AHR agonists

Abstract

The present disclosure relates to certain AHR agonist compounds, for example, having a. general formula: (I), to pharmaceutical compositions comprising the compounds, and to methods of using the compounds to treat immune -mediated diseases, such as psoriasis and atopic dermatitis.

Description

AHR AGONISTSFIELD OF THE INVENTION

[0001] The present disclosure relates to novel AHR agonist compounds, to pharmaceutical compositions comprising the compounds, and to methods of using ths compounds to treat certain immune-mediated diseases.BACKGROUND OF THE INVENTION

[0002] The present disclosure is m the field of treatment of certain immune-mediated diseases (IMD), in particular psoriasis and atopic dermatitis, via the activation of the aryl hydrocarbon receptor (AHR).

[0003] IMDs encompass a broad range of chronic and debilitating inflammatory conditions that affect approximately 4% of the population worldwide. In view of the limited efficacy of currently available treatments, and few small molecule treatment options, there is significant unmet need for alternative, potent, selective, and safer drugs for the treatment of IMDs.

[0004] AHR is a transcription factor which regulates many aspects of immunological function, most notably the suppression of adaptive immune responses (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)). Prototypical AHR agonists include halogenated dibenzodioxins, such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), tryptophan metabolites, such as L-kynurenine, bilirubin, and PGE2. Results from studies on AHR agonists, especially TCDD, suggest that immune suppression occurs as the result of AHR-induced expression of regulatory T ceils (Tregs), TH17 cells, and dendritic ceils (DCs) (Rothhammer et al., Nat. Rev, Immunol., 19, 184-197 (2019)). TCDD has been shown to be effective in the prevention of several murine models of IMD, including type- 1 diabetes (Kerkvliet et al., Immunotherapy, 1, 539-547 (2009)), autoimmune encephalomyelitis (Quintana et al.. Nature, 453, 65-71 , (2008)), autoimmune uveoretmitis (Zhang et al., Invest. Opthalmol. Vis. Sci., 51 , 2109-21 17 (2010)), inflammatory bowel disease (Takamura et al., Immunol. Cell. Biol., 88, 685-689 (2010), Benson et al., Toxicol. Sci., 120, 68-78 (201 1), Singh et al., PLoS One, 6(8), e23522. (2011)), as well asseveral models of transplant tolerance (Pauly at al., Toxicol. Environ. Chem., 94, 1175- 1 187 (2012)) and allergic diseases (Schulz et al,, Toxicol. Set., 123, 491-500 (201 1), Li et al, PLoS One, 11 , e0150551 (2016), Luebke et al„ Toxicol. Sci., 62, 71-79 (2001 )).

[0005] AHR also regulates the expression of CYP1 Al, CYPIA2, and CYP1B1, which catalyze the metabolism of polycyclic aromatic hydrocarbon (PAH) and other aromatic compounds (e.g., estrogen). While in some cases (for example in the case of benzo [a]pyrene) this metabolism results in the formation of reactive species, CYP induction is also believed to be critical for the detoxification and metabolic clearance of PAHs, which reduces the probability of bioactivation, and DNA adduct formation. Several marketed drugs were found to activate AHR (thus upregulating CYP 1 A l, CYP1A2, and CYP1B1) after their FDA approval, yet their long-term use is not associated with dioxin-like toxicities (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)). As such, CYP induction is no longer viewed as a barrier to the adoption of AHR agonists in therapy (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)).

[0006] The bacterial stilbenoid DMVT-505 (VTAMA® (tapinarof)) 1% cream, an aryl hydrocarbon receptor agonist, indicated for the topical treatment of plaque psoriasis in adults, has been approved by the U.S. Food and Drug Administration (FDA). Despite this, there remains a need for alternative novel, oral, selective, and potent AHR agonists for the treatment of IMDs. The present disclosure provides certain compounds that are agonists of AHR and potential treatment options.SUMMARY OF THE INVENTION

[0007] In some embodiments, provided herein is a compound of the Formula II:wherein:Z is NH or 0; each occurrence of Q1is independently CR1, N, S, or NR2, wherein R1is H, C1-3 alkyl, Ci- 3 haloalkyl, or C3-4 cycloalkyl, and R2is H, C1.3 alkyl, or C3-4 cycloalkyl;O represents ring aromaticity; andY is a bicyclic group including a 5- or 6- membered aromatic unit fused with a 5- or 6- membered monocycle, wherein ¥ attaches to the carbonyl through the 5- or 6- membered aromatic unit, and w herein the monocycle is an unsubstituted cycloalkyl, an unsubstituted heterocycle, a heteroaryl optionally substituted with methyl, or a phenyl optionally substituted with halo, C1.3 alkyl, C1-3 haloalkyl, C1.3 alkoxyl, C1-3 haloalkoxyl, or cyano, or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the 5- or 6- membered aromatic unit is a 5-membered aromatic unit, and the 5- or 6- membered monocycle is phenyl.

[0009] In some embodiments, the 5- or 6- membered aromatic unit is a 5-membered aromatic unit, and the 5- or 6- membered monocycle is an unsubstituted cycloalkyl.

[0010] In some embodiments, the 5- or 6- membered aromatic unit is a 5-membered aromatic unit, and the 5- or 6- membered monocycle is a heteroaryl.

[0011] In some embodiments, provided herein is a pharmaceutical composition, comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0012] In some embodiments, provided herein is a method of treating an immune- mediated disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof

[0013] In some embodiments, provided herein is a compound of Formula II or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn’s disease, graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus (SLE).DETAILED DESCRIPTION OF THE INVENTION

[0014] Various AHR agonists and their treatment options are presented in embodiments below. When a later embodiment refers to a previous “embodiment X”, such reference also includes references to “embodiment XA”, “embodiment XB”, and so on, unless such later embodiment cannot be properly constmed as a dependent embodiment (e.g. falling outside the scope of the referenced embodiment or having improper antecedent basis).For example, when “Embodiment 5'’ below refers to “any one of preceding embodiments”, such reference also includes reference to “embodiment 1A”, “embodiment IB”, “embodiment 2 A”, “embodiment 2B”, “embodiment 3 A”,“embodiment 3B”, “embodiment 4A”, and “embodiment 4B” among others.

[0015] Embodiment A 1. A compound of tire Formula II:wherein:Z is NH or O; each occurrence of Q1is independently CR1, N, S, or NR2, wherein R1is H, C1-3 alkyl, Cn 3 haloalkyl, or C3.4 cycloalkyl, and R2is H, C1-3 alkyl, or C3-4 cycloalkyl;O represents ring aromaticity; andY is a bicyclic group including a 5- or 6- membered aromatic unit fused with a 5- or 6- membered monocycle, wherein Y attaches to the carbonyl through the 5- or 6- membered aromatic unit, and wherein the monocycle is an unsubstituted cycloalkyl, an unsubstituted heterocycle, a heteroaryl optionally substituted with methyl, or a phenyl optionally substituted with halo, C1-3 alkyl. Cm haloalkyl, C1-3 alkoxyl, C1-3 haloalkoxyl, or cyano, or a pharmaceutically acceptable salt thereof.

[0016] Embodiment A2. The compound of embodiment A 1 or A2, wherein Z is O, or a pharmaceutically acceptable salt thereof.

[0017] Embodiment A3. The compound of embodiment A 1 or A2, wherein the 5- or6- membered aromatic unit includes at least one N, or a pharmaceutically acceptable salt thereof.

[0018] Embodiment A4. The compound of embodiment Al or A2, wherein the 5- or6- membered aromatic unit is a 5- membered heteroaryl, or a pharmaceutically acceptable salt thereof.

[0019] Embodiment A5. 'The compound of any one of preceding embodiments,wherein the 5- or 6- membered aromatic unit is , or a pharmaceutically acceptable salt thereof.

[0020] Embodiment A6. Tire compound of any one of embodiments A 1-A4, wherein the 5- or 6- membered aromatic unit isor a pharmaceutically acceptable salt thereof.

[0021] Embodiment A7. The compound of any one of preceding embodiments, wherein Y is phenyl fused with 5 -membered heteroaryl containing 1, 2, or 3 N and no other heteroatom, and the phenyl is optionally substituted with halo or cyano, or a pharmaceutically acceptable salt thereof.

[0022] Embodiment A8. The compound of embodiment Al or A2, wherein ¥ is, wherein the phenyl of Y is optionally substituted withmethyl, chlorine, methoxy, trifluoromethyl, or a pharmaceutically acceptable salt thereof.

[0023] Embodiment A9. The compound of embodiment A 1 or A2, wherein Y is, or a pharmaceutically acceptable salt thereof.

[0024] Embodiment Al 0. The compound of embodiment A 1 or A2, wherein Y is. , or a pharmaceutically acceptable salt thereof.

[0025] Embodiment Al l. The compound of embodiment A 1 or A2, wherein Y is, or a pharmaceutically acceptable salt thereof.

[0026] Embodiment A12. The compound of embodiment Al or A2, wherein Y is, or a pharmaceutically acceptable salt thereof.

[0027] Embodiment A 13. "Die compound of embodiment A 1 or A2, wherein tire 5 - or6- membered monocycle ipharmaceutically acceptable salt thereof.

[0028] Embodiment Al 4. The compound of embodiment A 1 or A2, wherein the 5- or6- membered monocycle is aromatic, or a pharmaceutically acceptable salt thereof.

[0029] Embodiment A 15. The compound of embodiment A l or A2, wherein the 5- or 6- membered monocycle is heteroaryl, or a pharmaceutically acceptable salt thereof.

[0030] Embodiment Al 6. The compound of embodiment A 15, wherein the heteroarylacceptable salt thereof.

[0031] Embodiment A 17. The compound of embodiment A 1 or A2, wherein the 5- or 6- membered monocycle is a phenyl optionally substituted with halo, C1.3 alkyl, C1-3 haloalkyl, C1-3 alkoxyl, C1-3 haloalkoxyl, or cyano, unsubstituted heteroaryl, unsubstituted carbocycle, and unsubstituted heterocycle, or a pharmaceutically acceptable salt thereof.

[0032] Embodiment A18. The compound of embodiment A17, wherein the 5- or 6- membered monocycle is unsubstituted phenyl, or a pharmaceutically acceptable salt thereof.

[0033] Em bodiment A 19. The compound of embodiment A 17, wherein the 5- or 6- membered monocycle is a phenyl substituted with halo, C1-3 alkoxyl, cyano, C1-3 alkyl, orCi-3 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0034] Embodiment A20. A compound of the Formula III:wherein: each occurrence of n is independently 1 or 2;Z is M l or O; each occurrence of Q!is independently CR!, N, S, or NR2, wherein R1is H, C1-3 alkyl, Ci-3 haloalkyl, or C3-4 cycloalkyl, and R2is II, C1-3 alkyl, or C3-4 cycloalkyl; each occurrence of Q2is independently CH, N, NH, or S; each occurrence of Q3is independently CR3, N, O, or S; each occurrence of R* is independently H, halo, C1-3 alkyl, Cj-3 haloalkyl, C1-3 alkoxyl,C1..3 haloalkoxyl, or cyano;O represents ring aromaticity'; and each occurrence of represents a single bond or a double bond that satisfies v alence, or a pharmaceutically acceptable salt thereof,

[0035] Embodiment A21. Hie compound of embodiment A20, wherein one Q2is N and tire other is NH, or a pharmaceutically acceptable salt thereof.

[0036] Embodiment A22. The compound of embodiment A20, wherein one Q2is N and the other is S, or a pharmaceutically acceptable salt thereof.

[0037] Embodiment A23. The compound of any of embodiments A20-A23, wherein n is 1 , or a pharmaceutically acceptable salt thereof.

[0038] Embodiment A2.4. The compound of any of embodiments A20-A23, wherein n is2, and all Q3are CR '. or a pharmaceutically acceptable salt thereof.

[0039] Embodiment A25. The compound of any preceding embodiment, wherein at least one R.1is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0040] Embodiment A26. 'The compound of any one of embodiments A 1 -A2.4, wherein at least one Ri is cyclopropyl or cyclobutyl, or a pharmacally acceptable salt thereof.

[0041] Embodiment A27. The compound of any of embodiments A1-A24, whereinpharmaceutically acceptable salt thereof.

[0042] Embodiment A28. The compound of any of embodiments A 1-A24, whereinand, or a pharmaceutically acceptable salt thereof.

[0043] Embodiment A29. The compound of any of embodiments A1-A24, w hereinpharmaceutically acceptable salt thereof.

[0044] Embodiment A30. A compound of the Formula IV :wherein: each occurrence of Q!is independently CH, N, S, or NR2, wherein R2is H, C1-3 alkyl, or C3-4 cycloalkyl; each occurrence of Q2is independently CH, N, NH, or S; each occurrence of R3is independently H, halo, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxyl,C1-3 haloalkoxyl, or cyano;O represents ring aromaticity; and each occurrence of represents a single bond or a double bond that satisfies valence; or a pharmaceutically acceptable salt thereof.

[0045] Embodiment A31. A compound selected from the table:

[0046] Embodiment A32. A pharmaceutical composition, comprising a compound of any of embodiments A 1 to A31, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0047] Embodiment A33. A method of treating an immune-mediated disease in a patsent in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments Al to A31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment A32.

[0048] Embodiment A34. A compound according to any one of embodiments A 1 toA31 or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn’s disease, graft-versus- host disease, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus (SEE).

[0049] Embodiment A35. A compound according to any one of embodiments Al toA31 or a pharmaceutically acceptable salt thereof, for use in treating psoriasis.

[0050] Embodiment A36. A compound according to any one of embodiments Al toA31 or a pharmaceutically acceptable salt thereof, for use in treating atopic dermatitis.

[0051] Embodiment A37. A compound according to any one of embodiments Al toA31 or a pharmaceutically acceptable salt thereof, for use in treating ulcerative colitis.

[0052] Embodiment A38. A compound according to any one of embodiments Al to A31 or a pharmaceutically acceptable salt thereof, for use in treating Crohn’s disease.

[0053] Embodiment A39. A compound according to any one of embodiments A 1 toA31 or a pharmaceutically acceptable salt thereof, for use in treating graft-versus-host disease.

[0054] Embodiment A40. A compound according to any one of embodiments Al to A31 or a pharmaceutically acceptable salt thereof, for use in treating rheumatoid arthritis.

[0055] Embodiment A41. A compound according to any one of embodiments Al to A31 or a pharmaceutically acceptable salt thereof, for use in treating multiple sclerosis.

[0056] Embodiment A42. A compound according to any one of embodiments Al to A31 or a pharmaceutically acceptable salt thereof, for use in treating systemic lupus erythematosus (SLE).

[0057] Embodiment 1. A compound of Formula I:wherein:Z is CH2, NH, or O; each occurrence of Q1is independently CR1, N, S, or NR2, wherein R1is H, C1-3 alkyl, Ci- 3 haloalkyl, or C3-4 cycloalkyl; and R2is H, C1-3 alkyl optionally substituted with C1-3 alkoxyl, or C3-4 cycloalkyl; andO represents ring aromaticity;Y is a bicyclic group including a 5- or 6- membered aromatic unit fused with a 5- or 6- membered monocycle that is optionally substituted with oxo, halo, C1-3 alkyl, C1.3haloalkyl, C1-3 alkoxyl, or cyano, wherein Y attaches to the carbonyl through the 5- or 6- membered aromatic unit, and wherein when the monocycle is substituted with oxo, the oxo is immediately attached to a sulfur (S) of the monocycle, or a pharmaceutically acceptable salt thereof, provided that when Z is CH?, Y is phenyl fused with 5-membered heteroaryl containing 1, 2, or 3 N and no other heteroatom, and the phenyl is optionally substituted with halo or cyano, and that the compound is not one of: lH-lndazol-3-yl(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-cjazepin-5(lH)-yi)methanone;(5-Chloro-lH-indazol-3-yl)(4,6,7,8-tetraliydro-l-methylpyrazolo[4,3-c]azepin-5(lH)- yl)methanone;(5-Bromo-lH-indazol-3-yl)(4,6,7,8~tetrahydro-l~metliylpyrazolo[4,3-c]azepin-5(lH)- yljmethanone;(4,7-Di fluoro- lH-indol-2-yl)(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-c]azepin-5(lH)- yl)methanone;(6-Chloro-lH-indazol-7-yl)(2,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(4H)- yl)methanone;(6-Chloro-lH“indazol-7-yl)(4,6,7,8-tetrahydro-l -methylpyrazolo[4,3“C]azepin-5(lH)“ yljmethanone;(5-fluoro~l H~benzimidazol-7-yl)(4,6,7,8~tetrahydro-l-methylpyrazolo[4,3~c]azepin- 5(lH)-yl)methanone; lH-Benzimidazol-7-yl(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-c]azepin-5(lH)- yl)niethanone; lH-Indazol-4-yl(4,6,7,8-tetrahydro-l -methylpyrazolo[4,3-c]azepin-5(lH)-yl)methanone;(5-Fluoro-lH-benzotriazol-7-yl)(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-c]azepin-5 ( 1 H) ~y l)niethanone ; lH-Indazol-7-yl(4,6,7,8~tetrahydro-l-methylpyrazolo[4,3~c]azepin-5(lH)-yl)methanone;(5-Bromo-lH-benzimidazol-7-yl)(4,6,7,8-tetrahydro-l-meihylpyrazolo[4,3-c]azepin-5(1 H)-yl)methanone ;(7 -Fluoro- 1 H-benzim idazol -6-yl)(2,6,7 , 8~tetrahydropyrazol o [4,3 -c]azepin-5 (4H)~ yl)methanone;(7-FIuoro-lH-benzimidazol-6-yl)(4,6,7,8-tetraliydro-l-methylpyrazolo|4,3-c]azepin-5(1 H)-yl)methanone ; lH-Benzotriazoi-6-yi(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-c]azepm-5(lH)- yl)methanone; and lH-Benzimidazol-6-yl(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-cJazepin-5(lH)- yl)rn ethanone.

[0058] Embodiment 1A. The compound of embodiment 1, wherein each occurrence of Q!is independently CR3, N, or NR2, wherein R1is H or C1.3 alkyl, and wherein R2is H or Cj-3 alkyl.

[0059] Embodiment IB. 'the compound of embodiment 1, wherein the 5- or 6- membered monocycle is substituted with halo, C1-3 alkyl, or cyano, wherein the aromatic unit is unsubstituted when it is 5-membered.

[0060] Embodiment 2. A compound of the formula:

[0061] wherein:Z is NH or O; each occurrence of Q1is independently CR1, N, S, or NR2, wherein R1is H, C1.3 alkyl, Cj- 3 haloalkyl, or C3.4 cycloalkyl, and R2is H, C1.3 alkyl optionally substituted with C1.3 alkoxyl, or C3-4 cycloalkyl; andO represents ring aromaticity;Y is a bicyclic group including a 5- or 6- membered aromatic unit fused with a 5- or 6- membered monocycle that is optionally substituted with oxo, halo, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxyl, or cyano, wherein Y attaches to the carbonyl through the 5- or 6- membered aromatic unit, and wherein when the monocycle is substituted with oxo, the oxo is immediately attached to a sulfur (S) of the monocycle, or a pharmaceutically acceptable salt thereof.

[0062] Embodiment 2A. The compound of embodiment 2, wherein each occurrence of Q1is independently CR1, N, or NR2, wherein R1is H or C1-3 alkyl, and wherein R2is H or C1.3 alkyl.

[0063] Embodiment 2B, The compound of embodiment 2, wherein the 5- or 6- membered monocycle is substituted with halo, C1.3 alkyl, or cyano, wherein the aromatic unit is unsubstituted when it is 5-membered.

[0064] Embodimen t 3. A compound of the formula:wherein: each occurrence of Q1is independently CR1, N, S, or NR2, wherein R1is H, C1.3 alkyl, Cj- 3 haloalkyl, or C3-4 cycloalkyl, and R2is H, C1-3 alkyl optionally substituted with C1-3 alkoxyl, or C3-4 cycloalkyl; andO represents ring aromaticity:Y is a bicyclic group including a 5- or 6- membered aromatic unit fused with a 5- or 6- membered monocycle that is optionally substituted with oxo, halo, C1-3 alkyl, C1-3 haloalkyl, Ci-3 alkoxyl, or cyano, wherein ¥ attaches to the carbonyl through the 5- or 6- membered aromatic unit, and wherein when the monocycle is substituted with oxo, the oxo is immediately attached to a sulfur (S) of the monocycle, or a pharmaceutically acceptable salt thereof.

[0065] Embodiment 3A. The compound of embodiment 3, wherein each occurrence of Q1is independently CR1, N, or NR2, wherein R1is H or C1.3 alkyl, and wherein R2is H or C1-3 alkyl.

[0066] Embodiment 3B. The compound of embodiment 3, wherein the 5- or 6- membered monocycle is substituted with halo, C1-3 alkyl, or cyano, wherein the aromatic unit is unsubstituted when it is 5-membered.

[0067] Embodiment 4. A compound of the formula:wherein: each occurrence of Q1is independently CR1, N, S, or NR2, wherein R1is H, C1-3 alkyl, Cj- 3 haloalkyl, or C3-4 cycloalkyl, and R2is H, C1.3 alkyl optionally substituted with C1.3 alkoxyl, or C3-4 cycloalkyl; andO represents ring aromaticity:Y is a bicyclic group including a 5- or 6- membered aromatic unit fused with a 5- or 6- membered monocycle that is optionally substituted with oxo, halo, C1-3 alkyl, C1-3 haloalkyl, C4.3 alkoxyl, or cyano, wherein ¥ attaches to the carbonyl through the 5- or 6- membered aromatic unit, and wherein when the monocycle is substituted with oxo, the oxo is immediately attached to a sulfur (S) of the monocycle, or a pharmaceutically acceptable salt thereof.

[0068] Embodiment 4A. The compound of embodiment 4, wherein each occurrence of Q!is independently CR1, N, or NR2, wherein R1is H or C1.3 alkyl, and wherein R2is H or C1-3 alkyl.

[0069] Embodiment 4B, The compound of embodiment 4, wherein the 5- or 6- membered monocycle is substituted with halo, C1-3 alkyl, or cyano, wherein the aromatic unit is unsubstituted when it is 5-membered.

[0070] Embodiment 5. The compound of any one of preceding embodiments, wherein the 5- or 6- membered aromatic unit includes at least one N.

[0071] Embodiment 6. Hie compound of any one of embodiments 1-4, wherein the5- or 6- membered aromatic unit is a 5- membered heteroaryl.

[0072] Embodiment 7. The compound of any one of preceding embodiments. wherein the 5- or 6- membered aromatic unit is

[0073] Embodiment 8. The compound of any one of preceding embodiments. wherein Y is phenyl fused with 5 -membered heteroaryl containing 1, 2, or 3 N and no other heteroatom, and the phenyl is optionally substituted with halo or cyano.

[0074] Embodiment 8A. The compound of any one of preceding embodiments, wherein Y is thiophene fused with 5 -membered heteroaryl containing 1, 2, or 3 N and no other heteroatom.

[0075] Embodiment 9. The compound of any one of embodiments 1-6, wherein Y

[0076] Embodiment 10. Hie compound of any one of embodiments 1-4, wherein Y

[0077] Embodiment 10A. The compound of any one of preceding embodiments,

[0078] Embodiment 1 1 . The compound of any one of embodiments 1 -4, wherein the5- or 6- membered monocycle is a 5-membered monocycl

[0079] Embodiment 12. The compound of any one of embodim ents 1-4 and 1 1,

[0080] Embodiment 13. Hie compound of any one of embodiments 1-4, wherein the5- or 6- membered monocycle is aromatic.

[0081] Embodiment 14. The compound of any one of embodiments 1-4, wherein the 5~ or 6- membered monocycle is heteroaryl.

[0082] Embodiment 15. Hie compound of embodiment 14, wherein the heteroaryl is

[0083] Embodiment 16. The compound of any one of embodiments 1-4, wherein the5- or 6- membered monocycle is phenyl.

[0084] Embodiment 17. The compound of any one of embodiments 11-16, wherein the 5- or 6- membered monocycle is unsubstituted.

[0085] Embodiment 18. 'The compound of embodiment 16, wherein the phenyl is substituted with halo, C1-3 alkoxyl, cyano, C1-3 alkyl, or C1-3 haloalkyl.

[0086] Embodiment 19. A compound of formula:wherein: each occurrence of n is independently 1 or 2;Z is M l or O; each occurrence of Q!is independently CR!, N, S, or NR2, wherein R1is H, C1-3 alkyl, Ci-3 haloalkyl, or Cs-4 cycloalkyl, and R2is H, C1.3 alkyl optionally substituted with C1-3 alkoxyl, or C3-4 cycloalkyl; each occurrence of Q2is independently CH, N, NH, O, or S; each occurrence of QJis independently CRJ, N, NR", O, or S; each occurrence of R' is independently H, halo, C1.3 alkyl, or cyano, and each occurrence of O represents ring aromaticity';each occurrence of ------- represents a single bond or a double bond that satisfies valence; or a pharmaceutically acceptable salt thereof.

[0087] Embodiment 19A. The compound of embodiment 19, wherein each occurrence of Q!is independently CR’1, N, or NR2, wherein R1is H or C1-3 alkyl, and R2is H or Ci-3 alkyl.

[0088] Embodiment 20. A compound of formula:wherein: each occurrence of n is independently 1 or 2;Z is CH2, NH or O; each occurrence of Q1is independently CR1, N, S, or NR2, wherein R1is H, C1-3 alkyl, Cj- 3 haloalkyl, or C3-4 cycloalkyl, and R2is H, C1-3 alkyl optionally substituted with C1-3 alkoxyl, or C3-4 cycloalkyl; each occurrence of Q3is independently CR3, N, NR3, O, or S; each occurrence of R3is independently H, halo, C1-3 alkyl, or cyano, andO represents ring aromaticity; each occurrence of -----1 represents a single bond or a double bond that satisfies valence; or a pharmaceutically acceptable salt thereof, provided that the compound is not one of the following:[(5R,7S)-l,4,5,7-Tetralrydro-5,7-dimethylpyrano[3,4-c]pyrazol-3-yl](2,6,7,8- tetrahydropyrazolo[4,3-c]azepin-5(4H)-yl)methanone;[(5R,7S)-l,4,5,7-Tetrahydro-5,7-dimethylpyrano[3,4-c]pyrazol-3-yl](4,6,7,8-tetrahydro- l-methylpyrazolo[4,3-c]azepm-5(lH)-yl)methanone;(2,6,7,8-Tetrahydropyrazolo[4,3-c]azepin-5(4H)-yl)(4,5,6,7-tetrahydro-lH-pyrazolo[3,4- b]pyridin-3-yl)methanone; lH-Indazol-3-yl(4,6,7,8-tetrahydro-l-methylpjTazolo[4,3-c]azepin-5(lH)-y1)me1hanone;(5-Chloro-lH-indazol-3-yl)(4,6,7,8-tetrahydro-l-methylpyrazoio[4,3-c]azepin-5(lH)- yl)methanone;(1,4, 5 ,6-Tetrahydro-3 -cyclopentapyrazolyl)(4,6,7, 8 -tetrahydro- 1 -methylpyrazolo [4,3- c]azepin-5(] H)-yl)methanone;(7-Methoxy-lH-indazol-3-yl)(4,6,7,8-tetrahydro-l-me1hylpyrazo1o[4,3-c]azepin-5(lH)- yljmethanone; arid(5-Bromo-lH-indazol-3-yl)(4,6,7,8-tetrahydro-l-mediylpyrazolo[4,3-c]azepin-5(lH)- yl)methanone.

[0089] Embodiment 20A. lire compound of embodiment 20, wherein each occurrence of Q1is independently CR1, N, or NR2, wherein R1is H or C1-3 alkyl, and R2is H or Ci-3 alkyl.

[0090] Embodiment 21.wherein: each occurrence of n is independently 1 or 2;Z is NH or O; each occurrence of Qlis independently CR1, N, S, or NR2, wherein Rsis H, C1-3 alkyl, Ct-3 haloalkyl, or Cs-4 cycloalkyl, and R2is H, Cr-3 alkyl optionally substituted with C1-3alkoxyl, or C3-4 cycloalkyl; each occurrence of Q3is independently CR3, N, NR5, O, or S; each occurrence of R' is independently H, halo, C1-3 alkyl, or cyano, andO represents ring aromaticity; each occurrence of represents a single bond or a double bond that satisfies valence; or a pharmaceutically acceptable salt thereof.

[0091] Embodiment 21 A. The compound of embodiment 21 , wherein each occurrence of Q!is independently CR!, N, or NR2, wherein R’ is H or C1-3 alkyl, and R2is H or C1-3 alkyl.

[0092] Embodiment 22. A compound of formula:wherein: each occurrence of n is independently 1 or 2;Z is MH or O; each occurrence of Q!is independently CR1, N, S, or NR2, wherein R1is H, C j-3 alkyl, Ci- 3 haloalkyl, or C3-4 cycloalkyl, and R2is H, C1-3 alkyl optionally substituted with C1-3 alkoxyl, or C3-4 cycloalkyl; each occurrence of Q3is independently CR3, N, NR3, O, or S; each occurrence of R* is independently H, halo, C1.3 alkyl, or cyano, andO represents ring aromaticity; each occurrence of represents a single bond or a double bond that satisfies valence;or a pharmaceutically acceptable salt thereof.

[0093] Embodiment 22A. The compound of embodiment 22, wherein each occurrence of Q1is independently CR1, N, or NR2, wherein R1is H or C1.3 alkyl, and R2is H or C1-3 alkyl.

[0094] Embodiment 23. A compound of formula:wherein: each occurrence of n is independently 1 or 2; each occurrence of Q1is independently CR1, N, S, or NR2, wherein R1is H, C1.3 alkyl. Ci-3 haloalkyl, or C3-4 cycloalkyl, and R2is H, Ci-3 alkyl optionally substituted with C1-3 alkoxyl, or C3-4 cycloalkyl; each occurrence of Q2is independently CH, N, NH, O, or S; each occurrence of Q3is independently CR3, N, NR3, O, or S; each occurrence of R ’ is independently H, halo, C1-3 alkyl, or cyano, and each occurrence of O represents ring aromaticity; each occurrence of represents a single bond or a double bond that satisfies valence; or a pharmaceutically acceptable salt thereof.

[0095] Embodiment 23A. The compound of embodiment 23, wherein each occurrence of Q1is independently CR1, N, or NR2, wherein R1is H or C1.3 alkyl, and R2is H or C1-3 alkyl.

[0096] Embodiment 24. A compound of formula:wherein: each occurrence of n is independently 1 or 2; each occurrence of Q!is independently CR1, N, S, or NR2, wherein R1is H, C j-3 alkyl, Ci- 3 haloalkyl, or C3-4 cycloalkyl, and R2is H, Ci-3 alkyl optionally substituted with C1-3 alkoxyl, or C3.4 cycloalkyl; each occurrence of Q2is independently CH, N, NH, O, or S; each occurrence of Q3is independently CR3, N, NR5, O, or S; each occurrence of R5is independently H, halo, C1.3 alkyl, or cyano, and each occurrence of O represents ring aromaticity; each occurrence of represents a single bond or a double bond that satisfies valence; or a pharmaceutically acceptable salt thereof.

[0097] Embodiment 24A. The compound of embodiment 24, wherein each occurrence of Q‘ is independently CR‘, N, or NR2, wherein R’ is H or C1-3 alkyl, and R2is H or C1-3 alkyl.

[0098] Embodiment 25. The compound of any of embodiments 23-24, wherein each occurrence of Q2is independently CH, N, NH, or S.

[0099] Embodiment 26. Tire compound of any of embodiments 23-25, wherein at least one Q2is N or NH.

[0100] Embodiment 27. The compound of any of embodiments 23-26, wherein at least one Q2is S.

[0101] Embodiment 28. Hie compound of any of embodiments 19-27, wherein each occurrence of Q3is independently CR3, N, NR3, or S.

[0102] Embodiment 29. The compound of any of embodiments 19-28, wherein each occurrence of Q3is independently CR3, T9, or NR3.

[0103] Embodiment 30. Hie compound of any of embodiments 19-28, wherein each occurrence of Q3is independently CR3.

[0104] Embodiment 31 . The compound of embodiment 30, wherein each occurrence of Q3is CH.

[0105] Embodiment 32. The compound of embodiment 30, wherein at least one occurrence of Q3is N.

[0106] Embodiment 33 , The compound of embodiment 30, wherein at least one occurrence of Q3is NR3.

[0107] Embodiment 34. The compound of embodiment 33, wherein R3is H or methyl.

[0108] Embodiment 35. Hie compound of embodiment 30, wherein at least one occurrence of Q3is S.

[0109] Embodiment 36. The compound of any of embodiments 19-35, wherein at least one occurrence of n is 1 .

[0110] Embodiment 37. Hie compound of any of embodiments 19-35, wherein atleast one occurrence of n is 2.

[0111] Embodiment 38. The compound of any preceding embodiment, wherein at least one Q1is CR1, and at least one R1is C1-3 alkyl.

[0112] Embodiment 39, The compound of any one of embodiments 1-37, wherein at least one Q1is CR1, and at least one R1is methyl.

[0113] Embodiment 40. The compound of any one of embodiments 1-37, wherein at least one Q1is CR1, and at least one R!is CF?.

[0114] Embodiment 41. The compound of any one of embodiments 1-37, wherein at least one Q1is CR1, and at least one R1is cyclopropyl or cyclobutyl.

[0115] Embodiment 42. The compound of any one of embodiments 1-37, wherein at least one Q1is CR1, and at least one R1is C1.3 alkyl substituted with C1-3 alkoxyl.

[0116] Embodiment 43. 'The compound of any one of embodiments 1-37, wherein

[0117] Embodiment 44. The compound of any one of embodiments 1-37, wherein

[0118] Embodiment 45. The compound of any one of embodiments 1-37, wherein

[0119] Embodiment 46, The compound of any one of embodiments 1-37, wherein

[0120] Embodiment 47. A compound selected from Table 1 below, or a pharmaceutically acceptable salt thereof:

[0121] Embodiment 47A. A compound selected from Table 1A below, or a pharmaceutically acceptable salt thereof:Table 1A

[0122] Embodiment 48. A compound selected from:or a pharmaceutically acceptable salt thereof.

[0123] Embodiment 49. A compound of formula:or a pharmaceutically acceptable salt thereof.

[0124] Embodiment 50. A pharmaceutical composition, comprising a compound of any of embodiments 1 to 49, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0125] Embodiment 51. A method of treating an immune-mediated disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 49, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 50.

[0126] Embodiment 52. A method of treating a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn’s disease, graft-versus-host disease,rheumatoid arthritis, and multiple sclerosis in a patient in need thereof, comprising administering to the patient an effecti ve amount of a compound according to any one of embodiments 1 to 49, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 50.

[0127] Embodiment 52A. A method of treating systemic lupus erythematosus (SEE) in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 49, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 50.[012.8] Embodiment 53. A compound according to any one of embodiments 1 to 49 or a pharmaceutically acceptable salt thereof, for use in therapy.

[0129] Embodiment 54. A compound according to any one of embodiments 1 to 49 or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn’s disease, graft- versus- host disease, rheumatoid arthritis, and multiple sclerosis.

[0130] Embodiment 55, A compound according to any one of embodiments 1 to 49 or a pharmaceutically acceptable salt thereof, for use in treating psoriasis.

[0131] Embodiment 56. A compound according to any one of embodiments 1 to 49 or a pharmaceutically acceptable salt thereof, for use in treating atopic dermatitis.

[0132] Embodiment 57. A compound according to any one of embodiments 1 to 49 or a pharmaceutically acceptable salt thereof, for use in treating ulcerative colitis.

[0133] Embodiment 58. A compound according to any one of embodiments 1 to 49 or a pharmaceutically acceptable salt thereof, for use in treating Crohn’s disease.

[0134] Embodiment 59. A compound according to any one of embodiments 1 to 49or a pharmaceutically acceptable salt thereof, for use in treating graft-versus-host disease.

[0135] Embodiment 60. A compound according to any one of embodiments 1 to 49 or a pharmaceutically acceptable salt thereof, for use in treating rheumatoid arthritis.

[0136] Embodiment 61, A compound according to any one of embodiments 1 to 49 or a pharmaceutically acceptable salt thereof, for use in treating multiple sclerosis.

[0137] Embodiment 62. A compound according to any one of embodiments 1 to 49 or a pharmaceutically acceptable salt thereof, for use in treating systemic lupus erythematosus (SLE).

[0138] Embodiment 63. A compound of formula of:

[0139] or a pharmaceutically acceptable salt thereof, for use m treating a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn’s disease, graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus (SLE).

[0140] Embodiment 64. A compound for use in treating an immune-mediated disease or disorder, the compound being selected from: lH-Indazol-3-yl(4,6,7,8~tetrahydro-l~metiiylpyrazolo[4,3"C]azepin-5(lH)-yl)methanone;(5-Chloro-lH-indazol-3-yl)(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-c]azepin-5(lH)- yl)methanone;(5-Bromo-lH-indazol-3-yl)(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-c]azepin-5(lH)- yl)methanone;(4,7-Difluoro-lH-indol-2-yl)(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-c]azepin-5(lH)- yl)methanone;(6-Chloro-lH-indazol-7-yl)(2,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(4H)- yl)mcthanone;(6-Chloro-lH-indazol-7-yl)(4,6,7,8-tetrahydro-1-methylpyTazolo[4,3-c]azepin-5(lH)- yl)methanone;(5-fluoro-lH-benzimidazol-7-yl)(4,6,7,8-tetrahydro-l-methylpj'razolo[4,3-c]azepin-5(lH)-yl)mcthanone; lH-Benzimidazol-7-yl(4,6,7,8-tetrahydro-l-methylpyrazolo|4,3-c]azepin-5(lH)- yl)niethanone; lH-Indazol-4-yi(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-c]azepm-5(lH)-yl)methanone;(5-Fluoro-lH-benzotriazol-7-yl)(4,6,7,8-tetrahydro-l-me1hylpyrazo1o[4,3-c]azepin-5 ( 1 H) ~y l)methanone ; lH-Indazol-7-yl(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-c]azepm-5(lH)-yl)methanone;(5-Bromo-lH-benzimidazol-7-yl)(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-c]azepin-5(1 H) -y 1 )me thanone ;(7-Fluoro-lH-benzimidazol-6-yl)(2,6,7,8-tetrahydropyrazolo[4,3-c]azepiii-5(4H)- yl)mcthanone;(7-Fluoro-lH-benzimidazol-6-yl)(4,6,7,8-tetraliydro-l-methylpyrazolo|4,3-c]azepin-5 ( 1 H) ~y l)methanone ; lH-Benzotriazol-6-yl(4,6,7,8-tetrahydro-l-methyipyrazoio[4,3-c]azepin-5(lH)- yl)methanone; lH-Benzimidazol-6-yl(4,6, 7,8-tetrahydro- 1 -methylpyrazolo[4,3-c]azepin-5 ( 1H)- yl)methanone;[(5R,7S)-1, 4,5, 7-Tetrahydro-5,7-dimethylpyrano[3,4-c]pyrazol-3-yl](2, 6,7,8- tetrahydropyrazolo[4,3-c]azepin-5(4H)-yl)methanone;[(5R,7S)-1, 4, 5, 7-Tetrahydro-5,7-dimethylpyrano[3,4-c]pyrazol-3-yl](4, 6, 7,8-tetrahydro-1 -methylpyrazolo [4,3 -cjazepin -5 ( lH)-yl)methanone;(2,6,7,8-Tetrahydropyrazolo[4,3-c]azepin-5(4H)-yl)(4,5,6,7-tetrahydro-lH-pyrazolo[3,4- b]pyridin-3 -yl)methanone : lH-Indazol-3-yi(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-c]azepm-5(lH)-yl)methanone;(5-Chloro-lH-indazol-3-yl)(4,6,7,8-tetrahydro-l-methylpyrazolo[4,3-c]azepin-5(lH)- yl)methanone;(1,4, 5 ,6-Tetrahydro-3 -cyclopentapyrazoiyl)(4,6,7, 8 -tetrahydro- 1 -methylpyrazolo [4,3- c]azepin-5(] H)-yl)methanone;(7-Methoxy-lH-indazol-3-yl)(4,6,7,8-tetrahydro-l-me1hylpyrazo1o[4,3-c]azepin-5(lH)- yl)methanone; and (5-Bromo-lH-indazol-3-yl)(4,6,7,8-tetrahydro-l-methyipyrazoio[4,3-c]azepin-5(lH)- yl)rn ethanone.

[0141] Tlw present disclosure further provides pharmaceutical composition, comprising a compound or a pharmaceutically acceptable salt thereof according to any of the above embodiments with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0142] The present disclosure provides a method of treating an immune-mediated disease in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition according to any of the above embodiments.

[0143] The present disclosure provides a method of treating an auto-antibody driven autoimmune diseases in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound, or a pharmaceutically acceptable salt thereof, or pharmacal composition according to any of the above embodiments.

[0144] The present disclosure also provides a method of treating a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn’s disease, graft-versus- host disease, rheumatoid arthritis, and multiple sclerosis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition according to any of the above embodiments.

[0145] The present disclosure also provides a method of treating a disease or disorder selected from systemic lupus erythematosus (SITS), rheumatoid arthritis, and myasthenia gravis (MG).

[0146] The present disclosure provides a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0147] The present disclosure also provides a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in the treatment of adisease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn’s disease, graft-versus-host disease, rheumatoid arthritis, and multiple sclerosis.

[0148] The present disclosure provides a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in treatment of an auto-antibody driven autoimmune diseases in a patient.

[0149] The present disclosure also provides a compound according to any of the above embodiments, or a pharmaceutically acceptable salt of each thereof, for use in the treatment of a disease or disorder selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, and myasthenia gravis (MG).

[0150] Furthermore, the present disclosure provides the use of a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, for tire manufacture of a medicament for the treatment of an immune-mediated disease. In addition, the present disclosure provides the use of a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn’s disease, graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus.

[0151] As used herein, the term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, straight, or branched chain hydrocarbon group containing one or more carbon atoms. As used herein, the terms “haloalkyl” refers to alkyl substituted with one or more halo. For example, “C1.3 haloalkyl” refers to C1-3 alkyl having one or more halo substitution.

[0152] As used herein, the term “alkoxy”, used alone or as part of a larger moiety, refers to a moiety having an oxygen directly atached to an alkyl group with the attachment point of the moiety on the oxygen atom. The term may be preceded with an indication of number of carbon atoms of the alkoxy. Accordingly, the term “C1-3 alkoxy” refers to -O- C1.3 alkyl. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tertbutoxy, and the like. As used herein, the terms “haloalkoxyl” refers to alkoxyl substituted with one or more halo. For example, “C1-3 haloalkoxyl” refers to C 1-3 alkoxyl having one or more halo substitution.

[0153] As used herein, the term “aryl”, used alone or as part of a larger moiety, refers to an aromatic hydrocarbon group, having 6, 10, or 14 re-electrons shared in a cyclic array. Aryl can be monocyclic (having one ring), bicyclic (having two rings), or polycyclic (having two or more rings). Exemplary' aryl includes phenyl, naphthyl, anthracenyl, and phenanthrenyl.

[0154] As used herein, the terms “aromatic group” and “aromatic unit”, refers to aryl and heteroaryl (as defined below) groups.

[0155] As used herein, the term “monocycle”, refers to a ring system of one cycle, where each ring atom of the cycle can be a carbon or a heteroatom . In other words, the monocycle can be a carbocycle or a heterocycle (each defined below).

[0156] As used herein, the term “cycloalkyl” refers to a saturated ring system containing at least three carbon atoms. Cycloalkyl can be monocyclic (having one ring), bicyclic (having two rings), or polycyclic (having two or more rings). Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0157] As used herein, the term “carbocycle” refers to a saturated or unsaturated ring system containing only carbons. Carbocycles include cycloalkyls and aryls and partially saturated rings.

[0158] As used herein, the term “halo” refers to halogen as a substituent, and specifically chloro, fluoro, bromo, or iodo.

[0159] As used herein, the term “heterocyclic” and “heterocycle” refers to an optionally substituted, saturated ring system containing at least two carbon atoms and at least one heteroatom. Exemplary heteroatoms are oxygen, nitrogen, and sulfur. Exemplary' heterocyclic rings (or heterocycles) include oxirane, aziridine, oxetane, oxolane, pyrrolidine, piperidine, and morpholine. Heterocycles can be monocycles (having one ring), bicycles (having two rings), or polycycles (having two or more rings) that may be, for example, fused with each other.

[0160] As used herein, the term “heteroaryl” refers to groups having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 re-electrons shared in a cyclic array, and having, in addition to carbon atoms, from one to five heteroatoms. Tire term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form ofnitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. The term “bicyclic heteroaiyl” includes groups m which a heteroaryl ring is fused to one or more aryl, or heteroaryl rings. Nonlimitmg examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, di benzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl.

[0161] When there are two or more rings, the rings may be arranged separate from each other or connected with each other. When two rings are connected with each other, they may be connected in a “fuse” arrangement (or connection motif), a “spiro” arrangement, or a “bridge” arrangement. As used herein, the term “fuse” refers to an arrangement where the two rings are connected with each other, side-by-side, sharing two bridgehead” atoms that are directly and immediately connected to each other. The fuse” connection motif differs from “spiro” connection motif in that there is one and only one “bridgehead" atom in the "spiro” motif; and differs from “bridge’' connection motif in that the two "bridgehead” atoms are not immediately connected to each other in the “bridge” motif. When a first ring is “fused with” a second ring, the "bridgehead” atoms are construed as belonging to both rings. Accordingly, if an embodiment provided here describes one such ring being a six-membered “carbocycle, then the six ring atoms include two “bridgehead” atoms and four additional atoms.And all these six ring atoms are carbons in order to be a “carbocycle.” For example, the group- faj]soutside the scope of “a 5-membered het.eroaryl fused with a 6- membered carbocycle” because one bridgehead atom is not carbon. For clarity, when one of the two rings fused together is aromatic, the shared bond does not disqualify the otherring from being a “cycloalkyl”' or “heterocycle”. For example, the groupHmay be interpreted as 5-membered heteroaiyl fused with a 5-membered cycloalkyl: and thegroupmay be interpreted as a 5-membered heteroaryl fused with a 6-membered heterocycle.

[0162] As used herein, the term “oxo” refers to the oxygen atom as a substituent connected to another atom by a double bond. It may be denoted as ' ()". The term oxo is the carbonyl group less the carbon atom.

[0163] As used herein, ™ represents a bond that is part of an aromatic system. It may be properly and alternatively represented as a single bond or double bond depending on how the aromatic system is depicted. For example,may be used to represent a 5- membered carbocycle fused with an aromatic system, such as a phenyl ring, at the two attachment points. The = bond may be properly represented as a single bond (e.g. as

[0164] refersw andQ"' , respectively. Moreover, each Qdmay be the same with each other or different from each other. Furthermore, when Q3is CR3, each RJmay be the same with each other or different from each other.

[0165] As used herein, the term “immune-mediated disease” encompasses a group of autoimmune or inflammatory' disorders in which immunological pathways play an important etiological and / or pathogenetic role. Such diseases are sometimes characterized by an alteration in cellular homeostasis. Immune-mediated diseases may be triggered by' environmental factors, dietary-' habits, infectious agents, and genetic predisposition. Immune-mediated disease includes, for example, psoriasis, atopic dermatitis, ulcerative colitis, Crohn’s disease, graft-versus-host disease, rheumatoid arthritis, and multiple sclerosis.

[0166] As used herein, the term “auto-antibody driven autoimmune disease” refers to a type of autoimmune disease that occurs when the immune system produces antibodies that attack the body’s own tissues or organs, causing inflammation and damage. Autoantibody driven autoimmune diseases includes, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and myasthenia gravis (MG).

[0167] As used herein, the term “treating” includes restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.

[0168] As used herein, the term "patient" refers to a human.

[0169] As used herein, the term “effective amount” refers to the amount or dose of compound of the disclosure, or a pharmaceutically acceptable salt thereof which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment.

[0170] An effective amount can be readily determined by one skilled in the art by the use of known techniques. In determining the effective amount for a patient, a number of factors are considered, including, but not limited to: die species of patient; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; die response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; the individual patient’s medical history; and other relevant circumstances.

[0171] The compounds of the present disclosure are generally effective over a wide dosage range. For example, dosages per day normally fall within the range of about 0.1 to about 15 mg / kg of body weight. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed with acceptable side effects, and therefore the above dosage range is not intended to limit the scope of the disclosure in any way.

[0172] The compounds of the present disclosure are preferably form ulated as pharmaceutical compositions administered by any route which makes the compound bioavailable, including oral and transdennal routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes forpreparing same are well known in the art (See, e.g., Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23rdEdition, Elsevier Academic Press, 2020).

[0173] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be prepared according to the following Preparations and Examples by methods well known and appreciated in the art. Suitable reaction conditions for the steps of these Preparations and Examples are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art. Likewise, it will be appreciated by those skilled in die art that synthetic intermediates may be isolated and / or purified by various well-known techniques as needed or desired, and that frequently, it will be possible to use various intennediates directly in subsequent synthetic steps with little or no purification. As an illustration, compounds of the preparations and examples can be isolated, for example, by silica gel purification, isolated directly by filtration, or crystallization. Furthermore, the skilled artisan will appreciate that in some circumstances, the order in which moieties are introduced is not critical. The particular order of steps required to produce the compounds of die present disclosure is dependent upon the particular compound being synthesized, the starting compound, and the relative lability of the substituted moieties, and is well appreciated by die skilled chemist. All substituents, unless otherwise indicated, are as previously defined, and all reagents are well known and appreciated in the art.

[0174] Certain abbreviations are as follows: “BSA” refers to bovine serum albumin; “BOP-Q” refers to bis(2-oxo-3-oxazolidinyl)phosphinic chloride; “CMV” refers to cytomegalovirus; “DCM” refers to dichloromethane; “DIEA” refers to N, N- diisopropylethylamine; “DMEM” refers to Dulbecco's modified eagle medium; “DMF” refers to dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “DPBS” refers to Dulbecco's phosphate-buffered saline; “EGFP” refers to enhanced green fluorescence protein; “EtOAc” refers to etbyd acetate; ‘TBS” refers to fetal bovine serum; “HATU” refers to (1 -[bis(dimethylamino)niethylene]-l H-l , 2, 3-triazolo[4,5-b [pyridinium 3-oxide hexafluorophosphate; “HCTU” refers to 2-(6-Chloro-lH-benzotriazole-l-yl)-l, 1,3,3- tetramethylamimum hexafluorophosphate; hr / hrs refers to hour / hours; “MeOH” refers to methanol and methyl alcohol; “Min” refers to minute / minutes; “MTBE” refers to “methyl tert-butyl ether” “TFA” refers to trifluoroacetic acid; and “THF” refers to tetrahydrofuran.Schemes

[0175] Scheme 1A. General scheme forthe preparation of Intermediate 8a

[0176] Scheme 1A depicts a general scheme for the synthesis of intermediate compound 8a. R2and O, are each defined as provided above with respect to embodiment 1 . PG represents a suitable protecting group, such as t-butyloxycarbonyl (BOC).

[0177] In Step 1, compound 1 reacts with compound 2a and compound 2b in the presence of aqueous HC1 (to adjust pH) and at a temperature of about 25 to 30 °C to give compound 3a.

[0178] In Step 2, the hydroxy-bearing compound 3a is contacted with halo-bearing compound 4 under conditions sufficient to provide compound 5a. For example, a solution of compound 3a and compound 4 in a suitable solvent (e.g., DMF), and a base (such as potassium carbonate) is heated at a suitable temperature (e.g., 60-85 °C) for several hrs., until the reaction completes. The reaction is quenched with water, extracted with a suitable solvent (e.g., EtOAc or MTBE), dried (e.g., over anhydrous NazSCh), concentrated under reduced pressure, and purified (e.g., via silica gel chromatography) to give compound 5a.

[0179] In Step 3, compound 5a is contacted with an acid (such as HC1) in dioxane under sufficient conditions to deprotect the amine group to give compound 6a as HC1 salt,

[0180] In Step 4, the HC1 salt compound 6a is contacted with a base under conditions sufficient to allow intramolecular ester-amide exchange reaction to occur to provide a cyclized compound 7a, For example, a solution of HC1 salt compound 6a in a suitable solvent (e.g., water) is treated with an appropriate base (e.g., lithium hydroxide) and stirred at ambient temperature for about an hr., until the reaction completes to give compound 7a,

[0181] In Step 5, compound 7a is then reduced under conditions sufficient (e.g., with borane) to compound 8a. For example, compound 7a is dissolved in a solution of borane- THF complex and stirred at a suitable temperature (e.g., 45-70 °C) for several hrs., until the reaction completes. The reaction mixture is quenched with an appropriate alcohol (e.g., MeOII), stirred at. a suitable temperature (e.g., 80-90 °C) for several hrs., and concentrated under reduced pressure to give compound 8a.

[0182] Scheme IB. General scheme for the preparation of Intermediate 8b8b 7b

[0183] Scheme IB depicts a general scheme for the synthesis of intermediate compound 8b. Scheme IB differs from scheme 1 in that, in step la preparing compound 3b, tire reaction is conducted in absence of diethylamine (2b). The product of step la is a mixture of compound 3a and 3b. Accordingly, step lb isolates compounds 3b (and compound 3a as well) which may be converted into compound 8b following protocols similar to that of Scheme 1A.

[0184] Scheme 1C. General scheme for the preparation of Intermediate 8c

[0185] Scheme 1C depicts a general scheme for the synthesis of intermediate compound8c. R1, and R2are each defined as provided above with respect to embodiment 1. In Step1, the hydrazine compound 2a reacts with an ortho ester compound la in the presence of an organic acid in a suitable solvent such as acetonitrile at reflux for an appropriate time, for example, 9 hrs. The mixture is cooled and evaporated to give Intermediate compound24.

[0186] In Step 2, compound 24 is oxidized under sufficient conditions and then treated with an alkyl halide in the presence of a suitable base such as cesium carbonate in a suitable solvent such as DMF at an appropriate temperature such as ambient temperature, and for an appropriate time such as 12 hrs., to give compound 25.

[0187] In step 3, the compound 25 is reacted with compound 4a in the presence of an appropriate base such as DIEA in an appropriate solvent such as DMF at an appropriate temperature such as 80 °C for a suitable time such as 12. hrs. The cyclized compound is reduced with an appropriate reducing agent such as borane-dimethylsufide complex or lithium aluminum hydride in an appropriate solvent such as THF at a suitable temperature such as ambient temperature or refluxing to give a compound of formula 8c.

[0188] Scheme ID. General scheme for tire preparation of compounds of Intermediate

[0189] Scheme ID depicts an alternate scheme for the synthesis of intermediate compound 3. In Step 1 , compound 9 reacts with an ortho ester for example trimethylorthoformate, and compound 10 in the presence of an organic acid such as glacial acetic acid in a suitable solvent such as acetonitrile at reflux for an appropriate time, for example 9 hrs. The mixture is cooled and evaporated. The residue is then treated with an amine such as methylamine in an alcohol solvent such as absolute ethanol at ambient temperature to give compound 3d . Compound 3d may be used in place of compound 3a or 3b of Scheme 1A or IB to form corresponding compound 8d:

[0190] Scheme 2. General scheme for the preparation of compounds of Intermediate 5.

[0191] Scheme 2 depicts an alternate scheme forthe synthesis of intermediate compound 5 (which may optionally take the form of compound 5a, 5b, or another similar intermediate), where Q3, R1, R2, O, are each defined as provided above with respect to embodiment 1, and X is a halo such as iodo. PG represents a suitable protecting group, such as t-butyloxycarbonyl (BOC).

[0192] In Step 1, compound 11 is esterified under acidic or basic conditions. For example, compound 11 is treated with an alkyl halide such as iodoethane in the presence of a suitable base such as cesium carbonate or an organic acid in a suitable solvent such as DMF at an appropriate temperature such as ambient temperature, and for an appropriate time such as 12 hrs., to give compound 12.

[0193] In Step 2, compound 12 is reacted with a compound 13 containing an appropriate pro tecting group such a t-butoxycarbonyl protecting group in the presence of a sui table base such as sodium hydride in a suitable solvent such as XMP, at appropriate temperature such as 80 °C, and for an appropriate time such as 12 hrs., to give compound 5.

[0194] Scheme 3. General scheme for the preparation of compounds of Intermediate 18.18 17

[0195] Scheme 3 depicts a general scheme for the synthesis of intermediate compound 18. Ql, R1, R2, O, are each defined as provided above with respect to embodiment 1, and X is a halo such as iodo. PG represents a suitable protecting group, such as t- butyl oxy carbonyl (BOC) .

[0196] In Step 1, compound 12 reacts with compound 14 in the presence of an appropriate base such as DIEA in an appropriate solvent such as NMP at an appropriate temperature such as 80 °C for an appropriate time such as 12 hrs., to give a compound 15.

[0197] In Step 2, the compound 15 is deprotected with appropriate deprotection conditions. For example, when the protecting group is a rert-butoxycarbonyl protecting group, compound 15 is contacted with an appropriate acid such as hydrochloric acid in a suitable solvent such as 1,4-dioxane or an appropriate time such as 4 hrs., to give a compound 16.

[0198] In Step 3, the compound 16 is treated with an appropriate base such as DIEA in an appropriate solvent such as DMF at an appropriate temperature such as 80 °C for a suitable time such as 12 hrs., to give a compound 17.

[0199] In Step 4, the compound 17 is reduced with an appropriate reducing agent such as borane-dimethylsufide complex or lithium aluminum hydride in an appropriate solvent such as THF at a suitable temperature such as ambient temperature or refluxing to give a compound 18.

[0200] Scheme 4. Alternate scheme for the preparation of Intermediate 17.17

[0201] Scheme 4 depicts an alternate scheme for the synthesis of intermediate compound 17. Q1, R1. R2, O, are each defined as provided above with respect to embodiment 1. In Step 1, compound 19 is treated with tert-butanol and heated at an appropriate temperature such as reflux for a suitable time such as 2 hrs., to give a compound 20.

[0202] In Step 2, compound 20 is contacted with (1 ,3-dioxolan-2-yl)methanamine under conditions sufficient (e.g., through an amide coupling reaction) to provide compound 21. For example, compound 20 and (l,3-dioxolan-2-yl)methanamine are dissolved in a suitable solvent (e.g., DMF, or THF), treated with an appropriate amide coupling agent (e.g., HATU, orHCTU) and an appropriate base (e.g., DIEA, or triethylamine), and stirred at ambient temperature for several hrs., until reaction completes to give a compound 21.

[0203] In Step 3, compound 21 in an alcohol solvent such as methanol is treated with a suitable acid such as a 37% methanolic solution of hydrochloric acid at an appropriate temperature such as ambient temperature for a suitable time such as 2 hrs., to give a compound 22.

[0204] In Step 4, compound 22 is treated with an organic acid such as glacial acetic acid and a reducing agent such as sodium cyan oborohyd ride in an alcohol solvent such as methanol at a suitable temperature such as 45 °C for an appropriate time such as 48 hrs., to give a compound 17.

[0205] Scheme 5. General scheme for the preparation of compounds of Intermediate 27.

[0206] Scheme 5 depicts a general scheme for the synthesis of intermediate compound27. Q1, O, are each defined as provided above with respect to embodiment 1 .

[0207] In Step 1, compound 23 is reacted with a base such as KOH in the presence of diphosgene and at a suitable temperature (tor example about 90 °C) to give compound 19a.

[0208] In Step 2, compound 19a is reacted with benzyl glycine in the presence of water and at a suitable temperature (for example about 100 °C) to give compound 24.

[0209] In Step 3, compound 24 is reduced in the presence of a strong reducing agent such as aluminum lithium hydride, in a solvent such as THF, and at a suitable temperature (for example, about 60 °C) to give compound 25.

[0210] Step 4 shows a trifluoroacetylation of amine reaction in which compound 25 is reacted with trifluoroacetic anhydride in the presence of triethylamine, and a solvent such as DCM, and at a suitable temperature (for example, at 0 °C) to give compound 26.

[0211] Step 5 shows a debenzylation or dealkylation of compound 26 to give compound 27 by using 1 -chloroethyl chloroformate in the presence of diisopropylethylamine and a suitable temperature (for example, about 35-45 °C).

[0212] Scheme 6. General scheme for the preparation of compounds of Formula I

[0213] Scheme 6 depicts a general scheme for the synthesis of compounds of Formula I. Q1, R1, R2, O, Z, and Y are each defined as provided above with respect to embodiment 1. Intermediate 8 (which may take, for example, the form of compound 8a. 8b, 8c, 8d, other similarly preparable compound, or a commercially available compound) is contacted with an appropriate carboxylic acid compound 28 under conditions sufficient (e.g., through an amide coupling reaction) to provide compound of Formula I. For example, compounds 8 and 28 are dissolved in a suitable solvent (e.g., DMF, or THF) and treated with an appropriate amide coupling agent (e.g., HATH) and an appropriate base (e.g., DIEA, or triethylamine) and stirred at ambient temperature for several hrs., until reaction completes. The reaction mixture is concentrated under reduced pressure and the residue purified (e.g., prep-HPLC) to give compound of Formula I.

[0214] Scheme 6b. General scheme for the preparation of compounds of Formula lb.

[0215] Scheme 6b depicts a general scheme forthe synthesis of compounds of Formula lb. Q1, and Y are each defined as provided above with respect to embodiment 1 .Intermediate 27 is contacted with an appropriate carboxylic acid compound 28 under conditions sufficient (e.g., through an amide coupling reaction) to provide compound of Formula lb. For example, compounds 27 and 28 are dissolved in a suitable solvent (e.g., DCM, DMF, or THF) and treated with an appropriate amide coupling agent (e.g., HATU, or BOP-CI) and an appropriate base (e.g., DIE A, or tri ethylamine) and stirred at ambient temperature for several hrs., until reaction completes. The reaction mixture is concentrated under reduced pressure and the residue purified (e.g., prep-HPLC) to give compound of Formula ib.

[0216] Formula lb can be converted to Formula I through deprotection of tri fluoroacetyl using a base such as NaOFI in a solvent such as MeOH or EtOH, and at a suitable temperature (for example, at about 60 °C).PREPARATIONSPreparation 1Step 1Ethyl 5-hydroxy-l-methy]-pyrazole-4-carboxylate

[0217] Diethylamine (450 g, 6.24 mol) was added dropwise to a solution of diethyl ethoxymethyl enemalonate (CAS Registry No. 87-13-8) (900 g, 4. 16 mol) in water (72 mL) keeping the internal temperature between 25 and 30 °C. To the resulting solution was added dropwise a solution of methylhydrazine (40% in water, 522 g, 4.56 mol) keeping the internal temperature between 25 and 30 °C. The resulting solution was stirred between 25 and 30 °C tor 16 hrs. 5M aqueous HC1 (900 mL) was added to adjust the pH to approximately 4. The aqueous solution was extracted with EtOAc (1.5 L x 12). 'The combined organic extracts were dried over sodium sulfate and filtered. The solvent was concentrated under reduced pressure to give the title compound (500 g, 77%) as a light-yellow solid. ES / MS (m / z): 171.1 (M+H).Step 2Ethyl 5-[2-(tert-butoxycarbonylamino)ethoxy]-l-methyl-pyrazole-4-carboxylate

[0218] ten-Butyl (2-chloroethyl)carbamate (1187 g, 6.61 mol) was added to a solution of ethyl 5 -hydroxy- 1 -methyl-pyrazole-4-carboxylate (450 g, 2,64 mol) in DMF (4.5 L.) followed by potassium carbonate (1096 g, 7.93 mol). Hie resulting mixture was heated at 80 °C for 16 hrs. The mixture was cooled to ambient temperature. The reaction mixturewas combined with another nm the same way starting with ethyl 5 -hydroxy- 1-methyl- pyrazole-4 -carboxylate (100 g, 0.59 mol). The combined reaction mixtures were poured into water (10 L) and MTBE (4 L). The layers were separated, and the aqueous layer was back extracted with MTBE (3 L). The combined organic extracts were washed with water (3 L x 2). The organic solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was passed through a short silica gel plug eluting stepwise with hexane in EtOAc (80: 1 ), hexane in EtOAc (60: 1), and finally hexane in EtOAc (40: 1). The appropriate fractions were combined and evaporated to give the title compound (1000 g, 99+%) as a yellow oil . ES / MS (m / z): 314.1 (M+H).Step 3Eth yl 5 -(2 -aminoethoxy) - 1 -m eth yl- 1 H-pyrazole -4-carboxylate hy drochlori de

[0219] 4M HC1 in dioxane (4440 mL) was added to a solution of ethyl 5-[2-(tert- butoxycarbonylamino)ethoxy]“l-methyl-pyrazole"4“Carboxylate (888 g, 2.84 mol) in 1,4- dioxane (888 mL) at 10-15 °C. The mixture was stirred at ambient temperature for 1 hr. Tire mixture was concentrated under reduced pressure. The residue was co-evaporated with MTBE (300 mL x 3) to give the title compound (840 g, 99+%) as a yellow solid used in the next step without purification. ES / MS (m / z): 214.1 (M+H).Step 41 -Methyl-6,7-dihydro-5H-pyrazol o [4,3 -f| [ 1 ,4]oxazepin-4-one

[0220] A solution of lithium hydroxide (321 g, 7.66 mol) in water (2352 mL) was added dropwise to a solution of ethyl 5-(2-aminoethoxy)~l -methyl- lH-pyrazole-4-carboxylate hydrochloride (840 g, 3.36 mol) in water (840 mL) at 0-10 °C. Hie mixture was stirred at ambient temperature for 1 hr. The pH was adjusted to approximately 4 with concentrated aqueous HC1 (750 mL), The resulting solids were collected by filtration and dried in an oven at 100 °C to give the title compound (352 g, 62%) as a white solid. ES / MS (m / z): 168.1 (M+H).S tep 5 ]oxazepane hydrochloride

[0221] A solution of l~methyl-6,7-dihydro-5H-pyrazolo[4,3~f][l,4]oxazepin-4~one (115 g, 0.69 mol) in THF (1 150 mL) was heated at 50 °C. Borane-tetrahydrofuran complex (IM in THF; 550 mL, 550 mmol) was added and the mixture was stirred at 50 °C for 24 hrs. The reaction mixture was dropwise added to a 50 °C methanol solution. The resulting mixture was heated at 70 °C for 16 hrs. Concentrated HO (115 mL, 1.38 mol) was dropwise added to form a white slurry. The resulting slurry was heated at 70 °C for an additional 1 hr. The mixture was cooled to 15 °C. The resulting solids wfere collected by filtration and dried in an oven at 100 °C to give the title compound (141 g, 99+%) as a white solid used without further purification. ES / MS (m / z): 154.2 (M+H).Preparation 2 l,4-Dihydropyrazolo[4,3-c]pyrazole~3-carboxylic acidStep 1Ethyl 5-methyl-4-nitro-lH-pyrazole-3-carboxylate

[0222] A solution of ethyl 5-methyl-lH-pyrazole-3-carboxylate (2000 mg, 12.32 mmol) was slowly added to sulfuric acid, fuming 60% (9.513 mL, 61.62 mmol) at 0 °C, the resulting mixture was stirred at 15 °C for 16 hrs. The reaction mixture was quenched with water (30 mL), the pH was adjusted to 7 with saturated potassium carbonate solution. The mixture was then extracted by EtOAc (20 mL). The combined organic extracts were washed with saturated aqueous NaCI (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% EtOAc in petroleum ether) to give ethyl 5 -methyl -4-nitro-lH- pyrazole-3 -carboxylate as a yellow oil (2.36 g, 66%). ES / MS (m / z): 200.2 (M+H).Step 2Ethyl 4-amino-5 -methyl- lH-pyrazole-3 -carboxylate

[0223] To a solution of ethyl 5 -methyl -4~nitro-lH-pyrazole~3 -carboxylate (2.36 g, 70% purity, 8.29 mmol) in MeOH (30 ml) was added wet Pd-C (1 .77 g, 10% Wt, 1 .66 mmol).The mixture was stirred at 25 °C for 12 hrs., under an atmosphere of hydrogen (15 psi).The mixture was filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-38% EtOAc in petroleum ether) to give ethyl 4-amino-5-methyl-lH-pyrazole-3-carboxylate as a white solid (958 mg, 67%).ES / MS (m / z): 170.2 (M+H).Step 3Ethyl 4-acetamido-l-acetyl-5-methyi-lH-pyrazole-3-carboxylate

[0224] To a solution of ethyl 4-amino-5 -methyl- lH-pyrazole-3 -carboxylate (858 mg, 4.97 mmol) in pyridine (10 mL) was added acetic anhydride (2.47 mL, 24.9 mmol), the resulting mixture was stirred at 25 °C for 12 hrs. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether) to give ethyl 4-acetamido-l-acetyl-5-methyl-lH-pyrazole-3- carboxylate as a white solid (1.19 g, 90%). ES / MS (m / z): 254.1 (M+H).Step 4Ethyl l,4-diacetyl-l,4-dihydropyrazolo[4,3-c]pyrazole-3-carboxylate andEthyl 4-acetyl-l,4-dihydropyrazolo[4,3-c]pyrazole-3-carboxylate

[0225] To a solution of ethyl 4-acetamido-l-acetyl-5-methyl- lH-pyrazole-3 -carboxylate (690 mg, 2.59 mmol) in toluene (10 mL) was added potassium acetate (535 mg, 5.18 mmol) and acetic anhydride (1 .29 mL, 12.9 mmol). The resulting mixture was stirred at 100 °C under nitrogen. Isoamyl nitrite (1.09 mL, 7.76 mmol) was added to the mixture, and the resulting mixture stirred at 100 °C for 12 hrs., under nitrogen. The reaction mixture was cooled to ambient temperature and quenched with water (10 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with saturated aqueous NaCl (20 mL x 2), dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by silica gel chromatography (0-50%EtOAc in petroleum ether) to give ethyl l,4-diacetyl-l,4-dihydropyrazolo[4,3-c]pyrazole-3-carboxylate as a yellow solid (238 mg, 28%), ES / MS (m / z): 265.2 (M+H) and ethyl 4- acetyl-l,4-dihydropyrazoIo[4,3-c]pyrazole-3-carboxylate as a yellow solid (329 mg.51%), ES / MS (m / z): 223.2 (M+H).Step 5 l,4-Dihydropyrazolo[4,3-c]pyrazole-3-carboxylic acid

[0226] To a solution of ethyl l,4-diaceiyl-l,4-dihydropyrazolo[4,3-c]pyrazole-3~ carboxylate (238 mg, 0.721 mmol) and ethyl 4-acetyl-l,4-dihydropyrazolo[4,3- c]pyrazole -3 -carboxylate (329 mg, 1 .33 mmol) in MeOH (5 mL) and water (5 mL) was added sodium hydroxide (281 mg, 6.66 mmol). The resulting mixture was stirred at 50 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% MeOH in DCM) to give 1,4- dihydropyrazolo[4,3“C]pyrazole-3-carboxylic acid as a yellow' solid (211 mg, 93%). ES / MS (m / z): 152.9 (M+H).Preparation 32,3,4,5-Tetrahydrothieno[3,4~f][l,4]oxazepine hydrochlorideStep 12-(((4-Bromothiophen-3~yl)methyl)amino)ethan-l-ol

[0227] To a solution of ethanolamine (3.121 mL, 50.77 mmol) in dichloroethane (50 mL) was added 4-bromothiophene-3-carbaldehyde (5 g, 25.39 mmol) and sodium cyanoborohydride (3.256 g, 50.77 mmol), the reaction was stirred at 50 °C for 2 hrs. The reaction mixture concentrated under reduced pressure to give a residue. The residue was diluted with water (50 ml) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-10% MeOH in DCM) to give 2-(((4- bromothiophen-3-yl)methyl)amino)ethan-l-ol as a yellow oil (3.7 g, 57%). ES / MS (m / z) (79Br / 81Br): 235.7, 237.7 (M+H).Step 2 tert-Butyl ((4-bromothiophen-3-yl)methyl)(2-hydroxyethyl)carbamate

[0228] To a solution of di-terr-butyl dicarbonate (6.491 g, 29. 14 mmol) in DCM (40 mL) was added 2-(((4-bromothiophen-3-yl)methyl)amino)ethan-l-ol (3.7 g, 14.57 mmol) and triethylamine (6.22 mL, 43.72 mmol). The reaction was stirred at 25 °C for one hr., then concentrated under reduced pressure to give a residue. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether) to give tert-butyl ((4- bromothiophen-3-yl)methyl)(2-hydroxyethyl)carbamate as a yellow oil (3.8 g, 74%).ES / MS (m / z) (79Br / 8iBr): 280.1, 282.1 (M-tBuvH).Step 3 fert-Butyl 2,3-dihydrothieno[3,4-f][l,4]oxazepine-4(5H)-carboxylat.e

[0229] To a solution of tert-butyl ((4-bromothiophen-3-yl)methyl)(2- hydroxyethyl)carbamate (1000 mg, 2.855 mmol) in toluene (10 mL) was added methanesulfonato(2-(di-t-butyiphosphino)-3-methoxy-6-methyl-2',4',6'-tri-i-propyl-l,r- biphenyl)(2'-amino-l,r-biphenyl-2-yl)palladium(II) (122.3 mg, 0.143 mmol) and cesium carbonate (2.848 g, 8.565 mmol). Tire resulting mixture was stirred at 100 °C tor 16 hrs under nitrogen. The reaction mixture was concentrated under reduced pressure to remove solvent. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCI (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether) to give tert-butyl 2,3-dihydrothieno[3,4-f][l,4]oxazepine-4(5H)- carboxylate as a yellow solid (210 mg, 25%). ES / MS (m / z): 200.0 (M-tBu+H).Step 42,3,4,5-Tetrahydrothieno[3,4-f][l,4]oxazepine hydrochloride

[0230] To a solution of tert-butyl 2,3-dihydrothieno[3,4-f][l,4]oxazepine-4(5H)- carboxylate (190 mg, 0.647 mmol) in MeOH (2 mL) was added HC1 in dioxane (4.86 mL, 2 molar, 9.71 mmol). The resulting mixture was stirred at 25 °C for 2 hrs. The reaction mixture was filtered to give the crude product. The crude product 2, 3,4,5- tetrahydrothieno[3,4-fj[l,4]oxazepme hydrochloride was used in the next step without further purification as a white solid (100 mg, 77%). ES / MS (m / z): 156.1 (M+H).

[0231] Compound of Table 2 below was prepared according to Preparation 3 using the appropriate reagents and adjusting reaction conditions (such as time) as needed.Table 2Preparation 41 -(4-Methoxybenzy 1 )-4,6-dihydro- 1 H-furo [3,4-c]pyrazole-3 -carboxyli c acidEthyl 2-oxo-2-(4-oxotetrahydrofuran-3-yl)acetate

[0232] A solution of 3-oxo-l,4-epoxybutane (4.480 mL, 56.92. mmol) in THF (160 ml.) cooled to -78 °C was treated with 2M LDA solution in THF (28.46 mL, 56.92 mmol) andstirred at -78 °C for 15 min. Diethyl oxalate (8.669 mL, 62.61 mmol) was added, and the reaction stirred for 30 minutes at -78 °C and then stirred for 3 hrs., at 20 °C. The reaction mixture was placed at ambient temperature overnight. The reaction mixture was quenched with aqueous IN HC1 and then partitioned between EtOAc (100 mL) and aqueous citric acid (100 ml.,). The mixture was extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Tlie crude product ethyl 2-oxo-2-(4-oxotetrahydrofiiran-3-yl)acetate (8.5 g, 48%) was used in the next step without further purification as a yellow oil , ES / MS (m / z): 187.2. (M+H),Ethyl l-(4-methoxybenzyl)-4,6-dihydro-lH-furo[3,4-c]pyrazole-3-carboxylate

[0233] To a solution of (4-methoxybenzyl)hydrazine dihydrochloride (2.291 g, 9.669 mmol) in EtOH (20 mL) was added ethyl 2-oxo-2-(4-oxotetrahydrofiiran-3-yl)acetaie (2000 mg, 6.446 mmol) and sulfuric acid (645.1 mg, 6.446 mmol). The reaction was stirred at 90 °C for 30 minutes., then concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether) to give ethyl l~(4-methoxybenzyl)-4,6-dihydro-lH-fiiro[3,4-c]pyrazole- 3-carboxylate as a yellow oil (700 mg, 34%). ES / MS (m / z): 303.2 (M+H).Step 3 l-(4~Methoxybenzyl)-4,6-dihydro-lH-fiiro[3,4-c]pyrazole-3-carboxylic acid

[0234] To a solution of ethyl l-(4-methoxybenzyl)-4,6-dihydro-lH-furo[3,4-c]pyrazole- 3-carboxylate (650 mg, 2.04 mmol) in THF (3 mL) and water (3 mL) was added lithium hydroxide monohydrate (175 mg, 4.08 mmol). The reaction was stirred at 25 °C for 2 hrs., then filtered and concentrated under reduced pressure to give a residue. The residue was purified by re-crystallization from EtOH (2.0 mL) to give the pure product l-(4- methoxybenzyl)-4,6-dihydro-lH-furo[3,4-c]pyrazole-3-carboxylic acid as a yellow solid (430 mg, 73%). ES / MS (m / z): 275.2 (M+H).Preparation 54,6-Dihydro-lH-thieno[3,4-c]pyrazole-3-carboxylic acid

[0235] To a solution of ethyl 4,6-dihydro-2H-thieno[3,4-cjpyrazole-3-carboxylate (100 mg, 479 pmol) in water (5 mL) and MeOH (5 mL) was added lithium hydroxide monohydrate (61.6 mg, 1 .44 mmol). Tire mixture was stirred at 50 °C for 2 hrs. The crude reaction mixture was acidified with aqueous HC1 (IM), and the mixture was adjusted to pH = 4, then extracted wdth EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCI (20 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product 4,6-dihydro-lH- thieno [3, 4-c]pyrazole~3 -carboxylic acid (80 mg, 97%) was used in the next step without further purification. ES / MS (m / z): 171.1 (M+H).Preparation 6 l-Propyi-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-f][l,4]oxazepine hydrochlorideStep 1Ethyl 5-hydroxy-l-(4-methoxybenzyl)4H-pyrazole-4-carboxylate

[0236] To a mixture of diethyl 2-(ethoxymethylene)malonate (9.559 g, 44.21 mmol) and potassium carbonate (18.90 g, 132.6 mmol) in MeOH (160 mL) and water (32 ml) was added (4-methoxybenzyl)hydrazme dihydrochloride (10.00 g, 44.21 mmol) in a single portion. The mixture was stirred at 80 °C for 3 hrs. Hie reaction mixture was quenched by addition of saturated aqueous ammonium chloride (100 ml) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (10-60% EtOAc in petroleum ether) to give ethyl 5- hydroxy-l-(4-methoxybenzyl)-lH-pyrazole-4-carboxylate as a purple solid (5.9 g, 41%). ES / MS (m / z): 277.2 (M+H),Step 2Ethyl 5-(2-((terr-butoxycarbonyl)amino)ethoxy)-l-(4-methoxybenzyl)-lH-pyrazole-4- carboxylate

[0237] To a mixture of tert-butyl (2~chloroetliyl)carbamate (6.654 g, 36.30 mmol) in DMF (50 mL) was added ethyl 5-hydroxy~l-(4-methoxybenzyl)-lH-pyrazole-4- carboxylate (5900 mg, 18.15 mmol) and potassium carbonate (7.679 g, 54.45 mmol). The reaction mixture was stirred at 80 °C for 16 hrs. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). 'lire combined organic layers were washed with saturated aqueous NaCI (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether) to give ethyl 5-(2-((te,rt~butoxycarbonyl)ammo)ethoxy)-l~(4-methoxybenzyl)-lH-pyrazole~4- carboxylate as a colorless oil (12.7 g, 71%). ES / MS (m / z): 420.3 (M+H).Step 3Ethyl 5-(2-aminoethoxy)-l-(4-me±oxybenzyl)-lH-pyrazole-4-carboxylaie hydrochloride

[0238] To a mixture of ethyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-l-(4- methoxybenzyl)-lH-pyrazole-4-carboxylate (12600 mg, 28.235 mmol) in HCl in dioxane (141.17 ml, 2 molar, 282.35 mmol) was stirred at 25 °C for 4 hrs. Hie reaction mixture concentrated under reduced pressure to give a residue. The residue was co-evaporated with MTBE (100 mL x 3) to give ethyl 5-(2-aminoethoxy)~l -(4-methoxybenzyl)-lH- pyrazole-4-carboxylate hydrochloride as a white solid (9.2 g, 89%). ES / MS (m / z): 320.2 (M+H).Step 41 -(4-Methoxybenzyl)-6,7-dihydro~ IH-pyrazolo [4,3-1] [ 1 ,4]oxazepin-4(5H)-one

[0239] A solution of ethyl 5-(2~aminoethoxy)-l-(4~methoxybenzyl)-lH-pyrazole-4~ carboxylate (9200 mg, 27.94 mmol) in water (100 ml.) was added dropwise to a solution of lithium hydroxide monohydrate (2.393 g, 55.89 mmol) in water (50 mL) at 5 °C. Tire mixture was stirred at 40 °C for 6 hrs. The pH was adjusted to approximately 4 with aqueous HCl (4 M). Then the mixture was extracted with EtOAc (100 mL. x 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Hie crude product l-(4-methoxybenzyl)-6J-dihydro-lH-pyrazolo[4,3-f][L4]oxazepin-4(5H)- one (5.9 g, 75%) w?as used in the next step without further purification as a yellow solid. ES / MS (m / z): 274.2 (M + H ).Step 5 l~(4-Methoxybenzyl)- oxazepine

[0240] A solution of l-(4-methoxybenzyl)-6,7-dihydro-lH-pyrazolo[4,3-f][l,4]oxazepin- 4(5H)-one (3000 mg, 10.65 mmol) in THF (30 mL) was added dropwise to a solution of borane methylsulfide complex (10.65 mL, 10M, 106.5 mmol) at 0 °C. The mixture was stirred at 60 °C for 24 hrs. The reaction mixture was dropwise added to a 50 °C MeOH (10 mL) solution. The resulting mixture was heated at 70 °C for 12 hrs. Hydrochloric acid (1.775 mL, 12M, 21.30 mmol) was dropwise added to form a white slurry. The resulting slurry' was heated at 70 °C for an additional 1 hr. The mixture was cooled to 15 °C. The resulting solids were collected by filtration and dried to give a residue. The residue was purified by silica gel chromatography (10-20% EtOAc in petroleum ether) to give l-(4-methoxybenzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-f|[l,4]oxazepine (3.0 g, 50%) as a yellow oil. ES / MS (m / z): 260.1 (M+H).Step 64,5 ,6,7-Tetrahydro- lH-pyrazoio[4,3 ~f] [ 1 ,4]oxazepine

[0241] To a mixture of l-(4-methoxybenzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[4,3- f][l,4]oxazepine (1400 mg, 5.345 mmol) in TFA (10.39 mL, 133.6 mmol) was stirred at 70 °C for 12 hrs. The mixture was concentrated under reduced pressure to give a residue.Tire crude reaction mixture was dissolved in DCM and was basified with triethylamine to pH::::8. The crude product solution containing 4,5,6,7-tetraliydro-lH-pyrazolo[4,3- f][l,4]oxazepine (1.65 g, 39% purity, 87%) was used in the next step without further purification as a yellow oil, ES / MS (m / z): 140,2 (M+H).Step 7 ferr-Butyl l,4,6,7-tetrahydro-5H-pyrazolo[4,3-f|[l,4]oxazepine-5-carboxylate

[0242] To a solution of 4,5,6,7-tetrahydro-lH-pyrazolo[4,3-f][l,4]oxazepine (1650 mg, 4.624 mmol) in DCM (15 mL) was added di-tert-butyl dicarbonate (1.545 g, 6.936 mmol) and triethylamine (1 ,32 mL, 9.248 mmol). The reaction was stirred at 20 °C for 2 hrs. The reaction mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). Hie combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Tire residue was purified by silica gel chromatography (0-30% EtOAc in petroleum ether) to give tert-butyl l,4,6,7-tetrahydro-5H-pyrazolo[4,3-f][l,4]oxazepine- 5-carboxylate (1.36 g, 99+%) as a yellow solid. ES / MS (m / z): 240.2 (M+H).Step 8 tert-Butyl l-propyl-l,4,6,7-tetrahydro-5H-pj'razolo[4,3-f][l,4]oxazepine-5-carboxylate and tert-Butyl 2-propyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-f][l,4]oxazepine-5-carboxylate

[0243] To a mixture of tert-butyl l,4,6,7-tetrahydro-5H-pyrazolo[4,3-fl[l,4]oxazepine-5- carboxylate (1350 mg, 5.304 mmol) and 1 -bromopropane (1.997 g, 15.91 mmol) in DMF (10 mL) was added potassium carbonate (2.221 g, 15.91 mmol) in a single portion. The mixture was stirred at 80 °C for 12 hrs. The reaction solution was filtered, and the filtrate collected. The crude product was purified by prep-HPLC (Instrument DD,Method Column Waters Xbridge 150*25mm* 5um, Condition water (formic acid)- acetonitrile Begin B 22%, End B 62% Gradient Time (min) 20.5, 100%, Hold Time(min) 5, FlowRate (ml / min) 60, Injections 1). The afforded flows were combined, concentrated under reduced pressure to remove most of acetonitrile and lyophilized to give tert-butyl l-propyl-l,4,6,7-tetrahydro-5H~pyrazolo[4,3-fj[l,4]oxazepine-5-carboxylate (640 mg, 42%) and tert-butyl 2-propyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-f|[l ,4]oxazepine-5- carboxylate (660 mg, 44%) as white solids. ES / MS (m / z): 282.2 (M+H).!H NMR (CDCh) d 4.34 (s, 2H), 4.14 (d, 2H), 3.90 (t, 2H), 3.81 (s, 2H). 1.76-1.81 (m, 2H), 1.44 (s, 9H), 0.89 (l. 3H),Step 9 l-Propyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-f[[l ,4]oxazepine hydrochloride

[0244] To a mixture of tert-butyl l-propyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3- fj[l,4joxazepine-5~carboxylate (70 mg, 0.25 mmol) in 2M HC1 in dioxane (0.12 mL, 0.25 mmol) was stirred at 20 °C for one hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product l-propyl-4,5,6,7-tetrahydro-lH- pyrazolo[4,3-f[[l,4]oxazepine hydrochloride (50 mg, 93%) was used without further purification as a white solid. ES / MS (m / z): 182.0 (M+H).

[0245] Compound of Table 2A below was prepared according to Preparation 6 using the appropriate reagents and adjusting reaction conditions (such as time) as needed.Table 2APreparation 8 l-Cyclobulyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-f] [1 ,4]oxazepineStep 1Ethyl l-cyclobutyl-5-hydroxy-lH-pyrazole-4-carboxylate

[0246] To a mixture of diethyl 2-(ethoxyniethylene)malonate (8.38 g, 38.7 mmol) and potassium carbonate (10,8 g, 77.5 mmol) in EtOH (80 mL) was added cyclobutylhydrazine hydrochloride (5.00 g, 38.7 mmol) at 20 °C in a single portion. The mixture was stirred at 90 °C for 16 hrs., under nitrogen. The mixture was quenched by addition of saturated aqueous ammonium chloride (100 ml) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue waspurified by silica gel chromatography (0-10% MeOH in DCM) to give ethyl 1-cyclobutyl- 5-hydroxy-lH-pyrazole-4~carboxylate as a brown oil (3,0 g, 33%). ES / MS (m / z): 211 ,2 (M+H).StepEthyl 5-(2-((tert-butoxycafbonyl)amino)ethoxy)-l-cyclobutyl-lH-pyrazole-4-cart)oxylati

[0247] To a mixture of ethyl 1 -cyclobutyl -5 -hydroxy- lH-pyrazole-4 -carboxylate (2.50 g, 10.7 mmol), potassium carbonate (4.53 g, 32.1 mmol) in DMF (30 ml) was added lert- butyl (2-chloroethyl)carbamate (6.87 g, 37.5 mmol) and potassium iodide (363 mg, 2.14 mmol). The reaction mixture was stirred at 80 °C for 16 hrs. The mixture was concentrated under reduced pressure. To the residue was added water (50 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with saturated aqueous NaCi (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-14% EtOAc in petroleum ether) to give ethyl 5-(2-((tert- butoxycarbonyl)amino)ethoxy)-l-cyclobutyl-lH-pyrazole-4-carboxylate as a yellow solid (2.19 g, 57%). ES / MS (m / z): 354,2. (M+H).Step 3Ethyl 5-(2 -aminoethoxy)- 1 -cyclobutyl- 1 H-pyrazole-4-carboxylate hydrochloride

[0248] A mixture of ethyl 5-(2-((te«-butoxycarbonyl)ammo)ethoxjO-l-cyclobutyl-lH- pyrazole-4 -carboxylate (1.65 g, 4,62 mmol) in 2M HC1 in dioxane (23.1 ml, 46.2 mmol) was stirred at 20 °C for 16 hrs. The mixture was concentrated under reduced pressure to give the product. The crude product ethyl 5-(2-aminoethoxy)-l-cyclobutyl-lH-pyrazole- 4-carboxylate hydrochloride (1 .32 g, 95%) was used without further purification as a colorless oil, ES / MS (m / z): 254.3 (M+H),Step 4 l-CyclobutyI-6,7-dihydro-lH-pyrazolo[4,3-f][l,4]oxazepin-4(5H)-one

[0249] A solution of ethyl 5-(2-aminoethoxy)-l-cyclobutyl-lH-pyrazole-4-carboxylate hydrochloride (1.3 g, 4.3 mmol) in water (10 mL) was added dropwise to a solution of lithium hydroxide monohydrate (0.37 g, 8.6 mmol) in water (10 mL) at 0 °C. The mixture was stirred at 30 °C for 16 hrs. The pH was adjusted to approximately 4 with aqueous hydrochloric acid (IM). Then the mixture was extracted with EtOAc (30 mL x 3), The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product l-cyclobutyl-6,7-dihydro~lH-pyrazolo[4,3- f][l,4]oxazepin-4(5H)-one (672 mg, 74%) was used without furflier purification as a colorless oil. ES / MS (m / z): 208.3 (M+H).Step 5 !-Cyclobutyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-f] [1 ,4]oxazepine

[0250] To a mixture of l-cyclobutyl-6,7-dihydro-lH-pyrazolo[4,3-f| [l,4]oxazepin- 4(5H)-one (700 mg, 3.31 mmol) in THF (15 mL) was added 2.5M LAH in THF (5.30 mL, 13.2 mmol) at 0 °C tinder nitrogen. Hie reaction mixture was stirred at 50 °C for 16 hrs. The mixture was added water (50 mL), filtered, and the filtrate extracted with EtOAc (50 mL, x 3). The combined organic layers were washed with saturated aqueous NaCl (50 ml.,), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (0-14% EtOAc in petroleum ether) to give l-cyclobutyl-4, 5,6,7- tetrahydro-lH-pyrazolo[4,3-f][l ,4]oxazepine as a colorless oil (332 mg, 47%). ES / MS (m / z): 194.2 (M+H).

[0251] Compounds on Table 3 below were prepared according to Preparation 8 using the appropriate reagents and adjusting reaction conditions (such as time) as needed.Table 3Preparation 163-Methyl-5,6,7,8-tetrahydro-3H-imidazo[4,5-f][l,4]oxazepineStep 15 -Chloro- 1 -methyl- 1 H-imidazole-4-carbaldehyde

[0252] Phosphorus oxychloride (1.139 mL, 12.11 mmol) was added slowly to a 0 °C solution of DMF (30 mL), followed by 2-amino-N-methylacetamide (2000 mg, 22.02 mmol). The mixture was wanned at 60 °C and stirred at 60 °C before phosphorus oxychloride (10.35 mL, 110.1 mmol) was added slowly. The solution was stirred at 90 °C for 12 hrs. After cooling to ambient temperature, the mixture was poured into ice / water(500 mL). Solid sodium carbonate was added until pH 7-8 was reached. The mixture was extracted with DCM (3 x 600 mL). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, evaporated, and dried in vacuo. The residue was dissolved in 1 ,4-dioxane (20 mL) and water (10 mL) was added potassium carbonate (10.46 g, 72.66 mmol) at 2.5 °C and the mixture was stirred at 60 °C for 4 hrs. The crude product was purified by prep-HPLC (Instrament prep-hplc-04, Method Column Welch Xtimate C18 250*50mm* lOum, Condition water (ammonium hydroxide + ammonium carbonate)~acetonitrile Begin B: 0%, End B: 30% Gradient Time (min) 20 ,100% B, Hold Time (min): 3, FlowRate (ml / mm) 100, Injections 1) to give 5-chloro-l -methyl-lH- imidazole-4-carbaldehyde as a yellow' solid (750 mg, 22%). ES / MS (m / z): 144.9 (M+H).Step 22-(((5 -Chloro- 1 -methyl- 1 H-imidazol-4-yl)methyl)amino)ethan- 1 -ol

[0253] To a solution of 5-chloro-l -methyl- lH-imidazole-4-carbaldehyde (750 mg, 4.82 mmol) and ethanolamine (440 pL, 7.24 mmol) in MeOH (15 mL) was added acetic acid (55.5 pL, 965 pmol) at 25 °C and tire mixture was stirred at 25 °C for 12 hrs., under nitrogen. To the reaction was then added sodium cyanoborohydride (613 mg, 9.65 mmol) at. 25 °C and the mixture was stirred at 25 °C for 5 hrs., under nitrogen. Tire reaction mixture was concentrated under reduced pressure to remove solvent. Tlie residue was purified by silica gel chromatography (0-7% MeOH in DCM) to give 2-(((5-chloro-l- methy]-lH-imidazol~4-yl)methyl)amino)ethan-l~o] as a yellow oil (800 mg, 75%). ES / MS (m / z): 189.9 (M+H).Step 3 tert-Butyl ((5-chloro-l-methyl-lH-imidazoI-4-yI)metliyl)(2-hydroxyethyl)carbamate

[0254] To a solution of 2-(((5-chloro-l-methyl-lH-imidazol-4-yl)methyl)amino)ethan-l- ol (800 rng, 3.63 mmol) in DCM (15 mL)was added triethylamine (1.03 mL, 7.26 mmol) and di-terf-butyl dicarbonate (1.21 g, 5.44 mmol) at 25 °C and the mixture was stirred at 25 °C for 12 hrs. The reaction mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-2% MeOH in DCM) to give terf-butyl ((5-chloro-l-methyl-lH- imidazol-4-yl)methyl)(2-hydroxyethyl)carbamate as a yellow oil (876 mg, 69%). ES / MS (ni / z): 290.1 (M+H).Step 4 re / 7-Butyl 3-methyl-3,5,6,8-tetrahydro-7H-imidazo[4,5-f][l,4]oxazepine-7-carboxylate

[0255] To a solution of fe / 7-butyl ((5-chloro-l-methyl-lH-imidazol-4-yl)methyl)(2- hydroxyethyl)carbamate (676 mg, 1.94 mmol) in 1,4-dioxane (10 mL) was added cesium carbonate (1.93 g, 5.81 mmol) and GPhos Pd G6 (92.6 mg, 96.8 pmol) at 25 °C. The reaction was stirred at 100 °C for 12 hrs., under a nitrogen. The reaction mixture wasplaced at ambient temperature for about 72 hrs. The reaction mixture was diluted with water (15 ml) and extracted with EtOAc (15 ml x 3). The combined organic layers were washed with saturated aqueous NaCl (20 mb), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-3% MeOH in DCM) to give tert-butyl 3-methyl- 3,5,6,8-tetrahydro-7H-imidazo[4,5-fj[l,4]oxazepme-7-carboxylate as a yellow oil (450 mg, 87%). ES / MS (m / z): 254.1 (M+H).Step 53-Metliyl-5,6,7,8-tetrahydro-3H-imidazo[4,5~f[[l,4]oxazepine hydrochloride

[0256] A solution of tert-butyl 3-methyl-3,5,6,8-tetrahydro-7H-imidazo[4,5- f][l,4]oxazepine-7-carboxylate (450 mg, 1.69 mmol) in 2 M HC1 in dioxane (8.44 mL, 2 molar, 16.9 mmol) was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product 3-methyl-5, 6,7,8- tetrahydro-3H-imidazo[4,5-f][l,4]oxazepine hydrochloride was used without further purification as a yellow7solid (268 mg, 71%). ES / MS (m / z): 153.8 (M+H).

[0257] Compounds of Table 4 below' were prepared according to Preparation 16 using the appropriate reagents and adjusting reaction conditions (such as the modifications noted in the table) as needed.Table 4Preparation 201 ,4,5,7 -Tetrahy drothiopyrano [3 ,4-c ]pyrazole -3 -carboxyl! c acidStep 1Ethyl 2-diazo- -thiopyran-4-y1)acetate

[0258] To a solation of 2M LDA in THF (6.33 ml, 12.7 mmol) in THF (10 mL) was added a mixture of ethyl diazoacetate (1 .62 g, 13.5 mmol) and dihydro-2H-thiopyran- 3(4H)-one (1.00 g, 8.44 mmol) in THF (10 mL) at -60 °C dropwise under nitrogen. The mixture was stirred at -60 °C for one hr. The reaction was quenched by addition of saturated aqueous ammonium chloride (20 ml), lire mixture was diluted with water (40 ml) and extracted with EtOAc (30 mL. * 3). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-25% EtOAc in petroleum ether) to give ethyl 2-diazo-2-(4-hydroxytetrahydro-2H-thiopyran-4-yl)acetate as a white oil (1.5 g, 69%).rH NMR (CDCh) d 4.26 (q, 2H), 3.79 (s, 1H), 3.12 (t, 2H), 2.43 (d, 2H), 2.28 (d, 2H), 1 .92 (t, 2H), 1.30 (t, 3H).Step 2Ethyl 1 ,4,5 ,7-tetrahydrothiopyrano [3,4-c]py razole-3 -carboxy 1 ate

[0259] To a mixture of ethyl 2-diazo-2-(4-hydroxytetrahydro-2H-thiopyran-4-yl)acetate (1.0 g, 3.9 mmol) in pyridine (2.0 mL) was added phosphorus oxychloride (1.7 mL, 18 mmol) at 0 °C. Hie mixture was stirred at 20 °C for 16 hrs. The mixture was added to water (50 mL), the pH was adjusted to approximately 8 with concentrated aqueous sodium bicarbonate and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (0-19% EtOAc in petroleum ether) to give ethyl l ,4,5,7-tetrahydrothiopyrano[3,4-c]pyrazole-3-carboxylate as a yellow solid (405 mg, 48%). ES / MS (m / z): 213.2 (M+H).Step 3 l,4,5,7-Tetrahydrothiopyrano[3,4-c]pyrazole-3-carboxylic acid

[0260] To a mixture of ethyl 1,4,5 ,7-tetrahydrothiopyrano [3 ,4-c]pyrazole-3 -carboxylate(400.0 mg, 1 .847 mmol) in water (4 mL) and THF (4 mL) was added lithium hydroxidemonohydrate (316.3 mg, 7.387 mmol). The reaction mixture was stirred at 50 °C for 3 hrs. The reaction mixture was added water (20 mL) and extracted with EtOAc (10 mb x 2). Tire pH of the aqueous phase was adjusted to around 5 by progressively adding IM HQ. The aqueous phase was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with saturated aqueous NaCI (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, Tlie residue was purified by silica gel chromatography (0-5% MeOH in DCM) to give 1,4,5, 7 -tetrahydrothiopyrano) 3, 4-c]pyrazole-3 -carboxylic acid as a white solid (328 mg, 91 %). ES / MS (m / z): 185.0 (M+H).Preparation 21 l ,5,6,7-Tetrahydropyrano[3,2-c]pyrazole< 5-carboxylic acidStep 14-(3,4-Dihydro-2H-pyran-5-yl)morpholine

[0261] To a solution of dihydro-2H-pyran-3(4H)-one (3000 mg, 29.36 mmol) in toluene (50 mL) was added morpholine (3.916 g, 44.05 mmol). The mixture was stirred at 1 10 °C for 4 hrs., under nitrogen. The solution was concentrated under reduced pressure. The crude product 4-(3,4-dihydro-2H-pyran-5-yl)morpholine was used without further purification as a yellow- oil (4.54 g, 78%). ES / MS (m / z): 170.25 (M+H).Step 2Ethyl 2-(5-morpholino-3,4-dihydro-2H-pyran-6-y1)-2 -oxoacetate

[0262] To a solution of 4-(3,4-dihydro-2H-pyran-5-yl)morpholine (2000 mg, 10.05 mmol) in chloroform (25 mL) was added ethylchloroglyoxalate (1.415 mL, 12.06 mmol) and triethylamine (2,95 mL, 20.09 mmol). The mixture was stirred at 60 °C for 12. hrs., under nitrogen. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-35% EtOAc in petroleum ether) to give ethyl 2-(5-morpholino-3,4- dihydro-2H-pyran-6-yl)-2-oxoacetate as a yellow oil (1.15 g, 40%). ES / MS (m / z): 270.7 (M-H).Step 3Ethyl 1 ,5 ,6,7-tetrahydropy rano [3 ,2-c]py razole-3 -carboxy 1 ate

[0263] To a solution of ethyl 2-(5-morpholino-3,4-dihydro-2H-pyran-6-yl)-2-oxoacetate (1150 mg, 4,057 mmol) in EtOH (12 ml) was added sulfuric acid (255.7 pL, 4.057 mmol) and hydrazine hydrate (316.1 pL, 5.193 mmol). The reaction was stirred at 90 °C for one hr., under nitrogen. The solution was evaporated on a water bath under reduced pressure using a rotary evaporator. The residue was purified by silica gel chromatography (0-7% MeOH in DCM) to give ethyl l,5,6,7-tetrahydropyrano[3,2- c]pyrazole-3-carboxylate as a yellow oil (304 mg, 40%). ES / MS (m / z): 197.3 (M+H).Preparation 22 l,4,5,6-Tetra]iydropyrano[2,3-c]pyrazole-3-carboxylic acidStep 1Ethyl 1 ,4,5 , 6-tetrahydropyrano[2, 3 -c]pyrazole -3 -carboxylate

[0264] To a mixture of dihydro-2H-pyran-3(4H)-one (2.001 g, 19.58 mmol) and pyrrolidine (166 pL, 1.958 mmol) in DMSO (15 mL) was added ethyl diazoacetate (1.098 mL, 9.791 mmol). The mixture was stirred at 20 °C for 16 hrs. Idle reaction mixture diluted with water (20 ml.,) and extracted with EtOAc (20 ml., x 3). The combined organic layers were washed with saturated aqueous NaCI (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-38% EtOAc in petroleum ether) to give ethyl l,4,5,6-tetrahydropyrano[2,3-c]pyrazole-3-carboxylate as a white solid (247 mg, 12%). ES / MS (m / z): 197.3 (M+H).Step 21 ,4,5,6-Tetrahydropyrano [2,3 ~c]py razole-3 -carboxylic acid

[0265] To a solution of ethyl l,4,5,6-tetrahydropyrano[2,3-c]pyrazole-3-carboxylate (197 mg, 954 pmol) in MeOH (1 mL) and water (0.5 mL) was added sodium hydroxide (156mg, 3.82 mmol). The resulting mixture was stirred at 50 °C for 4 hrs. The reaction mixture was placed at ambient temperature overnight, then diluted with water (10 mL) and extracted with EtOAc (10 mL). The aqueous phase was adjusted to pH < 7 with 1 N HQ. The aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with saturated aqueous NaCI (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The crude product 1,4,5, 6-tetrahydropyrano[2,3-c]pyrazole-3-carboxylic acid was used without further purification as a pale yellow solid (103 mg, 58%).!H NMR (DMSO-J6) dl2.40 (bs, 1H), 4.11 (t, 2H), 2.66 (t, 2H), 1.82 (m, 2H).Preparation 233 -Ethyl- 1 -methyl -4,5 ,6,7-tetrahydro- IH-pyrazolo [4,3-fj [ 1 ,4]oxazepineStep 15 -Chloro- 1 -methyl- lH-pyrazole-4-carbaldehyde

[0266] To a mixture of 1 -methyl- IH-pyrazol -5 -ol (8.4 g, 81 mmol) in DMF (40 mL) was added dropwise phosphorus oxychloride (46 mL, 0.49 mol) at 20 °C under nitrogen atmosphere, then the reaction was stirred at 80 °C for 16 hrs,, under nitrogen. The reaction mixture was cooled to ambient temperature. The reaction mixture was distilled to remove most of phosphorus oxychloride to give a crude viscous oil. The crude oil was slowly added to 400 mL water with stirring and adjusted to pH 8 by addition of aqueous 1 M NaOH, then extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with saturated aqueous NaCI (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue waspurified by silica gel chromatography (0-2% Me OH in DCM) to give 5-chloro-l-methyl- lH-pyrazole-4-carbaldehyde as a yellow oil (10.01 g, 84%). ES / MS (m / z): 145.1 (M+H).Step 22-((( 5 -Chloro- 1 -methyl- 1 H-pyrazol -4-y l)methyl)amino)ethan- 1 -ol

[0267] To a solution of 5-chloro-l-methyl-lH-pyrazole-4-carbaldehyde (10.0 g, 68.5 mmol) in MeOH (100 mL) was added ethanolamine (8.42 mL, 137 mmol) and acetic acid (2.01 mL, 34.2 mmol). The mixture was stirred at 50 °C for 16 hrs., then sodium cyanoborohydride (8.78 g, 137 mmol) was added and stirred at 50 °C for 3 hrs. Hie reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to give 2-(((5- chloro-1 -methyl- lH-pyrazol-4-yl)methyl)amino)ethan-l-ol as a white solid (10.3 g, 55%). ES / MS (m / z): 189.9 (M+H).Step 3 lert-Butyl ((5-chloro-l-methyl-lH-pyrazol-4-yl)methyl)(2-hydroxyethyl)carbamate

[0268] To a mixture of 2-(((5-chloro~l-methyl-lH-pyrazol-4~yl)methyl)amino)ethan-l-ol (10.3 g, 37.5 mmol) in DCM (100 mL) was added di-terEbutyl dicarbonate (8.61 g, 37.5 mmol). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure, added water (100 mL), and extracted with DCM (50 mL x 3), filtered, and concentrated under reduced pressure to give a crude product. The residue was purified by silica gel chromatography (0-36% EtOAc in petroleum ether) togive tertebutyl ((5-chloro-l-niethyl-lH-pyrazol-4-yl)methyl)(2-hydroxyethyl)carbamate as a yellow oil (17.2 g, 55%). ES / MS (m / z): 290.2 (M+H).Step 4 tert-Butyl l-methyl-l,4,6,7-tetra.hydro-5H-pyrazolo[4,3-f|[l,4]oxazepine-5-carboxylate

[0269] To a solution of tert-butyl ((5-chloro-l-metliyl-lH-pyrazol-4-yl)methyl)(2- hydroxyethyl)carbamate (11,7 g, 16.2 mmol) in 1,4-dioxane (120 ml,) was added cesium carbonate (16.1 g, 48.5 mmol) and Gphos Pd G6 (31 1 mg, 323 pmol), the reaction was stirred at 100 °C for 16 hrs., under nitrogen. The residue was concentrated under reduced pressure to give a residue. The residue was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-4% MeOH in DCM) to give tert-butyl l-methy1-l,4,6,7-tetrahydro- 5H-pyrazolo[4,3“f][l,4]oxazepine-5-carboxylate as a colorless oil (3.02 g, 52%). ES / MS (m / z): 254.1 ( M H ).Step 5 terr-Butyl 3-iodo-l -methyl-l,4,6,7-tetrahydro-5H-pyrazo1o[4,3-f][l,4]oxazepine-5- carboxylate

[0270] To a solution of tert-butyl l-methyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3- f][l,4]oxazepine-5-carboxyiate (3000 mg, 8.291 mmol) in EtOH (30 mL) was addedsilver sulfate (3.917 g, 12.44 mmol) and iodine (4.430 g, 16.58 mmol). The reaction was stirred at 25 °C for 12 hrs. The reaction mixture was filtered to give the crude product. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to give tert-butyl 3 -iodo- 1 -methyl- 1 ,4,6,7-tetrahy dro-5H-py razolo [4,3 -f] [ 1 ,4]oxazepine-5 - carboxylate as a yellow oil (1 .00 g, 30%). ES / MS (m / z): 380.1 (M+H).Step 6 terr-Butyl l-methyl-3-vinyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3-fj[l,4]oxazepine-5- carboxylate

[0271] To a solution of tert-butyl 3 -iodo- 1 -methyl- 1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3- f][l,4]oxazepine-5-carboxylate (900 mg, 2.25 mmol) in 1,4-dioxane (10 mL) and water (0.5 mL) was added potassium carbonate (492 mg, 3.38 mmol), potassium trifluoro vinyl borate (462 mg, 3.38 mmol) and 1 , T-bis(diphenylphosphino)ferrocene- palladium(II) dichloride (174 rng, 225 pmol), then the reaction was stirred at 100 °C for 12 hrs., under nitrogen. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 ml x 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-20% EtOAc in petroleum ether) to give tert-butyl l-methyl-3- vinyl-1, 4,6, 7-tetrahydro-5H-pyrazolo[4,3-f][l,4]oxazepine-5-carboxylate as a yellow' solid (410 mg, 60%). ES / MS (m / z): 280.3 (M+H).Step 7 terr-Butyl 3-ethyl-l -methyl- 1,4, 6,7-tetrahydro-5H-pyrazolo[4,3-f|[l ,4]oxazepme-5- carboxylate

[0272] To a solution of tert-butyl l-methyl-3-vinyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3- f][l,4]oxazepine-5-carboxylate (400 mg, 1.32 mmol) in THF (10 mL.) was added Pd / C (wet basis) (140 mg, 132 pmol) at 25 °C. The reaction mixture was evacuated and backfilled three times with hydrogem The mixture was stirred at 25 °C for one hour under an atmosphere of hydrogen 15 psi . The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give the ciude product. The crude product tert-butyl 3-ethyl-l-metliyl-l,4,6,7-tetrahydro-5H- pyrazolo[4,3-f][l,4]oxazepine-5-carboxylate was used without further purification as a pale colorless solid (410 mg, 92%). ES / MS (m / z): 282.2 (M+H).Step 83-Et.hyl-l-methyl-4,5,6,7-tet.rahydro~] H-pyrazolo[4,3-fj[l,4]oxazepine

[0273] To a solution of tert-butyl 3-ethyl-l-methyl-l,4,6,7-tetraliydro-5H-pyrazolo[4,3- f][l,4]oxazepme-5-carboxylate (410 mg, 1.21 mmol) in DCM (3 mL) was added TFA (194.1 pL, 1.21 mmol). The reaction was stirred at 40 °C for one hr. The residue was purified by silica gel chromatography (0-10% MeOH in DCM) to give 3-ethyl-l-methyl- 4,5,6,7-tet.rahydro~l H-pyrazolo[4,3-fJ[l,4]oxazepine as a yellow solid (300 mg, 75%). ES / MS (m / z): 182.3 (M+H).

[0274] Compound on Table 5 below was prepared according to Preparation 23 using the appropriate reagents and adjusting reaction conditions (such as the modifications noted in the table) as needed.Table 5Preparation 254, 5 ,6, 7-Tetrahy droisothiazol o [4,3 -f |[1 ,4] oxazepineStep 14-Bromoi sothiazol-3 -ol

[0275] To a solution of isothiazol-3-ol (5000 mg, 48.46 mmol) in acetonitrile (25 mb) was added NBS (10.56 g, 58.15 mmol). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched by addition water (10 mL) at 25 °C, and then diluted with water (10 ml.,) and extracted with EtOAc (10 mL x 3), The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue waspurified by silica gel chromatography (0-22% EtOAc in petroleum ether) to give 4- bromoisothiazol-3-ol as a yellow oil (5.91 g, 54%).rH NMR (DMSO-<76) d 12,31 (bs,H l). 8.93 (s. H l)Step 2 tert-Butyl (2-((4-bromoisothiazol-3-yl)oxy)ethyl)carbamate

[0276] To a solution of 4-bromoisothiazol-3-ol (5910 mg, 26.26 mmol) and tert-butyl (2- cliloroetliyl)carbamate (7.221 g, 39.40 mmol) in DMF (40 mL) was added cesium carbonate (17.46 g, 52.53 mmol) and potassium iodide (444.9 mg, 2.626 mmol). The reaction mixture was stirred at 80 °C for 12 hrs., under nitrogen . The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Tire residue was purified by silica gel chromatography (0-20% EtOAc in petroleum ether) to give tertebutyl (2~((4-bromoisothiazol-3-yl)oxy)ethyl)carbamate as a yellow oil (9.04 g, 96%). ES / MS (m / z): 269.0 (M-tBu+H).Step 3 terr-Butyl (2-((4-formylisothiazol-3-yl)oxy)ethyl)carbaraate

[0277] To a mixture of tert-butyl (2-((4-bromoisothiazol-3-yl)oxy)ethyl)carbamate (4500 mg, 12.53 mmol) m DMF (50 mL) was added phosphine, [l,T-biphenyl]-2 -ylbis(l,l- dimetbylethyl)- (763.1 mg, 2.506 mmol), palladium diacetate (2.87.1 mg, 1.253 mmol),tert-butyl isocyanide (2.90 mL, 25.06 mmol), sodium carbonate (2.710 g, 25.06 mmol), and triethyl silane (4.08 mL, 25.06 mmol). The mixture was filtered through diatomaceous earth under vacuum and rinsed. The filtrate was diluted with water (120 mL) and extracted with EtOAc (120 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (120 ml.,), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-25% EtOAc in petroleum ether) to give tert-butyl (2-((4- formylisothiazol-3-yl)oxy)ethyl)carbamate as a yellow oil (2.3 g, 62%). ES / MS (m / z): 173.0 (M-Boc+H).Step 46,7-Dihydroisothiazolo [4,3 -f] [ 1 ,4] oxazepme

[0278] A solution of tert-butyl (2-((4-formylisothiazol-3-yl)oxy)ethyl)carbamate (2600 mg, 8.784 mmol) in 2M HC1 in dioxane (21 .96 mL, 43.92 mmol) was stirred at 25 °C for 12 hrs. The reaction mixture was diluted with water (30 mL) and extracted with DCM (30 mL). The aqueous phase was adjusted to pH > 7 with aqueous IN NaOH. The aqueous phase was extracted with DCM (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The crude product 6,7- dihydroisothiazolo[4,3-f][l,4]oxazepine was used in the next step without further purification as a brown solid (1.2 g, 71%). ES / MS (m / z): 154.9 (M+H).Step 54,5,6,7-Tetrahydroisothiazolo[4,3-f|[l,4]oxazepine

[0279] To a solution of 6,7-dihydroisothiazolo[4,3-fJ[l,4]oxazepine (1200 mg, 6.226 mmol) in MeOH (13 mL) was added sodium cyanoborohydride (798.5 mg, 12.45 mmol). The mixture was stirred at 25 °C for 4 hrs. The mixture was filtered through filter paper under vacuum and rinsed. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase chromatography (SepaFlash; 120 g Cl 8 Flash Column, Eluent of 5~ 9% MeOH / Water (0.04%NHs.H20) gradient @ 70 mL / min) to give 4,5,6,7-tetrahydroisothiazoIo[4,3-f][l,4]oxazepine as a pale pink oil (392 mg, 40%). ES / MS (m / z): 156.9 (M+H).Preparation 262,2,2-Trifluoro-l-(2,3,4,5-tetrahydro-lH-thieno[2,3-ej[l,4]diazepin-l-yl)ethan-l-oneStep 12H-Tbieno[2,3-d][l,3]oxazine-2,4(lH)-dioni

[0280] To a mixture of methyl 2-aminothiophene-3-carboxylate (5.0 g, 31 mmol) in water (50 mL) was added KOH (3.6 g, 63 mmol). The reaction was stirred at 90 °C for one hr., then the reaction was cooled to 0 °C, diphosgene (8.36 g, 41.4 mmol) was addeddropwise, and the reaction stirred at 0 °C for 1 hr., under nitrogen. Tbc reaction mixture was filtered to give the crude product, the filter cake was collected in vacuo to give the residue. The crude product 2H-thieno[2,3-d][l,3]oxazine-2,4(lII)-dione was used m the next step without further purification, as a yellow' solid (4. 17 g, 63%). ES / MS (m / z): 156.9 (M+H).Step 24-Benzyl-3,4-dihydro-lH-thieno[2,3-e][l,4]diazepine-2,5-dione

[0281] To a solution of 2H-thieno[2,3~d][l,3]oxazine-2,4(lH)-dione (3000 mg, 14.19 mmol) in water (30 mL) was added benzyl glycine (6.168 g, 35.47 mmol), the reaction was stirred at 100 °C for 12 hrs. The reaction mixture was diluted w'itli water (30 mL) and extracted with EtOAc (30 nil x 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to give 4-benzyl-3,4-diliydro-lH-thieno[2,3- e][l,4]diazepine-2, 5-dione as a brown oil (1 .4 g, 31 %). ES / MS (m / z): 273.0 (M+H).Step 34-Benzyl-2,3,4,5-tetrahydro-lH-thieno[2,3-e][l,4]diazepine

[0282] To a solution of 4-benzyl-3,4-dihydro~rH-thieno[2,3~e][l,4]diazepine-2, 5-dione(1.6 g, 5.0 mmol) in THF (15 mL) was added aluminum lithium hydride in THF (16 mL,2.5 molar, 40 mmol) at 0 °C under nitrogen. After addition tire mixture was stirred at 60 °C for 12 hrs., under nitrogen. To the reaction mixture was added sodium sulfate decahydrate, then the mixture was filtered and washed with THF ( 10 mL x 3). The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (0-25% MeOH in DCM) to give 4-benzj'1-2,3,4,5-tetrahydro-lH- thieno[2,3-e][l,4]diazepine as a yellow oil (700 mg, 48%), ES / MS (m / z): 245.3 (M+H).Step 4 l-(4-Benzyl-2,3,4,5-tetrahydro-lH-thieno[2,3-e][l,4]diazepin-l-yl)-2,2,2-trifluoroethan- 1-one

[0283] Tri fluoroacetic anhydride (495 pL, 3.44 mmol) was added dropwise to a mixture of 4-benzyl-2,3,4,5-tetrahydro-lH-thieno[2,3-e][l,4]diazepine (500 mg, 1.72 mmol) and trietliylamine (733 pL, 5.16 mmol) in DCM (10 mL) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to give l-(4-benzyl-2,3,4,5-tetrahydro-lH- thieno[2,3-e][l,4]diazepin-l-yl)-2,2,2-trifluoroethan-l-one as a yellow oil (580 mg, 86%). ES / MS (m / z): 341.0 (M+H).Step 52,2,2-Trifluoro-l-(2,3,4,5-tetrahydro-lH-thieno[2,3-e][l,4]diazepin-l-yl)ethan-l-one

[0284] l-(4-Benzyl-2,3,4,5-tetrahydro-lH-thieno[2,3-e][L4]diazepin-l-yl)-2,2,2- trifluoroethan-l-one (580 mg, 1.48 mmol) in DCM (10 mL) was added diisopropylethylamine (537 pL, 2.97 mmol) and 1 -chloroethyl chloroformate (506 uL, 4.45 mmol) at 0 °C. The mixture was stirred at 40 °C for 12 hrs., under nitrogen, then concentrated under reduced pressure. The reaction mixture was dissolved in MeOH (10 mL) and was stirred at 60 °C for one hour under nitrogen. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by silica gel chromatography 0-5% MeOH in DCM) to give 2,2,2-trifluoro-l-(2,3,4,5- tetrahydro-lH-thieno[2,3-e][l,4]diazepin-l-yl)ethan-l -one as a red oil (400 mg, 89%). ES / MS (m / z): 351.1 ( M H ).Preparation 27( 1 -(4-Methoxybenzyl)-4,6-dihydro- 1 H-furo[3 ,4-c]pyrazol-3 -yl)( 1 -methyl- 1 ,4,6,7- tetrahydro-5H-pyrazolo [4, 3 -I] [ I „4] oxazepin-5 -yl)methanone

[0285] To a mixture of l-(4-methoxybenzyl)-4,6-dihydro-lH-fiiro[3,4-c]pyrazole-3- carboxylic acid (230 mg, 797 prnol) in DCM (3 mL) was added l-methyl-4,5,6,7- tetrahydro-lH-pyrazolo[4,3-f][l,4]oxazepine (147 mg, 797 pmol), HATU (309 mg, 797 pmol) and DIEA (142 pL, 797 pmol). Tire reaction mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent.Residue was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). Hiecombined organic layers were washed with saturated aqueous NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-10% MeOH in DCM) to give ( l-(4-methoxybenzyl )-4,6-dihydro- IH-furo [3,4-c]pyrazol-3 -y 1)( 1 -methyl- 1 ,4,6,7- tetrahydro-5H-pyrazolo[4,3-f][l,4]oxazepin-5-yl)methanone as a white solid (230 mg, 49%). ES / MS (m / z): 410.3 (M+H).

[0286] Compounds of Table 6 below were prepared according to Preparation 27 using the appropriate reagents and adjusting reaction conditions (such as modifications noted in the table) as needed.Table 6Preparation 304H-Thieno [3 ,2 -bjpyrrol e -6-carboxyli c acidStep 1Diethyl 2-(3-nitrotiiiophen-2-yl)malonate

[0287] To a mixture of ethyl malonate (22.72 ml.,, 119.8 mmol) in THF (80 mL) was added NaH (4.793 g, 119.8 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hrs., then 2-chloro-3-nitrothiophene (10.00 g, 59.91 mmol) was added at 0 °C. lire reaction mixture was stirred at 40 °C for 6 hrs., under nitrogen. The reaction mixture was quenched by addition of water (100 mL) at 25 °C, then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Tire residue was purified by silica gel chromatography (0-15% EtOAc in petroleum ether) to give diethyl 2-(3-nitrothiophen-2-yl)malonate as a yellow oil (17.21 g, 63%). ES / MS (m / z): 288.0 (M+H).Step 2Ethyl 2-(3-nitrothiophen-2-yl)acetate andMethyl 2 -(3 -ni troth iophen-2-yl)acetat<

[0288] To a solution of diethyl 2-(3-nitrothiophen-2-yl)malonate (18 g, 38 mmol) in MeOH (250 mL) was added potassium hydroxide (6.4 g, 94 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. Tire mixture was dissolved in EtOAc (150 mL), diluted with water (200 mL), and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-40% EtOAc in petroleum ether) to give a mixture of ethyl 2-(3- nitrothiophen-2-yl)acetate and methyl 2-(3-nitrothiophen-2-yi)acetate as a yellow' oil (4.5 g, 26%). ES / MS (m / z): 202.0, 216.0 (M H)Step 3Ethyl (Z)-3-(dimethylamino)-2-(3“iiitrothiophen-2-yl)aciylate andMethyl (Z)-3-(dimethylamino)-2-(3-nitrothiophen-2-yl)acrylate

[0289] A mixture of ethyl 2-(3-nitrothiophen-2-yl)acetate and methyl 2-(3-mtrothi ophen -2-yl)acetate (4.5 g, 9.7 mmol) in DMF-DMA (53 mL, 0.39 mol) was stirred at 50 °C for12 hrs. The reaction mixture was concentrated to dryness. The residue was purified by silica gel chromatography (0-35% EtOAc m petroleum ether) to give ethyl (Z)-3- (dimethylamino)-2-(3-nitrothiophen-2-yI)acrylate (1.4 g, 43%), ES / MS (m / z): 271.0 (M+H) and methyl (Z)-3-(dimethylamino)-2-(3-nitrothiophen-2-yl)acrylate as a yellow oil (2.4 g, 91%), ES / MS (m / z): 257.0 (M+H).Step 4Ethyl 4H-thieno[3,2-b]pyrrole-6-carboxylate andMethyl 4H-thieno[3,2-b]pyrroIe-6-carboxylate

[0290] A solution of ethyl (Z)-3-(dimethylamino)-2-(3-nitrothiophen-2-yl)acrylate (1 .4 g, 4.2 mmol) and methyl (Z)-3-(dimethylamino)-2-(3-nitrothiophen-2-yl)acrylate (2.4 g, 8.8 mmol) in THF (30 mL) was degassed with nitrogen, then platmum(IV) oxide (0.97 g, 4.2 mmol) and acetic acid (2.5 mL, 42 mmol) were added. Hie reaction mixture was evacuated and backfilled three times with hydrogen. The mixture was stirred at 70 °C for 12 hrs under an atmosphere of hydrogen at 50 psi. Upon completion, the reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to afford the crude product. The residue was purified by silica gel chromatography (0-40% EtOAc in petroleum ether) to give ethyl 4H-thieno[3,2- b]pyrrole-6~carboxylate (408 mg, 44%), ES / MS (m / z): 196.0 (M+H) and methyl 4H- thieno[3,2-b]pyrrole-6-carboxylate as a yellow oil (443 mg, 50%), ES / MS (m / z): 182.0 (M+H).Step 54H-Thieno[3,2-b]pyrrole-6-caiboxylic acid

[0291] To a solution of methyl 4H-tliieno[3,2-b]pyrrole-6-carboxylate (443 rag, 2. 10 mmol) in MeOH (7 mL) was added NaOH (687 mg, 16.8 mmol). Hie reaction was stirred at 50 °C for 24 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-25% MeOH in DCM) to give 4H- thieno[3,2-b]pyrrole-6-carboxylic acid (438 mg, 100%) as a brown solid. ES / MS (m / z): 168.0 (M-t-H).EXAMPLESExample 1 l H-Indazoi-3-yl~(l-methyl- yl)metbanone

[0292] To a solution of l-methyl-4,5,6,7-tetrahydropyrazoto[4,3-f][l,4]oxazepane hydrochloride (320 g, 1.69 mol) and lH-indazole-3-carboxylic acid (301 g, 1.86 mol) in THF (3.2 L) was added HATU (772 g, 2.03 mol). Triethylamine (513 g, 5.07 mol) was added dropwise, and the mixture stirred at ambient temperature for 1 hr. The reaction mixture was combined with two other reaction mixtures run in the same manner, one starting with 50 g of l-metiiyl-4,5,6,7-tetrahydropyrazolo[4,3-f|[l,4]oxazepane hydrochloride and another starting with 100 g of l-methyl-4,5,6,7- tetrahydropyrazolo[4,3-f][l,4]oxazepane hydrochloride. The combined reaction mixtures were filtered and concentrated under reduced pressure. The residue was added to a stirring mixture of 2-methyltetrahydrofiiran (3.5 L) and sodium hydroxide (169 g, 1.25 mol) in water (170 mL). The resulting mixture was stirred at 30 °C for 1 hr. The solids were collected by filtration and washed with 2-methyltetrahydrofuran (1 L). The filtrate was back extracted with 2-methyltetrahydrofuran (I L x 3). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to a yellow oil. The combined materials were purified by column chromatography eluting with MeOH in DCM (0-12.5%) to give a light-yellow oil (500 g). Heptane (1000 mL)was added, and the mixture was stirred for 1 hr. The solids were collected by vacuum filtration and the solids were washed with heptane. Water (1000 raL) was added, and the mixture was stirred tor 1 hr. The solids were collected by vacuum filtration and the solids were washed with water. The solids were dried in an oven at 55 °C. Ethanol (700 mL) was added to the solid and the mixture was heated to 80 °C until a clear solution persisted. Water ( 1400 mL) was added dropwise into the solution at 80 °C. The mixture was cooled to 25 °C. The resulting solids were collected by vacuum filtration and the solids were washed with ethanol / water. The solids were dried in an oven at 55 °C for 5 hrs., to give the title compound (300 g, 40.7%) as a light-yellow solid. ES / MS (m / z): 298.2 (M+H).

[0293] The compounds of Table 7 were prepared in a manner analogous to Example 1 (with modifications, such as those noted in the footnotes) using the corresponding appropriate reagents with the reaction time adjusted to reach completion.Table 7IllBOP-CI was used in place of HATU of Example 1.Mukaiyama reagent was used in place of HATU.

[0294] The compounds on Table 8 may be prepared in a manner analogous to Example 1 using the corresponding appropriate reagents with the reaction conditions (such as time) adjusted to reach completion.Table 8Example 58 hAHR Nuclear Translocation Assay

[0295] The purpose of this assay is to measure the ability of compounds to bind to, activate, and induce the translocation of AhR into the nucleus of a cell for transcription. Stable cell lines were established using Jump-In™ T-REx™ HEK293 Retargeting Kit (Life Technologies). Human AhR. cDNA was cloned into the pJTI R4 CMV-TO EGFPvector. The EGFP was cloned to the C -terminal of AHR to form AliR-EGFP chimera.The pJTT R4 CMV-TO AhR-EGFP vector was transfected using FuGENE® HD into Jump-In™ T-REx™ HEK293 cells. Transfected cells were selected using 2.5 mg / ml G418 for 10 to 14 days, then expanded, harvested, and suspended in freeze media (FBS with 8% DMSO) at 2x 107cells / ml, and aliquots wore stored in liquid nitrogen. One day before the assay date, cells were thawed and resuspended in DMEM with 5% FBS in the presence of Ipg / ml Doxycycline and plated into ploy-L-Lysine coated CELLCARRIER- 384 ULTRA Microplates (Perkin Elmer) at 12,000 to 15,000 cells per well and incubated at 37 °C and 5% CO2 overnight. On the assay date, compound was serially diluted (1:2) into 384-well nunc plates with DMSO using acoustic dispensing (ECHO®). The dose response was a 20-point curve. Compound was resuspended in 40 pl of DMEM plus 0.1% BSA. The culture media was damped and 25 pl of DMEM plus 0.1% BSA was added, then 25 pL of compound in DMEM plus 0.1% BSA was added into cell plates.Cells were incubated compounds at 37 °C and 5% CO2 for 45 minutes. The final DMSO concentration was 0.2%. The media was damped after 45 minutes incubation. The cells were fixed with 40 pl of cold MeOH (-20 °C) for 20 minutes. The MeOH was damped and 50 pL of DPBS containing 1 pg / mL Hochst was added into the cell plates. The intensity of EGFP was quantitated by using Opera PHENIX® or OPERETTA® high content image system (Perkin Elmer) with 20x Water Objecti ve and five field per well. The ratio of EGFP fluorescent intensity in nuclear over cytosol was analyzed using a 4- parameter nonlinear logistic equation to determine the potency of AhR agonists.

[0296] Hie hAHR nuclear translocation assay EC50 value (Rel EC 50 (nM) for Example 1 was 0.470, indicating it is an AHR agonist useful in the treatment of immune-mediated diseases (IMD). Particularly, it is believed that the compound of Example 1 is useful in treating psoriasis and atopic dermatitis, among others. Likewise, AHR activities for majority of Examples 1-55 are provided below in Table 9 (“NT” in Table 9 denotes those corresponding compounds not being tested). AHR activity (e.g. EC50) for other compounds may be tested using the same hAHR Nuclear Translocation Assay protocol as illustrated above.Table 9. hAHR Nuclear Translocation Assay EC so Values

Claims

CLAIMSWe claim:1 . A compound of the formula:Z is NH or O. each occurrence of Q1is independently CR1, N, S, or NR2, wherein R1is H, C4-3 alkyl, C1-3 haloalkyl, or C3-4 cycloalkyl, and R2is H, C1-3 alkyl, or C3-4 cycloalkyl;O represents ring aromaticity; andY is a bicyclic group including a 5- or 6- membered aromatic unit fused with a 5- or 6- membered monocycle, wherein Y attaches to the carbonyl through the 5- or 6- membered aromatic unit, and wherein the monocycle is an unsubstituted cycloalkyl, an unsubstituted heterocycle, a heteroaryl optionally substituted with methyl, or a phenyl optionally substituted with halo, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxyl, C1-3 haloalkoxyl, or cyano, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein Z is O, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein the 5- or 6- membered aromatic unit includes at least one N, or a pharmaceutically acceptable salt thereof.

4. Tire compound of claim 1 or 2, wherein the 5- or 6- membered aromatic unit is a 5- membered heteroaryl, or a pharmaceutically acceptable salt thereof.

5. The compound of any one of preceding claims, wherein the 5- or 6- membered aromaticunit is 11 , or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1 -4, wherein the 5- or 6- membered aromatic unit is, or a pharmaceutically acceptable salt, thereof.

7. The compound of any one of preceding claims, wherein Y is phenyl fused with 5- membered heteroaryl containing 1 , 2, or 3 N and no other heteroatom, and the phenyl is optionally substituted with halo or cyano, or a pharmaceutically acceptable salt thereof.The compound of claim 1 or 2, wherein Y isphenyl of Y is optionally substituted with methyl, chlorine, methoxy, trifluoromethyl, or a pharmaceutically acceptable salt thereof.Tire compound of claim 1 or 2, wherein ¥ isor a pharmaceutically acceptable salt thereof.pharmaceutically acceptable salt thereof.11 . Hie compound of claim 1 or 2, wherein Y is12. Hie compound of claim 1 or 2, wherein Y isor a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 or 2, wherein the 5- or 6- membered monocycle is aromatic, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 or 2, wherein the 5- or 6- membered monocycle is heteroaryl.or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15, wherein the heteroaryl is, or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 or 2, wherein the 5- or 6- membered monocycle is a phenyl optionally substituted with halo, C 1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxyl, C1-3 haloalkoxyl, or cyano, unsubstituted heteroaryl, unsubstituted carbocycle, and unsubstituted heterocycle, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17, wherein the 5- or 6- membered monocycle is unsubstituted phenyl, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 17, wherein the 5- or 6- membered monocycle is a phenyl substituted with halo, C1.3 alkoxyl, cyano, C1-3 alkyl, or Cj-3 haloalkyl, or a pharmaceutically acceptable salt thereof.

20. A compound of the formula:wherein: each occurrence of n is independently 1 or 2;Z is NH or O;each occurrence of Q1is independently CR1, N, S, or NR2, wherein R1is H, C1-3 alkyl, Ci- 3 haloalkyl, or C3-4 cycloalkyl, and R2is H, C1-3 alkyl, or C3-4 cycloalkyl; each occurrence of Q2is independently CH, N, NH, or S; each occurrence of QJis independently CRJ, N, O, or S; each occurrence of R3is independently H, halo, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy!,Ci -3 haloalkoxy 1, or cyano;O represents ring aromaticity; and each occurrence of - represents a single bond or a double bond that satisfies valence; or a pharmaceutically acceptable salt thereof,21 . Tire compound of claim 20, wherein one Q2is N and the other is NH, or a pharmaceutically acceptable salt thereof22. The compound of claim 20, wherein one Q2is N and the other is S, or a pharmaceutically acceptable salt thereof.

23. The compound of any of claims 20-22, wherein n is 1, or a pharmaceutically acceptable salt thereof.

24. The compound of any of claims 20-23, wherein n is 2, and all Qdare CR3, or a pharmaceutically acceptable salt thereof25. The compound of any preceding claim, wherein at least one R? is Ch-3 alkyl, or a pharmacally acceptable salt thereof.

26. 'The compound of any one of claims 1-24, wherein at least one Ri is cyclopropyl or cyclobutyl , or a pharmaceutically acceptable salt thereof.

27. The compound of any of claims 1-24, whereinselected frompharmaceutically acceptable salt thereof.

28. The compound of £my of claims 1-24, whereinpharmaceutically acceptable salt thereof.pharmaceutically acceptable salt thereof.

30. A compound of the formula:wherein:124 each occurrence of Q1is independently CH, N, S, or NR2, wherein R2is H, C1-3 alkyl, or C3-4 cycloalkyl; each occurrence of Q2is independently CH, N, NH, or S; each occurrence of R' is independently H, halo, C1.3 alkyl, C1.3 haloalkyl, C1.3 alkoxyl, C]-3 haloalkoxy L or cyano;O represents ring aromaticity; and each occurrence of ““v™™ represents a single bond or a double bond that satisfies valence; or a pharmaceutically acceptable salt thereof.31 . A compound selected from the table:

32. A pharmaceutical composition, comprising a compound of any of claims I to 31 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

33. A method of treating an immune-mediated disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to anyone of claims 1 to 31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 32.

34. A compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn’s disease, graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus (SLE).

Images