2.5 μm (4.6 x 30 mm); flow rate 2.5 - 4.5 mL -1 , with a H 2 O-MeCN gradient elution containing 0.1% v / v formic acid for 4 minutes at 254 and 215 nm. Gradient information: 0 - 3.00 minutes, rising from 95% H 2 O - 5% MeCN to 5% H 2 O - 95% MeCN; 3.00 - 3.01 minutes, held at 5% H2 O - 95% MeCN, flow rate increased to 4.5 mL -1 per minute; 3.01 - 3.50 minutes, maintained at 5% H 2 O - 95% MeCN; 3.50 - 3.60 minutes, restored to 95% H 2 O - 5% MeCN, flow rate decreased to 3.50 mL min -1 ; 3.60 - 3.90 minutes, maintained at 95% H 2 O - 5% MeCN; 3.90 - 4.00 minutes, maintained at 95% H 2 O - 5% MeCN, flow rate decreased to 2.5 mL min -1 。

[0676] Method three: Waters XBridge beh c18, 1.7 μm (2.1 x 30 mm) at 40 °C; flow rate 2.5 - 4.5 mL -1 with H containing 10 mM ammonium bicarbonate at 254 nm 2 O - MeCN gradient elution for 4 minutes. Gradient information: 0 - 0.11 minutes, maintained at 95% H 2 O - 5% MeCN, 0.11 - 2.15 minutes, from 95% H 2 O - 5% MeCN increased to 5% H 2 O - 95% MeCN; 2.15 - 2.49 minutes, maintained at 5% H 2 O - 95% MeCN, 2.49 - 2.56 minutes, from 5% H 2 O - 95% MeCN increased to 95% H 2 O - 5% MeCN; 2.56 - 3.00 minutes, maintained at 95% H 2 O - 5% MeCN.

[0677] Method four: Waters XSelect BEH C18 1.7 μm (2.1 x 30 mm) at 40 °C; flow rate 0.77 mL.min -1 with H containing 10 mM ammonium bicarbonate 2 O - MeCN gradient elution for 3 minutes, using UV detection between 210 and 400 nm. Gradient information: 0 - 0.11 minutes, maintained at 95% H 2 O - 5% MeCN, 0.11 - 2.15 minutes, from 95% H 2 O - 5% MeCN increased to 5% H 2 O - 95% MeCN; 2.15 - 2.49 minutes, maintained at 5% H 2 O - 95% MeCN, 2.49 - 2.56 minutes, from 5% H 2O - 95% MeCN to 95% H 2 O - 5% MeCN; 2.56 - 3.00 minutes, hold at 95% H 2 O - 5% MeCN.

[0678] Method 5: Waters XSelect CSH UPLC C18 at 40 °C, 1.7 μm (2.1 x 30 mm); flow rate 0.77 mL.min -1 Using H containing 0.1% v / v formic acid 2 O - MeCN gradient elution for 10 minutes, using UV detection between 210 and 400 nm. Gradient information: 0 - 9.52 minutes from 95% H 2 O - 5% MeCN to 5% H 2 O - 95% MeCN; 9.52 - 9.93 minutes, hold at 5% H 2 O - 95% MeCN, 9.93 - 10.00 minutes, from 5% H 2 O - 95% MeCN to 95% H 2 O - 5% MeCN; 10.00 - 10.20 minutes, at 95% H 2 Performed in O - 5% MeCN.

[0679] Method 6: Waters HClass; binary solvent pump, SM - FTN, CMA, PDA: 210 - 400 nm, QDa: ACQ - QDa ESI; column: Waters CSH C18, 30 x 2.1 mm, 1.7 μm, temperature: 40 °C, flow rate: 0.77 ml / min, gradient: t0 = 2% B, t2.5min = 100% B, t3.0min = 100% B, eluent A: 0.1% formic acid in water, eluent B: acetonitrile.

[0680] Method 7: Waters HClass; quaternary solvent pump, SM - FTN, CMA, PDA: 210 - 400 nm, QDa: ACQ - QDa ESI; column: Waters CSH C18, 30 x 2.1 mm, 1.7 μm, temperature: 40 °C, flow rate: 0.77 ml / min, gradient: t0 = 2% B, t2.5min = 100% B, t3.0min = 100% B, eluent A: 0.1% formic acid in water, eluent B: acetonitrile.

[0681] Method 8: UPLC_Basic, Equipment: Waters HClass; Binary Solvent Pump, SM-FTN, CMA, PDA: 210 - 400 nm, QDa: ACQ-QDa ESI; Column: Waters BEH C18, 30 x 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.

[0682] Nuclear magnetic resonance spectra were recorded using a Bruker 400 MHz Avance Neo spectrometer equipped with a Bruker 5 mm iProbe, or a Bruker 500 MHz Avance III HD spectrometer equipped with a Bruker 5 mm Smart Probe TM. Unless otherwise stated, spectra were measured at 298 K 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.

[0683] All chemical names were generated using ChemDraw.

[0684] Intermediate

[0685] Intermediate A: 4-Bromo-N-(4-fluorophenyl)-5-methyl-2-nitroaniline

[0686]

[0687] 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 silica gel chromatography (40 g, 0 - 20% EtOAc / isohexane) to afford 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).

[0688] Intermediate B: 4-Bromo-N1-(4-fluorophenyl)-5-methylbenzene-1,2-diamine

[0689]

[0690] 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) was added iron (2.070 g, 37.1 mmol), followed by aqueous HCl (2 M, 7.41 mL, 14.82 mmol), and then the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated aqueous NaHCO 3 solution (100 mL), filtered through diatomaceous earth, 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.

[0691] Intermediate C: 5-bromo-1-(4-fluorophenyl)-6-methyl-1H-benzo[d][1,2,3]triazole

[0692]

[0693] To a stirred suspension of 4-bromo-N1-(4-fluorophenyl)-5-methylbenzene-1,2-diamine (Intermediate B) (2.2 g, 7.45 mmol) in water (13 mL) at 0 °C was added 37% HCl (6.12 mL, 74.5 mmol). After 5 minutes, 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 hours. The reaction mixture was basified by adding 2 M NaOH (aq) and the resulting precipitate was collected by filtration and purified by silica gel chromatography (80 g, 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).

[0694] Example 1: (R)-1-(4-fluorophenyl)-5-(2-methyl-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperazin-1-yl)-1H-indazole

[0695] Intermediate D: 5-bromo-1-(4-fluorophenyl)-1H-indazole

[0696]

[0697] 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), opened to the air by puncturing the septum and stirred overnight. The reaction was filtered through a pad of celite, washed with dichloromethane (30 mL) and concentrated in vacuo. The crude product was purified by silica gel chromatography (80 g, 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 + ).

[0698] Intermediate E: (R)-4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

[0699]

[0700] A solution of 5-bromo-1-(4-fluorophenyl)-1H-indazole (Intermediate D) (1.0 g, 3.44 mmol), (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (688 mg, 3.44 mmol) and sodium tert-butoxide (528 mg, 5.50 mmol) in 1,4-dioxane (10 ml) was degassed with nitrogen bubbling for 5 minutes. Chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (69 mg, 0.172 mmol) was then added and the solution was degassed for another 5 minutes. The solution was then heated to 80°C and stirred overnight. The reaction mixture was cooled to room temperature and distributed between EtOAc (50 mL) and water (80 mL), the layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organics were washed with MgSO 4Dry, filter and concentrate in vacuo. The crude product was purified by silica gel chromatography (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 min (Method 1); m / z 411.85 (M + H) + (ES + )

[0701] Example 1: (R)-1-(4-Fluorophenyl)-5-(2-methyl-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperazin-1-yl)-1H-indazole

[0702]

[0703] HCl (4 M 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). The reaction mixture was stirred at room temperature for 3 h and then concentrated to dryness.

[0704] 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). 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 dried over MgSO 4 Dry, filter and concentrate in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0 - 50% EtOAc / isohexane) to give Example 1 of (R)-1-(4-fluorophenyl)-5-(2-methyl-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperazin-1-yl)-1H-indazole (70 mg, 0.152 mmol, 64.5% yield) as a colorless solid; Rt 1.49 min (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).

[0705] Example 2: (R)-(4-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone

[0706]

[0707] HCl (4 M, 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). The reaction mixture was stirred at room temperature for 3 h and then concentrated to dryness.

[0708] 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). 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), dried over MgSO 4 dried, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (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 min (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.

[0709] Example 3: 1-(4-Fluorophenyl)-5-(7-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,7-diazaspiro[2.5]octan-4-yl)-1H-indazole

[0710] Intermediate F: tert-Butyl 7-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0711]

[0712] 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). The mixture was stirred overnight at room temperature. Water (10 mL) and dichloromethane (10 mL) were added and the layers were separated. The organic layer was washed with water (10 mL), dried over MgSO 4 4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (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).

[0713] Example 3: 1-(4-Fluorophenyl)-5-(7-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,7-diazaspiro[2.5]octan-4-yl)-1H-indazole

[0714]

[0715] HCl (4 M, 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). The reaction was stirred at room temperature for 3 hours and then concentrated to dryness.

[0716] 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. The solution was degassed by bubbling with nitrogen for 5 minutes. Chlorotris(t-butylphosphine)palladium(II) (6.86 mg, 0.017 mmol) was added and the solution was further degassed for 5 minutes, then heated to 80 °C and stirred overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (15 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 15 mL). The combined organics were dried over MgSO 4 dried, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (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 minutes (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).

[0717] Example 4: (S)-N-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-yl)-1-propyl-1H-pyrazole-4-sulfonamide

[0718] Intermediate G. tert-Butyl (S)-(1-(4-fluorophenyl)-6-methyl-1H-imidazol-5-yl)pyrrolidin-3-yl)carbamate.

[0719]

[0720] A vial containing 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), RuPhos G3 precatalyst (219 mg, 0.262 mmol) and cesium carbonate (2.56 g, 7.87 mmol) was evacuated and backfilled with nitrogen (x3). 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 saturated sodium bicarbonate solution (10 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 dark yellow residue. The crude product was purified by silica gel chromatography (liquid loading DCM, 120 g frit, 0 - 50% EtOAc / isohexane) to give tert-butyl (S)-(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 (brd, 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).

[0721] (S)-N-(1-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-yl)-1-propyl-1H-pyrazole-4-sulfonamide

[0722]

[0723] To a solution of (S)-tert-butyl (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 turbid 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, washed with tert-butyl methyl ether (2 x 5 mL) and dried in vacuo to give (S)-1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-amine hydrochloride as a white solid, which was used without further purification.

[0724] To a solution of (S)-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. With saturated NaHCO 3The reaction mixture was quenched with aqueous solution (10 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, and the crude product was purified by silica gel chromatography (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; Rt 1.60 min (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).

[0725] Example 5: (S)-N-(1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-3-yl)-N-methyl-1H-propylpyrazole-4-sulfonamide

[0726]

[0727] At 0 °C, sodium hydride (60% in mineral oil) (4.77 mg, 0.119 mmol) was added in one portion 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). The resulting yellow solution was stirred at 0 °C for 30 minutes and iodomethane (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 x 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 silica gel chromatography (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).

[0728] Example 6: 1-(4-Fluorophenyl)-6-methyl-5-(1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole

[0729] Intermediate H: tert-Butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

[0730]

[0731] 5-Bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (prepared by the method of 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 diatomaceous earth, and then directly adsorbed onto silica gel. Chromatographic purification on silica gel (24 g cartridge, 0 - 100% EtOAc / isohexane) gave 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 min (Method 1); m / z 408.7 (M+H) + (ES + )。

[0732] Intermediate I: tert-butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)piperidine-1-carboxylate

[0733]

[0734] 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 carbon (type 39, 10% loading, 50% w / w water) (150 mg, 0.070 mmol) was added. The mixture was stirred under a hydrogen pressure of 5 bar for 4 h. The mixture was filtered through diatomaceous earth and eluted with ethanol (3 x 5 mL) and ethyl acetate (3 x 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 min (Method 1); m / z 410.3 (M+H) + (ES + )。

[0735] Example 6: 1-(4-Fluorophenyl)-6-methyl-5-(1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole

[0736]

[0737] Dissolve tert-butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)piperidine-1-carboxylate (0.05 g, 0.122 mmol) in hydrochloric acid (4 M in 1,4-dioxane) (2 mL, 8.00 mmol) and stir at room temperature for 1 h. Remove the solvent in vacuo and suspend the residue in dichloromethane (2 mL). Add pyridine (50 μL, 0.618 mmol) and methanesulfonyl chloride (20 μL, 0.258 mmol), and heat the mixture to 35 °C (bath temperature) for 3 days. Allow the mixture to reach room temperature and then quench with 1 M HCl (水性) (1 mL). Separate the organic phase through a hydrophobic frit and then concentrate in vacuo. Purify the crude product by silica gel chromatography (4 g cartridge, 0-100% EtOAc / isohexane) to give 1-(4-fluorophenyl)-6-methyl-5-(1-(methanesulfonyl)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).

[0738] Example 7: 1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-4-(methylsulfonyl)piperazin-2-one

[0739] Intermediate J: tert-butyl 4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-3-oxopiperazine-1-carboxylate

[0740]

[0741] 5-Bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (prepared by 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(I) 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 and filtered through a short pad of celite, and the solvent was removed in vacuo. 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 min (Method 1); m / z 425.3 (M+H) + (ES + )

[0742] Example 7: 1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-4-(methylsulfonyl)piperazin-2-one

[0743]

[0744] 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 hydrochloric acid (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 dimethyl sulfoxide (2 mL). The mixture was filtered and then purified directly by preparative HPLC (Method A, 20-50% MeCN in water). After concentration of the fractions containing the product (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).

[0745] Example 8: 1-(4-Fluorophenyl)-5-((2R)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole

[0746] Intermediate K: (2R)-tert-Butyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-hydroxy-2-methylpiperidine-1-carboxylate

[0747]

[0748] 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)-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (250 mg, 1.172 mmol) in tetrahydrofuran (3 mL) was added immediately, and the mixture was stirred at -78 °C for 30 minutes. The mixture was quenched at low temperature with saturated ammonium chloride (1 mL) and then with water (3 mL). Ethyl acetate (10 mL) was added. The organic phase was separated, washed with brine (2 mL), and then dried over MgSO 4 dried, filtered and concentrated in vacuo to give a yellow oil. The crude product was purified by silica gel chromatography (24 g cartridge, 0 - 70% EtOAc / isohexane, 20 minutes) to give (2R)-4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (Intermediate K) (103 mg, 0.232 mmol, 23.24% yield), as a colorless transparent glass; R t 0.74 minutes (Method 1); m / z 426.7 (M + H) + (ES + ).

[0749] 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

[0750]

[0751] Dissolve (2R)-4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (Intermediate K) (100 mg, 0.226 mmol) in hydrochloric acid (4 M in 1,4-dioxane) (3 mL, 12.00 mmol) and stir at room temperature for 15 minutes. Concentrate the yellow oily suspension in vacuo to give a 1:1 mixture (87 mg, 100%) 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-1,4-2,3,6-tetrahydropyridin-4-yl)-1H-indazole hydrochloride (Intermediate L), which can be used without further purification, R t 0.39 and 0.44 min (Method 1); m / z 308.2 (M+H) + (ES + )

[0752] 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

[0753]

[0754] 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 over a hydrophobic frit and concentrated in vacuo. The crude product was purified by silica gel chromatography (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 + )。

[0755] Example 8: 1-(4-Fluorophenyl)-5-((2R)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole

[0756]

[0757] (R)-1-(4-Fluorophenyl)-5-(2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole (25 mg, 0.048 mmol) and 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 (Intermediate M) (25 mg, 0.048 mmol) were dissolved in ethanol (2 mL) and tetrahydrofuran (1 mL). Palladium on 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 hours. The mixture was filtered through celite and concentrated in vacuo. The crude product was purified by silica gel chromatography (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 diastereomers; R t 1.74 and 1.76 minutes (Method 1); m / z 482.3 (M+H) + (ES + )

[0758] Example 9: 1-(4-Fluorophenyl)-5-((2R,4R)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole and

[0759] Example 10: 1-(4-Fluorophenyl)-5-((2R)-2-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole

[0760]

[0761] (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 diastereomers was dissolved in ethanol to 20 mg / mL without sonication or heating and then separated by chiral SFC on a Watersprep 15 with UV detection at 210 - 400 nm with DAD, 40 °C, 120 bar, on Ia, column flow rate (1 x 25 cm, 5 μm particle size) 15 mL / min -1, Use 25% ethanol. Then the combined fractions were 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) as a colorless glass; Rt 1.74 min (Method 1); R t 1.74 min (Method 1); 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, 1 h), 7.79 (dd, J 9.0, 4.8, 2 h), 7.72 (d, J 8.8, 1 h), 7.62 (s, 1 h), 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).

[0762] 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

[0763]

[0764] 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 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 (41 mg, 0.128 mmol), prepared by a method similar to that of Intermediate M, was dissolved in MeOH at 50 mg / ml without sonication or heating, filtered, and then separated by chiral SFC on a Watersprep15 with UV detection using DAD at 210 - 400 nm, at 40 °C, 120 bar, on a column (1 x 25 cm, 5 μm particle size) with a flow rate of 15 mL / min -1 , using 35% MeOH. The combined fractions were then concentrated in vacuo 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 min (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 regioisomer was not cleanly separated out.

[0765] 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

[0766] 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

[0767]

[0768] 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 by a method similar to that described in Example 7 was dissolved in MeOH at 50 mg / mL without sonication or heating, filtered, and then separated by chiral SFC on a Watersprep15 with UV detection using DAD at 210 - 400 nm, at 40 °C, 120 bar, on IA, column (1 x 25 cm, 5 μm particle size) flow rate 15 mL / min -1, 25% ethanol was used. The combined fractions were concentrated in vacuo to afford 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; Rt 1.80 min (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) 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).

[0769] Example 14: (S)-(1-((1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)sulfonyl)-4-(1-(4-fluorophenyl)-1H-indazol-5-yl)piperidin-2-yl)methanol

[0770]

[0771] At 0 °C, a solution of tetrabutylammonium fluoride (1 M in THF) (360 μL, 0.360 mmol) was added dropwise 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) prepared in a similar manner to that described in Example 3. 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 x 10 mL). The organic layers were combined, washed with brine (1 x 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 silica gel chromatography (24 g cartridge, 0 - 100% EtOAc / isohexane) to afford (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 viscous colorless gum; Rt 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).

[0772] Example 15: (S)-5-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)sulfonyl)-3-(methoxymethyl)piperazin-1-yl)-1-(4-fluorophenyl)-1H-indazole

[0773]

[0774] At 0 °C, sodium hydride (60% in mineral oil) (7.05 mg, 0.176 mmol) was added in one portion 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). The resulting white suspension was stirred at 0 °C for 30 minutes. Iodomethane (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 saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, washed with brine (5 mL), passed through a hydrophobic frit, and the solvent was removed under reduced pressure to afford a yellow residue. The crude product was purified by silica gel chromatography (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 viscous colorless oil; Rt 1.69 minutes (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 = 7.2 Hz, 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, overlapping with 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).

[0775] Example 16: 5-(3-Benzyl-1-(methylsulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole

[0776] Intermediate N: 1-(4-Fluorophenyl)-6-methyl-5-(4,4,5-trimethyl-1,3,2-dioxolan-2-yl)-1H-indazole

[0777]

[0778] Suspend 5-bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (prepared by the method described for Intermediate D) (1.00 g, 3.27 mmol), 4,4,4',4',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)Cl2.DCM (250 mg, 0.31 mmol) in 1,4-dioxane (15 mL). Evacuate the mixture and backfill with nitrogen (3x), then heat to 80 °C for 16 h. Cool the mixture to room temperature, then filter through celite, eluting with ethyl formate (50 mL). Wash the filtrate with water (2 x 50 mL) and brine (50 mL), then dry over Na 2 SO 4 2SO4, filter and concentrate in vacuo. Purify the crude product by silica gel chromatography (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 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).

[0779] Intermediate O: 1-Benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidine-2,5-dione

[0780]

[0781] 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 at 50 °C overnight. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by silica gel chromatography (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).

[0782] Intermediate P: 1,3-Dibenzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidine-2,5-dione

[0783]

[0784] At 0 °C, sodium hydride (66 mg, 60% Wt, 1.65 mmol) was added 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). The resulting dark purple solution was stirred at 0 °C for 30 minutes, at which time benzyl bromide (376 mg, 2.20 mmol) was added, and the resulting purple solution was stirred at room temperature for 2 hours. At 0 °C, the reaction mixture was quenched by the addition of a saturated solution of sodium bicarbonate (30 mL) and extracted with ethyl acetate (3 x 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).

[0785] Intermediate Q: 5-(1,3-dibenzylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole

[0786]

[0787] 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), lithium aluminum hydride (2 M, THF) (29 mg, 0.4 mL, 0.77 mmol) was added 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), then with 2 M aqueous sodium hydroxide (0.2 mL), and then water (0.4 mL). Na 2 SO 4 was added and the mixture was filtered. After concentrating 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 min (Method 1); m / z 476.5 (M+H) + (ES + ); The product was used in the next step without further purification.

[0788] Intermediate R: 5-(3-Benzylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole

[0789]

[0790] 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 overnight at 50 °C under a hydrogen pressure of 5 bar. The mixture was filtered through diatomaceous earth, eluting with ethyl acetate (3 x 5 mL) and methanol (3 x 5 mL). The combined filtrates were concentrated in vacuo 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.

[0791] Example 16: 5-(3-Benzyl-1-(methylsulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole

[0792]

[0793] 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 h. The reaction was quenched by addition of saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layers were combined and passed through a hydrophobic frit. The solvent was removed under reduced pressure to afford a black residue. The crude material was purified by silica gel chromatography (12 g cartridge, 0-50% EtOAc / isohexane) to give 5-(3-benzyl-1-(methanesulfonyl)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 min (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) overlapped with 3.00 (m, 1H), 2.50 (m, 1H, hidden in DMSO signal), 2.47 (2) (s, 3H), 2.21 (q, J = 10.6 Hz, 1H).

[0794] Example 17: (S)-5-(3-benzyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole

[0795] Example 18: (R)-5-(3-benzyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole

[0796]

[0797] The racemic product was dissolved in dichloromethane:methanol 1:1 by ultrasound and heating, then filtered and separated by chiral SFC on a Watersprep15 with UV detection at 210 - 400 nm using DAD, at 40 °C, 120 bar, using an IC (Daicel Ltd.) column (1 x 25 cm, 5 μm particle size), flow rate 15 mL / min-1, using 50% ethanol plus 0.1% ammonia. The clean fractions were combined, rinsed with ethanol and then evaporated to dryness using a rotary evaporator. The residue was redissolved in ethanol, transferred to a final vial and evaporated in a nitrogen stream at 40 °C. It was then further dried in a vacuum oven at 40 °C / 5 mbar 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%) 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).

[0798] Example 19: (3-Benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone

[0799]

[0800] 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 saturated sodium bicarbonate solution (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 afford (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 min (Method 1); m / z 494.5 (M + H) + (ES +); δH(DMSO-d6, 500 MHz, 363 K) 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).

[0801] Example 20: 5-(3-Benzyl-1-methylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole

[0802]

[0803] 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 solution of 37% formaldehyde (8.4 mg, 0.10 mmol) in water (1 mL). The resulting solution was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (33 mg, 0.16 mmol) was added. The resulting solution was stirred at room temperature overnight. The reaction was quenched by adding 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 colorless 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), 2.38 (s, 3H) and 2.36 - 2.31 (m, 1H), (3) 2.30 - 2.23 (m, 1H), 2.20 - 2.13 (m, 1H).

[0804] 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

[0805] Intermediate S: 1-(tert-Butyl) 4-methyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)piperidine-1,4-dicarboxylate

[0806]

[0807] To a solution of dicyclohexylamine (0.6 mL, 3.02 mmol) in toluene (5 mL) cooled to 0 °C was added n-butanol (2.5 M in hexanes) (1.1 mL, 2.75 mmol). The mixture was stirred at room temperature for 15 minutes and then 1,4-di-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (0.685 mL, 2.79 mmol) was added. After stirring for an additional 10 minutes, a solution of Pd - 162 (33 mg, 0.082 mmol) and 5-bromo-1-(4-fluorophenyl)-1H-indazole (Intermediate D) (0.5 g, 1.718 mmol) in toluene (5 mL) was added. The mixture was heated to 100 °C for 20 minutes. The mixture was directly adsorbed onto silica gel and purified by silica gel chromatography (40 g frit, 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 which gradually 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).

[0808] Example 21: Ethyl 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate

[0809]

[0810] 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 hydrochloric acid (4 M 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 (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), washed with 1 M aqueous HCl (2 x 5 mL) and brine (5 mL), then dried over 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 give 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 min (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).

[0811] 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

[0812] Intermediate T: 4-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylic acid

[0813]

[0814] 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). Aqueous 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 (5 mL). The mixture was heated to reflux for 3 days. The mixture was cooled to room temperature and ethanol was removed in vacuo. The mixture was acidified with 1 M aqueous hydrochloric acid. The solid formed was isolated and dried in vacuo 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, yield 174%) 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).

[0815] 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

[0816]

[0817] To a stirred suspension 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 for 15 minutes at room temperature, pyrrolidine (10 μL, 0.122 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (10 mL). The organic phase was washed with 1 M aqueous hydrochloric acid. The organic phase was washed with 1 M aqueous HCl (10 mL), saturated sodium bicarbonate (10 mL) and brine (10 mL), and then dried over Na 2 SO 4 and filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (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 min (Method 1); m / z 579.3 (M + H) + (ES +); δH (DMSO-d6, 500 MHz) 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 (brs, 2H), 2.49 - 2.42 (m, 4H), 2.32 (s, 3H), 2.03 (brs, 2H), 1.79 (h, J = 7.1 Hz, 2H), 1.58 - 1.42 (m, 4H), 0.76 (t, J = 7.4 Hz, 3H).

[0818] Example 23: 1-(4-Fluorophenyl)-5-(4-(methoxymethyl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole

[0819] Intermediate U: (4-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol

[0820]

[0821] 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), lithium aluminum hydride (2 M, THF) (0.3 mL, 0.60 mmol) was slowly added over 5 minutes. The mixture was stirred at room temperature for 2 hours. Water (0.05 mL) was added, then 2 M aqueous sodium hydroxide (0.05 mL), and then more water (0.15 mL). The mixture was stirred until gas evolution ceased, and then dried over Na 2 SO 4 and filtered through celite, eluting with tetrahydrofuran (3 x 5 mL). The filtrate was concentrated in vacuo. The residue was dissolved in the minimum amount of dichloromethane and then isooctane (5 mL) was added, giving a turbid 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 min (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).

[0822] Example 24: 1-(4-Fluorophenyl)-5-(4-(methoxymethyl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole

[0823]

[0824] 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 (2 M in THF) (40 μL, 0.080 mmol). The yellow mixture was stirred at room temperature for 1 h and then partitioned between dichloromethane (5 mL) and water (2 mL). The organic phase was separated, washed with brine (mL), dried over hydrophobic frit, and 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).

[0825] Example 25: 5-(4-Benzyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1-(4-fluorophenyl)-1H-indazole

[0826] Intermediate V: 4-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbaldehyde

[0827] At 0 °C, Dess-Martin periodinane 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)methanol (Intermediate U) (237 mg, 0.46 mmol) in dichloromethane (3 mL). The reaction was heated to room temperature and then stirred overnight. The reaction was diluted with dichloromethane (10 mL) and washed with 2M Na 2 S 2 O 3 (20 mL), and then washed with saturated sodium carbonate (20 mL). The organic layer was dried over MgSO 4 and filtered and concentrated in vacuo to give 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, and was used in the next step without further purification; R t 0.73 min (Method 1); m / z 510.35 (M + H) + (ES + ).

[0828] 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

[0829] At 0 °C, phenylmagnesium chloride (2 M in THF) (0.14 mL) was added to a 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 heated to room temperature and stirred overnight. The reaction was quenched with water (10 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (3 × 10 mL), and the combined organic layers were dried over MgSO 4 and filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g cartridge, 0 - 50% EtOAc / isohexane) to afford (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 + )

[0830] Example 25: 5-(4-Benzyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1-(4-fluorophenyl)-1H-indazole

[0831]

[0832] 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 in dichloroethane (76 μL, 0.48 mmol) was added boron trifluoride etherate (68 mg, 0.48 mmol), and the mixture was stirred at 80 °C for 4 h. The reaction was quenched with water (10 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (3 × 10 mL), and the combined organic layers were dried over MgSO 4 and filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g cartridge, 0 - 50% EtOAc / isohexane) to afford 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).

[0833] Example 26: 1-(4-Fluorophenyl)-6-methyl-5-(3-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole

[0834] Intermediate X: 1-(4-Fluorophenyl)-6-methyl-5-(3-methylpyridin-4-yl)-1H-indazole

[0835]

[0836] To a suspension of 5-bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (prepared using the method described for Intermediate D) (0.5 g, 1.64 mmol), (3-methylpyridin-4-yl)boronic acid (0.25 g, 1.83 mmol) and Pd(dppf)Cl2.DCM (0.1 g, 0.122 mmol) in dioxane (5 mL) was added an aqueous solution of potassium carbonate (0.75 g, 5.43 mmol) (2 mL). The mixture was evacuated and backfilled with nitrogen (3x), then heated to 90 °C for 3 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (10 mL). The organic phase was separated and directly adsorbed onto silica gel. The crude product was purified by silica gel chromatography (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 minutes (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).

[0837] Intermediate Y: 1-(4-Fluorophenyl)-6-methyl-5-(3-methylpiperidin-4-yl)-1H-indole

[0838]

[0839] Dissolve 1-(4-fluorophenyl)-6-methyl-5-(3-methylpyridin-4-yl)-1H-indazole (Intermediate X) (100 mg, 0.315 mmol) in acetic acid (2 mL). Add platinum(IV) oxide (50 mg, 0.220 mmol), and stir the mixture at 50 °C under a hydrogen pressure of 5 bar for 16 h. Filter the mixture through a short pad of diatomaceous earth eluted with methanol (5 × 10 mL). Treat the filtrate with SCX (3 g) and stir for 15 min. Wash the SCX with methanol (100 mL), and then elute the product with 0.7 M ammonia in methanol (5 × 10 mL). Concentrate the combined fractions 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. Carry the material through crude to the final step.

[0840] Example 26: 1-(4-Fluorophenyl)-6-methyl-5-(3-methyl-1-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-1H-indazole

[0841]

[0842] 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 purified directly by silica gel chromatography (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).

[0843] 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-indole

[0844] 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

[0845]

[0846] 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 was obtained by suspending 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) in tetrahydrofuran (3 mL) and stirring at room temperature. Trimethyl(trifluoromethyl)silane (50 μL, 0.338 mmol) was added and the mixture was heated to 60 °C overnight. More trimethyl(trifluoromethyl)silane (50 μL, 0.338 mmol) was added and the mixture was heated for an additional 24 h. The mixture was cooled to room temperature, adsorbed onto silica gel, and purified by silica gel chromatography (12 g frit, 0-50% EtOAc / isohexane) to give 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; Rt 1.99 min (Method 1); m / z 458.4 (M+H)+ (ES+); this was used directly in the next step as the NMR was spinning.

[0847] 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

[0848]

[0849] Step A: 5-(7,7-Difluoro-3-azabicyclo[4.1.0]heptan-6-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole, HCl (32 mg, 0.081 mmol, 93% yield) as a colorless solid was obtained by dissolving 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) in hydrochloric acid (4 M in dioxane) (3 mL, 12.00 mmol) and stirring at room temperature for 1 h. The solvent was removed in vacuo and triturated with diethyl ether (3 mL).

[0850] Step B: 5-(7,7-Difluoro-3-azabicyclo[4.1.0]heptan-6-yl)-1-(4-fluorophenyl)-6-methyl-1H-indole, 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 hour and then purified directly by silica gel chromatography (4 g frit, 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 by residual DMSO.

[0851] Example 28: 1-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-methylpyrrolidine-3-sulfonamide

[0852]

[0853] A vial containing RuPhos G3 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 by the method of Intermediate D) (50 mg, 0.164 mmol) in 1,4-dioxane (2 mL) was evacuated and backfilled with N 2(x3). A solution of 1M 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 saturated sodium bicarbonate solution (5 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 afford a black oil. The crude product was purified by silica gel chromatography (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 min (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).

[0854] Example 29: 1-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-methyl-N-(1-propyl-1H-pyrazol-4-yl)pyrrolidine-3-sulfonamide

[0855] Intermediate AA: tert-Butyl 3-(N-(1-propyl-1H-pyrazol-4-yl)aminosulfonyl)pyrrolidine-1-carboxylate

[0856]

[0857] 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 h. The reaction was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layers were combined and passed through a hydrophobic frit. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by silica gel chromatography (24 g cartridge, 0 - 100% EtOAc / isohexane) to afford tert-butyl 3-(N-(1-propyl-1H-pyrazol-4-yl)aminosulfonyl)pyrrolidine-1-carboxylate (Intermediate AA) (115 mg, 0.305 mmol, 41% yield) as a pale purple oil; R t 1.19 min (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).

[0858] Example 29: 1-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(1-propyl-1H-pyrazol-4-yl)pyrrolidine-3-sulfonamide

[0859]

[0860] The preparation method of this compound is similar to that described in 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 (brs, 3H), 2.27 (m, 2H), 1.74 (h, J = 7.3 Hz, 2H), 0.79 (t, J = 7.4 Hz, 3H).

[0861] Example 30: 1-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-methyl-N-(1-propyl-1H-pyrazol-4-yl)pyrrolidine-3-sulfonamide

[0862]

[0863] At 0 °C, sodium hydride (2.98 mg, 0.075 mmol) was added in one portion to a solution of 1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-(1-propyl-1H-pyrazol-4-yl)pyrrolidine-3-sulfonamide (Example 29) (30 mg, 0.062 mmol) in dimethylformamide (2 mL). The resulting yellow solution was stirred at 0 °C for 30 minutes and iodomethane (7.77 μL, 0.124 mmol) was added. The resulting white solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium 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 to give a pale yellow residue. The crude product was purified by silica gel chromatography (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 minutes (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, overlapping 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).

[0864] Example 31: 4-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-phenylpiperidine-1-carboxamide

[0865]

[0866] 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 purified by preparative HPLC (water, acidic (0.1% formic acid), acidic, Waters X-Select Prep-C18, 5 μm, 19 x 50 mm column, 35 - 65% MeCN in 0.1% aqueous formic acid solution) to afford 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).

[0867] Example 32: 4-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-N-isopropylpiperidine-1-carboxamide

[0868]

[0869] The preparation method of this compound is similar to that described in Example 31; Rt 1.59 minutes (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).

[0870] Example 33: 1-(4-Fluorophenyl)-6-methyl-5-(4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-1-yl)-1H-indazole

[0871] Intermediate AB: tert-Butyl 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine-1-carboxylate

[0872]

[0873] At 0 °C, hydrazine hydrate (1.3 mL, 26.1 mmol) was added to a solution of 1-methyl-1H-pyrazole-4-sulfonyl chloride (1.66 g, 9.19 mmol) in tetrahydrofuran (25 mL). The mixture was allowed to reach room temperature within 1 hour. 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 organic matter was dried through a hydrophobic filter and then concentrated in vacuo to give 1-methyl-1H-pyrazole-4-sulfonyl hydrazide (668 mg, 3.79 mmol, 41% yield) as a colorless solid. 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 colorless transparent oil; the chromophore was very poor, so the UPLC analysis was inconclusive. 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).

[0874] Intermediate AC: 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0875]

[0876] 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 dropwise hydrochloric acid (4 M in dioxane) (1 mL, 4.00 mmol) all at once, and the mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the resulting solid was dried in vacuo at 40 °C for 1 hour to give 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine·HCl (Intermediate AC), which was used in the next step without further purification.

[0877] Example 33: 1-(4-Fluorophenyl)-6-methyl-5-(4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-1-yl)-1H-indazole

[0878]

[0879] 5-Bromo-1-(4-fluorophenyl)-1H-indazole (prepared by 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 a stirred suspension in dioxane (2 mL) were evacuated and backfilled with nitrogen (3X), then heated to 90 °C for 16 h. The mixture was cooled to room temperature and then directly adsorbed onto silica gel. The crude product was purified by silica gel chromatography (12 g frit, 0-100% EtOAc / isohexane) to give 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 obscured by residual water in DMSO solvent.

[0880] Examples 34 - 96

[0881] Table 3: The examples shown in the following table were prepared by a method similar to that described for Example 1.

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904] Example 97 - 103

[0905] Table 4: The examples shown in the following table were prepared by a method similar to the method described in Example 2.

[0906]

[0907]

[0908]

[0909]

[0910] Example 104: (R)-1-(4-fluorophenyl)-5-(3-methyl-4-(propylsulfonyl)piperazin-1-yl)-1H-indazole

[0911]

[0912] The compound was prepared by a method similar to that described in Example 3. R t 1.71 minutes (Method 1); m / z 417.43 (M+H) + (ES + )

[0913] Examples 105 - 133

[0914] Table 5: The examples shown in the following table were prepared by a method similar to that described in Example 5

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926] Examples 134 - 146

[0927] Table 6: The examples shown in the following table were prepared by a method similar to that described in Example 6

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934] Examples 147 - 189

[0935] Table 7: The examples shown in the following table were prepared by a method similar to that described in Example 16.

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951] Examples 190 - 208

[0952] Table 8: The examples shown in the following table were prepared by a method similar to that described in Example 19.

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960] Example 209: 1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-4-((1-propyl-1H-pyrazol-4-yl)sulfonyl)piperazin-2-one

[0961]

[0962] The compound was prepared by a method similar to that described in Example 7. R t 1.44 min (Method 1); m / z 497.3 (M+H) + (ES + )

[0963] Examples 210 - 228

[0964] Table 9: The examples shown in the following table were prepared by a method similar to that described in Example 16

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973] Examples 229 - 235

[0974] Table 10: The examples shown in the following table were prepared by a method similar to that described in Example 19

[0975]

[0976]

[0977]

[0978] 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

[0979] Intermediate AD: 6-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)-1H-indazole

[0980]

[0981] 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 over 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. The 5-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (39 g, 87.3% Wt, 0.12 mol) was purged with N 2 A suspension 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'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (35 g, 0.14 mol), and potassium acetate (51 g, 0.52 mol) (51 g, 0.52 mol) in 1,4-dioxane (250 mL) was purged for 15 min. PdCl2(dppf)-CH2Cl2 adduct (4.7 g, 5.8 mmol) was added and the solution was purged with N 2 for 15 min, heated to 80 °C and stirred for 3.5 h. The reaction mixture was cooled to room temperature overnight and partitioned between EtOAc (500 mL) and 1:1 brine / H 2 O (250 mL), 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), dried over MgSO 4 , filtered and concentrated in vacuo to give 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)-1H-indazole (45 g, 0.11 mol, 94%) as a dark brown oil, which was used as such in the next step.

[0982] Intermediate AE: 1-Benzyl-3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyrrolidine-2,5-dione

[0983]

[0984] Purge with N 2 Purge 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) for 10 minutes. Purge with N 2 Purge 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 and water for 10 minutes. Add hydroxy(cyclooctadiene)rhodium(I) dimer (1.5 g, 3.3 mmol), and purge the solution with N 2 for 5 minutes, then heat at 80 °C and stir for 1 hour. The reaction mixture is cooled and concentrated to a low volume (~150 mL). The reaction mixture is partitioned between EtOAc (300 mL) and water (150 mL), the layers are separated, and the organic layer is washed with semi-saturated brine (100 mL). Dry the organic matter with MgSO 4 and filter and concentrate in vacuo to give a dark brown oil. The crude product is purified by silica gel chromatography (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 viscous tan gum; Rt 1.93 minutes (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).

[0985] Intermediate AF: 1,3-Dibenzyl-3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyrrolidine-2,5-dione

[0986]

[0987] Using N 2 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 purged with N for 10 minutes while cooling to 0 °C. Sodium hydride (685 mg, wt%, 17.1 mmol) was added in one portion, and the resulting solution was stirred at 0 °C for 30 minutes. (Bromomethyl)benzene (3.83 g, 2.66 mL, 22.4 mmol) was added, and the reaction mixture was allowed to warm to 20 °C and stirred for 23 hours. The reaction mixture was quenched with water (40 mL), and the aqueous phase was extracted with EtOAc (3 × 60 mL). The combined organic phases were dried over MgSO 4 dried, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (120 g cartridge, 0 - 50% EtOAc / isohexane) to give 1,3-dibenzyl-3-(6-methyl-1-(tetrahydro-2H-pyran)-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).

[0988] Intermediate AG: 5-(1,3-Dibenzylpyrrolidin-3-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0989]

[0990] In a 3-necked round-bottomed flask equipped with a bubbler, purge 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) with N 2 for 10 minutes, then cool to 0 °C. Add DIBAL-H (1 M in hexanes) (11.7 g, 82.0 mL, 1 mol, 82.0 mmol), then allow the resulting solution to warm to 20 °C and stir for 18 h. The reaction mixture is cooled to 0 °C and water (3.3 mL), 2 M NaOH (3.3 mL) and water (8.2 mL) are added very slowly in sequence. The reaction mixture is warmed to room temperature, MgSO 4 (in excess) is added, and then the reaction mixture is stirred for 15 minutes. The slurry is filtered, washed with EtOAc (2 × 50 mL) and concentrated in vacuo. The crude product is purified by silica gel chromatography (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).

[0991] Intermediate AH: 5-(3-benzylpyrrolidin-3-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0992]

[0993] 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) was added 10% palladium on carbon (1.06 g, 4% wt, 400 μmol). The reaction mixture was stirred in a H 2 (5 bar) atmosphere at 20 °C for 23 h. The reaction mixture was filtered through a glass microfiber filter, washed with EtOH (3 x 25 mL) and concentrated in vacuo to afford 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 pale brown oil; Rt 1.29 min (Method 7); m / z 376.3 (M+H)+ (ES+).

[0994] Intermediate AI: 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazole

[0995]

[0996] 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 similar method as 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 partitioned between dichloromethane (30 mL) and saturated NaHCO 3 aqueous solution (30 mL). The layers were separated and the aqueous phase was then extracted with dichloromethane (2 x 10 mL). The combined organic phases were dried over MgSO 4Dry, filter, and concentrate in vacuo. The crude product was purified by silica gel chromatography (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), a pale yellow solid; Rt 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).

[0997] 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

[0998]

[0999] 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) was added pyridine (130 mg, 0.13 mL, 1.65 mmol), and the mixture was stirred overnight in an open vessel. The reaction mixture 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; Rt 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).

[1000] Example 237: 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

[1001]

[1002] Using N 2Purge 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) for 5 minutes, then add copper iodide. Purge the reaction mixture for 5 minutes, then heat the reaction mixture at 120 °C for 21 hours. Cool the reaction mixture to room temperature, dilute with 5% LiCl(aq) solution (10 mL) and extract with EtOAc (4 × 5 mL). The combined organic phases are washed with 1:1 saturated brine(aq) / water (2 × 10 mL), dried over MgSO 2 4 4 4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (Waters, acidic (0.1% formic acid in water), acidic, Waters X-Select CSH C18 ODB pre-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; Rt 1.97 minutes (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).

[1003] Examples 238 - 243

[1004] Table 11: The examples shown in the following table were prepared by a method similar to that described in Example 236.

[1005]

[1006]

[1007]

[1008] Examples 244 - 274

[1009] Table 12: The examples shown in the following table were prepared by a method similar to that described in Example 237.

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022] Example 275: 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

[1023] Intermediate AJ: 5-Bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[1024]

[1025] 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% by weight potassium hydroxide (30 g, 20 mL, 1 mol, 20 mmol), and then SEM-Cl (21.72 g, 23.1 mL, 130.3 mmol) was added within 5 minutes. The reaction was then stirred at room temperature overnight. The reaction was partitioned between water (200 mL), the phases were separated and the aqueous phase was further extracted with dichloromethane (2 × 100 mL), then the organic matter was washed with brine (100 mL), and then with MgSO 4 dried and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (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% purity), as a yellow oil; Rt 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)

[1026] Intermediate AK: 5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[1027]

[1028] The compound was prepared by a similar method to that described in Example 16 to give 5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (Intermediate AK); Rt 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)

[1029] Intermediate AL: 5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1H-indazole

[1030]

[1031] 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 hydrochloric acid (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 in vacuo. The resulting purple residue was redissolved in dichloromethane (60 mL) and treated with ethan-1,2-diamine (5.8 g, 6.5 mL, 97 mmol), and the solution turned orange. The reaction mixture was stirred at room temperature for 90 minutes and then quenched with water (40 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined organic extracts were dried over MgSO 4Dry and concentrate in vacuo. The crude product was purified by silica gel chromatography (80 g cartridge, 0 - 50% EtOAc / heptane) to afford 5-(1,3-dibenzylpyrrolidin-3-yl)-6-methyl-1H-indazole (Intermediate AL) (3.03 g, 7.5 mmol, 77%) as a white solid; Rt 0.62 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 (obss, 3H), 2.41 - 2.30 (m, 3H), 2.22 - 2.09 (m, 1H).

[1032] Intermediate AM: 5-(3-benzylpyrrolidin-3-yl)-6-methyl-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one

[1033]

[1034] 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 Example 237) in dichloroethane (30 mL) was added 1-chloroethyl carbonate (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 in vacuo, and the residue was redissolved in MeOH (30 mL). The reaction mixture was stirred at 60 °C for 2 hours, then cooled to room temperature and concentrated onto silica gel. The crude product was purified by chromatography on silica gel (24 g frit, 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; Rt 1.08 minutes (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).

[1035] Example 275: 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

[1036]

[1037] The preparation method of this compound is similar to that described in Example 16. Using intermediate AM, 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) was obtained; Rt 1.78 minutes (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)

[1038] Examples 276 - 325

[1039] Table 13: The examples shown in the following table were prepared by a method similar to that described in Example 16.

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058] Examples 326 - 332

[1059] Table 14: The examples shown in the following table were prepared by a method similar to that described in Example 19.

[1060]

[1061]

[1062]

[1063] Example 333: 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

[1064] Intermediate AN: 5-(1,3-Dibenzylpyrrolidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinyl-1H-indazole

[1065]

[1066] A vial containing 6-chloro-5-(1,3-dibenzylpyrrolidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (prepared by 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 reinjected with N2 (x3). 1,4-Dioxane (5 mL) was added and the resulting solution was heated at 90 °C for 18 hours. The reaction mixture was cooled to room temperature and then with NaHCO 3The saturated solution (20 mL) was quenched and extracted with EtOAc (3 × 20 mL). The combined organic matter was washed with brine (10 mL) and dried over MgSO 4 and filtered. The solvent was removed under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (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 viscous yellow oil; Rt 1.35 min (Method 6); m / z 524.6 (M+H)+ (ES+).

[1067] Intermediate AO: 5-(3-benzylpyrrolidin-3-yl)-6-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[1068]

[1069] 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 carbon (Type 39) (61.0 mg, 10% Wt, 57.3 μmol), and the reaction mixture was stirred for 3 days under 5 bar of hydrogen. Additionally, palladium on 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 crude in the next step; Rt 0.55 min (Method 6); m / z 436.5 (M+H)+ (ES+).

[1070] 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

[1071]

[1072] The compound was prepared by a method similar to that described in 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); Rt 1.93 min (Method 6); m / z 581.5 (M+H)+ (ES+).

[1073] Intermediate AQ: 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-ethyl-1H-indazole

[1074]

[1075] The compound was prepared by a method similar 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)-6-ethyl-1H-indazole (Intermediate AQ); Rt 1.45 min (Method 6); m / z 451.5 (M+H)+ (ES+).

[1076] Example 333: 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

[1077]

[1078] The compound was prepared by a method similar to that described in 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); Rt 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), 2.43 - 2.33 (m，1H) , 2.14 - 2.04 (m, 1H), 1.29 (t, J = 7.3 Hz, 3H).

[1079] 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

[1080] Intermediate AR: 5-(1,3-Dibenzylpyrrolidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbonitrile

[1081]

[1082] A vial containing sodium carbonate (155 mg, 1.47 mmol), palladium(II) diacetate (21.9 mg, 97.7 μmol), potassium ferrocyanide tetrahydrate (413 mg, 977 μmol), 2-(2-(dicyclohexylphosphino)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 in Example 275) was evacuated under vacuum and reinjected with nitrogen (x3). 1,4-Dioxane (4 mL) and water (4 mL) were added, the solution was degassed with nitrogen for 10 minutes, and heated in a microwave at 130 °C for 12 hours. With NaHCO 3The reaction mixture was quenched with a saturated solution (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic matter was passed through a hydrophobic glass frit, and the solvent was removed under reduced pressure to obtain a pale yellow residue. The crude product was purified by silica gel chromatography (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 viscous yellow oil; Rt 1.28 min (Method 6); m / z 523.2 (M+H)+ (ES+).

[1083] Intermediate AS: 5-(3-benzyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-1H-indazole-6-carbonitrile

[1084]

[1085] This compound was prepared by a method similar 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); Rt 1.45 min (Method 6); m / z 451.5 (M+H)+ (ES+).

[1086] 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

[1087]

[1088] This compound was prepared by a method similar to that described in 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); RT 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).

[1089] Example 335: 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

[1090] Intermediate AT: 1,3-Dibenzyl-4-methyl-3-(6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)pyrrolidine-2,5-dione

[1091]

[1092] At 0 °C, 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 a similar method as described in Example 16 and Example 275) in THF (60 mL) was added diisopropyl lithium amide (2 M in THF) (1.1 g, 5.0 mL, 2.0 moles, 10 mmol). 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 warmed to room temperature and stirred overnight. Quench the reaction with saturated NaHCO 3 aqueous solution (50 mL) and extract with EtOAc (3 × 50 mL). Use MgSO 4The combined organic layers were dried, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (220 g cartridge, 0 - 40% EtOAc / isohexane) to afford 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 viscous yellow oil which solidified to a yellow solid upon standing overnight; Rt 2.61 min (Method 7); m / z 542.2 (MH) (ES)

[1093] Example 335: 5-(3-Benzyl-4-methyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indol-1-yl)-1-methylpyridin-2(1H)-one

[1094]

[1095] This compound was prepared by a similar method as described in Example 275 to afford 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. Rt 1.76 min (Method 7); m / z 558.2 (M + H)+ (ES+). δH (400 MHz, DMSO-d 6 ) δ8.29 (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 was obscured by water.

[1096] Example 336: 1,3-Dibenzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-5-hydroxypyrrolidin-2-one

[1097]

[1098] 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 a hexane solution of DIBAL-H (29.7 mg, 209 μL, 1 M, 209 μmol), and the reaction was stirred overnight at room temperature. The reaction was quenched with NaHCO 3 (10 mL), extracted with EtOAc (2 × 10 mL), and dried over MgSO 4 The organic matter was dried and concentrated in vacuo to give a crude product. The crude product was purified by silica gel chromatography (24 g cartridge, 0 - 100% EtOAc / isohexane) to give 5-(1,3-dibenzylpyrrolidin-3-yl)-1-(4-fluorophenyl)-6-methyl-1H-indazole (Example 336) as a yellow solid (Example 336) (52 mg, 0.21 mmol, 48%); Rt 1.76 min (Method 7); m / z 558.2 (M+H)+ (ES+).

[1099] Example 337: 1,3-Dibenzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)pyrrolidin-2-one

[1100]

[1101] 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 quenched with NaHCO 3 (10 mL), then EtOAc (2 × 10 mL) was added, the organic matters were combined, and then dried over MgSO 4Dry and concentrate in vacuo to give the crude product. The crude product was purified by silica gel chromatography (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. Rt 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).

[1102] Example 338: 3-Benzyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-(methylsulfonyl)pyrrolidin-2-one

[1103] Intermediate AU: 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-(4-methoxybenzyl)pyrrolidine-2,5-dione

[1104]

[1105] 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) degassed with nitrogen for 10 minutes was added 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), and then heated to 80 °C overnight. The reaction was cooled, partitioned between EtOAc (2 × 20 mL) and water (20 mL), and then dried over MgSO 4The organic matter was dried and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography (40 g cartridge, 0 - 100% EtOAc / isohexane) to obtain 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. Rt 2.49 min (Method 2); m / z 429.8 (M+H)+ (ES+).

[1106] Intermediate AV: 3-benzyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-one

[1107]

[1108] 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 similar method as described in Example 337) in MeCN (3 mL), ammonium cerium(IV) nitrate (284 mg, 518 μmol) was added and the reaction was stirred overnight at room temperature. Another portion of ammonium cerium(IV) nitrate (142 mg, 259 μmol) was added and the reaction was stirred overnight at room temperature. The reaction was partitioned between EtOAc (2×20 mL) and NaHCO 3 (20 mL), and dried over MgSO 4 The organic matter was dried and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography (12 g cartridge, 0 - 100% EtOAc / isohexane) to obtain 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. Rt 2.40 min (Method 2); m / z 385.8 (M+H)+ (ES+). δH (500 MHz, DMSO-d 6 ) δ8.34 (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).

[1109] Example 338: 3-Benzyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-1-(methanesulfonyl)pyrrolidin-2-one

[1110]

[1111] At 0 °C, 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) was added sodium hydride (5.1 mg, 60% by weight, 0.13 mmol), and the reaction mixture was stirred for 10 minutes. Then methanesulfonyl chloride (15 mg, 10 μL, 0.13 mmol) was added, and the reaction was warmed to room temperature and stirred overnight. The reaction was cooled again to 0 °C, sodium hydride (10 mg, 0.42 mmol) was added and the reaction mixture was stirred for 10 minutes. Then methanesulfonyl chloride (24 mg, 16 μL, 0.21 mmol) was added and the reaction was left overnight again. The reaction was quenched by slowly adding NaHCO 3 (10 mL), and then EtOAc (15 mL) was added. The aqueous solution was extracted again with EtOAc (15 mL), and then the organic matter was mixed and washed with brine (15 mL), and then dried over MgSO 4 and concentrated in vacuo to give the crude product. The crude product 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-(methanesulfonyl)pyrrolidin-2-one (0.005 g, 0.01 mmol, 20%, 98%) (Example 338) as a pale yellow solid. Rt 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).

[1112] Example 339: 3-Benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-(methanesulfonyl)pyrrolidin-2-one

[1113]

[1114] The compound was prepared by a similar method to that described in Example 338 to give 3-benzyl-3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-(methanesulfonyl)pyrrolidin-2-one (Example 339); Rt 1.70 min (Method 1); 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).

[1115] Example 340: 1-(4-Fluorophenyl)-5-(3-(methoxymethyl)-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)pyrrolidin-3-yl)-6-methyl-1H-indazole

[1116] 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

[1117]

[1118] In a microwave vial containing nickel chloride, dimethoxyethane adduct (230 mg, 1.05 mmol), DMA (7 mL) was added (). The blue solution was subjected to vacuum / nitrogen cycling (x3) and stirred at room temperature for 5 minutes. Meanwhile, to a solution of bis(pinacolato)diboron (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), tert-butyl 3-methylenepyrrolidine-1-carboxylate (600 mg...

Claims

1. A compound of formula IVa or a pharmaceutically acceptable salt thereof: wherein R 1 is a heterocycloalkyl having 5 to 6 ring members and 1 to 2 heteroatoms each being N, phenyl, or a heteroaryl having 5 to 6 ring members and 1 to 2 heteroatoms each independently being N or S, each independently substituted with 1 to 3 R 1a groups; Each R 1a is 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 heterocycloalkyl having 3 to 5 ring members and 1 to 2 heteroatoms each independently being N or O; A 1 ,A 2 and A 4 each independently is =CH-; A 3 ═CR 2 -; R 2 independently is 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; R 3b is 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-O-C 6-12 aryl, -C 2-6 alkoxyalkyl-C 6-12 aryl, -C(O)-C 6-12 aryl, or -C 1-6 alkyl - heteroaryl, wherein each heteroaryl has 5 to 10 ring members and 1 to 3 heteroatoms independently selected from N, O or S, and wherein each aryl and heteroaryl is substituted with 1 to 3 R 3b3 groups; Each R 3b3 is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, halogen or C 1-6 haloalkyl; R 4 is C 1-6 alkyl, C 1-6 haloalkyl, -CN, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from N, O or S, C 6-12 aryl or 5- to 10-membered heteroaryl having 1 to 5 heteroatoms each independently selected from N, O or S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently substituted by 1 to 5 R 4a groups; Each R 4a is 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 -O-C 6-12 aryl, where each aryl is optionally substituted by C 1-6 alkoxy; R 4b and R 4c are each hydrogen or a C 1-6 alkyl group; L 1 Does not exist; L 2 Absent, –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 -.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is piperidine, pyridin-2-one, phenyl, pyridine, pyrazole or thiazole, each substituted by from 1 to 3 R 1a groups; 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.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Yes 4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Yes 5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has the following structure:

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogen or -CN.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, methyl, ethyl, isopropyl, methoxy, F, Cl or -CN.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A 1 , A 2 and A 4 =CH-; and A 3 is = C(Me)-.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has the following structure:

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 3a is independently hydrogen, -OH or oxo.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 3a is hydrogen.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3b is 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 2-3 alkoxyalkyl-C 6-12 aryl, -C(O)-C 6-12 aryl, or C 1-3 alkyl-heteroaryl, wherein each heteroaryl has 5 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, and wherein each aryl and heteroaryl is substituted by 1 to 3 R 3b3 groups; and Each R 3b3 is hydrogen, C 1-3 alkyl, C 1-3 hydroxyalkyl, halogen or C 1-3 haloalkyl.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3b3 is hydrogen, methyl, -CH 2 OH, F, -CHF 2 or -CF 3 .

14. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3b is ethyl, -CH 2 C≡CH, -CH 2 OMe, 15. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3b Yes 16. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has the following structure:

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is -C(O)- or -S(O) 2 -.

18. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has the following structure:

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein R 4 is C 1-3 alkyl, C 1-3 haloalkyl, -CN, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl having 1 heteroatom each being N or O, C 6-12 aryl, or 5- to 10-membered heteroaryl having 1 to 4 heteroatoms each independently being N, O or S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently substituted by 1 to 2 R 4a groups; 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, wherein each aryl is optionally substituted by C 1-3 alkoxy; and Each R 4b and R 4c is hydrogen or C 1-3 alkyl.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein R 4 is methyl, ethyl, -CF 2 CH 3 , -CN, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl, pyrimidine-dione, phenyl, pyridyl, pyridin-2-one, quinolinyl, pyrazolyl, imidazolyl, pyridazinyl, pyrimidinyl, indolyl, triazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl, oxadiazolyl, thienyl, benzothienyl or thiazolyl; and Each R 4a is hydrogen, methyl, ethyl, n-propyl, isobutyl, -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 NHMe, cyclobutyl, 2-methoxyphenyl or -OPh.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein R 4 is methyl, -CF 2 CH 3 , -CN, 22. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is A 1 is =CH-; A 2 and A 4 are respectively =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 is ethyl, -CH 2 C≡CH, -CH 2 OMe, L 1 and L 2 together 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 is methyl, -CF 2 CH 3 , -CN, 23. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is A 1 is =CH-; A 2 and A 4 are respectively =CH-; A 3 is =CH-, =C(Me)-, =C(Et)-, =C(OMe)-, =C(Cl)-, or =C(CN)-; Each R 3a is hydrogen, -OH or oxo; R 3b is -CH 2 OMe, L 1 and L 2 together 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 is methyl, -CF 2 CH 3 , 24. The compound or a pharmaceutically acceptable salt thereof in claim 1, wherein, the compound is:

25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof has the structure:

26. The compound according to claim 1 or a pharmaceutically acceptable salt thereof has the structure:

27. The compound according to claim 1 or a pharmaceutically acceptable salt thereof has the structure:

28. The compound according to claim 1 or a pharmaceutically acceptable salt thereof has the structure: The compound according to claim 1 or a pharmaceutically acceptable salt thereof has the structure:

30. The compound or a pharmaceutically acceptable salt thereof according to claim 1, having the structure:

31. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

32. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30 or the pharmaceutical composition according to claim 31 in the preparation of a medicament for treating a disease or disorder by modulating the glucocorticoid receptor.

33. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30 or the pharmaceutical composition according to claim 31 in the preparation of a medicament for treating a disease or disorder by antagonizing the glucocorticoid receptor.

34. Use according to claim 32 or 33, wherein the disease or disorder is selected from amyotrophic lateral sclerosis (ALS), obesity, diabetes, hypertension, syndrome X, anxiety disorder, glaucoma, Alzheimer's disease, Parkinson's disease, cancer, liver disease, osteoporosis, muscle weakness, diseases caused by cortisol excess related to adrenal diseases, addiction, anorexia, cachexia, post-traumatic stress syndrome, postoperative fractures, metabolic disorders related to the glucocorticoid receptor (GR), severe psychotic depression, mild cognitive impairment, dementia, hyperglycemia, stress disorders, weight gain caused by antipsychotic drugs, delirium, cognitive impairment in patients with depression, postpartum psychosis, postpartum depression, and neurological diseases in premature infants.

35. Use according to claim 32 or 33, wherein the disease or disorder is selected from cardiovascular diseases, depression, neurodegenerative diseases, Cushing's syndrome.

36. Use according to claim 32 or 33, wherein the disease or disorder is psychosis.

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