AHR agonists

Abstract

To provide novel AHR agonist compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat specific immune-mediated diseases.SOLUTION: Provided is a compound represented by the following formula, where a ring A is a 5-membered or 6-membered carbocycle; a ring B is a phenyl, or a 5-membered or 6-membered heteroaryl having 1 or 3 heteroatoms, wherein each heteroatom of the heteroaryl is independently selected from N, S, and O; R is H or C1-3 alkyl; X is H, halo, C1-3 alkyl optionally substituted with one or more halo, or a C1-3 alkoxyl; Y is H, C1-4 alkyl, or C3-4 cycloalkyl, wherein the C1-4 alkyl is a primary or secondary alkyl; and Z is CH or N.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to novel AHR agonist compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds to treat certain immune-mediated diseases.

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

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

[0004] The AHR is a transcription factor that regulates many aspects of immunological function, most notably the suppression of adaptive immune responses (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)). Prototypic 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, particularly TCDD, suggest that immune suppression occurs as a result of AHR-induced expression of regulatory T cells (Tregs), TH17 cells, and dendritic cells (DCs) (Rothhammer et al., Nat. Rev, Immunol., 19, 184-197 (2019)). TCDD has been shown to be effective in treating type 1 diabetes (Kerkvliet et al., Immunotherapy, 1, 539-547 (2009)), autoimmune encephalomyelitis (Quintana et al., Nature, 453, 65-71, (2008)), autoimmune uveoretinitis (Zhang et al., Invest. Opthalmol. Vis. Sci., 51, 2109-2117 (2010)), inflammatory bowel disease (Takamura et al., Immunol. Cell. Biol., 88, 685-689 (2010), Benson et al., Toxicol. Sci., 120, 68-78 (2011), Singh et al., PLoS One, 6(8), e23522 (2011)), as well as several models of transplant tolerance (Pauly at al., Toxicol. Environ. Chem., 94, 1175-1187(2012)) and allergic diseases (Schulz et al., Toxicol. Sci., 123, 491-500(2011); Li et al., PLoS One, 11, e0150551(2016); Luebke et al., Toxicol. Sci., 62, 71-79(2001)).

[0005] The AHR also regulates the expression of CYP1A1, CYP1A2, and CYP1B1, which catalyze the metabolism of polycyclic aromatic hydrocarbons (PAHs) and other aromatic compounds (e.g., estrogens). In some cases (e.g., in the case of benzo[a]pyrene), this metabolism leads to the formation of reactive species, but CYP induction is also thought to be important for the detoxification and metabolic clearance of PAHs, which reduces the probability of bioactivation and DNA adduct formation. Although several marketed drugs have been found to activate the AHR after FDA approval (thus upregulating CYP1A1, CYP1A2, and CYP1B1), their long-term use has not been associated with dioxin-like toxicity (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)). Thus, CYP induction is no longer considered a barrier to the adoption of AHR agonists in therapy (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)).

[0006] WO 2008 / 014307 discloses certain bicyclic heteroaryl amides as inhibitors of undecaprenyl pyrophosphate synthase. EP 0059698 discloses certain heterocyclic carboxamides, compositions containing these compounds, and methods of treatment with these compositions.

[0007] The bacterial stilbenoid DMVT-505 (VTAMA® (tapinarof)) 1% cream, an aryl hydrocarbon receptor agonist) indicated for the topical treatment of psoriasis vulgaris in adults has been approved by the US Food and Drug Administration (FDA). Despite this, there remains a need for alternative novel, oral, selective, and / or potent AHR agonists for the treatment of IMD. The present disclosure provides certain compounds that are agonists of the AHR.

[0008] Thus, the present disclosure provides various embodiments, for example, as follows: When a later embodiment refers to a previous "Embodiment X," such reference also includes reference to "Embodiment XA," "Embodiment XB," etc., unless such later embodiment would not be properly construed as a dependent embodiment (e.g., outside the scope of the referenced embodiment or having an improper antecedent basis). For example, when "Embodiment 54" below refers to "Embodiment 53," such reference also includes reference to, among others, "Embodiment 53A," "Embodiment 53B," "Embodiment 53C," "Embodiment 53D," and "Embodiment 53E."

[0009] Embodiment 1A. A compound of the formula:

[0010] [ka] During the ceremony, Ring A is a 5- or 6-membered carbocyclic ring; Ring B is phenyl or a 5- or 6-membered heteroaryl having 1 or 3 heteroatoms, each heteroatom of the heteroaryl being independently selected from N, S, and O; R is H or C 1~3 is alkyl, X is H, halo, C optionally substituted with one or more halo. 1~3 Alkyl or C 1~3 is alkoxyl, Y is H, C 1~4 Alkyl or C 3~4 cycloalkyl, where C 1~4 The alkyl is a primary or secondary alkyl; Z is CH or N, A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0011] Embodiment 1. A compound of the formula:

[0012] [ka] During the ceremony, Ring A is a 5- or 6-membered carbocyclic ring; Ring B is phenyl or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, each heteroatom of the heteroaryl being independently selected from N, S, and O; X is H, halo, C optionally substituted with one or more halo. 1~3 Alkyl or C 1~3 alkoxyl, where alkoxyl and

[0013] [ka] are meta- or para- to each other, Y is H, C 1~4 Alkyl or C 3~4 cycloalkyl, where C 1~4 The alkyl is a primary or secondary alkyl; Z is CH or N, A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0014] Embodiment 2.

[0015] [ka] 2. The compound of embodiment 1, wherein The compound of embodiment 1, wherein Q is O or S and W is CH or N. A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0016] Embodiment 3.

[0017] [ka] The compound according to embodiment 1, selected from: A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0018] Embodiment 4. A compound according to embodiment 1, having the formula:

[0019] [ka] During the ceremony, X is H or halo; Y is H or C 1~3 is alkyl, The compound of embodiment 1, wherein W is CH or N. A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0020] Embodiment 5.

[0021] [ka] The compound according to any one of embodiments 1 to 4, selected from A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0022] Embodiment 6. A compound according to any one of embodiments 1-4, or a pharma- ceutically acceptable salt thereof, wherein Ring A is phenyl.

[0023] Embodiment 7. Ring A is

[0024] [ka] 5. The compound according to any one of embodiments 1 to 4, wherein:

[0025] Embodiment 8. A compound according to claim 1 having the formula:

[0026] [ka] During the ceremony, X is H or halo; Y is H or C 1~3 is alkyl, The compound of embodiment 1, wherein W is CH or N. A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0027] Embodiment 9. A compound according to any one of embodiments 1 to 6, wherein Z is N, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0028] Embodiment 10. A compound according to any one of embodiments 1 to 8, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein Z is CH.

[0029] Embodiment 11. A compound according to any one of embodiments 1 to 10, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein W is N.

[0030] Embodiment 12. A compound according to any one of embodiments 1 to 11, wherein X is F, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0031] Embodiment 13. A compound according to any one of embodiments 1-4 and 6-12, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein Y is methyl.

[0032] Embodiment 14. A compound selected from the table below, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0033] [Table 1-1]

[0034] [Table 1-2]

[0035] Embodiment 14A. A compound selected from the table below, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0036] [Table 2-1]

[0037] [Table 2-2]

[0038] Embodiment 15. A compound selected from the table below, or a pharma- ceutically acceptable salt thereof.

[0039] [Table 3-1]

[0040] [Table 3-2]

[0041] [Table 3-3]

[0042] Embodiment 15A. A compound selected from the table below, or a pharma- ceutically acceptable salt thereof.

[0043] [Table 4-1]

[0044] [Table 4-2]

[0045] [Table 4-3]

[0046] EMBODIMENT 16.

[0047] [ka] or a pharma- ceutically acceptable salt thereof.

[0048] EMBODIMENT 17.

[0049] [ka] or a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0050] EMBODIMENT 18.

[0051] [ka] or a respective pharma- ceutically acceptable salt thereof.

[0052] EMBODIMENT 19.

[0053] [ka] or a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0054] Embodiment 20. A compound selected from Table 2, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0055] Embodiment 21. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 20, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0056] Embodiment 22. A method of treating an immune-mediated disease in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound described in any one of embodiments 1 to 20, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 21.

[0057] Embodiment 23. 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 of such treatment, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 20, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, or a pharmaceutical composition according to embodiment 21.

[0058] Embodiment 24. A compound according to any one of embodiments 1 to 20, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, for use in therapy.

[0059] Embodiment 25. A compound according to any one of embodiments 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn's disease, graft-versus-host disease, rheumatoid arthritis, and multiple sclerosis.

[0060] Embodiment 26. A compound according to any one of embodiments 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of psoriasis.

[0061] Embodiment 27. A compound according to any one of embodiments 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of atopic dermatitis.

[0062] Embodiment 28. A compound according to any one of embodiments 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of ulcerative colitis.

[0063] Embodiment 29. A compound according to any one of embodiments 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of Crohn's disease.

[0064] Embodiment 30. A compound according to any one of embodiments 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of graft-versus-host disease.

[0065] Embodiment 31. A compound according to any one of embodiments 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis.

[0066] Embodiment 32. A compound according to any one of embodiments 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of multiple sclerosis.

[0067] Embodiment 33. A compound according to any one of embodiments 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of systemic lupus erythematosus (SLE).

[0068] Embodiment 34. The formula:

[0069] [ka] In the formula, R 0 is C 1~3 The compound or a salt thereof,

[0070] Embodiment 35. The formula:

[0071] [ka] In the formula, R 0 is C 1~3 The compound or a salt thereof,

[0072] Embodiment 36. A compound of the formula:

[0073] [ka] 36. A process for preparing a compound of embodiment 35, comprising contacting with molecular hydrogen under conditions sufficient to provide a compound of claim 35.

[0074] Embodiment 37. The process of embodiment 36, wherein the conditions include the presence of a chiral phosphine ligand.

[0075] Embodiment 37A. The process of embodiment 37, wherein the chiral phosphine ligand is a P-chiral phosphine ligand.

[0076] Embodiment 37B. The method of embodiment 37, wherein the chiral phosphine ligand is a P-stereogenic C1 symmetric diphosphine ligand.

[0077] Embodiment 38. The process of embodiment 37, wherein the chiral phosphine ligand is a ChenPhos ligand.

[0078] Embodiment 38A. The process of claim 38, wherein the ChenPhos ligand comprises two cyclohexyl groups bonded to P.

[0079] Embodiment 39. The process of embodiment 38, wherein the ChenPhos ligand is 1-(dicyclohexylphosphino)-1'-[(S)-[(1R)-2-[(1R)-1-(dimethylamino)ethyl]ferrocenyl]phenylphosphino]-ferrocene.

[0080] Embodiment 40. The process of embodiment 37, wherein the conditions comprise a chiral phosphine ligand in a stoichiometric ratio of about 0.01:1 to about 0.05:1 with respect to a compound of formula:

[0081] [ka]

[0082] Embodiment 41. The process of any of embodiments 37-40, wherein the conditions include the presence of a catalyst of a bis(norbornadiene)rhodium(I) salt.

[0083] Embodiment 42. The process of embodiment 41, wherein the conditions comprise a stoichiometric ratio of the catalyst to the compound of the formula:

[0084] [ka]

[0085] Embodiment 43. The process of embodiment 41, wherein the conditions comprise a stoichiometric ratio of the chiral phosphine ligand to the catalyst of about 1.2:1 to about 1:1.

[0086] Embodiment 44. The process of any one of embodiments 36-43, wherein the conditions include contacting under a substantially oxygen-free atmosphere.

[0087] Embodiment 45. The process of any one of embodiments 36 to 44, wherein the conditions comprise contacting in a protic medium.

[0088] Embodiment 46. The method of any one of embodiments 36 to 45, wherein the conditions include contacting at a temperature of about 10°C to about 50°C.

[0089] Embodiment 47. The process of any of embodiments 36-46, wherein the conditions include molecular hydrogen at a pressure of about 0.5 MPa to about 2.5 MPa.

[0090] Embodiment 47A. The process of any of embodiments 36-46, wherein the conditions comprise molecular hydrogen at a pressure of about 1 MPa to about 2 MPa.

[0091] Embodiment 48. The process of any one of embodiments 36-47, further comprising preparing a compound of the formula:

[0092] [ka] The compound of formula

[0093] [ka] with a Wittig reagent. The process according to any one of embodiments 36 to 47.

[0094] Embodiment 49. The process of any one of embodiments 36-48, further comprising preparing a compound of the formula:

[0095] [ka] The compound of formula

[0096] [ka] 49. The process of any one of embodiments 36-48, comprising contacting the compound of formula (I) with an acid (e.g., an organic acid) at a temperature of about 70° C. to about 110° C.

[0097] Embodiment 50. The process of any one of embodiments 36-49, further comprising preparing a compound of the formula:

[0098] [ka] The preparation comprises preparing a compound of the formula:

[0099] [ka] 50. The process of any one of embodiments 36-49, comprising contacting with a compound of formula:

[0100] [ka]

[0101] Embodiment 51. A compound of the formula:

[0102] [ka] Or its salt.

[0103] Embodiment 52. A process for preparing a compound of the formula:

[0104] [ka] A compound of the formula:

[0105] [ka] A compound of the formula:

[0106] [ka] In the formula, R 0 is C 1~3 The process comprising contacting a compound, said compound being an alkyl group, with a compound selected from the group consisting of aryl, ... and aryl groups.

[0107] Embodiment 53. A process for preparing a compound of the formula:

[0108] [ka] A racemic mixture of the formula

[0109] [ka] with a chiral acid under conditions sufficient to form a co-crystal.

[0110] Embodiment 53A. The process of embodiment 53, wherein the chiral acid is selected from D-(-)-tartaric acid, (+)-dibenzoyl-D-tartaric acid, di-p-toluoyl-L-tartaric acid, D-pyroglutamic acid, D-valine, L-isoleucine, L-histidine, N-acetyl-L-valine, D-proline, naproxen, N-acetyl-L-phenylalanine, L-(+)-arginine (acid), D-(-)-quinic acid, (+)-deoxycholic acid, and N-acetyl-L-leucine.

[0111] Embodiment 53B. The process of embodiment 53, wherein the chiral acid is selected from (+)-dibenzoyl-D-tartaric acid, di-p-toluoyl-L-tartaric acid, D-pyroglutamic acid, L-isoleucine, L-histidine, D-proline, and N-acetyl-L-leucine, under conditions sufficient to provide a cocrystal.

[0112] Embodiment 53C. The process of embodiment 53, wherein the chiral acid is (+)-dibenzoyl-D-tartaric acid.

[0113] Embodiment 53D. The chiral acid is of the formula:

[0114] [ka] The co-crystal is of the formula:

[0115] [ka] The process according to embodiment 53.

[0116] Embodiment 53E. The process of embodiment 53, 53A, 53B, 53C or 53D wherein the conditions comprise the use of a solvent selected from isopropanol, acetonitrile, isopropyl acetate, ethanol, butanone and dimethoxyethane.

[0117] Embodiment 54. The process of embodiment 53, further comprising contacting the crystalline product with an aqueous basic solution.

[0118] Embodiment 54A. The process of embodiment 54, wherein the aqueous solution is a sodium bicarbonate solution or a potassium carbonate solution.

[0119] Embodiment 55. A compound of the formula:

[0120] [ka] The process according to embodiment 52, prepared according to embodiment 53 or 54.

[0121] Embodiment 56. A compound of the formula

[0122] [ka] or a pharma- ceutically acceptable salt thereof, comprising the steps of: A compound of the formula:

[0123] [ka] under conditions to provide a compound of formula

[0124] [ka] A compound of the formula:

[0125] [ka] A compound of the formula:

[0126] [ka] A compound of the formula:

[0127] [ka] During the ceremony, Ring B is phenyl or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, each heteroatom of the heteroaryl being independently selected from N, S, and O; X is H, halo, C optionally substituted with one or more halo. 1~3 Alkyl or C 1~3 alkoxyl, where alkoxyl and

[0128] [ka] are meta- or para- to each other, Z is CH or N; R 0 is C 1~3 is alkyl, contacting under conditions sufficient to provide a compound.

[0129] Embodiment 57. A compound of the formula:

[0130] [ka] The process according to embodiment 56, which is prepared according to the process of embodiment 36, 52, or 55.

[0131] Embodiment 58. Z is N and the conditions to provide a compound of formula

[0132] [ka] A compound of the formula:

[0133] [ka] Phosphoryl chloride, formula:

[0134] [ka] and contacting under conditions sufficient to provide a compound of formula (I) A compound of the formula:

[0135] [ka] hydrolyzing under conditions sufficient to provide a compound of the formula:

[0136] [ka] A compound of the formula:

[0137] [ka] with hydrazine under conditions sufficient to provide a compound of the formula:

[0138] [ka] A compound of the formula:

[0139] [ka] with formic acid under conditions sufficient to provide a compound of the formula: 57. The process of embodiment 56, comprising:

[0140] [ka] Further, the present disclosure provides a compound of formula I,

[0141] [ka] During the ceremony, Ring A is a 5- or 6-membered carbocyclic ring; Ring B is phenyl or a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms, each heteroatom of the heteroaryl being independently selected from N, S, and O; R is H or C 1~3 is alkyl, X is H, halo, C optionally substituted with one or more halo. 1~3 Alkyl or C 1~3 is alkoxyl, Y is H, C 1~3 Alkyl or C 1~3 is alkoxyl, Z is CH or N, A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, is provided.

[0142] In some embodiments, Ring A is phenyl and Y is H, or Ring A is

[0143] [ka] wherein Y is methyl, ring B is pyridinyl or pyrimidinyl, R is H, X is H or F, and Z is CH or N, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0144] In some embodiments, the compound of formula I

[0145] [ka] is phenyl,

[0146] [ka] wherein Q is O or S and W is CH or N.

[0147] In some embodiments, provided herein is a compound of formula II,

[0148] [ka] wherein X, Y, Z and ring A are each as defined above for formula I, and W is CH or N; A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, is provided.

[0149] In some embodiments, ring A of the compound described in any of the preceding embodiments is phenyl. In some embodiments, ring A of the compound described in any of the preceding embodiments is

[0150] [ka] It is.

[0151] In some embodiments, provided herein is a compound of formula III,

[0152] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, wherein X, Y, Z and W are as described above for Formula I or Formula II.

[0153] In some embodiments, provided herein is a compound of formula IV,

[0154] [ka] wherein X, Y, Z and W are as described above for Formula I or Formula II, or a pharma- ceutically acceptable salt thereof.

[0155] In some embodiments, Z of the compound described in any of the preceding embodiments is N. In some embodiments, Z of the compound described in any of the preceding embodiments is CH.

[0156] In some embodiments, W is N in the compound described in any of the preceding embodiments.

[0157] In some embodiments, X is F in the compound described in any of the preceding embodiments.

[0158] In some embodiments, Y of the compound described in any preceding embodiment is methyl.

[0159] In some embodiments, the compound of any of the preceding embodiments is

[0160] [ka] is selected from the group consisting of:

[0161] In some embodiments, the compound of any of the preceding embodiments is

[0162] [ka] is selected from.

[0163] In some embodiments,

[0164] [ka] If the compound

[0165] [ka] as described in any preceding embodiment.

[0166] In some embodiments, the compound of any of the preceding embodiments is

[0167] [ka] or any of the compounds described in the preceding embodiments.

[0168] [ka] It is.

[0169] In some embodiments, the compound of any of the preceding embodiments is

[0170] [ka] or any of the compounds described in the preceding embodiments.

[0171] [ka] It is.

[0172] In some embodiments,

[0173] [ka] A compound selected from the group consisting of: Provided herein are stereoisomers or mixtures of stereoisomers, or pharma- ceutically acceptable salts of each thereof.

[0174] In some embodiments,

[0175] [ka] A compound selected from Mixtures of said stereoisomers or each of their pharma- ceutically acceptable salts are provided herein.

[0176] In some embodiments,

[0177] [ka] or a pharma- ceutically acceptable salt thereof.

[0178] In some embodiments,

[0179] [ka] Provided herein is a compound of the formula:

[0180] In some embodiments,

[0181] [ka] Provided herein is a compound of the formula:

[0182] The present disclosure further provides a pharmaceutical composition comprising a compound according to any of the above embodiments, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0183] 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 according to any of the above embodiments, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, or a pharmaceutical composition.

[0184] 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 according to any of the above embodiments, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, or a pharmaceutical composition.

[0185] The present disclosure provides a compound according to any of the above embodiments, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, for use in therapy.

[0186] The present disclosure also provides a compound according to any of the above embodiments, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, for use in the treatment of a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn's disease, graft-versus-host disease, rheumatoid arthritis, and multiple sclerosis.

[0187] In some embodiments, the present disclosure provides a compound of formula I-1:

[0188] [ka] A stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein Ring A is a 5- or 6-membered carbocyclic ring; Ring B is phenyl or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, each heteroatom of the heteroaryl being independently selected from N, S, and O; X is H, halo, C optionally substituted with one or more halo. 1~3 Alkyl or C 1~3 alkoxyl, where the alkoxyl is

[0189] [ka] is meta- or para- to Y is H, C 1~4 Alkyl or C 3~4 cycloalkyl, where C 1~4 The alkyl is a primary or secondary alkyl; Z is CH or N.

[0190] In some embodiments, Ring A is phenyl and Y is H, or Ring A is

[0191] [ka] wherein Y is alkyl or cycloalkyl, Ring B is pyrazolyl, triazolyl, pyridinyl or pyrimidinyl, X is H or F, and Z is CH or N, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof.

[0192] In some embodiments, provided herein is a compound of formula I-2,

[0193] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, wherein X, Y, Z, ring A and ring B are each as defined above for formula I-1.

[0194] In some embodiments, provided herein are compounds of formula I-3,

[0195] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, wherein X, Y, Z, ring A and ring B are each as defined above for formula I-1.

[0196] In some embodiments, the compound of formula I-1, I-2, or I-3

[0197] [ka] where Q is O or S and W is CH or N.

[0198] In some embodiments, the compound of formula I-1, I-2, or I-3

[0199] [ka] It is.

[0200] In some embodiments, the compound of any of the preceding embodiments is

[0201] [ka] is a substituted or unsubstituted 6-membered heteroaryl.

[0202] In some embodiments, the compound of any of the preceding embodiments is

[0203] [ka] is a substituted or unsubstituted 5-membered heteroaryl.

[0204] In some embodiments, the compound of any of the preceding embodiments is

[0205] [ka] It is.

[0206] In some embodiments, the compound of any of the preceding embodiments is

[0207] [ka] It is.

[0208] In some embodiments, provided herein is a compound of formula II-1,

[0209] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein X, Y, Z, and ring A are each as defined above for formula I-1, and W is CH or N.

[0210] In some embodiments, provided herein is a compound of formula II-2,

[0211] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein X, Y and ring A are each as defined above for formula I-1, and W is CH or N.

[0212] In some embodiments, provided herein is a compound of formula II-3,

[0213] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein X, Y and ring A are each as defined above for formula I-1, and W is CH or N.

[0214] In some embodiments, provided herein is a compound of formula II-1A,

[0215] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each, wherein X, Y, and ring A are each as defined above for formula I-1.

[0216] In some embodiments, for compounds of formula II-1, II-2, II-3, and II-1A, X is H or halo and Y is H or C. 1~3 It is an alkyl.

[0217] In some embodiments, the compound of any of the preceding embodiments is

[0218] [ka] is selected from.

[0219] In some embodiments, the compound of any of the preceding embodiments is

[0220] [ka] is selected from.

[0221] In some embodiments,

[0222] [ka] If the compound

[0223] [ka] as described in any preceding embodiment.

[0224] In some embodiments, ring A of the compound described in any of the preceding embodiments is phenyl. In some embodiments, ring A of the compound described in any of the preceding embodiments is

[0225] [ka] It is.

[0226] In some embodiments, provided herein is a compound of formula III-1,

[0227] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein X, Y, and Z are as described above for formula I-1, where W is CH or N.

[0228] In some embodiments, provided herein is a compound of formula III-2,

[0229] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein X and Y are as described above for formula I-1, where W is CH or N.

[0230] In some embodiments, provided herein is a compound of formula III-3,

[0231] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein X and Y are as described above for formula I-1, where W is CH or N.

[0232] In some embodiments, Ring B is phenyl.

[0233] In some embodiments, provided herein is a compound of formula III-1A,

[0234] [ka] Provided are compounds, stereoisomers or mixtures of stereoisomers thereof, or respective pharma- ceutically acceptable salts thereof, wherein X, Y and Z are as described above with respect to formula I-1.

[0235] In some embodiments, provided herein is a compound of formula IV-1,

[0236] [ka] wherein X and Z are as described above for formula I-1, where W is CH or N, or a pharma- ceutically acceptable salt thereof.

[0237] In some embodiments, provided herein is a compound of formula IV-2,

[0238] [ka] Compounds are provided in which X is as described above for formula I-1, where W is CH or N, or a pharma- ceutically acceptable salt thereof.

[0239] In some embodiments, provided herein is a compound of formula IV-3,

[0240] [ka] Provided are compounds, or pharma- ceutically acceptable salts thereof, wherein X is as described above for formula I-1, where W is CH or N.

[0241] In some embodiments, provided herein is a compound of formula IV-1A,

[0242] [ka] Provided is a compound, or a pharma- ceutically acceptable salt thereof, wherein X and Z are as described above for formula I-1.

[0243] In some embodiments, the compound of formula II-1, II-2, II-3, III-1, III-2, III-3, IV-1, IV-2, or IV-3

[0244] [ka] but [ka] It is.

[0245] In some embodiments, provided herein is a compound of formula V-1,

[0246] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein X, Y, and Z are as described above for formula I-1, and Q is O or S.

[0247] In some embodiments, provided herein is a compound of formula V-2,

[0248] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein X, Y, and Z are as described above for formula I-1, and Q is O or S.

[0249] In some embodiments, provided herein is a compound of formula V-3,

[0250] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein X, Y, and Z are as described above for formula I-1, and Q is O or S.

[0251] In some embodiments, provided herein is a compound of formula V-4,

[0252] [ka] Provided is a compound, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein X, Y, and Z are as described above for formula I-1, and W is CH or N.

[0253] In some embodiments, Z is N. In some embodiments, Z is N.

[0254] In some embodiments, for any of the compounds of formula I-1, I-2, I-3, II-1, II-2, II-3, II-1A, III-1, III-2, III-3, III-1A, IV-1, IV-2, IV-3, IV-1A, V-1, V-2, V-3, and V-4, X is H or halo. In some embodiments, X is H or F. In some embodiments, X is F. In some embodiments, X is H. In some embodiments, X is Cl.

[0255] In some embodiments, for any of the compounds of formula I-1, I-2, I-3, II-1, II-2, II-3, II-1A, III-1, III-2, III-3, III-1A, IV-1, IV-2, IV-3, IV-1A, V-1, V-2, V-3, and V-4, Y is H. In some embodiments, Y is C 1~4In some embodiments, Y is alkyl. In some embodiments, Y is methyl. In some embodiments, Y is ethyl. In some embodiments, Y is propyl. In some embodiments, Y is isopropyl. In some embodiments, Y is butyl. In some embodiments, Y is sec-butyl. In some embodiments, Y is C 3~4 In some embodiments, Y in the compound described in any of the preceding embodiments is cycloalkyl. In some embodiments, Y in the compound described in any of the preceding embodiments is cyclopropyl. In some embodiments, Y in the compound described in any of the preceding embodiments is cyclobutyl.

[0256] In some embodiments, with respect to the compound of any preceding embodiment, X is F. Y is C 3~4 It is cycloalkyl.

[0257] In some embodiments, with respect to compounds of any preceding embodiment, X is methyl.

[0258] In some embodiments, with respect to the compound of any of the preceding embodiments, X is C substituted with one or more halo. 1~3 It is an alkyl.

[0259] In some embodiments, with respect to compounds of any of the preceding embodiments, X is -CF3.

[0260] In some embodiments, with respect to the compound of any of the preceding embodiments, X is C 1~3 alkoxy, where alkoxyl and

[0261] [ka] are meta- to each other.

[0262] In some embodiments, with respect to the compound of any of the preceding embodiments, X is C 1~3 alkoxy, where alkoxyl and

[0263] [ka] are para- with respect to each other.

[0264] In some embodiments, with respect to the compound of any of the preceding embodiments, X is -OCH3, where -OCH3 and

[0265] [ka] are meta- to each other.

[0266] In some embodiments, with respect to the compound of any of the preceding embodiments, X is -OCH3, where -OCH3 and

[0267] [ka] are para- with respect to each other.

[0268] In some embodiments, W is N in the compound described in any of the preceding embodiments II-1, II-2, II-3, III-1, III-2, III-3, IV-1, IV-2, and IV-3.

[0269] In some embodiments, the compound of formula I-1, I-2, I-3, II-1, II-2, or II-3

[0270] [ka] or of the compound of formula III-1, III-2 or III-3

[0271] [ka] It is.

[0272] In some embodiments, the compound of formula I-1, I-2, I-3, II-1, II-2, or II-3

[0273] [ka] or of the compound of formula III-1, III-2 or III-3

[0274] [ka] It is.

[0275] In some embodiments, the present disclosure provides:

[0276] [ka] A compound selected from Provided are any stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0277] In some embodiments, provided herein is a compound selected from the table below, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof.

[0278] [Table 5]

[0279] In some embodiments, provided herein is a compound selected from the table below, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof.

[0280] [Table 6]

[0281] In some embodiments, the present disclosure provides:

[0282] [ka] A compound selected from or a pharma- ceutically acceptable salt thereof is provided.

[0283] In some embodiments, provided herein is a compound selected from the table below, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof.

[0284] [Table 7-1]

[0285] [Table 7-2]

[0286] In some embodiments, the present disclosure provides:

[0287] [ka] A compound selected from or a pharma- ceutically acceptable salt thereof is provided.

[0288] In some embodiments, the present specification provides

[0289] [ka] Compounds of or a pharma- ceutically acceptable salt thereof is provided herein.

[0290] In some embodiments, the present specification provides

[0291] [ka] Compounds of or a pharma- ceutically acceptable salt thereof is provided.

[0292] In some embodiments, the present specification provides

[0293] [ka] Compounds of or a pharma- ceutically acceptable salt thereof is provided.

[0294] In some embodiments, the present specification provides

[0295] [ka] Compounds of or a pharma- ceutically acceptable salt thereof is provided.

[0296] The present disclosure further provides a pharmaceutical composition comprising a compound according to any of the above embodiments, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0297] 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 according to any of the above embodiments, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, or a pharmaceutical composition.

[0298] The present disclosure provides a method of treating an autoantibody-driven autoimmune disease in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any of the above embodiments, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, or a pharmaceutical composition.

[0299] 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 according to any of the above embodiments, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, or a pharmaceutical composition.

[0300] The present disclosure also provides a method of treating a disease or disorder selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, and myasthenia gravis (MG).

[0301] The present disclosure provides a compound according to any of the above embodiments, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, for use in therapy.

[0302] The present disclosure provides a compound according to any of the above embodiments, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, for use in treating an immune-mediated disease in a patient.

[0303] The present disclosure provides a compound according to any of the above embodiments, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, for use in treating an autoantibody-driven autoimmune disease in a patient.

[0304] The present disclosure also provides a compound according to any of the above embodiments, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, for use in the treatment of a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn's disease, graft-versus-host disease, rheumatoid arthritis, and multiple sclerosis.

[0305] The present disclosure also provides a compound according to any of the above embodiments, a stereoisomer or mixture of stereoisomers, or a pharma- ceutically 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).

[0306] The present disclosure further provides the use of a compound according to any of the above embodiments, a stereoisomer or mixture of stereoisomers, or each of the pharma- ceutically acceptable salts thereof, for the manufacture of a medicament for treating an immune-mediated disease.The present disclosure further provides the use of a compound according to any of the above embodiments, a stereoisomer or mixture of stereoisomers, or each of the pharma-ceutically acceptable salts thereof, for the manufacture of a medicament for treating a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn's disease, graft-versus-host disease, rheumatoid arthritis, and multiple sclerosis.

[0307] 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.

[0308] 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 pi electrons shared in a cyclic arrangement. Aryl can be monocyclic (having one ring), bicyclic (having two rings), or polycyclic (having two or more rings). Exemplary aryls include phenyl, naphthyl, anthracenyl, and phenanthrenyl.

[0309] As used herein, the term "chiral phosphine ligand" refers to a class of organophosphine compounds useful as ligands for metals to form metal complexes, where the chirality arises from either their carbon backbone or phosphorus. The term "P-chiral phosphine ligand" refers to a chiral ligand in which the chirality arises from the stereogenic phosphorus atom (P *) refers to a subset of "chiral phosphine ligands" arising from chiral phosphine ligands. Examples of chiral phosphine ligands and P-chiral phosphine ligands are described in Imamoto, et.al., Proc. Jpn. Acad. Ser. B. Phys. Biol. Sci. 2021, Nov 11; 97(9):520-542.

[0310] As used herein, the term "ChenPhos" refers to a class of chiral phosphine ligands, such as those described in Chen, W., et al., Angew. Chem. Int. Ed., 52:8652-8656. For example, ChenPhos can have the structure:

[0311] [ka] where R is aryl or alkyl. Examples of suitable R groups include cyclohexyl, phenyl, t-butyl, isopropyl, ethyl, 4-fluorophenyl (4-FC6H4), 4-trifluoromethylphenyl (4-CF3C6H4), 2-norbornyl, 2-furyl, o-anisidyl, 3,5-dimethylphenyl (3,5-(CH3)2C6H3), 3,5-di-trifluoromethylphenyl (3,5-(CF3)2C6H3), 3,5-dimethyl-4-methoxy-phenyl (3,5-(CH3)2-4-(CHO)-C6H2), 1-naphthyl, and the like. ChenPhos, along with others, is a subset of P-chiral phosphine ligands.

[0312] 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.

[0313] As used herein, the term "carbocycle" refers to a saturated or unsaturated ring system containing only carbon. Carbocycles include cycloalkyl and aryl as well as partially saturated rings.

[0314] As used herein, the term "halo" refers to a halogen as a substituent, specifically chloro, fluoro, bromo, or iodo.

[0315] As used herein, the terms "heterocyclic" and "heterocycle" refer 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 monocyclic (having one ring), bicyclic (having two rings), or polycyclic (having more than two rings), which can be fused together, for example.

[0316] As used herein, the term "heteroaryl" refers to a group having 5-10 ring atoms, preferably 5, 6, 9 or 10 ring atoms, with 6, 10 or 14 pi electrons shared in a cyclic arrangement, and having 1-5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes the oxidized forms of nitrogen or sulfur, and the quaternized forms of 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 heteroaryl" includes groups in which a heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl and quinoxalinyl.

[0317] When two or more rings are present, the rings may be spaced apart from each other or connected to each other. When two rings are connected to each other, they may be connected in a "fused" configuration (or connecting motif), a "spiro" configuration, or a "bridge" configuration. As used herein, the term "fused" refers to a configuration in which two rings are connected adjacent to each other and share two "bridgehead" atoms directly and immediately connected to each other. A fused connecting motif differs from a "spiro" connecting motif in that there is only one "bridgehead" atom in the "spiro" motif, and differs from a "bridge" connecting motif in that the two "bridgehead" atoms are not directly connected to each other in the "bridge" motif. When a first ring is "fused" to a second ring, the "bridgehead" atoms are interpreted as belonging to both rings. Thus, when the embodiments provided herein describe one such ring that is a six-membered "carbocyclic ring", the six ring atoms include the two "bridgehead" atoms and four additional atoms. And all of these six ring atoms are carbon to make it a "carbocyclic ring". For example, this group

[0318] [ka] is outside the scope of "5-membered heteroaryl fused to a 6-membered carbocyclic ring" because one bridgehead atom is not carbon.

[0319] As used herein, the term "oxo" refers to an oxygen atom as a substituent attached to another atom by a double bond. It may be depicted as "=O". The term oxo is a carbonyl group with the carbon atom removed.

[0320] As used herein, the terms "ortho-", "meta-" and "para-" refer to the relative position between two substituents on a ring system. If two substituents are directly adjacent to each other (i.e., directly attached to two adjacent ring atoms), they are referred to as "ortho-" relative to each other. If they are separated by one other ring atom (in addition to the two ring atoms to which they are attached), they are referred to as "meta-" relative to each other. In the case of a six-membered ring system, if two substituents are separated by two other ring atoms (in addition to the two ring atoms to which they are attached), they are referred to as "para-" relative to each other. For example, in the following formula (A), A 1 and A 2 , A 2 and A 3 , A 3 and A 4 , A 4 and A 5 , A 5 and A 1 are considered to be ortho to each other. 1 and A 3 , A 2 and A 4 , A 3 and A 5 , A 4 and A 1 , and A 5 and A 2 are considered to be meta to each other. For example, in the following formula (B), A 1 and A 2 , A 2 and A 3 , A 3 and A 4 , A 4 and A 5 , A 5 and A 6 , A 6 and A 1 are considered to be ortho to each other. 1 and A 3 , A 2 and A 4 , A 3 and A 5 , A 4 and A 6 , and A 5 and A1 , A 6 and A 2 Each can be considered meta to the other. 1 and A 4 , A 2 and A 5 , and A 3 and A 6 are each considered to be para to each other.

[0321] [ka]

[0322] As used herein,

[0323] [ka] represents a bond that is part of an aromatic system. It can be appropriately and alternatively represented as a single bond or a double bond depending on how the aromatic system is depicted. For example,

[0324] [ka] may be used to represent a five-membered carbocyclic ring fused at two points to an aromatic system, such as a phenyl ring.

[0325] [ka] The bond can be a single bond (e.g.

[0326] [ka] ), or a double bond (e.g.,

[0327] [ka] can be appropriately expressed as (part of

[0328] As used herein, the term "stereoisomer" refers to isomers that are composed of the same atoms linked by the same bonds, but have different, non-exchangeable structures in three-dimensional space. The term stereoisomer includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and are not superimposable on one another. A one-to-one mixture of a pair of enantiomers is called a "racemic" mixture. The term stereoisomer also includes "diastereoisomers" (or "diastereomers"), which refer to two stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry of stereoisomers can be specified according to the Cahn-Ingold Prelog RS system, with the stereochemistry at each chiral center being specified as either R or S. When stereoisomers have been resolved but their absolute configuration is unknown, their stereocenters are designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) that they rotate the plane of polarized light at the wavelength of the sodium D line. Unless otherwise stated, "enantiomer 1" refers to the enantiomer that elutes first from the column during chiral separation of a racemic mixture under the stated separation conditions, and "enantiomer 2" refers to the enantiomer that elutes second during the same separation. The order of elution may differ between preparative (e.g., for separation) and analytical columns (e.g., for purity assessment). For clarity, the designations "enantiomer 1" and "enantiomer 2" are based on a spare column. Furthermore, multiple stereocenters may be present and two separations may be necessary to fully resolve the stereoisomers. For example, the first separation results in two bands, the first band eluting containing "enantiomer 1 / 1" and "enantiomer 1 / 2," the second band eluting containing "enantiomer 2 / 1" and "enantiomer 2 / 2." A subsequent separation (e.g., using the same or different column conditions) can be used to separate between "enantiomer 1 / 1" (the first eluting band in the subsequent separation) and "enantiomer 1 / 2" (the second eluting band in the subsequent separation).

[0329] As used herein, the term "immune-mediated disease" encompasses a group of autoimmune or inflammatory disorders in which immune pathways play an important etiological and / or pathogenic role. Such diseases are sometimes characterized by alterations in cellular homeostasis. Immune-mediated diseases can be caused by environmental factors, dietary habits, infectious agents, and genetic predisposition. Immune-mediated diseases include, for example, psoriasis, atopic dermatitis, ulcerative colitis, Crohn's disease, graft-versus-host disease, rheumatoid arthritis, and multiple sclerosis. Immune-mediated diseases can be mediated by autoantibodies, T cells, cytokines, complement, and the like.

[0330] As used herein, the term "autoantibody-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 include, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and myasthenia gravis (MG).

[0331] As used herein, the term "treating" includes limiting, slowing, stopping, or reversing the progression or severity of an existing condition or disorder.

[0332] As used herein, the term "patient" refers to a human.

[0333] As used herein, the term "effective amount" refers to an amount or dosage of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, that upon single or multiple administration to a patient, provides the desired effect in the patient being diagnosed or treated.

[0334] Effective amounts can be easily determined by those skilled in the art using known techniques. In determining the effective amount for a patient, several factors are taken into account, including, but not limited to, the patient's species, its size, age, and general health; the specific disease or disorder involved; the extent or involvement or severity of the disease or disorder; the response of the individual patient, the specific compound administered; the mode of administration, the bioavailability characteristics of the administered formulation, the selected dosing regimen; the use of concomitant medications; the medical history of the individual patient; and other relevant circumstances.

[0335] The compounds of the present disclosure are generally effective over a wide dosage range. For example, the daily dosage is usually within the range of about 0.1 to about 15 mg / kg body weight. In some cases, dosage levels lower than the lower limit of the aforementioned range may be more than sufficient, while in other cases, higher doses may be used with acceptable side effects, and therefore the above dosage ranges are not intended to limit the scope of the present disclosure in any way.

[0336] The compounds of the present disclosure are preferably formulated as pharmaceutical compositions to be administered by any route that makes the compounds bioavailable, including oral and transdermal routes. More preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for their preparation are well known in the art (e.g., Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23rd Edition). rd Edition, Elsevier Academic Press, 2020).

[0337] The compounds of the present disclosure or pharma- ceutically acceptable salts thereof can be prepared according to the following preparations and examples by methods well known and understood in the art. Suitable reaction conditions for the steps of these preparations and examples are well known in the art, and appropriate substitution of solvents and co-reagents is within the skill of the art. Similarly, those skilled in the art will appreciate that synthetic intermediates can be isolated and / or purified by various well-known techniques as necessary or desired, and in many cases, various intermediates can be used directly in subsequent synthetic steps with little or no purification. By way of example, the compounds of the preparations and examples can be isolated, for example, by silica gel purification, or directly by filtration or crystallization. Furthermore, those skilled in the art will appreciate that under some circumstances, the order in which the moieties are introduced is not critical. The particular order of steps required to produce the compounds of the present disclosure depends on the particular compound being synthesized, the starting compound, and the relative disadvantages of the substituting moieties, as is well understood by the skilled chemist. All substituents are as previously defined unless otherwise indicated, and all reagents are well known and understood in the art.

[0338] Specific abbreviations are as follows: "BSA" refers to bovine serum albumin, "CMV" refers to cytomegalovirus, "DCM" refers to dichloromethane, "DMA" refers to dimethylacetamide, "DMEM" refers to Dulbecco's modified Eagle's medium, "DMF" refers to dimethylformamide, "DMF-DMA" refers to N,N-dimethylformamide dimethylacetal, "DMSO" refers to dimethylsulfoxide, "DPBS" refers to Dulbecco's phosphate buffered saline, "EGFP" refers to enhanced green fluorescent protein, "EtOAc" refers to ethyl acetate, "FBS" refers to fetal bovine serum, "hr / hrs" refers to hours / hours, "MeOH" refers to methanol, "min" refers to minutes / minutes, "SFC" refers to supercritical fluid chromatography, and "THF" refers to tetrahydrofuran.

[0339] In any step, pharma- ceutically acceptable salts of the compounds according to any of the above embodiments can be formed by reacting a suitable free base with a suitable pharma- ceutically acceptable acid in a suitable solvent under standard conditions. The formation of such salts is well known and understood in the art. For example, see Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, RJ, et al. "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000); and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19, (1977). "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986). One of ordinary skill in the art will appreciate that compounds according to any of the above embodiments may be readily converted to, and isolated as, pharma- ceutically acceptable salts.

[0340] Compounds of formula I, formula II, formula III, formula IV, their stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, can be prepared by various procedures known in the art, some of which are illustrated in the following schemes, preparations and examples. The specific synthetic steps for each of the described routes can be prepared in different ways or in combination with steps from different schemes to prepare compounds of formula I, formula II, formula III, formula IV, their stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts. The products of each step in the following schemes can be recovered by conventional methods well known in the art, including, for example, extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. In the following schemes, all variables and substituents are as defined above unless otherwise indicated. The reagents and starting materials are readily available to one of ordinary skill in the art.

[0341] Scheme 1. General scheme for preparing compound 4

[0342] [ka] Scheme 1 shows a general scheme for the synthesis of carboxylic acid compound 4. All variables are as defined above for formula I. Additionally, R1 is C 1~3 In some embodiments, R is an alkyl group such as alkyl. In some embodiments, R is hydrogen.

[0343] Compound 1 is hydrolyzed under conditions sufficient to provide carboxylic acid compound 2a. For example, compound 1 may be dissolved in a suitable organic solvent, water, or a mixture thereof, and then an excess of base (e.g., lithium hydroxide) is added to the solution and stirred at ambient temperature for several hours. Upon completion of the reaction (e.g., by monitoring by thin layer chromatography (TLC)), the pH of the solution is adjusted to about 3 using an acid (e.g., 1N hydrochloric acid). The resulting mixture is then extracted with a suitable organic solvent (e.g., ethyl acetate), and the combined organic layers are dried (e.g., with anhydrous sodium sulfate), filtered, and concentrated under reduced pressure to provide compound 2a.

[0344] Compound 2a is then contacted with hydrazine under conditions sufficient to provide compound 3a (e.g., via nucleophilic aromatic substitution). For example, compound 2a is dissolved in a suitable organic solvent (1,4-dioxane). An excess of hydrazine is then added to the solution and heated at a suitable temperature (e.g., 40-80° C.) for several hours. The reaction mixture is concentrated under reduced pressure to provide compound 3a.

[0345] Compound 3a is contacted with a suitable organic acid under conditions sufficient to provide compound 4. For example, a mixture of compound 3a and formic acid is heated at a suitable temperature (e.g., 60-100° C.) for several hours. The reaction mixture is concentrated under reduced pressure to provide compound 4, where R is hydrogen. In some embodiments, compound 4 may be used in further reactions without workup or purification.

[0346] Alternatively, compound 1 is contacted with hydrazine under conditions sufficient to provide compound 2b (e.g., via nucleophilic aromatic substitution). For example, compound 1 can be dissolved in a suitable organic solvent (e.g., ethanol). An excess of hydrazine is then added to the solution and heated at a suitable temperature (e.g., 80-100° C.) for several hours. The reaction mixture is worked up (e.g., by quenching with a weak base), extracted with a suitable solvent (e.g., ethyl acetate), dried, concentrated under reduced pressure, and purified (e.g., by silica gel chromatography) to provide compound 2b.

[0347] Compound 2b is contacted with a suitable organic acid under conditions sufficient to provide compound 3b. For example, a mixture of compound 2b and formic acid can be heated at a suitable temperature (e.g., 60-100° C.) for several hours. The resulting mixture is then extracted with a suitable organic solvent (e.g., ethyl acetate), dried (e.g., anhydrous sodium sulfate), filtered, and concentrated under reduced pressure to provide compound 3b, where R is hydrogen.

[0348] Compound 3b is hydrolyzed under conditions sufficient to provide carboxylic acid compound 4. For example, compound 1 can be dissolved in a suitable organic solvent (e.g., THF, MeOH), water, or a mixture thereof. An excess of base (e.g., lithium hydroxide) is then added to the solution and stirred at ambient temperature for several hours. Upon completion of the reaction, the pH of the solution is adjusted to about 3 using an acid (e.g., 1N hydrochloric acid). The resulting mixture is then extracted with a suitable organic solvent (e.g., ethyl acetate), dried (e.g., anhydrous sodium sulfate), filtered, and concentrated under reduced pressure to provide compound 4.

[0349] In some embodiments, compound 1 of Scheme 1 is

[0350] [ka] and compound 4 in Scheme 1 is

[0351] [ka] It is.

[0352] In some embodiments,

[0353] [ka] can be prepared by a suitable method, such as chiral separation using column chromatography under suitable conditions.

[0354] [ka] It can be prepared by separating the racemic mixture of:

[0355] In some embodiments,

[0356] [ka] As provided in the above embodiments (e.g., embodiment 58),

[0357] [ka] It can be prepared from

[0358] In some embodiments,

[0359] [ka] can be prepared by a suitable method, such as chiral separation using column chromatography under suitable conditions.

[0360] [ka] It can be prepared by separating the racemic mixture of:

[0361] In some embodiments, as described in the above embodiments (e.g., embodiments 36 to 47),

[0362] [ka] Provided herein is a method for preparing

[0363] In some embodiments, as described in the above embodiments (such as embodiment 48),

[0364] [ka] Provided herein is a method for preparing

[0365] In some embodiments, as described in the above embodiments,

[0366] [ka] Provided herein is a method for preparing

[0367] In some embodiments, as described in the above embodiments,

[0368] [ka] Provided herein is a method for preparing

[0369] Alternatively, in some embodiments, as described in the above embodiments,

[0370] [ka] Provided herein is a method for preparing

[0371] In some embodiments,

[0372] [ka] A method for preparing A racemic mixture of the formula:

[0373] [ka] with a compound of the formula

[0374] [ka] contacting under conditions sufficient to provide a co-crystal of the formula:

[0375] [ka]

[0376] Provided herein is a method of preparation by contacting the co-crystal with an aqueous solution of sodium bicarbonate or potassium carbonate.

[0377] Scheme 2. General scheme for preparing compound 8

[0378] [ka] Scheme 2 shows a general scheme for the synthesis of carboxylic acid intermediate 8. All variables are as defined above for formula I. Additionally, R 2 is H, —CHCH(OCH), or —CHC(O)R. In some embodiments, R is hydrogen.

[0379] Compound 5 is converted, for example, by amination via a Buchwald reaction, under conditions sufficient to provide compound 6. For example, compound 5 is treated with tert-butyl carbamate, a suitable palladium catalyst (e.g., palladium(II) acetate), a suitable ligand (e.g., 2-dicyclohexylphosphio-2',4',6'-triisopropylbiphenyl), and a suitable base (e.g., cesium carbonate) in a suitable solvent (e.g., toluene) with heating at a suitable temperature (e.g., 60-120°C) for several hours. The mixture is concentrated under reduced pressure and purified to provide compound 6.

[0380] Alternatively, compound 5 is aminated with an aminoacetaldehyde equivalent via nucleophilic aromatic substitution to compound 6. For example, compound 5 is treated with aminoacetaldehyde dimethyl acetal in a suitable solvent (e.g., ethanol) with heating at a suitable temperature (e.g., 60-120° C.) for several hours. The mixture is concentrated under reduced pressure and purified to give compound 6.

[0381] Compound 6 is converted under conditions sufficient to provide imidazole compound 7, such as by cyclization with a haloacetaldehyde or halomethylketone. 2 When R is H, compound 6 is treated with chloroacetaldehyde in a suitable solvent (e.g., ethanol) and heated at a suitable temperature (e.g., 60-100° C.) for several hours. 2When is CH2CH(OCH3)2, compound 6 is treated with a halomethyl ketone in a suitable solvent (e.g., xylene) and heated at a suitable temperature (e.g., 140° C.) for several hours. In either case, the mixture is concentrated under reduced pressure and purified to give compound 7.

[0382] Compound 7 is converted (e.g., by hydrolysis) under conditions sufficient to provide a carboxylic acid intermediate compound 8. For example, compound 7 is dissolved in a suitable organic solvent (e.g., THF, MeOH), water, or a mixture thereof, treated with an excess of a strong base (e.g., lithium hydroxide), and stirred at ambient temperature for several hours. The pH of the solution is adjusted to about 3 with an acid (e.g., 1N hydrochloric acid, etc.). The solid is filtered and washed with water to provide compound 8.

[0383] In some embodiments, compound 5 of Scheme 2 is

[0384] [ka] and compound 8 in Scheme 2 is

[0385] [ka] It is.

[0386] Alternatively, compound 1 or 5 is compound 11,

[0387] [ka] When this is the case, compounds 4 and 8 can be prepared via Scheme 2a below and are designated compounds 14a and 14b, respectively.

[0388] Scheme 2a. General scheme for preparing compounds 14a and 14b

[0389] [ka] Scheme 2a shows a general scheme for the synthesis of compounds 14a and 14b from compound 11. All variables are as defined above for Schemes 1 and 2.

[0390] Scheme 3. General scheme for preparing compounds of formula I

[0391] [ka] Scheme 3 shows a general scheme for the synthesis of compounds of formula I. All variables are as defined above for formula I. In some embodiments, carboxylic acid compound 9 is in the form of carboxylic acid compound 14a or 14b.

[0392] Carboxylic acid compound 9 is contacted with a suitable amine compound 10 (e.g., via an amide coupling reaction) under conditions sufficient to provide a compound of formula I. For example, carboxylic acid 9 and a suitable amine compound 10 are dissolved in a suitable solvent (e.g., dichloromethane), treated with a suitable catalyst (e.g., pyridine) and a suitable chlorinating agent (e.g., phosphoryl chloride), and stirred at ambient temperature for several hours. The reaction mixture is concentrated under reduced pressure, and the residue is triturated with a suitable solvent (e.g., DMF). The solid is filtered to provide a compound of formula I. In some embodiments, intermediate compound 9 is compound 4 described above. In some embodiments, intermediate compound 9 is compound 8 described above.

[0393] In some embodiments, compound 10 is compound 10a and the compound of formula I is a compound of formula II, where W is as defined above.

[0394] [ka]

[0395] In some embodiments, compound 10 is 10b and the compound of formula I is a compound of formula II-1, where Q is as defined above.

[0396] [ka]

[0397] In some embodiments, compound 10 is 10c and the compound of formula I is a compound of formula II-2, where Q is as defined above.

[0398] [ka]

[0399] In some embodiments, compound 10 is 10d and the compound of formula I is a compound of formula II-3, where Q is as defined above.

[0400] [ka]

[0401] In some embodiments, compound 10 is compound 10e and the compound of formula I is a compound of formula II-4.

[0402] [ka]

[0403] In some embodiments, ring A of compound 9 is phenyl, such that the compound of formula II also conforms to formula IV when Y is hydrogen.

[0404] In some embodiments, ring A of compound 9 is:

[0405] [ka] It is.

[0406] In some embodiments, compounds of formula I take the form of formula I-1, I-2, I-3, II-1, II-2, II-3, II-1A, III-1, III-2, III-3, III-1A, IV-1, IV-2, IV-3, IV-1A, V-1, V-2, V-3, or V-4 and can be prepared from appropriate starting materials and methods similar to those described.

[0407] Preparation 1 [1,2,4]Triazolo[4,3-a]quinoline-4-carboxylic acid

[0408] [ka]

[0409] Process 1 Ethyl 2-chloroquinoline-3-carboxylate

[0410] [ka] Ethyl 2-oxo-1,2-dihydroquinoline-3-carboxylate (1 g, 4.37 mmol) was mixed with N,N-diisopropylethylamine (2.29 mL, 13.1 mmol) and phosphoryl chloride (4.1 g, 26 mmol) in toluene (10 mL). The mixture was stirred at 120° C. for 18 h. After this, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (12 g) using ethyl acetate in petroleum ether as the eluent with a 0-10% gradient to give a clear, colorless oil. The oil was triturated with petroleum ether (20 mL) at 20° C. for 10 min to give ethyl 2-chloroquinoline-3-carboxylate as a white solid (0.713 g, 61.5%). ES / MS (m / z): 236.1 (M+H).

[0411] Process 2 Ethyl 2-hydrazinylquinoline-3-carboxylate

[0412] [ka] 2-Chloroquinoline-3-carboxylate (500 mg, 1.89 mmol) was dissolved in ethanol (10 mL). Hydrazine (250 mg, 7.72 mmol) was introduced and the mixture was stirred at 40° C. for 18 h. After this, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (20 g) with ethyl acetate in petroleum ether as the eluent in a 0-33% gradient to give ethyl 2-hydrazinylquinoline-3-carboxylate as a yellow solid (240 mg, 50.7%). ES / MS (m / z): 232.2 (M+H).

[0413] Process 3 Ethyl [1,2,4]triazolo[4,3-a]quinoline-4-carboxylate

[0414] [ka] Ethyl 2-hydrazinylquinoline-3-carboxylate (240 mg, 0.96 mmol) was stirred in formic acid (5 mL) at 100° C. for 18 hours. After this time, the reaction was quenched with saturated aqueous sodium carbonate (30 mL) and extracted with ethyl acetate (30 mL×3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl [1,2,4]triazolo[4,3-a]quinoline-4-carboxylate as a yellow solid (240 mg, 98.8%). ES / MS (m / z): 242.2 (M+H).

[0415] Process 4 [1,2,4]Triazolo[4,3-a]quinoline-4-carboxylic acid

[0416] [ka] Ethyl [1,2,4]triazolo[4,3-a]quinoline-4-carboxylate (240 mg, 0.945 mmol) was stirred in a mixture of THF (8 mL) and water (1 mL). Lithium hydroxide (200 mg, 4.77 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 h. After this time, the reaction mixture was concentrated under reduced pressure to remove volatile organics, and then the pH of the solution was adjusted to about 3 by adding 1N aqueous HCl. The solid was filtered and washed with water to give [1,2,4]triazolo[4,3-a]quinoline-4-carboxylic acid as a pale yellow solid (204 mg, 96.5%). ES / MS (m / z): 214.2 (M+H).

[0417] Preparation 2 6-Methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid

[0418] [ka]

[0419] Process 1 (Z)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one

[0420] [ka] Cuprous iodide (56 g, 294 mmol) and tributylphosphine (150 mL, 570 mmol) were stirred in THF (300 mL) under N2 for 10 min. The mixture was then cooled to -78°C. Methyllithium (1.6 mol / L in diethyl ether) (180 mL, 290 mmol) was then added dropwise. After the addition was complete, the mixture was further stirred at -78°C under N2 for 30 min. Boron trifluoride diethyl etherate (34 mL, 268.8 mmol) was then added and the mixture was further stirred for 5 min. Cyclopent-2-en-1-one (20 g, 243.6 mmol) was also added. The mixture was stirred at -68°C for 10 min, warmed to -55°C, stirred for 20 min, then warmed again to -40°C and stirred under N2 for 10 min. DMF-DMA (81 mL, 607 mmol) was then added and the mixture was warmed to 20° C. and stirred under N2 for 16 h. The yellow mixture was poured into saturated aqueous NaCl (500 mL) and extracted with EtOAc (4×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (330 g) using EtOAc in petroleum ether as eluent with a 0-100% gradient to give (Z)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one as a yellow oil (34 g, 82%). ES / MS (m / z): 154.2 (M+H).

[0421] Process 2 Methyl 5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0422] [ka] (Z)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one (13.46 g, 87.85 mmol) was dissolved in MeOH (100 mL). To this mixture was added piperidine (7.5 g, 88 mmol) followed by methyl cyanoacetate (17.6 g, 176 mmol). The mixture was heated to 80 °C under N2 and maintained for 18 h. After this time, the volatile organics were concentrated under reduced pressure and the residue was purified on a silica gel column (120 g) using EtOAc in petroleum ether as eluent with a 0-60% gradient to give methyl 5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate as a brown solid (14 g, 69%). 1 H NMR(CDCl3):7.96(s,1H),7.21(s,1H),3.86(s,3H),3.12-3.03(m,1H),2.9 2-2.82(m,2H),2.35-2.28(m,1H),1.64-1.55(m,1H),1.19(d,J=6.9Hz,3H).

[0423] Process 3 Methyl 2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0424] [ka] Methyl 5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (2 g, 9.65 mmol) in toluene (5 mL) was added to N,N-diisopropylethylamine (3.3 mL, 19 mmol) followed by phosphoryl chloride (10 mL). The reaction mixture was heated to 100 °C for 16 h. After this time, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (40 g, 0-20% ethyl acetate in petroleum ether) to give methyl 2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate as a yellow oil (800 mg, 35.3%). ES / MS (m / z): 226.0 (M+H).

[0425] Process 4 2-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid

[0426] [ka] Methyl 2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (800 mg, 3.4 mmol) was dissolved in a mixture of THF (6 mL), MeOH (3 mL) and water (1.5 mL). Lithium hydroxide (330 mg, 16.5 mmol) was added to the solution and stirred at 25° C. for 2 hours. After this, the pH of the solution was adjusted to about 3 using 1N HCl. The mixture was then extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. This gave 2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid as a white solid (570 mg, 79.1%). ES / MS (m / z): 212.1 (M+H).

[0427] Process 5 2-Hydrazineyl-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid

[0428] [ka] 2-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (400 mg, 1.89 mmol) was added to 1,4-dioxane (8 mL). To this mixture, hydrazine (2 g, 61.8 mmol) was added and the mixture was stirred at 80° C. for 16 hours. After this time, the reaction mixture was concentrated under reduced pressure to give 2-hydrazineyl-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid as a yellow oil (400 mg, 91.9%). ES / MS (m / z): 208.2 (M+H).

[0429] Process 6 6-Methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid

[0430] [ka] 2-Hydrazineyl-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (400 mg, 1.7 mmol) was added to formic acid (10 mL) and the mixture was stirred at 100° C. for 16 h. After this time, the mixture was concentrated to dryness under reduced pressure to give 6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid as a yellow oil (320 mg, 59.4%). ES / MS (m / z): 218.2 (M+H).

[0431] Preparation 3 Imidazo[1,2-a]quinoline-4-carboxylic acid

[0432] [ka]

[0433] Process 1 Ethyl 2-((2,2-dimethoxyethyl)amino)quinoline-3-carboxylate

[0434] [ka] Ethyl 2-chloroquinoline-3-carboxylate (1 g, 4.12 mmol) was dissolved in ethanol (10 mL) and aminoacetaldehyde dimethyl acetal (4.6 mL, 42 mmol) was added to the solution. The mixture was heated to 80° C. and maintained for 2 days. After this time, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (12 g, 0-2% ethyl acetate in petroleum ether) to give ethyl 2-((2,2-dimethoxyethyl)amino)quinoline-3-carboxylate as a yellow oil (1.02 g, 78.3%). ES / MS (m / z): 305.3 (M+H).

[0435] Process 2 Imidazo[1,2-a]quinoline-4-carboxylate

[0436] [ka] Ethyl 2-((2,2-dimethoxyethyl)amino)quinoline-3-carboxylate (300 mg, 0.95 mmol) was stirred in xylene (10 mL) containing acetic acid (1 mL, 17.4 mmol) at 140° C. for 18 h. After this time, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (12 g, 0-50% ethyl acetate in petroleum ether) to give ethyl imidazo[1,2-a]quinoline-4-carboxylate as a grey solid (115 mg, 47.8%). ES / MS (m / z): 241.2 (M+H).

[0437] Process 3 Imidazo[1,2-a]quinoline-4-carboxylic acid

[0438] [ka] Ethyl imidazo[1,2-a]quinoline-4-carboxylate (115 mg, 0.454 mmol) was stirred in a mixture of THF (2 mL) and water (0.5 mL). Lithium hydroxide (91 mg, 2.2 mmol) was added and the mixture was stirred at ambient temperature for 18 h. After this time, the reaction mixture was concentrated under reduced pressure to remove volatile organics. The pH of the solution was adjusted to about 3 by adding 1N HCl solution. The solid was filtered and washed with water to give imidazo[1,2-a]quinoline-4-carboxylic acid as a grey solid (60 mg, 60.3%). ES / MS (m / z): 213.1 (M+H).

[0439] Preparation 4 6-Methyl-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyridine-4-carboxylic acid

[0440] [ka]

[0441] Process 1 Methyl 2-amino-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0442] [ka] Methyl 2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (2 g, 8.86 mmol) was added to toluene (20 mL). tert-Butyl carbamate (4.3 g, 36 mmol) was then added, followed by cesium carbonate (8.6 g, 26 mmol), palladium(II) acetate (400 mg, 1.8 mmol) and 2-dicyclohexylphosphio-2',4',6'-triisopropylbiphenyl (1.73 g, 3.6 mmol). The mixture was heated to 120° C. under nitrogen and maintained for 16 hours. After this time, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (12 g, 0-40% ethyl acetate in petroleum ether) to give methyl 2-amino-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate as a yellow oil (1.8 g, 89%). ES / MS (m / z): 207.1 (M+H).

[0443] Process 2 Methyl 6-methyl-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyridine-4-carboxylate

[0444] [ka] Methyl 2-amino-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (1.9 g, 8.3 mmol) was placed in ethanol (50 mL). Chloroacetaldehyde (3.3 g, 17 mmol) was added to the mixture and stirred at 80 °C for 16 h. After this time, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (12 g, 0-40% ethyl acetate in petroleum ether) to give methyl 6-methyl-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyridine-4-carboxylate as a yellow solid (1.5 g, 63%). ES / MS (m / z): 231.1 (M+H).

[0445] Process 3 6-Methyl-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyridine-4-carboxylic acid

[0446] [ka] Methyl 6-methyl-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyridine-4-carboxylate (1.5 g, 6.5 mmol) was stirred in a mixture of MeOH (6 mL), THF (12 mL) and water (3 mL). To this mixture was added lithium hydroxide (640 mg, 26 mmol) and stirred at ambient temperature for 16 h. After this time, the reaction mixture was concentrated under reduced pressure to remove volatile organics and then 1N HCl solution was added to adjust the pH of the solution to about 3. The solid was filtered and washed with water to give 6-methyl-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyridine-4-carboxylic acid as an off-white solid (1 g, 71%). ES / MS (m / z): 216.9 (M+H).

[0447] Preparation 5 Methyl 2-chloro-5-cyclobutyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0448] [ka]

[0449] Process 1 Methyl 2-chloro-5-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0450] [ka] Phosphorus oxychloride (3 g, 0.02 mol) followed by diisopropylethylamine (2 g, 0.02 mol) was added dropwise to a solution of methyl 2,5-dioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (2 g, 9 mmol) in toluene (20 mL). The reaction mixture was heated at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel chromatography eluting with a gradient of 0-40% EtOAc in hexanes to give methyl 2-chloro-5-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (734 mg, 30%) as a yellow solid. ES / MS (m / z): 225.9 (M+H).

[0451] Process 2 Methyl (Z)-2-chloro-5-(2-tosylhydrazinylidene)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0452] [ka] 4-Methylbenzenesulfonic acid hydrazide (825 mg, 4.34 mmol) was added to a solution of methyl 2-chloro-5-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (1.00 g, 4.34 mmol) in MeOH (10.0 mL) at 25° C. The solution was stirred under N2 at ambient temperature for 6 h. The resulting solid was filtered, washed with cold ether, and dried to give methyl (Z)-2-chloro-5-(2-tosylhydrazineylidene)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (1.75 g, 99+%) as a white solid, which was used without further purification. ES / MS (m / z): 393.9 (M+H).

[0453] Process 3 Methyl 2-chloro-5-cyclobutyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0454] [ka] Cyclobutylboronic acid (673 mg, 6.67 mmol) was added to a solution of methyl (Z)-2-chloro-5-(2-tosylhydrazineylidene)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (1.75 g, 4.44 mmol) and cesium carbonate (2.19 g, 6.67 mmol) in 1,4-dioxane (15.0 mL) under N2. The mixture was heated at 110 °C for 16 h. The mixture was cooled to ambient temperature. Water (20 mL) was added to the mixture and the mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with saturated aqueous NaCl and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography eluting with a gradient of 0-20% EtOAc in hexanes to give methyl 2-chloro-5-cyclobutyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (451 mg, 37%) as a yellow oil. ES / MS (m / z): 266.1 (M+H).

[0455] Preparation 6 Methyl (S)-5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0456] [ka]

[0457] Process 1 (E)-2-(2-cyano-3-methoxy-3-oxoprop-1-en-1-yl)-3-oxocyclopent-1-en-1-oleate dimethylammonium

[0458] [ka] DMF-DMA (58.3 g, 489.3 mmol) was added to a solution of cyclopentane-1,3-dione (40 g, 407.7 mmol) in toluene (120 mL) at 0-10 °C. The reaction mixture was stirred at 30-40 °C for 16 h. Toluene (160 mL) and methyl 2-cyanoacetate (48.5 g, 489.3 mmol) were added at 0-10 °C. The reaction mixture was stirred at 25-35 °C for 16 h. After cooling, the reaction mixture was filtered and washed with toluene (160 mL). The cake was dried under reduced pressure at 45-55 °C to give (E)-2-(2-cyano-3-methoxy-3-oxoprop-1-en-1-yl)-3-oxocyclopent-1-en-1-oleate dimethylammonium as a tan solid (86.0 g, 78.2%). ES / MS m / z: 252.11(C 12 H 16 N2O4);ES / MS m / z: 208.13 (M+H) as the free base. 1 H NMR (DMSO-d6): δppm 2.10-2.30 (m, 4H), 2.55 (s, 6H), 3.65 (s, 3H), 7.62 (s, 1H), 7.97-8.38 (brs, 1H).

[0459] Process 2 Methyl 2,5-dioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0460] [ka] Acetic acid (228.5 g, 3.81 mol) was added to a solution of (E)-2-(2-cyano-3-methoxy-3-oxoprop-1-en-1-yl)-3-oxocyclopent-1-en-1-oleate dimethylammonium (80 g, 317.1 mmol) in toluene (2.4 L) at 0-10 °C. The reaction mixture was stirred at 85-95 °C for 16 h. After cooling, the reaction mixture was filtered and washed with toluene (160 mL). The cake was dried under reduced pressure at 45-55 °C to give methyl 2,5-dioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate as a brown solid (39.1 g, 49.5%). ES / MS m / z: 208.06 (M+H). 1 H NMR (DMSO-d6): ppm 2.45-2.65 (m, 2H), 2.90-3.10 (m, 2H), 3.75 (s, 3H), 8.06 (s, 1H), 12.90 (brs, 1H).

[0461] Process 3 Methyl 5-methylene-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0462] [ka] Methyl 2,5-dioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (38.4 g, 185.2 mmol) was added to a solution of methyltriphenylphosphonium bromide (330.8 g, 926.0 mmol) and t-BuOK (99.7 g, 889 mmol) in toluene (1.15 L) at 20-30° C. The reaction mixture was stirred at 35-45° C. for 16 h. After cooling, the reaction mixture was filtered through diatomaceous earth (77 g, twice) and filtered. The filter cake was slurried in DCM (576 mL) and filtered. The filter cake was then slurried again in water / 10% citric acid (pH: 6.2-6.8) and filtered. The filter cake was slurried again in DCM (576 mL) and filtered. The filtrate was then concentrated under reduced pressure to give methyl 5-methylene-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate as a brown solid (24.0 g, 59.3%). ES / MS m / z: 206.08 (M+H). 1 H NMR (DMSO-d6): ppm2.66-2.74(m,2H),2.82-2.88(m,2H),3.74(s,3H),4.70-4.85(m,1H),5.10-5.25(m,1H),8.20(s,1H),12.49(brs,1H).

[0463] Process 4 Methyl (S)-5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0464] [ka] Bis(norbornadiene)rhodium(I) tetrafluoroborate (Rh(NBD)2BF4) (109 mg, 0.29 mmol) and 1-(dicyclohexylphosphino)-1'-[(S)-[(1R)-2-[(1R)-1-(dimethylamino)ethyl]ferrocenyl]phenylphosphino]ferrocene (CAS: 952586-19-5, 218 mg, 0.29 mmol) were added to MeOH (6.0 mL) under N2 and stirred at 20-30 °C for 1 h. MeOH (14.0 mL) and methyl 5-methylene-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (2.0 g, 9.62 mmol) were added, followed by washing with hydrogen three times.

[0465] The reaction mixture was stirred at 25-35 °C under H2 at 1.4-1.6 MPa for 16 h. The reaction mixture was concentrated and purified by column chromatography (DCM:MeOH, 200:1-100:1) to give methyl (S)-5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate as a pale yellow solid (1.3 g, 65.3%, 98.0% HPLC purity, 90.3% chiral purity). ES / MS m / z: 208.1 (M+H). 1 H NMR (DMSO-d6):ppm1.15(d,J=6.78Hz,3H),1.49-1.61(m,1H),2.19-2.32(m,1H) ,2.70-2.80(m,2H),2.97-3.05(m,1H),3.71(s,3H)7.95(s,1H)12.23(brs,1H).

[0466] Preparation 7 Methyl (S)-5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0467] [ka]

[0468] Process 1 (E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one

[0469] [ka] Tributylphosphine (4.93 kg) was added dropwise to a solution of cuprous iodide (2.78 kg, 1.20 equiv.) in THF (20.0 L, 15 V) at 25° C. The mixture was stirred at 25° C. for 1 h and then cooled to −70° C. ℃ The mixture was cooled to RT. Methyllithium (2.5M, 5.85L) was added dropwise to the cold mixture and stirred at -70°C for 1 h. Boron trifluoride diethyl etherate (1.90kg) was added dropwise to the mixture and stirred for 1 h while maintaining the reaction temperature at -70°C. Cyclopent-2-en-1-one (1.00kg) was then added dropwise into the reaction mixture at -70°C and stirred for 2 h before DMF-DMA (2.90kg) was added dropwise while maintaining the temperature at -70°C. After stirring at -70°C for 1 h, the reaction mixture was warmed to 25°C and maintained for 6 h. The reaction was quenched by slow addition of 15% sodium diphosphate (3V) over 30 min. The solids were filtered off and washed with EtOAc (1V). The mother liquor was concentrated under reduced pressure, extracted with EtOAc (2V x 3) and concentrated under reduced pressure to give a crude mixture containing the desired product. The crude mixture was poured into acetonitrile (5V) and extracted with petroleum ether (5V x 3). The phases were separated and concentrated separately. The acetonitrile phase gave 600 g (32%) of a residue containing the desired product, which was used in the next step without further purification.

[0470] Process 2 (S,E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one (2S,3S)-2,3-bis(benzoyloxy)succinate

[0471] [ka] A solution of (E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one (1.60 kg, crude from step 1) in butanone (5V) was treated at 25° C. with a solution of (2S,3S)-2,3-dibenzoyloxybutanedioic acid (0.6 equiv.) in butanone (15V). The mixture was stirred at 60° C. for 2 hours. The reaction was then cooled to ambient temperature and stirred for 12 hours. The mixture was filtered and washed with butanone to give the crude (S,E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one (2S,3S)-2,3-bis(benzoyloxy)succinate salt with 85% chiral purity. The salt was treated with a mixture of acetonitrile / water (5V / 1V) and heated at 65° C. for 2 hours, then cooled at ambient temperature for 12 hours. The solid was filtered, the cake washed with acetonitrile (1V) and dried under vacuum to give (S,E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one (2S,3S)-2,3-bis(benzoyloxy)succinate (6.4 kg, 23%, 99% optical purity) as a white solid.

[0472] Process 3 (S,E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one

[0473] [ka] A solution of (S,E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one (2S,3S)-2,3-bis(benzoyloxy)succinate (4.05 kg) in water (20.2 L, 5 V) and DCM (8.10 L, 2 V) was treated with sodium bicarbonate (1.12 kg, 2.00 equiv.) and the mixture was stirred at 25° C. for 30 min. The organics were extracted with DCM (2 V×3), washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (S,E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one (1.1 kg, 88%) as a pale yellow oil.

[0474] Process 4 Methyl (S)-5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0475] [ka] A solution of (S,E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one (550 g) in MeOH (3.30 L, 6 V) was treated with methyl 2-cyanoacetate (582 g) and the mixture was stirred at 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was then treated with EtOAc (2 V) and the slurry was stirred at ambient temperature for 30 min. The solid was filtered and the cake was washed with EtOAc (0.5 V) and dried under vacuum to give methyl (S)-5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (800 g, 55%) as a white solid.

[0476] Example 1 N-(5-fluoropyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide

[0477] [ka] [1,2,4]Triazolo[4,3-a]quinoline-4-carboxylic acid (100 mg, 0.447 mmol) and 5-fluoropyrimidin-2-amine (80 mg, 0.672 mmol) were dissolved in DCM (5 mL). To this mixture was added pyridine (180 mg, 2.26 mmol), followed by phosphoryl chloride (350 mg, 2.24 mmol). The reaction mixture was stirred at ambient temperature for 18 h. After this time, the reaction mixture was concentrated under reduced pressure and the residue was triturated with DMF at 20° C. for 5 min. The solid was filtered and washed with DMF to give N-(5-fluoropyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide as a white solid (77 mg, 48.0%). ES / MS (m / z): 309.1 (M+H).

[0478] Example 2 N-(5-fluoropyrimidin-2-yl)imidazo[1,2-a]quinoline-4-carboxamide

[0479] [ka] Imidazo[1,2-a]quinoline-4-carboxylic acid was reacted with 5-fluoropyrimidin-2-amine using a procedure similar to that of Example 1 to give N-(5-fluoropyrimidin-2-yl)imidazo[1,2-a]quinoline-4-carboxamide as a white solid (166 mg, 95%). ES / MS (m / z): 308.3 (M+H).

[0480] Example 3 (R)-6-Methyl-N-(pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide or (S)-6-Methyl-N-(pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide (Enantiomer 1) and Example 4 (R)-6-Methyl-N-(pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide or (S)-6-Methyl-N-(pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide (enantiomer 2)

[0481] [ka] 6-Methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid (Preparation 2) (300 mg, 0.80 mmol) and pyridin-2-amine (120 mg, 1.6 mmol) were dissolved in dichloromethane (5 mL). To this mixture was added pyridine (220 mg, 2.77 mmol), followed by phosphoryl chloride (200 mg, 1.3 mmol). The reaction mixture was stirred at ambient temperature for 18 h. After this time, the reaction mixture was poured into saturated aqueous NaCl solution (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (4 g, 0-80% ethyl acetate in petroleum ether) to give the crude product. The crude product is then subjected to chiral separation on a preparative column under the following conditions to obtain the enantiomers.

[0482] Separation condition A: Column: DAICEL CHIRALPAK AD 250×30mm ID, 10μm Mobile phase A: CO2 Mobile phase B: Ethanol (0.1% NH4OH) Gradient: 40% B. Flow rate: 80mL / min

[0483] Analysis was performed by supercritical fluid chromatography (SFC) under the following conditions to obtain retention times (RT): Column: Chiralpak OJ-3 50×4.6mm ID, 3μm. Mobile phase A: CO2 Mobile phase B: Ethanol (0.05% DEA) Gradient: a) 0–2.5 min: 5% B–95% A increasing to 40% B–60% A; b) 2.5 min to 3.0 min: hold at 40% B to 60% A; c) 3.0 min to 4.0 min: 40%B-60%A, increasing to 5%B-95%A. Flow rate: 4ml / min Column temperature: 35℃ Automatic Back Pressure Regulator (ABPR) Pressure: 1500psi Enantiomer 1 retention time: 1.458 min Retention time of enantiomer 2: 1.566 min

[0484] Enantiomer 1 and Enantiomer 2 are obtained at the above retention times (RT) and are each dried to give a white solid. Enantiomer 1: (16.0 mg, 6.7%). ES / MS (m / z): 294.1 (M+H). Enantiomer 2: (17.6 mg, 7.4%). ES / MS (m / z): 294.1 (M+H).

[0485] The compounds in Table 1A were prepared under similar conditions to those in Examples 3 and 4 using appropriate starting materials. The starting materials may be commercially available or may be synthesized by reference to the examples and general knowledge provided herein. The reaction time may be adjusted, for example, by monitoring by chromatography or similar means to allow the reaction to go to completion. Furthermore, the separation and analysis conditions used are the same as those described for Examples 3 and 4.

[0486] [Table 8]

[0487] The compounds in Table 1B were prepared under similar conditions to those in Examples 3 and 4 using appropriate starting materials. The starting materials may be commercially available or may be synthesized by reference to the examples and general knowledge provided herein. The reaction time can be adjusted, for example, by monitoring by chromatography or similar means to allow the reaction to go to completion. The crude product is then chirally separated on a preparative column under separation condition A. Separation condition A: Column: DAICEL CHIRALPAK AD 250×30mm ID, 10μm Mobile phase A: CO2 Mobile phase B: Ethanol (0.1% NH4OH) Gradient: 40% B. Flow rate: 80mL / min

[0488] Retention times were analyzed using an analytical column under the following conditions and are shown in Table 1B. Column: (S,S)-Welk-0-1.8 50×4.6 mm ID, 1.8 μm Mobile phase A: CO2 Mobile phase B: 40% ethanol (0.05% DEA) Flow rate: 2.8mL / min Column temperature: 35℃ ABPR Pressure: 1500psi

[0489] [Table 9]

[0490] The compounds in Table 1C were prepared under similar conditions to those in Examples 3 and 4 using appropriate starting materials. The starting materials may be commercially available or may be synthesized by reference to the examples and general knowledge provided herein. The reaction time may be adjusted, for example, by monitoring by chromatography or similar means to allow the reaction to go to completion. The crude products are then chirally separated on a preparative column to obtain the enantiomers under conditions similar to those of separation condition A (with necessary variations in the mobile phase (e.g., MeOH, EtOH, isopropanol, ACN or a 1:1 mixture thereof) and gradient (e.g., 35% B, 40% B, 55% B, or 60% B) used to optimize performance). The analytical conditions used are as follows, and the retention times are shown in Table 1C.

[0491] Column: AD-3 50×4.6mm ID, 3μm Mobile phase A: CO2 Mobile phase B: Isopropanol (0.05% DEA) Gradient: a) 0–2.5 min: 5% B–95% A increasing to 40% B–60% A; b) 2.5 min to 3.0 min: hold at 40% B to 60% A; c) 3.0 min to 4.0 min: 40%B-60%A, increasing to 5%B-95%A. Flow rate: 4ml / min Column temperature: 35℃ Automatic Back Pressure Regulator (ABPR) Pressure: 1500psi

[0492] [Table 10]

[0493] For clarity, Enantiomer 1 above refers to the enantiomer which elutes first from the stationary phase of the preparatory column, and Enantiomer 2 above refers to the enantiomer which elutes second from the stationary phase of the preparatory column.

[0494] The compounds described in Examples 1 to 14 are referred to as Compounds 1 to 14, respectively.

[0495] Compound 15 of Example 15 in Table 2 below can be synthesized according to Schemes 1 and 3 above with reference to the conditions described for Examples 3 and 4, and isolated using conditions similar to those described for Examples 3-14.

[0496] [Table 11]

[0497] Compounds 16-57 in Table 2A below were synthesized according to Schemes 1-3 above with reference to the conditions described for Examples 3 and 4, and separated on a preparative column under similar conditions to Separation Condition A (with necessary modifications of the type of column, mobile phase and gradient specified in Table 2A).

[0498] [Table 12-1]

[0499] [Table 12-2]

[0500] [Table 12-3]

[0501] [Table 12-4]

[0502] [Table 12-5]

[0503] [Table 12-6]

[0504] Compounds 58-68 in Table 3 below were synthesized according to Schemes 1-3 above with reference to the conditions described for Examples 3 and 4, and separated on a preparative column under similar conditions to Separation Condition A (with necessary modifications of the column, mobile phase and gradient specified in Table 3).

[0505] [Table 13-1]

[0506] [Table 13-2]

[0507] Example 69 (S)-N-(5-fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide

[0508] [ka]

[0509] Process 1 Methyl (5S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0510] [ka] Phosphoryl chloride (POCl3) (740 g) was added to a solution of methyl (5S)-5-methyl-2-oxo-1,5,6,7-tetrahydrocyclopenta[b]pyridine-3-carboxylate (100 g) and DMF (705 mg). The mixture was stirred at 100° C. for 12 h. The reaction mixture was concentrated under reduced pressure to remove POCl3. The residue was diluted with water (4.00 L, 5 V) and extracted with EtOAc (1.60 L×3). The combined organic layers were washed with saturated aqueous NaCl (800 mL, 1 V), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (5S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (985 g) as a brown solid.

[0511] Process 2 (5S)-2-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid

[0512] [ka] Sodium hydroxide NaOH (232 g) was added to a solution of methyl (5S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (328 g) in HO (984 mL) and THF (984 mL). Methanol (984 mL, 3 V) was added at 25-30 °C. The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The pH of the mixture was adjusted to about 2-3 at 5-10 °C using 3 M HCl (10 V). The solid was slowly separated from the mixture and filtered to give (5S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (550 g, 67.5%) as a white solid.

[0513] Process 3 (5S)-2-Hydrazino-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid

[0514] [ka] N2H 4· HO (3.32 kg) was added to a solution of (5S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (275 g) in dioxane (1.65 L, 6 V). The mixture was stirred at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give N 4· The H2O was removed. The residue was diluted with MeCN (2.20 L, 4 V) and then filtered to remove insoluble material. The combined organic layers were concentrated under reduced pressure to give (5S)-2-hydrazino-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (1.30 kg, crude) as a brown solid.

[0515] Process 4 (S)-6-Methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid

[0516] [ka] A solution of (5S)-2-hydrazino-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (1.30 kg) in formic acid (5.20 L, 4 V) was stirred at 100° C. for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with ice water (3.25 L, 2.5 V) and stirred at 0° C. for 1 h. The mixture was filtered, washed with water (3.90 L, 3 V), and filtered to give (S)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid (360 g, 64%) as a brown solid.

[0517] Process 5 (S)-N-(5-fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide

[0518] [ka] A mixture of pyridine (1.11 kg) and 5-fluoropyrimidin-2-amine (296 g) was added to a solution of (S)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid (412 g) in DCM (2.47 L, 6 V). POCl3 (402 g) was added dropwise to the mixture at 25° C. The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was quenched by adding H2O (2.00 L, 5 V) at 25° C., then extracted with DCM (2.46 L, 2 V×3). The combined organic layers were washed with saturated aqueous NaCl (410 mL, 1 V), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography eluting with EtOAc containing DCM (1 / 0 to 1 / 1) to give (S)-N-(5-fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide (365 g, yield 61.7%, purity 99.6) as an off-white solid.

[0519] hAHR nuclear translocation assay The purpose of this assay is to measure the ability of compounds to bind, activate, and induce translocation of AhR to the nucleus of cells for transcription. Stable cell lines were established using the Jump-In™ T-REx™ HEK 293 Retargeting Kit (Life Technologies). Human AhR cDNA was cloned into the pJTI R4 CMV-TO EGFP vector. EGFP was cloned into the C-terminus of AHR to form AhR-EGFP chimeras. The pJTI R4 CMV-TO AhR-EGFP vector was transfected into Jump-In™ T-REx™ HEK293 cells using FuGENE® HD. Transfected cells were selected using 2.5 mg / ml G418 for 10-14 days, then expanded, harvested, and cultured at 2 × 10 7Cells were suspended in freezing medium (FBS with 8% DMSO) at 1000 cells / ml and aliquots were stored in liquid nitrogen. One day before the assay day, cells were thawed, resuspended in DMEM with 5% FBS in the presence of 1 μg / ml doxycycline, and seeded at 12,000-15,000 cells / well on ploy-L-lysine coated CELLCARRIER-384 ULTRA Microplates (Perkin Elmer) and incubated overnight at 37°C and 5% CO2. On the assay day, compounds were serially diluted (1:2) in 384-well nunc plates with DMSO using acoustic dispensing (ECHO®). Dose response was a 20-point curve. Compounds were resuspended in 40 μl DMEM+0.1% BSA. Culture medium was moistened and 25 μl DMEM+0.1% BSA was added, then 25 μL of compound in DMEM+0.1% BSA was added to the cell plate. Cells were incubated with compounds for 45 min at 37°C and 5% CO2. The final DMSO concentration was 0.2%. After 45 min incubation, the medium was quenched. Cells were fixed with 40 μl cold MeOH (-20°C) for 20 min. MeOH was quenched and 50 μL DPBS containing 1 μg / mL Hochst was added to the cell plate. EGFP intensity was quantified by using an Opera PHENIX® or OPERETTA® high content imaging system (Perkin Elmer) with a 20 x Water Objective and 5 fields per well. To determine AhR agonist potency, the ratio of nuclear to cytoplasmic EGFP fluorescence intensity was analyzed using a 4-parameter nonlinear logistic equation.

[0520] Table 3 shows the hAHR nuclear translocation assay data for certain compounds of the above examples. 50 ≦1nM. "B" means 1nM <EC 50 <=10nM. "C" means 10nM <EC 50 <=50nM; "D" is EC 50 >50 nM. "-" indicates untested activity.

[0521] [Table 14]

[0522] Certain compounds of the present disclosure are novel agonists of the aryl hydrocarbon receptor (AHR), as demonstrated by the hAHR nuclear transfer assay described above.Additional compounds of formula I-1, I-2, I-3, II-1, II-2, II-3, II-1A, III-1, III-2, III-3, III-1A, IV-1, IV-2, IV-3, IV-1A, V-1, V-2, V-3, or V-4 can be shown to be AHR agonists using the same or similar assay techniques described above.These compounds, and examples provided herein, are believed to be useful, inter alia, for the treatment of immune-mediated diseases (IMD), particularly psoriasis and atopic dermatitis.

Claims

1. A compound of the formula: 【Chemistry 1】 During the ceremony, Ring A is a 5- or 6-membered carbocyclic ring; Ring B is phenyl or a 5- or 6-membered heteroaryl having 1 or 3 heteroatoms, each heteroatom of said heteroaryl being independently selected from N, S, and O; R is H or C １～３ is alkyl, X is H, halo, C optionally substituted with one or more halo １～３ Alkyl, or C １～３ is alkoxyl, Y is H, C １～４ Alkyl, or C ３～４ cycloalkyl, wherein said C １～４ The alkyl is a primary or secondary alkyl; The compound, wherein Z is CH or N, A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein R is H, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof. 【Request 3】 【Chemistry 2】 The compound according to claim 1, selected from A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

4. formula: 【Chemistry 3】 (In the formula, X is H or halo; Y is H or C １～３ is alkyl, and W is CH or N. A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof. 【Request 5】 【Chemical 4】 but, 【Chemistry 5】 5. The compound according to any one of claims 1 to 4, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

6. 5. The compound according to any one of claims 1 to 4, or each of its pharma- ceutically acceptable salts, wherein Ring A is phenyl.

7. Ring A is 【Chemistry 6】 5. The compound according to any one of claims 1 to 4, wherein:

8. formula: 【Chemistry 7】 (In the formula, X is H or halo; Y is H or C １～３ is alkyl, and W is CH or N. A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

9. 9. The compound according to any one of claims 1 to 8, wherein Z is N, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

10. 9. The compound according to any one of claims 1 to 8, wherein Z is CH, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

11. 9. The compound according to claim 4 or 8, wherein W is N, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

12. 12. The compound according to any one of claims 1, 2, and 4 to 11, wherein X is F, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

13. 13. The compound according to any one of claims 1 to 4 and 6 to 12, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein Y is methyl.

14. 2. A compound according to claim 1, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, selected from the table below. 【Table 1-1】 【Table 1-2】

15. 2. A compound according to claim 1 selected from the table below, or a pharma- ceutically acceptable salt thereof. 【Table 2-1】 【Table 2-2】 【Table 2-3】

16. formula: 【Chemistry 8】 The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt thereof.

17. formula: 【Chemistry 9】 The compound of claim 1 having the formula: A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

18. formula: 【Chemistry 10】 The compound of claim 1 having the formula: or their respective pharma- ceutically acceptable salts.

19. formula: 【Chemistry 11】 The compound of claim 1 having the formula: A stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

20. A compound, a stereoisomer or mixture of stereoisomers thereof, selected from Tables 2, 2A, and 3, or a pharma- ceutically acceptable salt thereof.

21. 21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents, or excipients.

22. 22. A method of treating an immune-mediated disease in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound according to any one of claims 1 to 20, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21.

23. 23. 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 of such treatment, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 20, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21.

24. A compound according to any one of claims 1 to 20, a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt of each thereof, for use in therapy.

25. 21. A compound according to any one of claims 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn's disease, graft versus host disease, rheumatoid arthritis and multiple sclerosis.

26. 21. A compound according to any one of claims 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of psoriasis.

27. 21. A compound according to any one of claims 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of atopic dermatitis.

28. 21. A compound according to any one of claims 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of ulcerative colitis.

29. 21. A compound according to any one of claims 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of Crohn's disease.

30. 21. A compound according to any one of claims 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of graft-versus-host disease.

31. 21. A compound according to any one of claims 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis.

32. 21. A compound according to any one of claims 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of multiple sclerosis.

33. 21. A compound according to any one of claims 1 to 20, a stereoisomer or a mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof, for use in the treatment of systemic lupus erythematosus (SLE).

34. A compound of the formula: 【Chemistry 12】 or a salt thereof, wherein R ０ is C １～３ The compound or a salt thereof,

35. A compound of the formula: 【Chemistry 13】 or a salt thereof, wherein R ０ is C １～３ The compound or a salt thereof,

36. A compound of the formula: 【Chemistry 14】 36. A process for preparing a compound of claim 35 comprising contacting with molecular hydrogen under conditions sufficient to provide a compound of claim 35.

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