AHR agonists

Abstract

The present disclosure relates to certain AHR agonist compounds, methods of their preparation and pharmaceutical compositions comprising these compounds and methods of using these compounds in the treatment of immune-mediated diseases, such as psoriasis and atopic dermatitis.

Description

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

[0002] The present disclosure relates to the field of treating certain immune-mediated diseases (IMDs), such as psoriasis and atopic dermatitis, by activating the aryl hydrocarbon receptor (AHR).

[0003] IMDs include a wide range of chronic and debilitating inflammatory conditions that affect approximately 4% of the world's population. Given the limited efficacy of currently available treatments and the scarcity of small molecule treatment options, the need for alternative, potent, selective, and safer drugs for treating IMDs is significantly unmet.

[0004] The AHR is a transcription factor that regulates many aspects of immune function, most notably the suppression of the adaptive immune response (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)). Typical AHR agonists include halogenated dibenzo-p-dioxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), tryptophan metabolites such as L-kynurenine, bilirubin, and PGE2. Results from studies of AHR agonists, particularly TCDD, suggest that immunosuppression is the result of the expression of AHR-induced 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 effectively prevent several murine IMD models, including 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. Ophthalmol. 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 transplant tolerance models (Pauly et 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 such as estrogens. Although in some cases (e.g., in the case of benzo[a]pyrene) this metabolism results in the formation of reactive species, CYP induction is also considered crucial for the detoxification and metabolic clearance of PAHs, thereby reducing the likelihood of bioactivation and DNA adduct formation. Some marketed drugs have been found to activate the AHR (and thus upregulate CYP1A1, CYP1A2 and CYP1B1) after FDA approval, however their long-term use is not associated with dioxin-like toxicity (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)). Thus, CYP induction is no longer considered an obstacle to treatment with AHR agonists (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)).

[0006] WO 2008 / 014307 discloses certain bicyclic heteroaryl amides as inhibitors of geranylgeranyl 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( (tapinarof)) 1% cream, an aryl hydrocarbon receptor agonist, has been approved by the US Food and Drug Administration (FDA) for the topical treatment of plaque psoriasis in adults. Nevertheless, there remains a need for alternative new, oral, selective, and / or potent AHR agonists for the treatment of IMD. The present disclosure provides certain compounds that act as AHR agonists.

[0008] Accordingly, the present disclosure provides various embodiments as described, for example, below. When a subsequent embodiment refers to a foregoing "Embodiment X", such reference also includes a reference to "Embodiment XA", "Embodiment XB", etc., unless the subsequent embodiment cannot be reasonably construed as a dependent embodiment (e.g., outside the scope of the referenced embodiment or having an inappropriate antecedent basis). For example, when "Embodiment 54" refers to "Embodiment 53" below, such reference also includes a reference to "Embodiment 53A", "Embodiment 53B", "Embodiment 53C", "Embodiment 53D", and "Embodiment 53E", etc.

[0009] Embodiment 1A. A compound of the following formula, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof:

[0010]

[0011] Wherein:

[0012] Ring A is a 5- or 6-membered carbocyclic ring;

[0013] Ring B is phenyl, or a 5- or 6-membered heteroaryl having 1 or 3 heteroatoms, wherein each heteroatom of the heteroaryl is independently selected from N, S, and O;

[0014] R is H or C 1-3 alkyl;

[0015] X is H, halogen, C 1-3 alkyl optionally substituted with one or more halogens, or C 1-3 alkoxy;

[0016] Y is H, C 1-4 alkyl or C 3-4 cycloalkyl, wherein C 1-4 alkyl is a primary or secondary alkyl; and

[0017] Z is CH or N.

[0018] Embodiment 1. A compound of the following formula, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof:

[0019]

[0020] Wherein:

[0021] Ring A is a 5- or 6-membered carbocyclic ring;

[0022] Ring B is phenyl, or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, wherein each heteroatom of the heteroaryl is independently selected from N, S, and O;

[0023] X is H, halogen, C 1-3 alkyl optionally substituted with one or more halogens, or C 1-3 alkoxy, wherein the alkoxy and are meta or para to each other;

[0024] Y is H, C 1-4 alkyl or C 3-4 cycloalkyl, wherein C 1-4 alkyl is a primary or secondary alkyl; and

[0025] Z is CH or N.

[0026] Embodiment 2. The compound according to Embodiment 1, its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein is

[0027] wherein Q is O or S, and W is CH or N.

[0028] Embodiment 3. The compound according to Embodiment 1, its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein is selected from

[0029] Embodiment 4. The compound according to Embodiment 1, its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, which has the following formula:

[0030]

[0031] wherein:

[0032] X is H or halogen;

[0033] Y is H or C 1-3 alkyl; and

[0034] W is CH or N.

[0035] Embodiment 5. The compound according to any one of Embodiments 1-4, its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein

[0036]

[0037] is selected from:

[0038]

[0039] Embodiment 6. The compound according to any one of Embodiments 1-4, or its respective pharmaceutically acceptable salts, wherein ring A is phenyl.

[0040] Embodiment 7. The compound according to any one of Embodiments 1-4, its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein ring A is

[0041] Embodiment 8. The compound according to Embodiment 1, its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, which has the following formula:

[0042]

[0043] Wherein:

[0044] X is H or halogen;

[0045] Y is H or C 1-3 alkyl; and

[0046] W is CH or N.

[0047] Embodiment 9. The compound, its stereoisomers or a mixture of stereoisomers, or their respective pharmaceutically acceptable salts, as described in any of the foregoing embodiments, wherein Z is N.

[0048] Embodiment 10. The compound, its stereoisomers or a mixture of stereoisomers, or their respective pharmaceutically acceptable salts, as described in any one of Embodiments 1-8, wherein Z is CH.

[0049] Embodiment 11. The compound, its stereoisomers or a mixture of stereoisomers, or their respective pharmaceutically acceptable salts, as described in any one of Embodiments 1-10, wherein W is N.

[0050] Embodiment 12. The compound, its stereoisomers or a mixture of stereoisomers, or their respective pharmaceutically acceptable salts, as described in any one of Embodiments 1-11, wherein X is F.

[0051] Embodiment 13. The compound, its stereoisomers or a mixture of stereoisomers, or their respective pharmaceutically acceptable salts, as described in any one of Embodiments 1-4 and 6-12, wherein Y is methyl.

[0052] Embodiment 14. The compound, its stereoisomers or a mixture of stereoisomers, or their respective pharmaceutically acceptable salts, which are selected from the following table:

[0053]

[0054]

[0055] Embodiment 14A. The compound, its stereoisomers or a mixture of stereoisomers, or their respective pharmaceutically acceptable salts, which are selected from the following table:

[0056]

[0057]

[0058] Embodiment 15. The compound or its pharmaceutically acceptable salt, which is selected from the following table:

[0059]

[0060]

[0061]

[0062] Embodiment 15A. A compound or a pharmaceutically acceptable salt thereof, selected from the following table:

[0063]

[0064]

[0065]

[0066] Embodiment 16. A compound or a pharmaceutically acceptable salt thereof.

[0067] Embodiment 17. A compound its stereoisomers or a mixture of stereoisomers, or their respective pharmaceutically acceptable salts.

[0068] Embodiment 18. A compound or their respective pharmaceutically acceptable salts.

[0069] Embodiment 19. A compound its stereoisomers or a mixture of stereoisomers, or their respective pharmaceutically acceptable salts.

[0070] Embodiment 20. A compound, its stereoisomers or a mixture of stereoisomers, or their respective pharmaceutically acceptable salts, selected from Table 2.

[0071] Embodiment 21. A pharmaceutical composition comprising a compound, its stereoisomers or a mixture of stereoisomers, or their respective pharmaceutically acceptable salts according to any one of Embodiments 1 to 20, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0072] Embodiment 22. A method for treating an immune-mediated disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound, its stereoisomers or a mixture of stereoisomers, or their respective pharmaceutically acceptable salts according to any one of Embodiments 1 to 20, or a pharmaceutical composition according to Embodiment 21.

[0073] Embodiment 23. A method 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 in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of Embodiments 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 21.

[0074] Embodiment 24. A compound according to any one of Embodiments 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for use in treatment.

[0075] Embodiment 25. A compound according to any one of Embodiments 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically 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.

[0076] Embodiment 26. A compound according to any one of Embodiments 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis.

[0077] Embodiment 27. A compound according to any one of Embodiments 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of atopic dermatitis.

[0078] Embodiment 28. A compound according to any one of Embodiments 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of ulcerative colitis.

[0079] Embodiment 29. A compound according to any one of Embodiments 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of Crohn's disease.

[0080] Embodiment 30. A compound according to any one of Embodiments 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of graft-versus-host disease.

[0081] Embodiment 31. A compound according to any one of Embodiments 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis.

[0082] Embodiment 32. A compound according to any one of Embodiments 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of multiple sclerosis.

[0083] Embodiment 33. A compound according to any one of Embodiments 1 to 20, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of systemic lupus erythematosus (SLE).

[0084] Embodiment 34. A compound of the following formula:

[0085]

[0086] or a salt thereof, wherein R 0 is C 1-3 alkyl.

[0087] Embodiment 35. A compound of the following formula:

[0088]

[0089] or a salt thereof, wherein R 0 is C 1-3 alkyl.

[0090] Embodiment 36. A method for preparing the compound of Embodiment 35, which comprises contacting a compound of the following formula:

[0091]

[0092] with molecular hydrogen under conditions sufficient to obtain the compound of Embodiment 35.

[0093] Embodiment 37. The method according to Embodiment 36, wherein the conditions include the presence of a chiral phosphine ligand.

[0094] Embodiment 37A. The method according to Embodiment 37, wherein the chiral phosphine ligand is a P-chiral phosphine ligand.

[0095] Embodiment 37B. The method according to Embodiment 37, wherein the chiral phosphine ligand is a P-chiral (stereogenic) C1-symmetric diphosphine ligand.

[0096] Embodiment 38. The method according to Embodiment 37, wherein the chiral phosphine ligand is a ChenPhos ligand.

[0097] Embodiment 38A. The method according to Embodiment 38, wherein the ChenPhos ligand comprises two cyclohexyl groups bonded to P.

[0098] Embodiment 39. The method according to embodiment 38, wherein the ChenPhos ligand is 1-(dicyclohexylphosphino)-1′-[(S)-[(1R)-2-[(1R)-1-(dimethylamino)ethyl]ferrocenyl]phenylphosphino]-ferrocene.

[0099] Embodiment 40. The method according to embodiment 37, wherein the conditions include a stoichiometric ratio of the chiral phosphine ligand to the compound of the following formula of about 0.01:1 to about 0.05:1:

[0100]

[0101] Embodiment 41. The method according to any one of embodiments 37 to 40, wherein the conditions include the presence of a bis(norbornadiene)rhodium(I) salt catalyst.

[0102] Embodiment 42. The method according to embodiment 41, wherein the conditions include a stoichiometric ratio of the catalyst to the compound of the following formula of about 0.01:1 to about 0.05:1:

[0103]

[0104] Embodiment 43. The method according to embodiment 41, wherein the conditions include a stoichiometric ratio of the chiral phosphine ligand to the catalyst of about 1.2:1 to about 1:1.

[0105] Embodiment 44. The method according to any one of embodiments 36 - 43, wherein the conditions include contacting in a substantially oxygen-free atmosphere.

[0106] Embodiment 45. The method according to any one of embodiments 36 - 44, wherein the conditions include contacting in a protonic medium.

[0107] Embodiment 46. The method according to any one of embodiments 36 - 45, wherein the conditions include contacting at a temperature of about 10°C to about 50°C.

[0108] Embodiment 47. The method according to any one of embodiments 36 - 46, wherein the conditions include molecular hydrogen at a pressure of about 0.5 MPa to about 2.5 MPa.

[0109] Embodiment 47A. The method according to any one of embodiments 36 - 46, wherein the conditions include molecular hydrogen at a pressure of about 1 MPa to about 2 MPa.

[0110] Embodiment 48. The method according to any one of embodiments 36 - 47, further comprising preparing a compound of the following formula:

[0111]

[0112] wherein said preparation comprises contacting a compound of the formula:

[0113]

[0114] with a Wittig reagent.

[0115] Embodiment 49. The method according to any one of embodiments 36 - 48, further comprising preparing a compound of the formula:

[0116]

[0117] wherein said preparation comprises contacting a compound of the formula:

[0118]

[0119] with an acid such as an organic acid at a temperature of from about 70 °C to about 110 °C.

[0120] Embodiment 50. The method according to any one of embodiments 36 - 49, further comprising preparing a compound of the formula:

[0121]

[0122] wherein said preparation comprises contacting a compound of the formula:

[0123]

[0124] with a compound of the formula:

[0125]

[0126] Embodiment 51. A compound of the formula:

[0127]

[0128] or a salt thereof.

[0129] Embodiment 52. A method for preparing a compound of the formula:

[0130]

[0131] which comprises contacting a compound of the formula:

[0132]

[0133] with a compound of the formula:

[0134]

[0135] wherein R0 is C 1-3 alkyl group.

[0136] Embodiment 53. A method for preparing a compound of the following formula:

[0137]

[0138] comprising contacting a racemic mixture of the following formula:

[0139]

[0140] with a chiral acid under conditions sufficient to form a eutectic.

[0141] Embodiment 53A. The method according to 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.

[0142] Embodiment 53B. The method according to Embodiment 53, wherein under conditions sufficient to obtain a eutectic, 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.

[0143] Embodiment 53C. The method according to Embodiment 53, wherein the chiral acid is (+)-dibenzoyl-D-tartaric acid.

[0144] Embodiment 53D. The method according to Embodiment 53, wherein the chiral acid has the following formula:

[0145]

[0146] and the eutectic has the following formula:

[0147]

[0148] Embodiment 53E. The method according to Embodiment 53, 53A, 53B, 53C, or 53D, wherein the conditions include using a solvent selected from the following: isopropanol, acetonitrile, isopropyl acetate, ethanol, methyl ethyl ketone, and dimethoxyethane.

[0149] Embodiment 54. The method according to Embodiment 53, further comprising contacting the crystalline product with an aqueous alkaline solution.

[0150] The method according to Embodiment 54A, wherein the aqueous solution is a sodium bicarbonate solution or a potassium carbonate solution.

[0151] Embodiment 55. The method according to Embodiment 52, wherein the compound of the following formula:

[0152]

[0153] is prepared according to Embodiment 53 or 54.

[0154] Embodiment 56. A method for preparing a compound of the following formula:

[0155]

[0156] or a pharmaceutically acceptable salt thereof, which comprises:

[0157] placing a compound of the following formula:

[0158]

[0159] under conditions sufficient to obtain a compound of the following formula:

[0160] and

[0161] contacting a compound of the following formula:

[0162]

[0163] with a compound of the following formula:

[0164]

[0165] under conditions sufficient to obtain a compound of the following formula:

[0166]

[0167] wherein:

[0168] Ring B is phenyl or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, wherein each heteroatom of the heteroaryl is independently selected from N, S, and O;

[0169] X is H, halogen, C 1-3 alkyl optionally substituted by one or more halogens, or C 1-3 alkoxy, wherein the alkoxy and are meta or para to each other;

[0170] Z is CH or N, and

[0171] R 0 is C 1-3 alkyl.

[0172] Embodiment 57. The method according to embodiment 56, wherein the compound of the following formula:

[0173]

[0174] is prepared according to the method of embodiment 36, 52 or 55.

[0175] Embodiment 58. The method according to embodiment 56, wherein Z is N, and the conditions for obtaining the compound of the following formula are:

[0176]

[0177] which comprises:

[0178] contacting a compound of the following formula:

[0179]

[0180] with phosphorus oxychloride under conditions sufficient to obtain a compound of the following formula:

[0181]

[0182] hydrolyzing the compound of the following formula:

[0183]

[0184] under conditions sufficient to obtain a compound of the following formula:

[0185]

[0186] contacting a compound of the following formula

[0187]

[0188] with hydrazine under conditions sufficient to obtain a compound of the following formula:

[0189] and

[0190] contacting a compound of the following formula:

[0191]

[0192] with formic acid under conditions sufficient to obtain a compound of the following formula:

[0193]

[0194] In addition, the present disclosure provides a compound of formula I:

[0195]

[0196] Wherein:

[0197] Ring A is a 5- or 6-membered carbon ring;

[0198] Ring B is phenyl, or a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms, each heteroatom of said heteroaryl being independently selected from N, S, and O;

[0199] R is H or C 1-3 alkyl;

[0200] X is H, halogen, C 1-3 alkyl optionally substituted with one or more halogens, or C 1-3 alkoxy;

[0201] Y is H, C 1-3 alkyl or C 1-3 alkoxy; and

[0202] Z is CH or N, its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts.

[0203] In some embodiments, Ring A is phenyl and Y is H; or Ring A is and Y is methyl; Ring B is pyridyl or pyrimidinyl; R is H; X is H or F; and Z is CH or N, its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts.

[0204] In some embodiments, the compounds of formula I are selected from phenyl, wherein Q is O or S, and W is CH or N.

[0205] In some embodiments, provided herein are compounds of formula II:

[0206]

[0207] wherein X, Y, Z, and Ring A are each as defined above for formula I, and W is CH or N, its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts.

[0208] In some embodiments, the A ring of the compounds described in any of the foregoing embodiments is phenyl. In some embodiments, the A ring of the compounds described in any of the foregoing embodiments is

[0209] In some embodiments, provided herein are compounds of formula III:

[0210]

[0211] Its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein X, Y, Z and W are as described above with respect to Formula I or Formula II.

[0212] In some embodiments, provided herein are compounds of Formula IV:

[0213]

[0214] or their pharmaceutically acceptable salts, wherein X, Y, Z and W are as described above with respect to Formula I or Formula II.

[0215] In some embodiments, Z of the compounds described in any of the foregoing embodiments is N. In some embodiments, Z of the compounds described in any of the foregoing embodiments is CH.

[0216] In some embodiments, W of the compounds described in any of the foregoing embodiments is N.

[0217] In some embodiments, X of the compounds described in any of the foregoing embodiments is F.

[0218] In some embodiments, Y of the compounds described in any of the foregoing embodiments is methyl.

[0219] In some embodiments, of the compounds described in any of the foregoing embodiments selected from:

[0220]

[0221] In some embodiments, of the compounds described in any of the foregoing embodiments selected from

[0222] In some embodiments, the compound is as described in any of the foregoing embodiments, provided that when is then the of the compound is

[0223] In some embodiments, of the compounds described in any of the foregoing embodiments or of the compounds described in any of the foregoing embodiments is

[0224] In some embodiments, of the compounds described in any of the foregoing embodiments or of the compounds described in any of the foregoing embodiments is

[0225] In some embodiments, provided herein are compounds selected from:

[0226]

[0227] their stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts.

[0228] In some embodiments, provided herein are compounds selected from:

[0229]

[0230]

[0231] mixtures of their stereoisomers, or their respective pharmaceutically acceptable salts.

[0232] In some embodiments, provided herein are compounds or their pharmaceutically acceptable salts.

[0233] In some embodiments, provided herein are compounds, their stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts.

[0234] In some embodiments, provided herein are compounds, their stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts.

[0235] The present disclosure further provides pharmaceutical compositions comprising a compound, its stereoisomers or mixtures of stereoisomers, or its respective pharmaceutically acceptable salts according to any one of the above embodiments, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0236] The present disclosure provides a method of treating an immune-mediated disease in a patient, which comprises administering to a patient in need of such treatment an effective amount of a compound, its stereoisomers or mixtures of stereoisomers, or its respective pharmaceutically acceptable salts according to any one of the above embodiments, or a pharmaceutical composition according to any one of the above embodiments.

[0237] 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, which comprises administering to a patient in need of such treatment an effective amount of a compound, its stereoisomers or mixtures of stereoisomers, or its respective pharmaceutically acceptable salts according to any one of the above embodiments, or a pharmaceutical composition according to any one of the above embodiments.

[0238] The present disclosure provides a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0239] The present disclosure further provides a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn's disease, graft-versus-host disease, rheumatoid arthritis, and multiple sclerosis.

[0240] In some embodiments, the present disclosure provides a compound of formula I-1:

[0241]

[0242] its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:

[0243] Ring A is a 5- or 6-membered carbocyclic ring;

[0244] Ring B is phenyl, or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, wherein each heteroatom of the heteroaryl is independently selected from N, S, and O;

[0245] X is H, halogen, C 1-3 alkyl optionally substituted with one or more halogens or C 1-3 alkoxy, wherein the alkoxy is meta or para with respect to being meta or para.

[0246] Y is H, C 1-4 alkyl or C 3-4 cycloalkyl, wherein C 1-4 alkyl is primary or secondary alkyl; and

[0247] Z is CH or N.

[0248] In some embodiments, Ring A is phenyl and Y is H; or Ring A is and Y is alkyl or cycloalkyl; Ring B is pyrazolyl, triazolyl, pyridyl, or pyrimidinyl; X is H or F; and Z is CH or N, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, the present disclosure provides a compound of formula I-2:

[0250]

[0251] Its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein X, Y, Z, ring A and ring B are each as defined above for formula I-1.

[0252] In some embodiments, provided herein are compounds of formula I-3:

[0253]

[0254] Its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein X, Y, Z, ring A and ring B are each as defined above for formula I-1.

[0255] In some embodiments, for the compounds of formula I-1, I-2 or I-3 is wherein Q is O or S, and W is CH or N.

[0256] In some embodiments, for the compounds of formula I-1, I-2 or I-3 is

[0257] In some embodiments, for the compounds described in any of the foregoing embodiments is a substituted or unsubstituted 6-membered heteroaryl.

[0258] In some embodiments, for the compounds described in any of the foregoing embodiments is a substituted or unsubstituted 5-membered heteroaryl.

[0259] In some embodiments, for the compounds described in any of the foregoing embodiments is

[0260] In some embodiments, for the compounds described in any of the foregoing embodiments is

[0261] In some embodiments, provided herein are compounds of formula II-1:

[0262]

[0263] Its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein X, Y, Z and ring A are each as defined above for formula I-1, and W is CH or N.

[0264] In some embodiments, provided herein are compounds of formula II-2:

[0265]

[0266] Its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein X, Y and ring A are each as defined above for formula I-1, and W is CH or N.

[0267] In some embodiments, provided herein are compounds of formula II-3:

[0268]

[0269] Its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein X, Y and ring A are each as defined above for formula I-1, and W is CH or N.

[0270] In some embodiments, provided herein are compounds of formula II-1A:

[0271]

[0272] Its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein X, Y and ring A are each as defined above for formula I-1.

[0273] In some embodiments, for the compounds of formula II-1, II-2, II-3 and II-1A, wherein X is H or halogen, and Y is H or C 1-3 alkyl.

[0274] In some embodiments, the selected from:

[0275]

[0276] In some embodiments, the selected from:

[0277]

[0278] In some embodiments, the compound is as described in any of the foregoing embodiments, provided that when is then the is

[0279] In some embodiments, the A ring of the compound described in any of the foregoing embodiments is phenyl. In some embodiments, the A ring of the compound described in any of the foregoing embodiments is

[0280] In some embodiments, the present disclosure provides compounds of Formula III-1:

[0281]

[0282] or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each, wherein X, Y, and Z are as described above for Formula I-1, and wherein W is CH or N.

[0283] In some embodiments, the present disclosure provides compounds of Formula III-2:

[0284]

[0285] or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each, wherein X and Y are as described above for Formula I-1, and wherein W is CH or N.

[0286] In some embodiments, the present disclosure provides compounds of Formula III-3:

[0287]

[0288] or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each, wherein X and Y are as described above for Formula I-1, and wherein W is CH or N.

[0289] In some embodiments, Ring B is phenyl.

[0290] In some embodiments, the present disclosure provides compounds of Formula III-1A:

[0291]

[0292] or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each, wherein X, Y, and Z are as described above for Formula I-1.

[0293] In some embodiments, the present disclosure provides compounds of Formula IV-1:

[0294]

[0295] or a pharmaceutically acceptable salt thereof, wherein X and Z are as described above for Formula I-1, and wherein W is CH or N.

[0296] In some embodiments, the present disclosure provides compounds of Formula IV-2:

[0297]

[0298] or a pharmaceutically acceptable salt thereof, wherein X is as described above for formula I-1, and wherein W is CH or N.

[0299] In some embodiments, provided herein are compounds of formula IV-3:

[0300]

[0301] or a pharmaceutically acceptable salt thereof, wherein X is as described above for formula I-1, and wherein W is CH or N.

[0302] In some embodiments, provided herein are compounds of formula IV-1A:

[0303]

[0304] or a pharmaceutically acceptable salt thereof, wherein X and Z are as described above for formula I-1.

[0305] In some embodiments, the compounds of formula II-1, II-2, II-3, III-1, III-2, III-3, IV-1, IV-2 or IV-3 are

[0306] In some embodiments, provided herein are compounds of formula V-1:

[0307]

[0308] a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each, wherein X, Y and Z are as described above for formula I-1, and Q is O or S.

[0309] In some embodiments, provided herein are compounds of formula V-2:

[0310]

[0311] a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each, wherein X, Y and Z are as described above for formula I-1, and Q is O or S.

[0312] In some embodiments, provided herein are compounds of formula V-3:

[0313]

[0314] a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each, wherein X, Y and Z are as described above for formula I-1, and Q is O or S.

[0315] In some embodiments, the present disclosure provides compounds of formula V-4:

[0316]

[0317] their stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein X, Y and Z are as described above for formula I-1, and W is CH or N.

[0318] In some embodiments, for any compound of formula V-1, V-2, V-3 or V-4, wherein Z is N.

[0319] In some embodiments, for any compound 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 halogen. 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.

[0320] In some embodiments, for any compound 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 1-4 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 cycloalkyl. In some embodiments, Y of the compounds described in any of the foregoing embodiments is cyclopropyl. In some embodiments, Y of the compounds described in any of the foregoing embodiments is cyclobutyl.

[0321] In some embodiments, for the compounds of any of the foregoing embodiments, X is F; and Y is C 3-4 cycloalkyl.

[0322] In some embodiments, for the compounds of any of the foregoing embodiments, X is methyl.

[0323] In some embodiments, for the compounds of any of the foregoing embodiments, X is C 1-3 alkyl substituted with one or more halogens.

[0324] In some embodiments, for the compounds of any of the foregoing embodiments, X is -CF3.

[0325] In some embodiments, for the compounds of any of the foregoing embodiments, X is C 1-3 alkoxy, wherein the alkoxy and are meta to each other.

[0326] In some embodiments, for the compounds of any of the foregoing embodiments, X is C 1-3 alkoxy, wherein the alkoxy and are para to each other.

[0327] In some embodiments, for the compounds of any of the foregoing embodiments, X is -OCH3, wherein -OCH3 and are meta to each other.

[0328] In some embodiments, for the compounds of any of the foregoing embodiments, X is -OCH3, wherein -OCH3 and are para to each other.

[0329] In some embodiments, for the compounds of any of the foregoing embodiments, W of the compounds described in any one of II-1, II-2, II-3, III-1, III-2, III-3, IV-1, IV-2, and IV-3 is N.

[0330] In some embodiments, of the compounds of formula I-1, I-2, I-3, II-1, II-2, or II-3 or of the compounds of formula III-1, III-2, or III-3 is

[0331] In some embodiments, of the compounds of formula I-1, I-2, I-3, II-1, II-2, or II-3 or of the compounds of formula III-1, III-2, or III-3 is

[0332] In some embodiments, provided herein are compounds selected from:

[0333]

[0334]

[0335] their stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts.

[0336] In some embodiments, provided herein are compounds selected from the following table, their stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts:

[0337]

[0338]

[0339] In some embodiments, provided herein are compounds selected from the following table, their stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts:

[0340]

[0341] In some embodiments, provided herein are compounds selected from the following:

[0342]

[0343]

[0344] or their respective pharmaceutically acceptable salts.

[0345] In some embodiments, provided herein are compounds selected from the following table, their stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts:

[0346]

[0347]

[0348] In some embodiments, provided herein are compounds selected from the following:

[0349]

[0350] or their respective pharmaceutically acceptable salts:

[0351] In some embodiments, provided herein is the compound or its pharmaceutically acceptable salt.

[0352] In some embodiments, provided herein is the compound or its respective pharmaceutically acceptable salt.

[0353] In some embodiments, provided herein is the compound or its respective pharmaceutically acceptable salt.

[0354] In some embodiments, provided herein is the compound or its respective pharmaceutically acceptable salt.

[0355] The present disclosure further provides a pharmaceutical composition comprising a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0356] The present disclosure provides a method for treating an immune-mediated disease in a patient, which comprises administering to a patient in need of such treatment an effective amount of a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the above embodiments.

[0357] The present disclosure provides a method for treating an autoantibody-driven autoimmune disease in a patient, which comprises administering to a patient in need of such treatment an effective amount of a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the above embodiments.

[0358] The present disclosure further provides a method 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 in a patient, which comprises administering to a patient in need of such treatment an effective amount of a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the above embodiments.

[0359] The present disclosure further provides a method for treating a disease or disorder selected from systemic lupus erythematosus (SLE), rheumatoid arthritis and myasthenia gravis (MG).

[0360] The present disclosure provides a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, for use in treatment.

[0361] The present disclosure provides a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, for use in treating an immune-mediated disease in a patient.

[0362] The present disclosure provides a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, for use in treating an autoantibody-driven autoimmune disease in a patient.

[0363] The present disclosure also provides a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, 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.

[0364] The present disclosure also provides a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, for treating a disease or disorder selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, and myasthenia gravis (MG).

[0365] Furthermore, the present disclosure provides the use of a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an immune-mediated disease. Additionally, the present disclosure provides the use of a compound according to any one of the above embodiments, its stereoisomers or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof in the preparation 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.

[0366] As used herein, the term "alkyl", used alone or as part of a larger moiety, refers to a saturated, straight-chain or branched hydrocarbon group containing one or more carbon atoms.

[0367] As used herein, the term "aryl", used alone or as part of a larger moiety, refers to an aromatic hydrocarbon group sharing 6, 10, or 14 π electrons in a cyclic array. An 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 phenanthryl.

[0368] As used herein, the term "chiral phosphine ligand" refers to a class of organophosphorus compounds that can be used as metal ligands to form metal complexes, where the chirality originates from its carbon skeleton or phosphorus. The term "P-chiral phosphine ligand" refers to a subset of "chiral phosphine ligands", where the chirality originates from a chiral phosphorus atom (P*). 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.

[0369] 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 following structural formula:

[0370]

[0371] wherein R is aryl or alkyl. Examples of suitable R groups include cyclohexyl, phenyl, tert - 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 - bis - trifluoromethylphenyl (3,5 - (CF3)2C6H3), 3,5 - dimethyl - 4 - methoxyphenyl (3,5 - (CH3)2 - 4 - (CH3O) - C6H2), 1 - naphthyl, etc. ChenPhos, like other compounds, is a subset of P - chiral phosphine ligands.

[0372] As used herein, the term "cycloalkyl" refers to a saturated ring system containing at least three carbon atoms. The 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.

[0373] As used herein, the term "carbocyclic" refers to a saturated or unsaturated ring system containing only carbon atoms. Carbocycles include cycloalkyls, aryls and partially saturated rings.

[0374] As used herein, the term "halogen" refers to a halogen as a substituent, specifically chlorine, fluorine, bromine or iodine.

[0375] 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 include oxygen, nitrogen and sulfur. Exemplary heterocycles include ethylene oxide, aziridine, oxetane, oxolane, pyrrolidine, piperidine and morpholine. The heterocycles can be monocyclic (having one ring), bicyclic (having two rings) or polycyclic (having two or more rings), and they can be fused to each other, for example.

[0376] As used herein, the term "heteroaryl" refers to a group having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms, sharing 6, 10 or 14 π electrons in a cyclic array, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, including any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl includes, for example, thienyl, furyl, 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, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl and quinoxalinyl.

[0377] When two or more rings are present, these rings may be arranged separately from each other or connected to each other. When two rings are connected to each other, they may be connected in a "fused" arrangement (or connection motif), a "spiro" arrangement or a "bridged" arrangement. As used herein, the term "fused" refers to an arrangement in which two rings are connected side by side, sharing two "bridgehead" atoms that are directly connected to each other. The "fused" connection motif is different from the "spiro" connection motif in that there is one and only one "bridgehead" atom in the "spiro" mode; the "fused" connection motif is different from the "bridged" connection motif in that the two "bridgehead" atoms in the "bridged" mode are not directly connected. When the first ring is "fused" to the second ring, the "bridgehead" atoms are understood to belong to both rings. Thus, if an embodiment provided herein describes such a ring as a six-membered "carbocyclic" ring, the six ring atoms include two "bridgehead" atoms and four additional atoms. And all six of these ring atoms are carbon in order to be a "carbocyclic" ring. For example, the group falls outside the scope of a "5-membered heteroaryl fused to a 6-membered carbocyclic ring" because one of the bridgehead atoms is not carbon.

[0378] As used herein, the term "oxo" refers to an oxygen atom connected to another atom by a double bond as a substituent. It may be represented as "=O". The term oxo refers to a carbonyl group minus a carbon atom.

[0379] As used herein, the terms "ortho," "meta," and "para" refer to the relative positions between two substituents in a ring system. When two substituents are adjacent to each other (i.e., directly bonded to two adjacent ring atoms), they are referred to as "ortho" relative to each other. When they are separated by one other ring atom (in addition to the two ring atoms to which they are bonded), they are referred to as "meta" relative to each other. For a 6-membered ring system, when two substituents are separated by two other ring atoms (in addition to the two ring atoms to which they are bonded), they are referred to as "para" relative to each other. For example, for the following formula (A), A 1 and A 2 、A 2 and A 3 、A 3 and A 4 、A 4 and A 5 as well as A 5 and A 1 are each considered ortho to each other; A 1 and A 3 、A 2 and A 4 、A 3 and A 5 、A 4 and A 1 as well as A 5 and A 2 are each considered meta to each other. For example, for 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 as well as A 6 and A 1 are each considered ortho to each other; A 1 and A 3 、A 2 and A 4 、A 3 and A 5 、A 4 and A 6 、A 5 and A 1 as well as A 6 and A 2 are each considered meta to each other; A 1 and A 4 、A 2 and A 5 as well as A 3and A 6 are each considered to be in register with respect to each other.

[0380]

[0381] As used herein, represents a bond in an aromatic system. It may alternatively or optionally be represented as a single bond or a double bond, depending on how the aromatic system is described. For example, can be used to represent a five-membered carbon ring fused to an aromatic system (such as a benzene ring) at two attachment points. This bond may optionally be represented as a single bond (e.g., as part of ), or as a double bond (e.g., as part of ).

[0382] As used herein, the term "stereoisomer" refers to isomers that are composed of the same atoms bonded by the same bonds, but have different and non-interchangeable structures in three-dimensional space. The term "stereoisomer" includes "enantiomers", which are two stereoisomers that are mirror images of each other and non-superimposable. A one-to-one mixture of a pair of enantiomers is referred to as a "racemic" mixture. The term stereoisomers also includes "diastereoisomers" (or "diastereomers"), which are two stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry of a stereoisomer can be assigned according to the Cahn-Ingold-Prelog R,S system, where the stereochemistry of each chiral center is assigned as R or S. When a stereoisomer is resolved but its absolute configuration is unknown, these stereocenters are assigned as (+) or (-) according to the direction (right-handed or left-handed) in which they rotate the plane of polarization at the sodium D-line wavelength. Unless otherwise explicitly stated, "enantiomer 1" refers to the enantiomer that elutes first from the column during the chiral separation of a racemic mixture under defined separation conditions; and "enantiomer 2" refers to the enantiomer that elutes second during the same separation process. Sometimes, the elution order is different between a preparative column (e.g., for separation) and an analytical column (e.g., for purity assessment). For clarity, the names "enantiomer 1" and "enantiomer 2" are based on the preparative column. In addition, there may be multiple stereocenters, and two separations may be required to fully resolve all stereoisomers. For example, the first separation will produce two bands, with the first band eluting containing "enantiomer 1 / 1" and "enantiomer 1 / 2", and the second band eluting containing "enantiomer 2 / 1" and "enantiomer 2 / 2". A subsequent separation (e.g., using the same or different chromatographic column conditions) can be used to resolve "enantiomer 1 / 1" (the first band eluting in the subsequent separation) and "enantiomer 1 / 2" (the second band eluting in the subsequent separation).

[0383] As used herein, the term "immune-mediated disease" encompasses a group of autoimmune or inflammatory disorders in which immune pathways play an important role in etiology and / or pathogenesis. Such diseases are sometimes characterized by alterations in cellular homeostasis. Immune-mediated diseases can be triggered by environmental factors, dietary habits, infectious agents, and genetic susceptibility. 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, or other mediators.

[0384] As used herein, the term "autoantibody-driven autoimmune disease" refers to a class of autoimmune diseases in which inflammation and damage are caused by the immune system producing antibodies that attack its own tissues or organs. Autoantibody-driven autoimmune diseases include, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and myasthenia gravis (MG).

[0385] As used herein, the term "treatment" includes inhibiting, slowing, halting, or reversing the progression or severity of existing symptoms or disorders.

[0386] As used herein, the term "patient" refers to a human being.

[0387] As used herein, the term "effective amount" refers to the amount or dose of a compound of the present disclosure or a pharmaceutically acceptable salt thereof that, upon administration to a patient in a single dose or multiple doses, provides the desired effect in the patient being diagnosed or treated.

[0388] One of ordinary skill in the art can readily determine the effective amount by using known techniques. When determining the effective amount for a patient, a variety of factors are considered, including but not limited to: the patient species; the patient's size, age, and general health; the specific disease or disorder involved; the degree of or involvement or severity of the disease or disorder; the response of the individual patient; the specific compound being administered; the mode of administration; the bioavailability characteristics of the administered formulation; the chosen dosing regimen; the use of concomitant medications; the individual patient's medical history; and other relevant circumstances.

[0389] The compounds of the present disclosure are generally effective within a broad dosage range. For example, the daily dosage generally falls within the range of about 0.1 to about 15 mg / kg body weight. In some cases, dosage levels below the lower limit of the above range may be more than adequate; while in other cases, even larger dosages may still be employed with acceptable side effects. Accordingly, the above dosage range is not intended to limit the scope of the present disclosure in any way.

[0390] The compounds of the present disclosure are preferably formulated into pharmaceutical compositions and administered by any route that renders the compound bioavailable, including oral and transdermal routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and methods for their preparation are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy, A. Adejare, editor, 23rd Edition, Elsevier Academic Press, 2020).

[0391] The compounds of the present disclosure or their pharmaceutically acceptable salts can be prepared by methods well known and understood in the art according to the following Preparation Examples and Examples. The appropriate reaction conditions for the steps of these Preparation Examples and Examples are well known in the art, and appropriate substitutions of solvents and co-reagents are within the skill of the art. Similarly, those skilled in the art will understand that synthetic intermediates can be separated and / or purified by various well-known techniques as needed or desired, and generally various intermediates can be used directly in subsequent synthetic steps with little or no purification. For example, the compounds of the Preparation Examples and Examples can be separated by, for example, silica gel purification, direct separation by filtration, or crystallization. In addition, those skilled in the art will understand that in some cases, the order of introduction of moieties is not critical. The specific order of steps required to prepare the compounds of the present disclosure depends on the particular compound being synthesized, the starting compounds, and the relative lability of the substituent moieties, and is understood by those skilled in the art of chemistry. Unless otherwise specified, all substituents are as previously defined, and all reagents are well known and understood in the art.

[0392] Certain 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 Medium; “DMF” refers to dimethylformamide; “DMF-DMA” refers to N,N-dimethylformamide dimethyl acetal; “DMSO” refers to dimethyl sulfoxide; “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 hour; “MeOH” refers to methanol; “min” refers to minute; “SFC” refers to supercritical fluid chromatography; and “THF” refers to tetrahydrofuran.

[0393] In an optional step, a pharmaceutically acceptable salt of a compound according to any one of the above embodiments can be formed by reacting a suitable free base of the compound with a suitable pharmaceutically acceptable acid under standard conditions in a suitable solvent. The formation of such salts is well known and understood in the art. See, for example, Gould, P.L., “Salt selection for basic drugs,” International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, R.J. et al., “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,” Organic Process Research and Development, 4:427-435 (2000); and Berge, S.M. 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 understand that a compound according to any one of the above embodiments can be readily converted to and isolated as a pharmaceutically acceptable salt.

[0394] 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 a variety of methods known in the art, some of which are illustrated in the schemes, preparation examples and examples below. The specific synthetic steps of each route can be combined in different ways, or combined with steps from different schemes, to prepare compounds of Formula I, Formula II, Formula III, Formula IV, their stereoisomers or mixtures thereof, or their respective pharmaceutically acceptable salts. The products of the steps 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, unless otherwise indicated, all variables and substituents are as defined above. Reagents and starting materials are readily available to those of ordinary skill in the art.

[0395] Scheme 1. General Scheme for the Preparation of Compound 4

[0396]

[0397] Scheme 1 describes a general scheme for the synthesis of carboxylic acid compound 4.

[0398] All variables are as defined above for Formula I, and R 1 is alkyl (e.g., C 1-3 alkyl). All variables are as defined above for Formula I. Additionally, R 1 is alkyl such as C 1-3 alkyl. In some embodiments, R is hydrogen.

[0399] Compound 1 is hydrolyzed under conditions sufficient to obtain carboxylic acid compound 2a. For example, compound 1 can be dissolved in a suitable organic solvent, water, or a mixture thereof. Then an excess of base (e.g., lithium hydroxide) is added to the solution and stirred at ambient temperature for several hours. After completion of the reaction (e.g., monitored by thin layer chromatography (TLC)), the pH of the solution is adjusted to about 3 with 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 obtain compound 2a.

[0400] Compound 2a is then contacted with hydrazine under conditions sufficient to obtain compound 3a (e.g., by nucleophilic aromatic substitution). For example, compound 2a is dissolved (taken up) in a suitable organic solvent (1,4-dioxane). Then an excess of hydrazine is 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 obtain compound 3a.

[0401] Compound 3a is then contacted with a suitable organic acid under conditions sufficient to afford Compound 4. For example, a mixture of Compound 3a and formic acid is heated at a suitable temperature (e.g., 60 to 100 °C) for several hours. The reaction mixture is concentrated under reduced pressure to afford Compound 4, where R is hydrogen. In some embodiments, Compound 4 can be used in further reactions without post-treatment or purification.

[0402] Alternatively, Compound 1 is contacted with hydrazine under conditions sufficient to afford Compound 2b (e.g., by nucleophilic aromatic substitution). For example, Compound 1 is dissolved in a suitable organic solvent (e.g., ethanol). Excess hydrazine is then added to the solution and the mixture is 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 afford Compound 2b.

[0403] Compound 2b is contacted with a suitable organic acid under conditions sufficient to afford Compound 3b. For example, a mixture of Compound 2b and formic acid is 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., over anhydrous sodium sulfate), filtered, and concentrated under reduced pressure to afford Compound 3b, where R is hydrogen.

[0404] Compound 3b is hydrolyzed under conditions sufficient to afford 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. Excess base (e.g., lithium hydroxide) is then added to the solution and the mixture is stirred at ambient temperature for several hours. After completion of the reaction, the pH of the solution is adjusted to about 3 with 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., over anhydrous sodium sulfate), filtered, and concentrated under reduced pressure to afford Compound 4.

[0405] In some embodiments, Compound 1 in Scheme 1 is Compound 4 in Scheme 1 is

[0406] In some embodiments, can be separated by using suitable methods, such as by chiral separation using column chromatography under suitable conditions of the racemic mixture.

[0407] In some embodiments, can be prepared from the above-described embodiments (such as Embodiment 58) provided thereof.

[0408] In some embodiments, it can be prepared by separating the racemic mixture by using a suitable method, such as chiral separation by column chromatography under suitable conditions.

[0409] In some embodiments, provided herein are methods for preparing from those described in the above embodiments (such as embodiments 36 to 47).

[0410] In some embodiments, provided herein are methods for preparing from those described in the above embodiments (such as embodiment 48).

[0411] In some embodiments, provided herein are methods for preparing from those described in the above embodiments.

[0412] In some embodiments, provided herein are methods for preparing and from those described in the above embodiments.

[0413] Alternatively, in some embodiments, provided herein are methods for preparing from those described in the above embodiments.

[0414] In some embodiments, provided herein is a method for preparing by contacting a racemic mixture of the formula:

[0415]

[0416] with a compound of the formula:

[0417]

[0418] under conditions sufficient to obtain a eutectic of the formula:

[0419]

[0420] and contacting the eutectic with an aqueous solution of sodium bicarbonate or potassium carbonate to prepare

[0421] Scheme 2. General scheme for preparing Compound 8

[0422]

[0423] ​​​​​​​Scheme 2 describes 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, -CH2CH(OCH3)2, or -CH2C(O)R. In some embodiments, R is hydrogen.

[0424] Compound 5 is converted under conditions sufficient to obtain compound 6, such as by amination via a Buchwald reaction. 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-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), and a suitable base (e.g., cesium carbonate) in a suitable solvent (e.g., toluene) and heated at a suitable temperature (e.g., 60 - 120 °C) for several hours. The mixture is concentrated and purified under reduced pressure to obtain compound 6.

[0425] Alternatively, compound 5 is aminated with an equivalent of aminoacetaldehyde via a nucleophilic aromatic substitution reaction to obtain compound 6. For example, compound 5 is treated with aminoacetaldehyde dimethyl acetal in a suitable solvent (e.g., ethanol) and heated at a suitable temperature (e.g., 60 - 120 °C) for several hours. The mixture is concentrated and purified under reduced pressure to obtain compound 6.

[0426] Compound 6 is converted under conditions sufficient to obtain imidazole compound 7, such as by cyclization with haloacetaldehyde or halomethyl ketone. For example, when R 2 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. When R 2 is CH2CH(OCH3)2, compound 6 is treated with 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 and purified under reduced pressure to obtain compound 7.

[0427] Compound 7 is converted under conditions sufficient to obtain carboxylic acid intermediate compound 8 (e.g., by hydrolysis). 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 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 or the like). The solid is filtered and washed with water to obtain compound 8.

[0428] In some embodiments, compound 5 in Scheme 2 is Compound 8 in Scheme 2 is

[0429] Alternatively, when compound 1 or 5 is compound 11 When, compounds 4 and 8 can be prepared by the following Scheme 2a and are designated as compounds 14a and 14b, respectively:

[0430] Scheme 2a. General Scheme for Preparing Compounds 14a and 14b

[0431]

[0432] Scheme 2a describes the general scheme for synthesizing compounds 14a and 14b from compound 11. All variables are defined as above with respect to Schemes 1 and 2.

[0433] Scheme 3. General Scheme for Preparing Compounds of Formula I

[0434]

[0435] Scheme 3 describes the general scheme for synthesizing compounds of Formula I. All variables are defined as above with respect to Formula I. In some embodiments, the carboxylic acid compound 9 is in the form of carboxylic acid compound 14a or 14b.

[0436] Contact the carboxylic acid compound 9 with a suitable amine compound 10 under conditions sufficient to obtain a compound of Formula I (e.g., by an amide coupling reaction). For example, dissolve carboxylic acid 9 and a suitable amine compound 10 in a suitable solvent (e.g., dichloromethane), treat with a suitable catalyst (e.g., pyridine) and a suitable chlorinating agent (e.g., phosphorus oxychloride), and stir at ambient temperature for several hours. Concentrate the reaction mixture under reduced pressure and triturate the residue with a suitable solvent (e.g., DMF). Filter the solid to obtain a compound of Formula I. In some embodiments, the intermediate compound 9 is compound 4 as described above. In some embodiments, the intermediate compound 9 is compound 8 as described above.

[0437] In some embodiments, the compound 10 is compound 10a, and the compound of Formula I is a compound of Formula II, wherein W is defined as above.

[0438]

[0439] In some embodiments, the compound 10 is 10b, and the compound of Formula I is a compound of Formula II-1, wherein Q is defined as above.

[0440]

[0441] In some embodiments, the compound 10 is 10c, and the compound of Formula I is a compound of Formula II-2, wherein Q is defined as above.

[0442]

[0443] In some embodiments, compound 10 is 10d, and the compound of formula I is the compound of formula II-3, wherein Q is as defined above.

[0444]

[0445] In some embodiments, compound 10 is compound 10e, and the compound of formula I is the compound of formula II-4.

[0446]

[0447] In some embodiments, ring A of compound 9 is phenyl, such that when Y is hydrogen, the compound of formula II also conforms to formula IV.

[0448] In some embodiments, ring A of compound 9 is such that the compound of formula II also includes the compound of formula III.

[0449] In some embodiments, the compound of formula I is in 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 suitable starting materials and methods similar thereto.

[0450] Preparation Example 1

[0451] [1,2,4]Triazolo[4,3-a]quinoline-4-carboxylic acid

[0452]

[0453] Step 1 2-Chloroquinoline-3-carboxylic acid ethyl ester

[0454]

[0455] Ethyl 2-oxo-1,2-dihydroquinoline-3-carboxylate (1 g, 4.37 mmol) was mixed with a solution of N,N-diisopropylethylamine (2.29 mL, 13.1 mmol) and phosphorus oxychloride (4.1 g, 26 mmol) in toluene (10 mL). The mixture was stirred at 120 °C for 18 h. Thereafter, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column (12 g) using a petroleum ether solution of ethyl acetate as the eluent with a concentration gradient of 0 - 10% 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).

[0456] Step 2

[0457] Ethyl 2-hydrazinoquinoline-3-carboxylate

[0458]

[0459] Ethyl 2-chloroquinoline-3-carboxylate (500 mg, 1.89 mmol) was dissolved in ethanol (10 mL). Hydrazine (250 mg, 7.72 mmol) was added and the mixture was stirred at 40 °C for 18 h. Thereafter, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column (20 g) using a petroleum ether solution of ethyl acetate as the eluent with a concentration gradient of 0 - 33% to give ethyl 2-hydrazinoquinoline-3-carboxylate as a yellow solid (240 mg, 50.7%). ES / MS (m / z): 232.2 (M+H).

[0460] Step 3

[0461] Ethyl [1,2,4]triazolo[4,3-a]quinoline-4-carboxylate

[0462]

[0463] At 100 °C, ethyl 2-hydrazinoquinoline-3-carboxylate (240 mg, 0.96 mmol) was stirred in formic acid (5 mL) for 18 h. Thereafter, the reaction was quenched with saturated aqueous sodium carbonate (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were 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).

[0464] Step 4

[0465] [1,2,4]Triazolo[4,3-a]quinoline-4-carboxylic acid

[0466]

[0467] 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. Thereafter, the reaction mixture was concentrated under reduced pressure to remove volatile organic compounds, then 1N aqueous HCl was added to adjust the pH of the solution to about 3. 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).

[0468] Preparation Example 2

[0469] 6-Methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid

[0470]

[0471] Step 1

[0472] (Z)-2-((Dimethylamino)methylene)-3-methylcyclopentan-1-one

[0473]

[0474] Under N2, cuprous iodide (56 g, 294 mmol) and tributylphosphine (150 mL, 570 mmol) were stirred in THF (300 mL) for 10 min. Then the mixture was cooled to -78 °C. Thereafter, methyllithium (1.6 mol / L in diethyl ether) (180 mL, 290 mmol) was added dropwise. After the addition was complete, the mixture was further stirred at -78 °C under N2 for 30 min. Then boron trifluoride diethyl etherate (34 mL, 268.8 mmol) was added, and the mixture was stirred for another 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 and stirred for 20 min, then warmed again to -40 °C and stirred under N2 for 10 min. Then DMF-DMA (81 mL, 607 mmol) was added, the mixture was warmed to 20 °C, and stirred under N2 for 16 h. The yellow mixture was poured into saturated aqueous NaCl solution (500 mL) and extracted with EtOAc (4 × 200 mL). The combined organic layers were 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 a petroleum ether solution of EtOAc as the eluent with a concentration gradient of 0 - 100% to give (Z)-2-((dimethylamino)methylene)-3-methylcyclopent-1-one as a yellow oil (34 g, 82%). ES / MS (m / z): 154.2 (M+H).

[0475] Step 2 Methyl 5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0476]

[0477] (Z)-2-((Dimethylamino)methylene)-3-methylcyclopent-1-one (13.46 g, 87.85 mmol) was dissolved in MeOH (100 mL). Piperidine (7.5 g, 88 mmol) was added to the mixture, followed by methyl cyanoacetate (17.6 g, 176 mmol). The mixture was heated to 80 °C under N2 and maintained for 18 h. Thereafter, the volatile organic compounds were concentrated under reduced pressure, and the residue was purified by silica gel column (120 g) using a petroleum ether solution of EtOAc as the eluent with a concentration gradient of 0 - 60% 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%). 11H NMR (CDCl3): 7.96 (s, 1H), 7.21 (s, 1H), 3.86 (s, 3H), 3.12 - 3.03 (m, 1H), 2.92 - 2.82 (m, 2H), 2.35 - 2.28 (m, 1H), 1.64 - 1.55 (m, 1H), 1.19 (d, J = 6.9 Hz, 3H).

[0478] Step 3 Methyl 2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0479]

[0480] A toluene solution (5 mL) of methyl 5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (2 g, 9.65 mmol) was added to N,N-diisopropylethylamine (3.3 mL, 19 mmol), and then added to phosphorus oxychloride (10 mL). The reaction mixture was heated to 100 °C for 16 h. Thereafter, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (40 g, petroleum ether solution of 0 - 20% ethyl acetate) to obtain 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).

[0481] Step 4 2-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid

[0482]

[0483] 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 this solution and stirred at 25 °C for 2 h. Thereafter, the pH of the solution was adjusted to about 3 with 1N HCl. Then the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. 2-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid was obtained as a white solid (570 mg, 79.1%). ES / MS (m / z): 212.1 (M + H).

[0484] Step 5 2-Hydrazino-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid

[0485]

[0486] 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). Hydrazine (2 g, 61.8 mmol) was added to the mixture, and the mixture was stirred at 80 °C for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure to give 2-hydrazino-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).

[0487] Step 6 6-Methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid

[0488]

[0489] 2-Hydrazino-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 hours. Thereafter, 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).

[0490] Preparation Example 3

[0491] Imidazo[1,2-a]quinoline-4-carboxylic acid

[0492]

[0493] Step 1 Ethyl 2-((2,2-dimethoxyethyl)amino)quinoline-3-carboxylate

[0494]

[0495] 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. Thereafter, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (12 g, petroleum ether solution of 0 - 2% ethyl acetate) to obtain 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).

[0496] Step 2

[0497] Ethyl imidazo[1,2-a]quinoline-4-carboxylate

[0498]

[0499] At 140 °C, ethyl 2-((2,2-dimethoxyethyl)amino)quinoline-3-carboxylate (300 mg, 0.95 mmol) was stirred in xylene (10 mL) and acetic acid (1 mL, 17.4 mmol) for 18 hours. Thereafter, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (12 g, petroleum ether solution of 0 - 50% ethyl acetate) to obtain ethyl imidazo[1,2-a]quinoline-4-carboxylate as a gray solid (115 mg, 47.8%). ES / MS (m / z): 241.2 (M+H).

[0500] Step 3

[0501] Imidazo[1,2-a]quinoline-4-carboxylic acid

[0502]

[0503] 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 hours. Thereafter, the reaction mixture was concentrated under reduced pressure to remove volatile organic compounds. 1N HCl solution was added to adjust the pH of the solution to about 3. The solid was filtered and washed with water to obtain imidazo[1,2-a]quinoline-4-carboxylic acid as a gray solid (60 mg, 60.3%). ES / MS (m / z): 213.1 (M+H).

[0504] Preparation Example 4

[0505] 6-Methyl-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyridine-4-carboxylic acid

[0506]

[0507] Step 1 Methyl 2-amino-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0508]

[0509] 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). Then tert-butyl carbamate (4.3 g, 36 mmol) was added, followed by cesium carbonate (8.6 g, 26 mmol), palladium(II) acetate (400 mg, 1.8 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.73 g, 3.6 mmol). The mixture was heated to 120 °C under nitrogen and maintained for 16 h. Thereafter, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (12 g, petroleum ether solution of 0-40% ethyl acetate) 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).

[0510] Step 2 Methyl 6-methyl-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyridine-4-carboxylate

[0511]

[0512] 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. Thereafter, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (12 g, petroleum ether solution of 0-40% ethyl acetate) 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).

[0513] Step 3 6-Methyl-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyridine-4-carboxylic acid

[0514]

[0515] 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). Lithium hydroxide (640 mg, 26 mmol) was added to the mixture and stirred at ambient temperature for 16 h. Thereafter, the reaction mixture was concentrated under reduced pressure to remove volatile organic compounds, 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).

[0516] Preparation Example 5

[0517] Methyl 2-chloro-5-cyclobutyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0518]

[0519] Step 1 Methyl 2-chloro-5-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0520]

[0521] 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 hexane 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).

[0522] Step 2

[0523] (Z)-Methyl 2-chloro-5-(2-p-toluenesulfonylhydrazono)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0524]

[0525] At 25 °C, 4-methylbenzenesulfonyl 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). The solution was stirred at ambient temperature under N2 for 6 h. The resulting solid was filtered, washed with cold ether and dried to give methyl (Z)-2-chloro-5-(2-toluenesulfonylhydrazono)-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).

[0526] Step 3 Methyl 2-chloro-5-cyclobutyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0527]

[0528] Under N2, cyclobutylboronic acid (673 mg, 6.67 mmol) was added to a solution of methyl (Z)-2-chloro-5-(2-toluenesulfonylhydrazono)-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). 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 hexane, 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).

[0529] Preparation Example 6

[0530] (S)-Methyl 5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0531]

[0532] Step 1

[0533] (E)-2-(2-Cyano-3-methoxy-3-oxoprop-1-en-1-yl)-3-oxocyclopent-1-en-1-ol dimethylammonium salt

[0534]

[0535] At 0 - 10 °C, 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). The reaction mixture was stirred at 30 - 40 °C for 16 h. At 0 - 10 °C, toluene (160 mL) and methyl 2 - cyanoacetate (48.5 g, 489.3 mmol) were added. 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 filter cake was dried at 45 - 55 °C under reduced pressure to give (E)-2-(2 - cyano - 3 - methoxy - 3 - oxoprop - 1 - en - 1 - yl)-3 - oxocyclopent - 1 - en - 1 - ol dimethylammonium salt as a brownish - yellow 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), for the free base. 1 1H NMR (DMSO - d6): δ ppm 2.10 - 2.30 (m, 4H), 2.55 (s, 6H), 3.65 (s, 3H), 7.62 (s, 1H), 7.97 - 8.38 (brs, 1H).

[0536] Step 2 Methyl 2,5 - dioxo - 2,5,6,7 - tetrahydro - 1H - cyclopenta[b]pyridine - 3 - carboxylate

[0537]

[0538] At 0 - 10 °C, 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 - ol dimethylammonium salt (80 g, 317.1 mmol) in toluene (2.4 L). 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 filter cake was dried at 45 - 55 °C under reduced pressure 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 1H 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).

[0539] Methyl 35 - methylene - 2 - oxo - 2,5,6,7 - tetrahydro - 1H - cyclopenta[b]pyridine - 3 - carboxylate

[0540]

[0541] At 20 - 30 °C, 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). The reaction mixture was stirred at 35 - 45 °C for 16 h. After cooling, the reaction mixture was filtered through Celite (77 g, twice) and filtered. The filter cake was slurried with DCM (576 mL) and filtered. Then the filter cake was slurried again with water / 10% citric acid (pH: 6.2 - 6.8) and filtered. The filter cake was slurried again with DCM (576 mL) and filtered. Then the filtrate was 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): ppm 2.66 - 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).

[0542] Step 4

[0543] (S) - Methyl 5 - methyl - 2 - oxo - 2,5,6,7 - tetrahydro - 1H - cyclopenta[b]pyridine - 3 - carboxylate

[0544]

[0545] Under N2, 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), and the mixture was 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, and then the mixture was flushed with hydrogen three times.

[0546] 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 1H NMR (DMSO-d6): δ ppm 1.15 (d, J = 6.78 Hz, 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).

[0547] Preparation Example 7

[0548] Methyl (S)-5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0549]

[0550] Step 1

[0551] (E)-2-((Dimethylamino)methylene)-3-methylcyclopent-1-one

[0552]

[0553] At 25 °C, tributylphosphine (4.93 kg) was added dropwise to a solution of copper(I) iodide (2.78 kg, 1.20 equiv) in THF (20.0 L, 15 V). The mixture was stirred at 25 °C for 1 h and then cooled to -70 °C. Methyllithium (2.5 M, 5.85 L) was added dropwise to the cooled mixture and stirred at -70 °C for 1 h. Boron trifluoride diethyl etherate (1.90 kg) was added dropwise to the mixture and stirred for 1 h while maintaining the reaction temperature at -70 °C. Then cyclopent-2-en-1-one (1.00 kg) was added dropwise to the reaction mixture at -70 °C and stirred for 2 h, and then DMF-DMA (2.90 kg) was added dropwise while maintaining the reaction 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. 15% Disodium hydrogen phosphate (3 V) was added slowly over 30 min to quench the reaction. The solid was filtered and washed with EtOAc (1 V). The mother liquor was concentrated under reduced pressure, extracted with EtOAc (2 V x 3), and concentrated under reduced pressure to give a crude mixture containing the desired product. The crude mixture was poured into acetonitrile (5 V) and extracted with petroleum ether (5 V x 3). The phases were separated and concentrated separately. A residue of 600 g (32%) containing the desired product was obtained in the acetonitrile phase and was used in the next step without further purification.

[0554] Step 2

[0555] (S,E)-2-((Dimethylamino)methylene)-3-methylcyclopent-1-one (2S,3S)-2,3-bis(benzoyloxy)succinate

[0556]

[0557] At 25 °C, a solution of (E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one (1.60 kg, crude from step 1) in methyl ethyl ketone (5V) was treated with a solution of (2S,3S)-2,3-dibenzoyloxysuccinic acid (0.6 eq) in methyl ethyl ketone (15V). The mixture was stirred at 60 °C for 2 h. Then, the reaction was cooled to ambient temperature and stirred for 12 h. The mixture was filtered and washed with methyl ethyl ketone to give the crude salt of (S,E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one (2S,3S)-2,3-bis(benzoyloxy)succinate with a chiral purity of 85%. This salt was treated with a mixture of acetonitrile / water (5V / 1V), heated at 65 °C for 2 h, and then cooled at ambient temperature for 12 h. The solid was filtered, the filter cake was 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.

[0558] Step 3

[0559] (S,E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one

[0560]

[0561] 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, 5V) and DCM (8.10 L, 2V) was treated with sodium bicarbonate (1.12 kg, 2.00 eq), and the mixture was stirred at 25 °C for 30 min. The organic layer was extracted with DCM (2V x 3), washed with saturated aqueous NaCl solution, 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.

[0562] Step 4

[0563] (S)-Methyl 5-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0564]

[0565] A solution of (S,E)-2-((dimethylamino)methylene)-3-methylcyclopentan-1-one (550 g) in MeOH (3.30 L, 6V) 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 (2V), and the slurry was stirred at ambient temperature for 30 min. The solid was filtered, and the filter cake was washed with EtOAc (0.5V) 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.

[0566] Example 1

[0567] N-(5-Fluoropyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide

[0568]

[0569] [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). Pyridine (180 mg, 2.26 mmol) was added to the mixture, followed by phosphorus oxychloride (350 mg, 2.24 mmol). The reaction mixture was stirred at ambient temperature for 18 h. Thereafter, 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).

[0570] Example 2

[0571] N-(5-Fluoropyrimidin-2-yl)imidazo[1,2-a]quinoline-4-carboxamide

[0572]

[0573] Imidazo[1,2-a]quinoline-4-carboxylic acid was reacted with 5-fluoropyrimidin-2-amine in a method similar to 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).

[0574] Example 3

[0575] (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)

[0576] and

[0577] Example 4

[0578] (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)

[0579]

[0580] Dissolve 6-methyl-7,8-dihydro-6H-cyclopenta-[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid (Preparation Example 2) (300 mg, 0.80 mmol) and pyridin-2-amine (120 mg, 1.6 mmol) in dichloromethane (5 mL). Add pyridine (220 mg, 2.77 mmol) to the mixture, and then add phosphorus oxychloride (200 mg, 1.3 mmol). Stir the reaction mixture at ambient temperature for 18 h. Thereafter, pour the reaction mixture into saturated aqueous NaCl (10 mL), and extract with ethyl acetate (20 mL×3). Combine the organic phases, dry over sodium sulfate, filter, and concentrate to dryness under reduced pressure. Purify the residue by silica gel chromatography (4 g, petroleum ether solution of 0-80% ethyl acetate) to obtain the crude product. Subsequently, perform chiral separation of the crude product on a preparative column under the following conditions to obtain the enantiomers:

[0581] Separation condition A:

[0582] Column: DAICEL CHIRALPAK AD 250×30 mm I.D., 10 μm

[0583] Mobile phase A: CO2

[0584] Mobile phase B: ethanol (0.1% NH4OH)

[0585] Gradient: 40% B

[0586] Flow rate: 80 mL / Min

[0587] Analysis was carried out by supercritical fluid chromatography (SFC) under the following conditions to obtain the retention time (RT):

[0588] Column: Chiralpak OJ-3 50×4.6 mm I.D., 3 μm

[0589] Mobile phase A: CO2

[0590] Mobile phase B: ethanol (0.05% DEA)

[0591] Gradient: a) 0 - 2.5 min: 5% B - 95% A ramping to 40% B - 60% A;

[0592] b) 2.5 min - 3.0 min: held at 40% B - 60% A;

[0593] c) 3.0 min - 4.0 min: 40% B - 60% A adjusted to 5% B - 95% A.

[0594] Flow rate: 4 mL / min

[0595] Column temperature: 35 °C

[0596] Auto backpressure regulator (ABPR) pressure: 1500 psi

[0597] Retention time of enantiomer 1: 1.458 min

[0598] Retention time of enantiomer 2: 1.566 min

[0599] Enantiomer 1 and enantiomer 2 were obtained at the above retention times (RT). After drying each, a white solid was obtained. 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).

[0600] The compounds in Table 1A were prepared using suitable starting materials under conditions similar to those of Examples 3 and 4. The starting materials can be commercially available or can be synthesized by reference to the examples provided herein and common general knowledge. For example, the reaction time can be adjusted by monitoring by chromatography or similar means to complete the reaction. In addition, the separation and analysis conditions used are the same as those described in Examples 3 and 4.

[0601] Table 1A. Examples 5 to 8

[0602]

[0603]

[0604] The compounds in Table 1B were prepared from suitable starting materials under conditions similar to those of Examples 3 and 4. The starting materials may be commercially available or may be synthesized by reference to the examples provided herein and common general knowledge. For example, the reaction time may be adjusted by monitoring by chromatography or similar means to complete the reaction. The crude product was then subjected to chiral separation on a preparative column under separation condition A. Separation condition A:

[0605] Column: DAICEL CHIRALPAK AD 250×30mm I.D., 10μm

[0606] Mobile phase A: CO2

[0607] Mobile phase B: ethanol (0.1% NH4OH)

[0608] Gradient: 40%B

[0609] Flow rate: 80mL / Min

[0610] The retention times were analyzed using an analytical column under the following conditions, and the retention times are provided in Table 1B:

[0611] Column: (S,S)-Welk-0-1.8 50×4.6mm I.D., 1.8μm

[0612] Mobile phase A: CO2

[0613] Mobile phase B: 40% ethanol (0.05% DEA)

[0614] Flow rate: 2.8mL / min

[0615] Column temperature: 35°C

[0616] ABPR pressure: 1500psi.

[0617] Table 1B. Examples 9 to 12

[0618]

[0619] The compounds in Table 1C were prepared from suitable starting materials under conditions similar to those of Examples 3 and 4. The starting materials may be commercially available or may be synthesized by reference to the examples provided herein and common general knowledge. For example, the reaction time may be adjusted by monitoring by chromatography or similar means to complete the reaction. The crude product was then subjected to chiral separation on a preparative column under conditions similar to Separation Condition A to obtain the enantiomers (necessary variations were made to the mobile phase used (e.g., MeOH, EtOH, isopropanol, ACN, or a 1:1 mixture thereof) and the gradient (e.g., 35% B, 40% B, 55% B, or 60% B) to optimize performance). The analytical conditions used were as follows, and the retention times are provided in Table 1C:

[0620] Column: AD-3 50x4.6mm I.D., 3μm

[0621] Mobile Phase A: CO2

[0622] Mobile Phase B: isopropanol (0.05% DEA)

[0623] Gradient: a) 0 - 2.5 min: 5% B - 95% A adjusted to 40% B - 60% A;

[0624] b) 2.5 min - 3.0 min: held at 40% B - 60% A;

[0625] c) 3.0 min - 4.0 min: 40% B - 60% A adjusted to 5% B - 95% A.

[0626] Flow Rate: 4 mL / min

[0627] Column Temperature: 35°C

[0628] Auto Back Pressure Regulator (ABPR) Pressure: 1500 psi.

[0629] Table 1C. Examples 13 and 14

[0630]

[0631] For clarity, Enantiomer 1 above refers to the enantiomer that elutes first from the preparative column stationary phase; and Enantiomer 2 above refers to the enantiomer that elutes second from the preparative column stationary phase.

[0632] Each of the compounds described in Examples 1 - 14 is referred to as Compound 1 - 14, respectively.

[0633] The compound 15 of Example 15 in Table 2 below can be synthesized according to Schemes 1 and 3 above and with reference to the conditions described in Examples 3 and 4, and separated using conditions similar to those described in Examples 3 - 14.

[0634] Table 2. Example 15

[0635]

[0636] Compounds 16 to 57 in Table 2A below were synthesized according to the above Schemes 1-3 with reference to the conditions described in Examples 3 and 4, and separated on a preparative column under conditions similar to Separation Condition A (with necessary variations in column type, mobile phase, and gradient as shown in Table 2A).

[0637] Table 2A. Examples 16 to 57

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644] Compounds 58 to 68 in Table 3 below were synthesized according to the above Schemes 1-3 with reference to the conditions described in Examples 3 and 4, and separated on a preparative column under conditions similar to Separation Condition A (with necessary variations in mobile phase and gradient as shown in Table 3).

[0645] Table 3: Examples 58 - 68

[0646]

[0647]

[0648]

[0649]

[0650] Example 69

[0651] (S)-N-(5-Fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[d][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide

[0652]

[0653] Step 1

[0654] (5S)-Methyl 2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0655]

[0656] Phosphorus oxychloride (POCl3) (740 g) was added to a solution of (5S)-methyl 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, 5V) and extracted with EtOAc (1.60 L x 3). The combined organic layers were washed with saturated aqueous NaCl solution (800 mL, 1V), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (5S)-methyl 2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (985 g) as a brown solid.

[0657] Step 2

[0658] (5S)-2-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid

[0659]

[0660] Sodium hydroxide NaOH (232 g) was added to a solution of (5S)-methyl 2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (328 g) in H2O (984 mL) and THF (984 mL). Methanol (984 mL, 3V) 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 with 3M HCl (10V) at 5 - 10 °C. The solid was gradually 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.

[0661] Step 3

[0662] (5S)-2-Hydrazino-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid

[0663]

[0664] N2H 4·H2O (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, 6V). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove N2H 4· H2O. The residue was diluted with MeCN (2.20 L, 4V), then filtered and the insoluble matter was removed. 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.

[0665] Step 4

[0666] (S)-6-Methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid

[0667]

[0668] At 100 °C, 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, 4V) was stirred 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, 2.5V) and stirred at 0 °C for 1 h. The mixture was filtered and washed with water (3.90 L, 3V), then 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.

[0669] Step 5

[0670] (S)-N-(5-Fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide

[0671]

[0672] 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, 6V). 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 at 25 °C by the addition of H2O (2.00 L, 5V), then extracted with DCM (2.46 L, 2V x 3). The combined organic layers were washed with saturated aqueous NaCl solution (410 mL, 1V), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography, eluting with an EtOAc solution of 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, 61.7% yield, 99.6 purity) as an off-white solid.

[0673] hAHR nuclear translocation assay

[0674] The purpose of this assay was to determine the ability of the compound to bind, activate, and induce the translocation of AhR to the nucleus for transcription. A stable cell line was established using the Jump-In TM T-REx TM HEK293 Retargeting Kit (Life Technologies). The human AhR cDNA was cloned into the pJTI R4 CMV-TO EGFP vector. EGFP was cloned to the C-terminus of AHR to form an AhR-EGFP chimera. Using HD, the pJTI R4 CMV-TO AhR-EGFP vector was transfected into Jump-In TM T-REx TM HEK293 cells. The transfected cells were screened with 2.5 mg / ml G418 for 10 to 14 days, then amplified, harvested, and seeded at 2x10 7Cells / ml were suspended in cryopreservation medium (FBS containing 8% DMSO), and aliquots were stored in liquid nitrogen. One day before the detection date, the cells were thawed and resuspended in DMEM medium containing 5% FBS and 1 μg / ml doxycycline, and seeded into a poly-L-lysine-coated CELLCARRIER-384 ULTRA microplate (Perkin Elmer) at 12,000 to 15,000 cells per well and incubated overnight at 37 °C and 5% CO2. On the day of the detection date, an acoustic dispenser The compounds were serially diluted (1:2) with DMSO into a 384-well nunc plate. The dose-response curve was a 20-point curve. The compounds were resuspended in 40 μl of DMEM plus 0.1% BSA. The medium was damped and 25 μl of DMEM plus 0.1% BSA was added, and then 25 μL of DMEM containing the compounds plus 0.1% BSA was added to the cell plate. The cells were incubated with the compounds at 37 °C and 5% CO2 for 45 minutes. The final DMSO concentration was 0.2%. After incubating for 45 minutes, the medium was damped. The cells were fixed with 40 μl of cold methanol (-20 °C) for 20 minutes. After wetting with methanol, 50 μL of DPBS containing 1 μg / mL Hochst was added to the cell plate. By using Opera or a high-content imaging system (Perkin Elmer), equipped with a 20x aqueous objective lens, and 5 fields of view per well, the intensity of EGFP was quantified. The ratio of the EGFP fluorescence intensity in the nucleus to that in the cytoplasm was analyzed using a four-parameter non-linear logistic equation to determine the potency of the AhR agonist.

[0675] Table 3 shows the hAHR nuclear translocation assay data of certain compounds in the above examples. The name "A" refers to EC 50 <= 1 nM; "B" refers to 1 nM < EC 50 <= 10 nM; "C" refers to 10 nM < EC 50 <= 50 nM; "D" refers to EC 50 > 50 nM. "-" indicates that the activity was not tested.

[0676] Table 3. hAHR nuclear translocation assay EC 50 value

[0677]

[0678] Certain compounds of the present disclosure are novel aryl hydrocarbon receptor (AHR) agonists, as shown in the above-described hAHR nuclear translocation assay. Other 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 demonstrated to be AHR agonists using the same or similar assay techniques described above. These compounds and examples provided herein are considered useful for treating immune-mediated diseases (IMDs), particularly psoriasis and atopic dermatitis, etc.

Claims

1. A compound of the following formula, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each 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 or 3 heteroatoms, wherein each heteroatom of said heteroaryl is independently selected from N, S, and O; R is H or C 1-3 alkyl; X is H, a halogen, a C 1-3 alkyl optionally substituted by one or more halogens, or a C 1-3 alkoxy; Y is H, C 1-4 alkyl or C 3-4 cycloalkyl, wherein C 1-4 alkyl is primary or secondary alkyl; and Z is CH or N.

2. The compound, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof according to claim 1, wherein R is H.

3. The compound according to claim 1, its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts, wherein selected from 4. The compound, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof according to claim 1, which has the following formula: Wherein: X is H or halogen; Y is H or C 1-3 alkyl; and W is CH or N.

5. The compound, its stereoisomers or mixtures of stereoisomers, or their respective pharmaceutically acceptable salts according to any one of claims 1-4, wherein selected from:

6. The compound or a pharmaceutically acceptable salt of each thereof according to any one of claims 1-4, wherein ring A is phenyl.

7. A compound, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4, wherein ring A is 8. The compound, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof according to claim 1, which has the following formula: Wherein: X is H or halogen; Y is H or C 1-3 alkyl; and W is CH or N.

9. The compound, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof according to any of the preceding claims, wherein Z is N.

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

11. The compound, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof according to claim 4 or 8, wherein W is N.

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

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

14. The compound, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof according to claim 1, which is selected from the following table:

15. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the following table:

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

17. The compound, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof according to claim 1, which has the following formula:

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

19. The compound, stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof according to claim 1, which has the following formula:

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

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

22. A method for treating an immune-mediated disease in a patient in need thereof, which comprises administering to the patient an effective amount of a compound, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, or a pharmaceutical composition according to claim 21.

23. A method 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 in a patient in need thereof, which comprises administering to the patient an effective amount of a compound, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, or a pharmaceutical composition according to claim 21.

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

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

26. A compound, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, for use in treating psoriasis.

27. A compound, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, for use in treating atopic dermatitis.

28. A compound, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, for use in treating ulcerative colitis.

29. A compound, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, for use in treating Crohn's disease.

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

31. A compound, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, for use in treating rheumatoid arthritis.

32. A compound, a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, for use in treating multiple sclerosis.

33. The compound, its stereoisomers or mixtures of stereoisomers, or its pharmaceutically acceptable salts according to any one of claims 1 to 20, for use in the treatment of systemic lupus erythematosus (SLE).

34. A compound of the following formula: or a salt thereof, wherein R 0 is C 1-3 alkyl.

35. A compound of the following formula: or a salt thereof, wherein R 0 is C 1-3 alkyl.

36. A process for preparing the compound of claim 35, which comprises contacting a compound of the following formula: with molecular hydrogen under conditions sufficient to obtain the compound of claim 35.

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