Rxfp1 receptor agonists

Abstract

The present invention provides compounds of the following formula: wherein G1, G2, -X-, R1, R2, R3, R4, and ring A are as described herein, pharmaceutically acceptable salts thereof, and methods of using these compounds and pharmaceutically acceptable salts thereof to treat cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders in a patient.

Description

Technical Field

[0001] This invention relates to small molecule RXFP1 agonists and their uses. Background Technology

[0002] Human relaxin-2 (relaxin) is an insulin-like peptide known to regulate cardiovascular, renal, and pulmonary adaptations during pregnancy. Preclinical studies and recent clinical trials using the short-acting recombinant relaxin serelaxin have shown promise as a therapeutic agent for cardiovascular and fibrotic diseases.

[0003] However, relaxin has several limitations, such as poor oral bioavailability, short half-life, and high production and storage costs. Similarly, relaxin family peptide receptor-1 (RXFP1) peptide agonists require subcutaneous / intravenous administration.

[0004] Small molecule modulators of RXFP1 have also been sought. For example, McBride A et al. (2017) ScientificReports 7:10806 discussed small molecule orthoallosteric modulators of RXFP1. WO2022 / 122773 discloses small molecule carboxylic acid derivatives that can be used as modulators of RXRP1.

[0005] There remains a need to provide alternative small-molecule RXFP1 agonists. In particular, there is a need to provide orally deliverable RXFP1 agonists for the treatment of cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders. Furthermore, there is a need to provide RXFP1 receptor agonists exhibiting better pharmacokinetic / pharmacodynamic properties. Additionally, there is a need to provide RXFP1 receptor agonists that exhibit potency and have reduced or minimized adverse or undesirable effects. More specifically, there is a need to provide small-molecule RXFP1 receptor agonists that are selective for RXFP1 relative to relaxin family peptide receptor-2 (RXFP2). This invention addresses one or more of these needs by providing novel small-molecule RXFP1 agonists. Summary of the Invention

[0006] This article provides compounds of formula I. Formula I in G1 is -C(R) a - or -N-; G2 is -C(R) b - or -N-; Ring A is a group of the following formula , , , , or , in , or For unsubstituted or by one or more halogens or C 1-3 Alkyl substitution; -X- is either -NH- or -S-; R a -H or -F; R b -H or -F; R1 is C 1-3 alkoxy or cyclopropoxy, wherein C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; R2 is a group in the following formula , , , , , , , , , , , or ; R 2a For one or more C 1-3 Alkyl, -OH, -N(R)2, oxo, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazolium, pyrimidine, piperazine, pyrrolidine, pyrazine, thiomorpholine 1,1-dioxide or , Wherein C 1-3 The alkyl group is unsubstituted or substituted with one or more -OH, oxo, or morpholine groups, wherein the morpholine group is unsubstituted or substituted with C. 1-3 Alkyl-bridged substitution, wherein the oxadiazole, thiadiazole, pyrimidine, piperazine, pyrazine, or morpholine is unsubstituted or substituted with an oxo group, wherein the pyrimidine, piperazine, and pyrazine are unsubstituted or substituted with an oxo group. 1-3 Alkyl substitution, wherein the pyrrolidine is unsubstituted or substituted with -OH, and wherein the pyrrole is unsubstituted or substituted with -OH; Each R is independently C 1-3 alkyl; -G 3a -for-CHR 2b -or -CH2-O-CH2-; -Y- is C 1-3 Alkylene; R 2b-COOH; R 2c It is -H or halogen; R3 is a group in the following formula: , , or ; -G4- is either -CH- or -N-; R 3a Each occurrence is independently -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; R 3b Each time it appears, it is independently -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN, or C. 1-4 alkyl; R 3c It is independently -H or halogen each time it appears; R 3d -H, halogen, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; R4 is -H, -CN, or C 1-3 Alkyl, wherein C 1-3 The alkyl group is either unsubstituted or substituted with -CN; Or its pharmaceutically acceptable salt.

[0007] The following are further numbered aspects of the invention: 1. Compounds with the following formula: G1 is -C(R) a - or -N-; G2 is -C(R) b - or -N-; Ring A is a group of the following formula , , , or , in , or For unsubstituted or by one or more halogens or C 1-3 Alkyl substitution; -X- is either -NH- or -S-; R a -H or halogen; R b It is -H or halogen; R1 is C 1-3 alkoxy or cyclopropoxy, wherein C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; R2 is a group in the following formula , , , , , , , , , , , or ; R 2a For one or more C 1-3 Alkyl, -OH, oxo, -N(R)2, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazolium, pyrimidine, piperazine, pyrrolidine, pyrazine, thiomorpholine 1,1-dioxide or , Wherein C 1-3 The alkyl group is unsubstituted or substituted with one or more -OH, oxo, or morpholine groups, wherein the morpholine group is unsubstituted or substituted with C. 1-3 Alkyl-bridged substitution, wherein the oxadiazole, thiadiazole, pyrimidine, piperazine, pyrazine, or morpholine is unsubstituted or substituted with an oxo group, wherein the pyrimidine, piperazine, and pyrazine are unsubstituted or substituted with an oxo group. 1-3 Alkyl substitution, wherein the pyrrolidine is unsubstituted or substituted with -OH, and wherein the pyrrole is unsubstituted or substituted with -OH; Each R is independently C 1-3 alkyl; -G 3a -for-CHR 2b -or -CH2-O-CH2-; -Y- is C 1-3 Alkylene; R 2b -COOH; R 2c It is -H or halogen; R3 is a group in the following formula: , , or ; -G4- is either -CH- or -N-; R 3a Each occurrence is independently -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; R 3b Each time it appears, it is independently -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN, or C. 1-4 alkyl; R 3c It is independently -H or halogen each time it appears; R 3d Each occurrence is independently of -H, halogen, or C. 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; R4 is -H, -CN, or C 1-3 Alkyl, wherein C 1-3 The alkyl group is either unsubstituted or substituted with -CN; Or its pharmaceutically acceptable salt.

[0008] This document also provides methods for treating cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders using compounds of Formula I, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. The methods include administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need.

[0009] This document further provides for use in therapeutics of Formula I compounds and pharmaceutically acceptable salts thereof. This document also provides for use in the treatment of cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders of the cardiovascular, pulmonary, and / or renal nature. This document further provides for the use of Formula I compounds or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders of the cardiovascular, pulmonary, and / or renal nature. Detailed Implementation

[0010] This article describes novel RXFP1 receptor agonists. These new compounds address some or all of the aforementioned need for novel RXFP1 receptor agonists for the treatment of cardiovascular, pulmonary and / or renal conditions, diseases and / or disorders.

[0011] This invention provides a compound of formula I: Formula I G1, G2, R1, -X-, R2, R3, R4 and ring A are as defined above, or their pharmaceutically acceptable salts.

[0012] The following are further numbered aspects of the invention: 1. The following compound: Formula I in: G1 is -C(R) a - or -N-; G2 is -C(R) b - or -N-; Ring A is a group of the following formula , , , or , in , or For unsubstituted or by one or more halogens or C 1-3 Alkyl substitution; -X- represents -NH- or -S-; R a It is -H or halogen; R b It is -H or halogen; R1 is C 1-3 alkoxy or cyclopropoxy, wherein C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; R2 is a group in the following formula: , , , , , , , , , , , or ; R 2a C 1-3 Alkyl, -OH, oxo, -N(R)2, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazolium, pyrimidine, piperazine, pyrrolidine, pyrazine, thiomorpholine 1,1-dioxide or , Wherein C 1-3 The alkyl group is unsubstituted or substituted with one or more -OH, oxo, or morpholine groups, wherein the morpholine group is unsubstituted or substituted with C. 1-3 Alkyl-bridged substitution, wherein the oxadiazole, thiadiazole, pyrimidine, piperazine, pyrazine, or morpholine is unsubstituted or substituted with an oxo group, wherein the pyrimidine, piperazine, and pyrazine are unsubstituted or substituted with an oxo group. 1-3 Alkyl substitution, wherein the pyrrolidine is unsubstituted or substituted with -OH, and wherein the pyrrole is unsubstituted or substituted with -OH; Each R is independently C 1-3 alkyl; -G 3a -for-CHR 2b -or -CH2-O-CH2-; -Y- is C 1-3 Alkylene; R 2b -COOH; R 2c It is -H or halogen; R3 is a group in the following formula: , , or ; -G4- is either -CH- or -N-; R 3a -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; R 3b -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN or C 1-4 alkyl; R 3c It is independently -H or halogen each time it appears; R 3d -H, halogen, C 1-4Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; R4 is -H, -CN, or C 1-3 Alkyl, wherein C 1-3 The alkyl group is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof.

[0013] 2. The compound according to aspect 1, wherein: R1 is C 1-3 Alkyl groups; or pharmaceutically acceptable salts thereof.

[0014] 3. The compound according to aspect 1 or 2, wherein ring A is a group of the following formula: , , , or , in It is either unsubstituted or substituted with halogens; R1 is C 1-3 Alkoxy; Where R 2a For -OH, -N(R)2, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazolium, pyrimidine, pyrazine, thiomorpholine 1,1-dioxide, or , The pyrimidine, pyrazine, or morpholine therein is unsubstituted or substituted with an oxo group, wherein the pyrimidine and pyrazine are unsubstituted or substituted with an oxo group. 1-3 Alkyl substitution, wherein the pyrrole is unsubstituted or substituted with -OH; R 2c It is -H or halogen; R 3a Each occurrence is independently -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; and R4 is -H or C 1-3 Alkyl, wherein C 1-3 The alkyl group is either unsubstituted or substituted with -CN; Or its pharmaceutically acceptable salt.

[0015] 4. The compound according to aspect 1 or 2, wherein Ring A is a group of the following formula , , or ; R a For –H or -F; R b For –H or -F; R1 is C 1-3 Alkoxy; R2 is a group in the following formula , , , , , , or , Where R 2a The oxadiazole, thiadiazole, morpholine or thiomorpholine 1,1-dioxide is -OH, -N(R)2, oxadiazole, thiadiazole, morpholine or thiomorpholine, wherein the oxadiazole, thiadiazole or morpholine is unsubstituted or substituted with an oxo group; R 3a -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; and R 3d -H, halogen, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; and R4 is -H; or a pharmaceutically acceptable salt thereof.

[0016] 5. The compound according to any one of aspects 1-4, wherein ring A is a group of the following formula. , , or ; R a -H or -F; R b -H or -F; R1 is C 1-3 Alkoxy; R2 is a group in the following formula , , , , , , or ; R 2a The alkane is -OH, -N(R)2, oxadiazole, thiadiazole, morpholine or thiomorpholine 1,1-dioxide, wherein the oxadiazole, thiadiazole or morpholine is unsubstituted or substituted with an oxo group; R3 is a group in the following formula: or ; R 3a -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; Each R 3c Independently -H or -F; and R4 is -H; Or its pharmaceutically acceptable salt.

[0017] 6. The compound according to any one of aspects 1-5, wherein ring A is selected from the group consisting of: and Or, or a pharmaceutically acceptable salt thereof.

[0018] 7. The compound according to any one of aspects 1-3, wherein ring A is a group of the following formula. or Or, or a pharmaceutically acceptable salt thereof.

[0019] 8. The compound according to any one of aspects 1-3, wherein ring A is a group of the following formula. , , or Or its pharmaceutically acceptable salt.

[0020] 9. The compound according to aspect 8, wherein ring A is a group of the following formula Or its pharmaceutically acceptable salt.

[0021] 10. The compound according to aspect 1 or 2, wherein ring A is a group of the following formula Or its pharmaceutically acceptable salt.

[0022] 11. The compound according to any one of aspects 1-10, wherein R4 is -H or a pharmaceutically acceptable salt thereof.

[0023] 12. If the compound defined in any of aspects 1-7 is of formula... Or, or a pharmaceutically acceptable salt thereof.

[0024] 13. The compound defined in any of aspects 1-6 or 8 is of formula [formula missing]. Or, or a pharmaceutically acceptable salt thereof.

[0025] 14. A compound as defined in any one of aspects 1-13, wherein G1 is -N- or a pharmaceutically acceptable salt thereof.

[0026] 15. A compound as defined in any one of aspects 1-13, wherein G1 is -C(R a )-, or its pharmaceutically acceptable salt.

[0027] 16. A compound as defined in aspect 15, wherein R a It is -H, or a pharmaceutically acceptable salt thereof.

[0028] 17. A compound as defined in any one of aspects 1-16, wherein G2 is -N- or a pharmaceutically acceptable salt thereof.

[0029] 18. A compound as defined in any one of aspects 1-16, wherein G2 is -C(R b )-, or its pharmaceutically acceptable salt.

[0030] 19. A compound as defined in aspect 18, wherein R b It is -H, or a pharmaceutically acceptable salt thereof.

[0031] 20. A compound as defined in any one of aspects 1-14 or 17, wherein G1 is -N- and G2 is -N-, or a pharmaceutically acceptable salt thereof.

[0032] 21. A compound as defined in any one of aspects 1-14 or 18, wherein G1 is -N- and G2 is -C(R) b )-, or its pharmaceutically acceptable salt.

[0033] 22. A compound as defined in any one of aspects 1-13 or 16-17, wherein G1 is -C(H)- and G2 is -N-, or a pharmaceutically acceptable salt thereof.

[0034] 23. A compound as defined in any one of aspects 1-13, 16, 18-19, wherein G1 is -C(H)- and G2 is -C(R)-. b )-, or its pharmaceutically acceptable salt.

[0035] 24. A compound as defined in any one of aspects 1, 6-23, wherein R1 is a methoxy, difluoroethoxy, or a pharmaceutically acceptable salt thereof.

[0036] 25. A compound as defined in aspect 24, wherein R1 is a methoxy group or a pharmaceutically acceptable salt thereof.

[0037] 26. The compound as defined in aspect 25 is of formula... Or, or a pharmaceutically acceptable salt thereof.

[0038] 27. The compound as defined in aspect 25 is of formula... Or, or a pharmaceutically acceptable salt thereof.

[0039] 28. A compound as defined in any of aspects 1-4 or 6-27, wherein R3 is a group of the following formula or Or, or a pharmaceutically acceptable salt thereof.

[0040] 29. A compound as defined in aspect 28, wherein R3 is a group of the following formula or Or, or a pharmaceutically acceptable salt thereof.

[0041] 30. A compound as defined in aspect 29, wherein R3 is a group of the following formula Or, or a pharmaceutically acceptable salt thereof.

[0042] 31. A compound as defined in any of aspects 28-30, wherein R 3a It is tert-butyl, -SF5, -SO2CF3 or -SCF3, and R 3b It is -H or a halogen, or a pharmaceutically acceptable salt thereof.

[0043] 32. A compound as defined in any of aspects 28-30, wherein R 3a It is -F, -Cl, -Br, difluoromethyl, difluorochloromethyl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy, and R 3b It is -H, -F, -Cl, -Br, trifluoromethyl, -CN or methyl, or a pharmaceutically acceptable salt thereof.

[0044] 33. A compound as defined in any of aspects 28-30, wherein R 3a and R 3b All are methoxy groups or their pharmaceutically acceptable salts.

[0045] 34. A compound as defined in any one of aspects 1-33, wherein R3 is a group of the following formula Or, or a pharmaceutically acceptable salt thereof.

[0046] 35. The compound according to any one of claims 1-34, wherein -X- is -NH- or a pharmaceutically acceptable salt thereof.

[0047] 36. A compound as defined in any one of aspects 1-35, wherein R2 is a group of the following formula , Or its pharmaceutically acceptable salt.

[0048] 37. The compound according to claim 36, wherein R2 is a group of the following formula. , And R 2a Choose from the following groups: -OH, , , , , , , , , , , , , and Or, or a pharmaceutically acceptable salt thereof.

[0049] 38. The compound according to claim 37, wherein R 2a Choose from the following groups: , and Or, or a pharmaceutically acceptable salt thereof.

[0050] 39. A compound as defined in any one of aspects 1-36, wherein R2 is a group of the following formula , , , or Or, or a pharmaceutically acceptable salt thereof.

[0051] 40. A compound as defined in aspect 39, wherein R2 is a group of the following formula , , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

[0052] 41. A compound as defined in any one of aspects 1-36, wherein R2 is a group of the following formula or Or, or a pharmaceutically acceptable salt thereof.

[0053] 42. A compound as defined in aspect 41, wherein R2 is a group of the following formula , , Or, or a pharmaceutically acceptable salt thereof.

[0054] 43. The compound according to aspect 1, selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

[0055] 44. The compound according to aspect 1 or 2, selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

[0056] 45. The compound according to any one of aspects 1-3, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

[0057] 46. ​​The compound according to any one of aspects 1-5, wherein the compound is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

[0058] 47. A pharmaceutical composition comprising a compound as defined in any one of aspects 1-46 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0059] 48. A method for treating an individual with cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders, the method comprising administering to the individual an effective amount of any one of aspects 1-46 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of aspect 47.

[0060] 49. A method for treating cardiovascular, pulmonary and / or renal conditions, diseases and / or disorders in an individual with such need, the method comprising administering to the individual a therapeutically effective amount of any one of aspects 1-46 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of aspect 47.

[0061] 50. The method of claim 49, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.

[0062] 51. The method of claim 50, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.

[0063] 52. The method of claim 49, wherein the condition, disease, or disorder to be treated is a lung condition, disease, or disorder.

[0064] 53. The method of claim 52, wherein the lung condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

[0065] 54. The method of claim 49, wherein the condition, disease, or disorder to be treated is a kidney condition, disease, or disorder.

[0066] 55. The method of claim 54, wherein the kidney condition, disease, or disorder is acute kidney disease, chronic kidney disease, or diabetic nephropathy.

[0067] 56. The compound of any one of aspects 1-46, used in a therapeutic manner.

[0068] 57. The compound of any one of aspects 1-46, for the treatment of cardiovascular, pulmonary and / or renal conditions, diseases and / or disorders.

[0069] 58. The compound for use according to claim 57, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.

[0070] 59. The compound for use according to claim 58, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.

[0071] 60. The compound for use according to claim 57, wherein the condition, disease, or disorder to be treated is a lung condition, disease, or disorder.

[0072] 61. The compound for use according to claim 60, wherein the lung condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

[0073] 62. The compound for use according to claim 57, wherein the condition, disease, or disorder to be treated is a kidney condition, disease, or disorder.

[0074] 63. The compound for use according to claim 62, wherein the kidney condition, disease, or disorder is acute kidney disease, chronic kidney disease, or diabetic nephropathy.

[0075] 64. The compound of aspect 57 for use, wherein the disease or disorder to be treated is selected from cardiovascular conditions, diseases or disorders such as acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction or ventricular hypertrophy.

[0076] 65. The compound of aspect 57 for use, wherein the disease or disorder to be treated is a lung condition, disease or disorder selected from pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

[0077] 66. The compound of aspect 57 for use, wherein the disease or disorder to be treated is a kidney condition, disease or disorder selected from acute kidney disease, chronic kidney disease or diabetic nephropathy.

[0078] 67. Use of any compound of any one of aspects 1-46 in the manufacture of a medicament for treating cardiovascular, pulmonary and / or renal conditions, diseases and / or disorders.

[0079] 68. The use described in aspect 67, wherein the disease or disorder to be treated is a cardiovascular condition, disease or disorder selected from acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction or ventricular hypertrophy.

[0080] 69. The use described in aspect 67, wherein the disease or disorder to be treated is a lung condition, disease, or disorder selected from pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

[0081] 70. The use described in aspect 67, wherein the disease or disorder to be treated is a kidney condition, disease, or disorder selected from acute kidney disease, chronic kidney disease, or diabetic nephropathy.

[0082] In one embodiment, ring A is a group of the following formula. , , , or , in It is either unsubstituted or substituted with halogens; Where R 2a For -OH, -N(R)2, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazolium, pyrimidine, pyrazine, thiomorpholine 1,1-dioxide, or , The pyrimidine, pyrazine, or morpholine therein is unsubstituted or substituted with an oxo group, wherein the pyrimidine and pyrazine are unsubstituted or substituted with an oxo group. 1-3 Alkyl substitution, wherein the pyrrole is unsubstituted or substituted with -OH; R 3a Each occurrence is independently -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; and R4 is -H or C 1-3 Alkyl, wherein C 1-3 The alkyl group is either unsubstituted or substituted with -CN; Or its pharmaceutically acceptable salt.

[0083] In another embodiment, ring A is a group of the following formula , , or ; R a -H or -F; R b -H or -F; R2 is a group in the following formula , , , , , , or , Where R 2a The oxadiazole, thiadiazole, morpholine or thiomorpholine 1,1-dioxide is -OH, -N(R)2, oxadiazole, thiadiazole, morpholine or thiomorpholine, wherein the oxadiazole, thiadiazole or morpholine is unsubstituted or substituted with an oxo group; R3a -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; Each R 3c Independently -H or -F; R 3d -H, halogen, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; and R4 is -H; or a pharmaceutically acceptable salt thereof.

[0084] In another embodiment, the compound has the formula: , Ring A is a group of the following formula , , or ; R a -H or -F; R b -H or -F; R2 is a group in the following formula , , , , , , or ; R 2a The oxadiazole, thiadiazole, morpholine or thiomorpholine 1,1-dioxide is -OH, -N(R)2, oxadiazole, thiadiazole, morpholine or thiomorpholine, wherein the oxadiazole, thiadiazole or morpholine is unsubstituted or substituted with an oxo group; R3 is a group in the following formula: or ; R 3a -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; Or its pharmaceutically acceptable salt.

[0085] In another implementation, ring A is selected from the group consisting of: and Or, or a pharmaceutically acceptable salt thereof.

[0086] In another embodiment, the compound has the formula: in C 1-3 Alkyl-substituted, or a pharmaceutically acceptable salt thereof.

[0087] In another implementation, ring A is selected from the group consisting of: and Or its pharmaceutically acceptable salt.

[0088] In another embodiment, the compound has the formula: Or its pharmaceutically acceptable salt.

[0089] In another embodiment, the compound is of formula [formula missing]. Or, or a pharmaceutically acceptable salt thereof.

[0090] In another embodiment, G1 is -N-, or a pharmaceutically acceptable salt thereof.

[0091] In another implementation, G1 is -C(R) a )-, or its pharmaceutically acceptable salt.

[0092] In another implementation, R a It is -H, or a pharmaceutically acceptable salt thereof.

[0093] In another embodiment, G2 is -N-, or a pharmaceutically acceptable salt thereof.

[0094] In another implementation, G2 is -C(R) b )-, or its pharmaceutically acceptable salt.

[0095] In another implementation, R b It is -H, or a pharmaceutically acceptable salt thereof.

[0096] In another embodiment, R1 is a methoxy group or a pharmaceutically acceptable salt thereof.

[0097] In another implementation, R3 is selected from the group consisting of: or Or, or a pharmaceutically acceptable salt thereof.

[0098] In another implementation, R3 is selected from the group consisting of: or Or, or a pharmaceutically acceptable salt thereof.

[0099] In another embodiment, R3 is a group of the following formula Or, or a pharmaceutically acceptable salt thereof.

[0100] In another implementation, R 3a It is tert-butyl, -SF5, -SO2CF3 or -SCF3, and R 3b It is -H or -F, or a pharmaceutically acceptable salt thereof.

[0101] In another implementation, R 3a It is -F, -Cl, -Br, difluoromethyl, difluorochloromethyl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy, and R 3b It is -H, -F, -Cl, -Br, trifluoromethyl, -CN or methyl, or a pharmaceutically acceptable salt thereof.

[0102] In another implementation, R 3a and R 3b It is a methoxy group or a pharmaceutically acceptable salt thereof.

[0103] In another embodiment, R2 is a group of the following formula , Or its pharmaceutically acceptable salt.

[0104] In another implementation, R 2a Choose from the following groups: , , Or its pharmaceutically acceptable salt.

[0105] In another implementation, R2 is selected from the group consisting of: , , , and Or, or a pharmaceutically acceptable salt thereof.

[0106] In another implementation, R2 is selected from the group consisting of: , , , , , , , , and Or, or a pharmaceutically acceptable salt thereof.

[0107] In another implementation, R2 is selected from the group consisting of: and Or, or a pharmaceutically acceptable salt thereof.

[0108] In another implementation, R2 is selected from the group consisting of: , and Or, or a pharmaceutically acceptable salt thereof.

[0109] In another embodiment, the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

[0110] In another embodiment, the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

[0111] In another embodiment, the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

[0112] In another embodiment, the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0113] In another embodiment, a method for treating cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders in an individual with such need, the method comprising administering to the individual a therapeutically effective amount of a compound of formula I or a pharmaceutical composition of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0114] In another embodiment, the method relating to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.

[0115] In another embodiment, the method relating to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.

[0116] In another embodiment, the method relating to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a lung condition, disease, or disorder.

[0117] In another embodiment, the method relating to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the lung condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

[0118] In another embodiment, the method relating to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a kidney condition, disease, or disorder.

[0119] In another embodiment, the method relating to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the kidney condition, disease, or disorder is acute kidney disease, chronic kidney disease, or diabetic nephropathy.

[0120] In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is used in the therapy.

[0121] In another embodiment, the Formula I compound or a pharmaceutically acceptable salt thereof is used to treat cardiovascular, pulmonary and / or renal conditions, diseases and / or disorders.

[0122] In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is used, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.

[0123] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is used, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.

[0124] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is used, wherein the condition, disease, or disorder to be treated is a lung condition, disease, or disorder.

[0125] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is used, wherein the lung condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

[0126] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is used, wherein the condition, disease, or disorder to be treated is a kidney condition, disease, or disorder.

[0127] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is used, wherein the kidney condition, disease, or disorder is acute kidney disease, chronic kidney disease, or diabetic nephropathy.

[0128] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cardiovascular, pulmonary and / or renal conditions, diseases and / or disorders.

[0129] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.

[0130] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.

[0131] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a lung condition, disease, or disorder.

[0132] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the lung condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

[0133] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a kidney condition, disease, or disorder.

[0134] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the kidney condition, disease, or disorder is acute kidney disease, chronic kidney disease, or diabetic nephropathy.

[0135] In another embodiment, a method for exhibiting agonist activity in the RXFP1 receptor in an individual with this need comprises administering to the individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0136] In embodiments of the compounds of Formula I above, or pharmaceutically acceptable salts thereof, the chemical structural formula is shown in planar form without chiral information. These compounds typically have multiple chiral centers and are expected to exist in various forms and combinations of chiral centers. Furthermore, these compounds have various enantiomers, diastereomers, and transisomers that may exist and are included herein.

[0137] In one embodiment of a compound of formula I or a pharmaceutically acceptable salt thereof, the compound is an isotopic derivative of any of the compounds described herein or a pharmaceutically acceptable salt thereof.

[0138] It should be understood that the isotope derivatives can be prepared using any of a variety of techniques recognized in the art. For example, the isotope derivatives can typically be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents, by performing the procedures disclosed in the schemes and / or examples described herein, or by using a pharmaceutically acceptable salt thereof.

[0139] In one embodiment of a compound of formula I or a pharmaceutically acceptable salt thereof, said compound is a deuterated compound of any of the compounds described herein or a pharmaceutically acceptable salt thereof.

[0140] In the compounds of this invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when an atom is specifically designated as "H" or "hydrogen", that atom should be understood as hydrogen having its naturally occurring isotopic composition. Furthermore, unless otherwise stated, when an atom is specifically designated as "D" or "deuterium", that atom should be understood as deuterium having a significantly greater natural abundance than deuterium (which is 0.015%).

[0141] Compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the compound is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Or, or a pharmaceutically acceptable salt thereof.

[0142] This document also provides pharmaceutical compositions comprising a compound according to Formula I or a pharmaceutically acceptable salt thereof (examples of which include, but are not limited to, the compounds disclosed herein), and a pharmaceutically acceptable carrier, diluent, or excipient.

[0143] This article further provides methods for treating cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders, comprising administering to a patient in need an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof. This article further provides methods for treating cardiovascular conditions, diseases, and / or disorders, comprising administering to a patient in need an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof. This article further provides methods for treating pulmonary conditions, diseases, and / or disorders, comprising administering to a patient in need an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof. This article further provides methods for treating renal conditions, diseases, and / or disorders, comprising administering to a patient in need an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.

[0144] This article further provides compounds of formula I or thereof for use in therapeutics, or pharmaceutically acceptable salts thereof. This article further provides compounds of formula I or thereof for use in the treatment of cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders, or pharmaceutically acceptable salts thereof. This article further provides compounds of formula I or thereof for use in therapeutics, or pharmaceutically acceptable salts thereof. This article further provides compounds of formula I or thereof for use in the treatment of cardiovascular conditions, diseases, and / or disorders, or pharmaceutically acceptable salts thereof. This article further provides compounds of formula I or thereof for use in therapeutics, or pharmaceutically acceptable salts thereof. This article further provides compounds of formula I or thereof for use in the treatment of pulmonary conditions, diseases, and / or disorders, or pharmaceutically acceptable salts thereof. This article further provides compounds of formula I or thereof for use in therapeutics, or pharmaceutically acceptable salts thereof. This article further provides compounds of formula I or thereof for use in the treatment of renal conditions, diseases, and / or disorders, or pharmaceutically acceptable salts thereof.

[0145] In the methods or uses described herein, cardiovascular conditions, diseases, and disorders include, but are not limited to, acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, and ventricular hypertrophy. In the methods or uses described herein, pulmonary conditions, diseases, and disorders include, but are not limited to, pulmonary hypertension and chronic obstructive pulmonary disease (COPD). In the methods or uses described herein, kidney conditions, diseases, and disorders include, but are not limited to, acute kidney disease, chronic kidney disease, and diabetic nephropathy.

[0146] The method may also include the step of administering a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with an effective amount of at least one additional therapeutic agent. In summary, standard care for many conditions / diseases / disorders described herein includes anticoagulants, ACE inhibitors, ARBs, ARNIs, beta-blockers, diuretics, digitalis, digoxin, hydralazine / isosorbide dinitrate, MRAs or other aldosterone antagonists, SGLT2 inhibitors, statins and / or antiglycemic agents, as well as other therapeutic agents for controlling comorbidities, including but not limited to high cholesterol, high blood pressure, atrial fibrillation, diabetes, and obesity. In some cases, the additional therapeutic agent may be administered simultaneously, separately, or sequentially with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0147] This document further provides compounds of Formula I or their pharmaceutically acceptable salts for use in the treatment of cardiovascular, pulmonary and / or renal conditions, diseases and / or disorders, concurrently, separately or sequentially with at least one additional therapeutic agent. The additional therapeutic agents include, but are not limited to, anticoagulants, ACE inhibitors, ARBs, ARNIs, beta-blockers, diuretics, digitalis, digoxin, hydralazine / isosorbide dinitrate, MRAs or other aldosterone antagonists, SGLT2 inhibitors, statins and / or antiglycemic agents, and other therapeutic agents for the control of comorbidities, including but not limited to high cholesterol, high blood pressure, atrial fibrillation and diabetes.

[0148] The methods or uses described herein may include the steps described herein, and these steps may be performed in the order described, but are not required to be so. However, other orders are also contemplated. Furthermore, single or multiple steps may be performed in parallel, and / or overlap in time, and / or performed individually or as repeated steps. In addition, the methods may include additional unspecified steps.

[0149] Therefore, such methods or uses may include selecting individuals with cardiovascular conditions, diseases, or disabilities, or those with a predisposition to them. Alternatively, the methods may include selecting individuals with pulmonary conditions, diseases, or disabilities, or those with a predisposition to them. Alternatively, the methods may include selecting individuals with kidney conditions, diseases, or disabilities, or those with a predisposition to them. In some cases, the methods may include selecting individuals with diabetes, hypertension with impaired kidney function, and / or obesity.

[0150] In some cases, the individuals in need are those with diabetes, hypertension with impaired kidney function, and / or obesity.

[0151] The methods or uses described may also be combined with diet and exercise, and / or with other therapeutic agents besides those discussed above.

[0152] As used herein, the term “pharmaceuticalally acceptable salt” refers to a salt of a compound that is considered acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and common methods of their preparation can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use”, P. Stahl et al., 2nd revised edition, Wiley-VCH, 2011 and SM Berge et al., “Pharmaceutical Salts”, 1977, 66(1), 1-19.

[0153] Pharmaceutical compositions containing a compound of Formula I as described herein or a pharmaceutically acceptable salt thereof may be prepared using pharmaceutically acceptable additives. As used herein, the term "pharmaceutically acceptable additive" in relation to a pharmaceutical composition refers to one or more carriers, diluents, and excipients that are compatible with other additives in the composition or formulation and are harmless to the patient. Examples of pharmaceutical compositions and methods of their preparation can be found in "Remington: The Science and Practice of Pharmacy", edited by Loyd, V et al., 22nd edition, Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include: saline, water, starch, sugars, mannitol, and silica derivatives; binders such as carboxymethyl cellulose, alginate, gelatin, and polyvinylpyrrolidone; kaolin and bentonite; and polyethylene glycol.

[0154] As used herein, "effective amount" means the amount or dose of a Formula I compound or a pharmaceutically acceptable salt thereof that, when administered to an individual in need in a single or multiple doses, provides the desired effect in that individual for diagnosis or treatment (i.e., produces a clinically measurable difference in the individual's condition, such as increased angiogenesis, increased vascular compliance, increased cardiovascular blood flow, increased hepatic blood flow, increased pulmonary blood flow, increased renal blood flow, increased glomerular filtration rate, decreased blood pressure, decreased (or prevented) inflammation, and / or reduced (or prevented) fibrosis in the heart, kidneys, liver, or lungs). Effective amounts can be readily determined by those skilled in the art using known techniques and by observing results obtained in similar circumstances. In determining an individual's effective amount, a variety of factors are considered, including but not limited to the mammalian species, its size, age, and general health condition, the specific disease or disorder involved, the extent or severity of the disease or disorder, the individual's response, the specific Formula I compound or a pharmaceutically acceptable salt thereof administered, the route of administration, the bioavailability characteristics of the administered formulation, the chosen dosing regimen, the use of concomitant medications, and other relevant circumstances.

[0155] As used herein, “treatment” or “to be treated” refers to the management and care of an individual with a condition, disease, disorder, or symptom, and the administration of a Formula I compound or a pharmaceutically acceptable salt thereof indicated to reduce, inhibit, reverse, slow, or prevent the progression or severity of the condition, disease, disorder, and / or symptom. Treatment includes administering to an individual a Formula I compound or a pharmaceutically acceptable salt thereof, or a composition containing a Formula I compound or a pharmaceutically acceptable salt thereof, to prevent the onset of symptoms or complications, reduce symptoms or complications, or eliminate the condition, disease, disorder, or symptom. Treatment includes administering to an individual a Formula I compound or a pharmaceutically acceptable salt thereof, or a composition containing a Formula I compound or a pharmaceutically acceptable salt thereof, to produce, for example, increased angiogenesis, increased vascular compliance, increased cardiovascular blood flow, increased hepatic blood flow, increased pulmonary blood flow, increased renal blood flow, increased glomerular filtration rate, decreased blood pressure, reduced (or prevented) inflammation, and / or reduced (or prevented) fibrosis in the heart, kidneys, liver, or lungs. The individual to be treated is a mammal, particularly a human.

[0156] As used herein, “individual,” “patient,” and “subject” are used interchangeably and refer to mammals, particularly humans. In some cases, the individual is further characterized by a condition, disease, disorder, and / or symptom that would benefit from administration of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0157] As used herein, the term halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). As used herein, the term alkyl refers to a saturated straight-chain or branched monovalent hydrocarbon group with one to a specified number of carbon atoms, such as "C". 1-4 "alkyl" or "C" 1-3 Alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, and isobutyl. As used herein, the term alkylene refers to a saturated straight-chain or branched divalent hydrocarbon group with one to a specified number of carbon atoms, such as "C". 1-3 Alkylene. Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, 1-propylene, and isopropylene. As used herein, the term alkoxy refers to an alkyl substituent to which an oxygen group is attached, such as "C". 1-3 Alkoxy group. C 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 1-propoxy, and isopropoxy.

[0158] Some abbreviations are defined as follows: "ACN" refers to acetonitrile; "AcOH" refers to acetic acid; "BOC" or "Boc" refers to tert-butyloxycarbonyl; "Boc2O" refers to ditert-butyl dicarbonate; "BOP-Cl" refers to bis(2-oxo-3-oxazolyl)phosphinochloride; "CH3ONa" refers to sodium methoxide; "DCE" refers to 1,2-dichloroethane; "DEE" refers to diethyl ether; "DiPEA" refers to diisopropylethylamine; "DCM" refers to dichloromethane; "DMF" refers to dimethylformamide; "EtOAc" refers to ethyl acetate; "ES-MS" refers to electrospray mass spectrometry; "EtOH" refers to ethanol; "FA" refers to nail acid; "h" refers to hour; "HATU" refers to azirzotriazole tetramethylurea hexafluorophosphate; "HPLC" refers to high performance liquid chromatography; "IPA" refers to isopropanol; "KOBu" refers to potassium tert-butoxide; "LD" refers to... "A" refers to lithium diisopropylamino; "CPBA" refers to m-chloroperoxybenzoic acid; "MeOH" refers to methanol; "min" refers to minutes; "MTBE" refers to methyl tert-butyl ether; "NaBH3CN" refers to sodium cyanoborohydride; "NMI" refers to methylimidazole; "NMP" refers to methyl-2-pyrrolidone; "PG" refers to protecting group; "PPACA" refers to 1-propanephosphonic anhydride; "Preparative-HPLC" refers to preparative high-performance liquid chromatography; "Preparative-TLC" refers to preparative thin-layer chromatography; "TsOH" refers to p-toluenesulfonic acid; "RT" refers to room temperature; "sat." refers to saturated; "SCX" refers to strong cation exchange; "TCFH" refers to tetramethylformamidinium hexafluorophosphate; "TEA" refers to triethylamine; "TFA" refers to trifluoroacetic acid; "TFAA" refers to trifluoroacetic anhydride; and "THF" refers to tetrahydrofuran.

[0159] As used herein, the term "alkyl" refers to a hydrocarbon chain that can be straight or branched and contains a specified number of carbon atoms. For example, as used herein, the term "C" refers to a hydrocarbon chain that is straight or branched and contains a specified number of carbon atoms. 1-4 "Alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group having one, two, three, or four carbon atoms. 1-4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, and 2-methyl-2-propyl. For example, as used herein, the term "C 1-3 "Alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group having one, two, or three carbon atoms. C 1-3 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, or isopropyl.

[0160] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group containing a specified number of carbon atoms. For example, as used herein, the term "C60" refers to a cyclic hydrocarbon group containing a specified number of carbon atoms. 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group having three, four, five, or six carbon atoms. C 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0161] As used in this article, the term "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine), and I (iodine).

[0162] As used in this article, the term "oxo" refers to the substitution of CH2 with O to form C(O).

[0163] Individual isomers, enantiomers, diastereomers, and transisomers may be separated or resolved at any convenient point in the synthesis of the compounds listed below by means of methods such as selective crystallization or chiral chromatography (see, for example, J. Jacques et al., "", John Wiley and Sons, Inc., 1981, and EL Eliel and SH Wilen, "", Wiley-Interscience, 1994). This specification is intended to include all possible isomers, enantiomers, diastereomers, and transisomers of the compounds disclosed herein, or all isomers, enantiomers, diastereomers, and transisomers that can be prepared using the compounds disclosed herein. In the molecules described herein, only those molecules in which the absolute configuration (or transisomer configuration) of the chiral center is known are indicated by nomenclature or drawn chemical formulas. Those skilled in the art will readily understand when other chiral centers are present in the molecules described herein and will be able to identify them.

[0164] Any compound in Formula I capable of chemically forming a salt is readily converted and can be separated as a pharmaceutically acceptable salt. Salt formation can occur upon the addition of a pharmaceutically acceptable acid to form an acid addition salt. Salts can also form simultaneously with the deprotection of nitrogen or oxygen (i.e., removal of the protecting group). Examples, reactions, and conditions of salt formation can be found in Gould, PL, "Saltselection for basic drugs," 33: 201-217 (1986); Bastin, RJ et al., "SaltSelection and Optimization Procedures for Pharmaceutical New Chemical Entities," 4: 427-435 (2000); and Berge, SM et al., "Pharmaceutical Salts," 66: 1-19, (1977).

[0165] The compounds of the present invention or their salts can be prepared by a variety of procedures, some of which are illustrated in the following schemes, preparations, and examples. Specific synthetic steps in the described routes can be combined in different ways, or combined with steps from different routes, to prepare the compounds or salts of the present invention. The products of each step in the preparations below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, grinding, and crystallization.

[0166] Furthermore, some intermediates described in the following preparations may contain one or more nitrogen protecting groups. It should be understood that the protecting groups can vary, as will be understood by those skilled in the art, depending on the specific reaction conditions and the specific transformation to be performed. Those skilled in the art will understand that deprotected amines can be functionalized via various methods known in the literature. Protecting and deprotecting conditions are well known to those skilled in the art and are described in the literature (see, for example, "Greene's Protective Groups in Organic Synthesis", 5th edition, by Peter GM Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2014).

[0167] Examples of known procedures and methods include those described in general reference texts, such as *Comprehensive Organic Transformations*, VCH Publishers Inc, 1989; *Compendium of Organic Synthetic Methods*, Volumes 1-10, 1974-2002, Wiley Interscience; *Advanced Organic Chemistry*, *Reactions Mechanisms, and Structure*, 5th edition, Michael B. Smith and Jerry March, Wiley Interscience, 2001; *Advanced Organic Chemistry*, 4th edition, Part B, *Reactions and Synthesis*, Francis A. Carey and Richard J. Sundberg, Kluwer Academic / Plenum Publishers, 2000, etc., and the references cited therein.

[0168] In the following scheme, R1, R2, R3, R4, G1, G2, X, and A are defined as in Equation I.

[0169] Option 1 Scheme 1 describes the preparation of the compound of the present invention starting from a suitable amine 1 and a carboxylic acid 2. The PG moiety on the amine of carboxylic acid 2 is a standard amine protecting group known to those skilled in the art, including urethane and amide protecting groups. Carboxylic acid 2 reacts with amine 1 under standard amide coupling conditions to prepare amide 3 in step 1. Suitable amide coupling conditions are known to those skilled in the art and include reacting a solution of carboxylic acid 2 and the desired amine 1 in a suitable solvent such as ACN with a suitable coupling agent such as TCFH or PPACA in the presence of a suitable organic base such as DiPEA or NMI, wherein stirring is carried out at room temperature for at least 35 minutes. Removal of the PG moiety from the amine of amide 3 is carried out under standard conditions in the art. For example, if PG is BOC, intermediate amine 4 is obtained by reacting a suitable acid such as TFA with a stirred solution of amide 3 in a suitable solvent such as DCM at room temperature for at least 18 hours. The resulting amine 4 reacts with a suitable acid 5 (“W” indicates a halogen) under amide coupling conditions known to those skilled in the art as shown in step 3. A suitable coupling agent, such as oxalyl chloride, is introduced into a stirred solution of carboxylic acid 5 at 0°C, followed by dropwise addition of DMF. Once the reaction mixture has been stirred at room temperature for at least 30 minutes, amine 4 is added, followed by a suitable organic base, such as DiPEA, and the reaction mixture is further stirred at room temperature for at least 1.5 hours.

[0170] In step 4, intermediate 6 is reacted with a suitable amine 7 under nucleophilic aromatic substitution conditions known to those skilled in the art to yield 8. Suitable nucleophilic aromatic substitution conditions involve reacting a compound with a suitable halogen W (such as fluorine or chlorine) on its aromatic moiety with a suitable nucleophilic reactant such as an amine. The reaction is carried out at at least 60°C in a suitable organic solvent such as NMP or DMF, in the presence of a suitable organic base such as DiPEA. Alternatively, TsOH can be used instead of DiPEA, using an organic solvent such as IPA, with stirring at 80°C for at least 2 hours. Another alternative is to couple intermediate 6 with amine 7 under transition metal-catalyzed coupling conditions, for example in an organic solvent such as 1,4-dioxane using dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) and an inorganic base such as Na₂CO₃, at a high temperature, for example, at 80°C with stirring for at least 16 hours.

[0171] Option 2 In Scheme 2, amines 13, 14, and 15 of the present invention can be prepared starting from a suitable amine 9. The PG moiety on amine 9 is a standard amine protecting group known to those skilled in the art, including urethane and amide protecting groups. In step 1, amine 9 is reacted with 1-bromo-2-(2-bromoethoxy)ethane under standard nucleophilic substitution conditions, and includes the use of NaI at at least 95°C, in a suitable organic solvent such as EtOH, and in the presence of a suitable base such as K₂CO₃. In step 2, intermediate 11 is generated by reacting amine 9 with (vinylsulfonyl)ethylene in a suitable organic solvent such as EtOH under reflux conditions. In step 3, amine 9 is reacted with 2-(2-chloroethoxy)acetic acid under standard amide coupling conditions. Suitable amide coupling conditions are known to those skilled in the art and include reacting a solution of 2-(2-chloroethoxy)acetic acid and amine 9 in a suitable solvent such as DMF with a suitable coupling agent such as HATU in the presence of a suitable organic base such as DiPEA, wherein stirring is carried out at room temperature for at least 16 hours. The resulting intermediates were treated at at least 80°C in a suitable organic solvent such as DMF, in the presence of a suitable base such as K₂CO₃, under standard nucleophilic substitution conditions. Deprotection of intermediates 10, 11, and 12 was achieved under standard acidic conditions in the art when the PG moiety was a BOC group. Amines 13, 14, and 15 were obtained by adding a suitable acid, such as TFA, to a stirred solution of intermediates 10, 11, and 12, respectively, in a suitable solvent such as DCM at room temperature, and stirring for at least 18 hours.

[0172] Option 3 Scheme 3 represents an alternative route for preparing intermediate 4. At room temperature, in a suitable organic solvent such as DCM, under standard amide coupling conditions and with a suitable organic base such as DiPEA, a suitable acyl chloride 16 is reacted with a suitable amine 1. The resulting amide 17 is treated under reducing conditions, including reacting amide 17 with zinc and NH4Cl at at least 50°C in a suitable organic solvent such as MeOH.

[0173] Option 4 Scheme 4 describes the preparation of the compound of the invention starting from a suitable aryl halide 18 (where "W" is a halogen). Intermediate 18 is reacted with a suitable amine 7 at at least 80°C in a suitable organic solvent such as NMP or DMF, in the presence of a suitable organic base such as DiPEA, under nucleophilic aromatic substitution conditions known to those skilled in the art, to give 19 in step 1. Carboxylic acid 20 can be prepared from a suitable ester 19 in a suitable organic solvent such as a mixture of THF or EtOH, under standard saponification conditions using a suitable strong inorganic base such as NaOH or LiOH, stirred at 60°C for at least 1.5 hours. Carboxylic acid intermediate 20 is reacted with a suitable amine 21 under amide coupling conditions known to those skilled in the art. A suitable coupling agent such as oxaloyl chloride is introduced into a stirred solution of carboxylic acid 20 at 0°C, followed by dropwise addition of DMF. Once the reaction mixture has been allowed to stir at room temperature for at least 30 minutes, amine 21 is added, followed by the addition of a suitable organic base such as DiPEA, and the reaction mixture is further stirred at room temperature for at least 1.5 hours. In step 4, ester 22 is treated in a suitable organic solvent such as a mixture of THF or EtOH under standard saponification conditions with a suitable strong inorganic base such as NaOH or LiOH, and stirred at 60°C for at least 1.5 hours. Carboxylic acid 23 is reacted with a suitable amine 1 under standard amide coupling conditions to prepare amide 8 in step 5. Suitable amide coupling conditions are well known to those skilled in the art and include reacting a solution of carboxylic acid 23 and the desired amine in a suitable solvent such as ACN, DMF, or DCM with a suitable coupling agent such as TCFH, HATU, or PPACA in the presence of a suitable organic base such as DiPEA, TEA, or NMI, wherein stirring is carried out at room temperature for at least 35 minutes.

[0174] Option 5 Scheme 5 describes the preparation of the compound of the invention starting from a suitable carboxylic acid 5. Carboxylic acid 5 reacts with a suitable amine 21 under amide coupling conditions known to those skilled in the art. A suitable coupling agent, such as oxaloyl chloride, is introduced into a stirred solution of carboxylic acid 5 at 0°C, followed by dropwise addition of DMF. Once the reaction mixture is stirred at room temperature for at least 30 minutes, amine 21 is added, followed by the addition of a suitable organic base, such as DiPEA, and the reaction mixture is further stirred at room temperature for at least 1.5 hours. At at least 80°C, in a suitable organic solvent, such as NMP or DMF, in the presence of a suitable organic base, such as DiPEA, under standard nucleophilic aromatic substitution conditions, an aryl halide intermediate 24 (where “W” is a halogen and “G2” is N) is reacted with a suitable amine 7 to give 22 in step 2. Carboxylic acid 23 can be prepared from a suitable ester 22 in a suitable organic solvent, such as a mixture of THF or EtOH, under standard saponification conditions using a suitable strong inorganic base, such as NaOH or LiOH, stirred at 60°C for at least 1.5 hours. Carboxylic acid 23 is reacted with a suitable amine 1 under standard amide coupling conditions to prepare amide 8 in step 4. Suitable amide coupling conditions are well known to those skilled in the art and include reacting a solution of carboxylic acid 23 and the desired amine in a suitable solvent such as ACN with a suitable coupling agent such as TCFH or PPACA in the presence of a suitable organic base such as DiPEA or NMI, wherein the mixture is stirred at room temperature for at least 35 minutes.

[0175] Option 6 Scheme 6 illustrates the preparation of the compound of the present invention from acid intermediate 25 and amine intermediate 4 to obtain compound 8. Suitable amide coupling conditions are well known to those skilled in the art and include reacting carboxylic acid 25 and amine 4 in a suitable solvent such as NMP with a coupling agent such as PPACA and an organic base such as TEA at room temperature, optionally adding 4-dimethylaminopyridine and optionally heating to 85°C.

[0176] In schemes 1, 4, 5, and 6, if the R2- group of 8 contains a carboxylic acid ester, it can be treated in a suitable organic solvent such as a mixture of THF or EtOH under standard saponification conditions with a suitable strong inorganic base such as NaOH or LiOH, stirred at 60°C for at least 1.5 hours, to obtain a carboxylic acid. This carboxylic acid is then coupled with an amine using a suitable coupling agent such as HATU and an organic amine base such as DIPEA to obtain the carboxylic acid in which R... 2a For example or Compound of formula I.

[0177] Preparation 1 Pentafluoro(2-fluoro-5-nitrophenyl)-λ 6 -Thiones Pentafluoro(2-fluoro-5-nitrophenyl)-λ 6 -Thiones Pentafluoro(2-fluorophenyl)-λ 6 A mixture of thionine (5.00 g, 22.5 mmol) and sulfuric acid (18.3 g, 9.96 mL, 187 mmol) was cooled to 0 °C. Nitric acid (14.0 g, 9.96 mL, 223 mmol) was then added to the reaction mixture; after 5 minutes, the ice bath was removed, and the reaction was stirred at 25 °C for 3 hours. The reaction mixture was then poured onto 300 mL of ice, and the resulting mixture was extracted with DEE (300 mL). The combined organic layers were washed with a saturated aqueous solution of NaCl (150 mL), dried over MgSO4, filtered, and concentrated to give the title compound (2.5 g, 9.3 mmol, 41%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 8.71 (dd, = 5.8, 2.7 Hz, 1H), 8.45 (dt, = 9.2, 3.2 Hz, 1H), 7.44 (t, = 9.5 Hz, 1H).

[0178] Preparation 2 4-Fluoro-3-(pentafluoro-λ) 6 -Thioalkyl)aniline Pentafluoro(2-fluoro-5-nitrophenyl)-λ 6 A mixture of thionine (2.5 g, 9.4 mmol), iron (2.6 g, 47 mmol), ethanol (60 mL), and concentrated HCl (2.4 mL) was heated under reflux at 105 °C for 3 hours. The mixture was then filtered, cooled to room temperature, and made slightly alkaline by adding NH4OH. The solvent was evaporated under vacuum, and the residue was washed with water (100 mL) and extracted with a mixture of chloroform:PrOH (4:1) (600 mL). The organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and then purified by reversed-phase column chromatography (C18, 0.1% FA in H2O, 0.1% FA in ACN), followed by a second column chromatography (C18, 0.1% FA in H2O, 0.1% FA in ACN) to give the title compound (1.56 g, 6.58 mmol, 70%) as a brown solid. ES-MS 238 (M+H).

[0179] Preparation 3 (3-(1,1-dioxothiomorpholino)bicyclo[1.1.1]pent-1-yl)tert-butyl carbamate A solution of (vinylsulfonyl)ethylene (596 mg, 524 μL, 5.04 mmol) in EtOH (5 mL) was added dropwise to a reflux solution of (3-aminobicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (1.00 g, 5.04 mmol) in EtOH (5 mL). The resulting mixture was stirred under reflux for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The resulting solid was milled with MTBE and dried under reduced pressure to give the title compound (1.05 g, 3.32 mmol, 66%) as a white solid. ES-MS 317 (M+H).

[0180] Preparation 4 (3-morpholinobicyclo[1.1.1]pent-1-yl) tert-butyl carbamate A mixture of (3-aminobicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (2.0 g, 10 mmol), 1-bromo-2-(2-bromoethoxy)ethane (2.7 g, 12 mmol), sodium iodide (1.5 g, 10 mmol), and potassium carbonate (2.8 g, 20 mmol) in DMF (6.7 mL) was sealed and heated at 95 °C. After 75 minutes, the mixture was quenched with water (125 mL), extracted with EtOAc (250 mL), dried over MgSO4, filtered, and concentrated to give the title compound (2.0 g, 7.5 mmol, 74%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 3.73 – 3.67 (m, 4H), 2.42 (dd, J= 5.7, 3.8 Hz, 4H), 1.98 (s, 6H), 1.42 (s, 9H).

[0181] Preparation 5 (3-(2-(2-chloroethoxy)acetamido)bicyclo[1.1.1]pent-1-yl)carbamate tert-butyl A mixture of 2-(2-chloroethoxy)acetic acid (116 mg, 837 μmol), tert-butyl (3-aminobicyclo[1.1.1]pent-1-yl)carbamate (199 mg, 1.00 mmol), HATU (382 mg, 1.00 mmol), and DiPEA (216 mg, 292 μL, 1.67 mmol) was stirred in DMF (4.19 mL). After 16 hours, the reaction was quenched with water and extracted with EtOAc. The combined organic phases were washed with water, saturated NaHCO3 solution, and then with saturated NaCl aqueous solution. The crude product was dried over MgSO4, filtered, and concentrated to dryness to give the title compound (337 mg, quantitative yield) as is used in the next step. ES-MS 319 (M+H).

[0182] Preparation of 6 (3-(3-oxomorpholino)bicyclo[1.1.1]pent-1-yl)tert-butyl carbamate A mixture of (3-(2-(2-chloroethoxy)acetamido)bicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (50 mg, 0.16 mmol) and K₂CO₃ (43 mg, 0.31 mmol) was stirred in DMF (0.78 mL) at 80 °C. The reaction mixture was cooled, diluted with EtOAc, and filtered to remove solids. The filtrate was collected and washed with water, followed by washing with a saturated aqueous solution of NaCl. The organic matter was dried over MgSO₄, filtered, and concentrated to dryness to obtain the title compound (30 mg, 0.11 mmol, 69%) as a white solid. ES-MS 283 (M+H).

[0183] Preparation 7 N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-nitrobenzamide At ambient temperature, 4-fluoro-3-(trifluoromethyl)aniline (1.25 g, 6.95 mmol) and DIPEA (2.70 g, 3.63 mL, 20.9 mmol) were added to a solution of 2-nitrobenzoyl chloride (1.29 g, 6.95 mmol) in DCM (23.2 mL). After 3 hours, the crude mixture was concentrated under vacuum, and the residue was purified by normal-phase chromatography (EtOAc / heptane 0–100%) to give the title compound (1.98 g, 6.03 mmol, 87%) as a white solid. ES-MS 329 (M+H).

[0184] Preparation of 8 2-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)benzamide At ambient temperature, zinc (3.94 g, 60.3 mmol) and NH4Cl (3.23 g, 60.3 mmol) were added to a solution of N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-nitrobenzamide (1.98 g, 6.03 mmol) in MeOH (20.1 mL). The reaction mixture was heated to 50 °C and stirred for 3 hours. The reaction mixture was cooled and filtered through diatomaceous earth. The filter cake was washed with MeOH, and the filtrate was collected and concentrated under vacuum. The residue was partitioned between EtOAc and water. The organic layer was washed with a saturated aqueous solution of NaCl, dried over MgSO4, filtered, and concentrated to dryness to give the title compound (1.68 g, 5.63 mmol, 93%) as a white solid. ES-MS 299 (M+H).

[0185] Preparation 9 ((1S,2R,3S,4R)-3-((4-Fluoro-3-(pentafluoro-λ)) 6 -Thioalkyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)tert-butyl carbamate To (1R,2S,3R,4S)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptane-2-carboxylic acid (2.02 g, 7.89 mmol) and 4-fluoro-3-(pentafluoro-λ) 6 A mixture of (-thioalkyl)aniline (1.56 g, 6.58 mmol) was added to TCFH (2.21 g, 7.89 mmol) and 1-methylimidazole (1.30 g, 1.25 mL, 15.8 mmol) in ACN (26.3 mL). The reaction mixture was stirred at 25 °C for 35 min. The reaction mixture was then concentrated, and the residue was purified by reversed-phase column chromatography (C18, 0.1% FA in H2O, 0.1% FA in ACN) to give the title compound (1.50 g, 3.16 mmol, 48%) as a brown solid. ES-MS 473 (M+H).

[0186] The following compounds are prepared essentially as described in Preparation 9 using appropriate aniline:

[0187] Preparation 15 (1R,2S,3R,4S)-3-amino-N-(4-fluoro-3-(pentafluoro-λ) 6 (-thioalkyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide The ((1S,2R,3S,4R)-3-((4-fluoro-3-(pentafluoro-λ)) in DCM (25 mL) and TFA (6.32 mL) 6 A solution of thioalkyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamate tert-butyl ester (1.50 g, 3.16 mmol) was stirred at 25 °C for 1 h. The solution was concentrated and purified by reversed-phase C18 column chromatography (C18, 0.1% FA in H2O, 0.1% FA in ACN) to give the title compound (1.06 g, 2.83 mmol, 90%) as a white solid. ES-MS 375 (M+H).

[0188] The following compounds were prepared essentially as described in Preparation 15 using starting materials with appropriate BOC protection:

[0189] Preparation 24 4-Chloro-N-((1S,2R,3S,4R)-3-((4-Fluoro-3-(pentafluoro-λ) 6 -thioalkyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-6-methoxypyrimidine-5-carboxamide Oxaloyl dichloride (58.2 mg, 39.3 μL, 459 μmol) was added to a solution of 4-chloro-6-methoxypyrimidine-5-carboxylic acid (72.1 mg, 382 μmol) in DCM (15 mL), followed by dropwise addition of DMF (27.9 mg, 29 μL, 382 μmol). After bubbling was stopped, (1R,2S,3R,4S)-3-amino-N-(4-fluoro-3-(pentafluoro-λ)) was added. 6 (-thioalkyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (196.9 mg, 526.0 μmol) was followed by the addition of DiPEA (148 mg, 0.20 mL, 1.15 mmol). The reaction was stirred for 20 min, then directly loaded onto silica gel and purified with 0–100% EtOAc / heptane to give the title compound (130 mg, 239 μmol, 62%) as a white solid. ES-MS 545 (M+H).

[0190] The following compounds are prepared essentially as described in Preparation 24 using appropriate amines and carboxylic acids:

[0191] Preparation of 35 6-((5-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-6-methoxypyrimidin-4-yl)amino)spiro[3.3]heptane-2-carboxylic acid methyl ester (mixture of isomers) DiPEA (360.5 mg, 0.49 mL, 2.789 mmol) was added to a mixture of 4-chloro-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-6-methoxypyrimidine-5-carboxamide (226.3 mg, 464.8 μmol) and methyl 6-(chloro-15-azalkyl)spiro[3.3]heptane-2-carboxylate (mixture of isomers, 141.1 mg, 686.0 μmol) in DMF (3 mL), and the reaction was stirred at 60 °C for 2.5 h. After the reaction was complete, the reaction was cooled to ambient temperature and partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was washed with saturated aqueous NaCl solution (20 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified on silica gel using a gradient of 0–100% EtOAc in heptane to give the title compound as a white solid (194.8 mg, 314.4 μmol, 68%). ES-MS 620 (M+H).

[0192] The following compounds are prepared essentially as described in Preparation 35 using appropriate aniline / amine and carboxylic acid:

[0193] Preparation 43 (1R,2S,3R,4S)-3-(4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidin-5-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid To a stirred solution of methyl (1R,2S,3R,4S)-3-(4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidin-5-carboxamido)bicyclo[2.2.1]heptane-2-carboxylate (1090 mg, 2.311 mmol) in THF (10 mL), LiOH (553.6 mg, 11.56 mL, 23.11 mmol) and EtOH (1.9 mL) were added. The reaction mixture was heated to 60 °C and stirred for 1.5 h. After 1.5 h, 1 M HCl was added until the mixture showed pH = 2. The reaction mixture was concentrated under reduced pressure and then purified directly by reversed-phase column chromatography (C18, 0.1% FA in H2O, 0.1% FA in ACN) to give the title compound (896 mg, 1.96 mmol, 85%) as an off-white solid. ES-MS 458 (M+H).

[0194] Preparation of 44 4-Chloro-6-methoxy-2-methylpyrimidine-5-carboxaldehyde CH3ONa (933.35 mg, 17.28 mmol) was added fractionally to a stirred solution of 4,6-dichloro-2-methylpyrimidine-5-carboxaldehyde (3 g, 16 mmol) in MeOH (30 mL) at 0 °C under N2 atmosphere. The reaction mixture was stirred overnight at room temperature under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (33% EtOAc in petroleum ether) to give the title product (600 mg, 20%) as a white solid. ES-MS 187 (M+H).

[0195] The following compounds were prepared essentially as described in Preparation 44:

[0196] Preparation of 46 methyl 4-chloro-6-methoxy-2-methylpyrimidine-5-carboxylate A solution of 4-chloro-6-methoxy-2-methylpyrimidine-5-carboxaldehyde (300 mg, 2 mmol) in MeOH (3 mL) at 0 °C was treated with I₂ (1224.16 mg, 4.82 mmol) in MeOH (3 mL), followed by dropwise addition of KOH (270.60 mg, 4.82 mmol) in MeOH (3 mL) at 0 °C. The reaction mixture was stirred at room temperature under N₂ atmosphere for 1.5 h. The reaction mixture was quenched with a saturated aqueous solution of NaHSO₃ at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was diluted with H₂O (20 mL) and filtered. The filter cake was washed with H₂O (3 x 20 mL). The resulting solid was dried under reduced pressure to give the title product (140 mg, 37%) as a yellow solid. ES-MS 217 (M+H).

[0197] Preparation 47 4-Methoxy-2-methyl-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid methyl ester A solution of methyl 4-chloro-6-methoxy-2-methylpyrimidin-5-carboxylate (140 mg, 1 mmol), 3-(morpholin-4-yl)bicyclo[1.1.1]pentan-1-amine (217.46 mg, 0.97 mmol), and DiPEA (417.66 mg, 3.23 mmol) in NMP (25 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to give the title product (130 mg, 55%) as a white solid. ES-MS 349 (M+H).

[0198] The following compounds were prepared essentially as described in Preparation 47:

[0199] Preparation 49 4-Chloro-2,5-Difluoronicotinic acid A solution of 4-chloro-2,5-difluoropyridine (11 g, 74 mmol) in THF (150 mL) was treated with LDA (55.18 mL, 110.35 mmol, 2 M in THF) for 1 hour under a nitrogen atmosphere at -78 °C, followed by the addition of dry ice (CO2, 1 g) in portions at -78 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was quenched at 0 °C with a saturated aqueous NH4Cl solution. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with DCM / MeOH (10:1, 200 mL). The resulting mixture was washed with H2O (2 x 50 mL) and a saturated aqueous NaCl solution (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% MeOH in DCM) to give the title product (17 g) as a yellow solid. ES-MS 194 (M+H).

[0200] The following compounds were prepared essentially as described in Preparation 49:

[0201] Preparation 51 4-Methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid At -40 °C, 5-bromo-6-methoxy-N-(3-morpholinobicyclo[1.1.1]pent-1-yl)pyrimidine-4-amine (176 mg, 0.495 mmol) dissolved in anhydrous THF (2.0 mL) was added dropwise to a stirred solution of n-butyllithium (2.5 M, 700 μL, 1.75 mmol) in diethyl ether (2.0 mL). The reaction mixture was stirred at -40 °C for 10 min, and then at 0 °C for 20 min under a carbon dioxide atmosphere. The reaction mixture was quenched with water (5 mL) and acidified with a saturated aqueous NH4Cl solution (until pH ~ 7), and then CHCl3:iPrOH (3:1, 10 mL) was added. The aqueous layer was extracted with CHCl3:iPrOH (3:1) (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was then divided in half. Half of the residue was purified by silica gel chromatography using a 0% to 35% MeOH gradient with 1% AcOH in DCM to give the title compound (20 mg) as a white solid. A second batch of the title compound was obtained by acidifying the aqueous phase with 3N citric acid aqueous solution (until pH ~ 5) and adding CHCl3:iPrOH (3:1, 10 mL). The aqueous layer was extracted with CHCl3:iPrOH (3:1) (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to give the title compound (62 mg) as a white solid. ES-MS 321 (M+H).

[0202] Preparation of 52 4-Chloro-2,5-Difluoronicotinic acid methyl ester CH3I (27.34 mL, 439.21 mmol) was added dropwise to a solution of 4-chloro-2,5-difluoronicotinic acid (17 g) and K2CO3 (72.84 g, 527.05 mmol) in 1,4-dioxane (200 mL) at room temperature. The reaction mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction mixture was filtered, and the filter cake was washed with 1,4-dioxane (3 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% EtOAc in petroleum ether) to give the title compound (7 g, 47%) as a yellow oil. 1 H NMR (400 MHz, DMSO-) δ 8.66-8.61 (m, 1H), 3.98 (s, 3H).

[0203] The following compounds were prepared essentially as described in Preparation 52:

[0204] Preparation of 54 2-Fluoro-4-methoxynicotinic acid benzyl ester A solution of 2-fluoro-4-methoxynicotinic acid (19 g, 111 mmol), benzyl bromide (94.95 g, 555.15 mmol), and TEA (77.17 mL, 555.15 mmol) in DCM (500 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with H2O (300 mL) and extracted with DCM (3 x 500 mL). The combined organic layers were washed with saturated aqueous NaCl solution (2 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50-66% EtOAc in petroleum ether) to give the title product (20 g, 69%) as a white solid. ES-MS 262 (M+H).

[0205] Preparation of 55 2-Chloro-(2-chloroethyl)-methylacetamide Chloroacetyl chloride (4.78 g, 42.31 mmol) was added dropwise to a stirred solution of (2-chloroethyl)(methyl)amine hydrochloride (5 g, 39 mmol) and TEA (11.68 g, 115.38 mmol) in DCM (100 mL) at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (700 mL). The resulting mixture was extracted with DCM / MeOH (4 / 1) (5 x 150 mL). The combined organic layers were washed with saturated aqueous NaCl solution (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% MeOH in DCM) to give the title product (3 g, 33%) as a pale yellow oil. ES-MS 170 (M+H).

[0206] Preparation of 56 (3-(3-hydroxypyrrolidone-1-yl)bicyclo[1.1.1]pent-1-yl)tert-butyl carbamate (racemic mixture) At room temperature, Cs₂CO₃ (9.86 g, 30.26 mmol) and KI (2.51 g, 15.13 mmol) were added in portions to a stirred mixture of tert-butyl 3-(3-aminobicyclo[1.1.1]pent-1-yl)carbamate (3 g, 15 mmol) and 1,4-dichlorobut-2-ol (racemic mixture, 2.60 g, 18.16 mmol) in DMF (30 mL). The reaction mixture was stirred at 90 °C for 5 hours. The reaction was quenched with H₂O (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaCl solution (2 x 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-25% MeOH in DCM) to give the title compound (1.0 g, 25%) as a light brown oil. ES-MS 269 (M+H).

[0207] The following compounds were prepared essentially as described in Preparation 56: a. 2-Chloro-N-(2-Chloroethyl)-N-methylacetamide was used as the starting material.

[0208] Preparation of 58 (3-(hydrazylcarbonyl)bicyclo[1.1.1]pent-1-yl)tert-butyl carbamate Hydrazine hydrate (778.03 mg, 12.43 mmol) was added dropwise to a stirred solution of methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (1 g, 4 mmol) in MeOH (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min, and then stirred at 80 °C for 3 h. The resulting mixture was concentrated under vacuum to give the title product (970 mg, 97%) as a white solid. ES-MS 242 (M+H).

[0209] Preparation 59 (3-(1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pent-1-yl)tert-butyl carbamate A solution of (3-(hydrazylcarbonyl)bicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (0.97 g, 4.02 mmol) and TsOH (69.23 mg, 0.40 mmol) in triethyl orthoformate (20 mL) was stirred at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-50% EtOAc in petroleum ether) to give the title product (700 mg, 69%) as a white solid. ES-MS 252 (M+H).

[0210] Preparation of 60 (3-Carbamoylbicyclo[1.1.1]pent-1-yl)tert-butyl carbamate A solution of methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (1 g, 4 mmol) in NH3 (g) at room temperature was stirred overnight under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give the title product (900 mg) as a white solid. ES-MS 227 (M+H).

[0211] Preparation of 61 (3-(4-1,2,4-triazol-3-yl)bicyclo[1.1.1]pent-1-yl)tert-butyl carbamate A solution of (3-carbamoylbicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (900 mg, 4 mmol) in (dimethoxymethyl)dimethylamine (10 mL) was stirred at 100 °C for 1 hour under N2 atmosphere. The reaction mixture was allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in AcOH (15 mL) and hydrazine hydrate (637.31 mg, 15.91 mmol) was added at room temperature. The reaction mixture was stirred at 100 °C for 1 hour under N2 atmosphere. The reaction mixture was concentrated under vacuum. The residue was diluted with DCM (100 mL), washed with saturated NaHCO3 aqueous solution (3 x 50 mL) and saturated NaCl aqueous solution (2 x 50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% MeOH in DCM) to give the title product (160 mg, 15%) as a white solid. ES-MS 251 (M+H).

[0212] Preparation of 62 (3-Thiocarbamoylbicyclo[1.1.1]pent-1-yl) tert-butyl carbamate A mixture of (3-carbamoylbicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (1.00 g, 4.42 mmol) and 2,4-bis(4-methoxyphenyl)-2,4-dithio-1,3,2,4-dithiadiphosphonobutane (2.68 g, 6.63 mmol) in THF (10 mL) was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature. The reaction mixture was alkalized to pH 8 with a saturated aqueous solution of NaHCO3. The reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with a saturated aqueous solution of NaCl (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (20-50% EtOAc in petroleum ether) to give the title product (440 mg, 41%) as a white solid. ES-MS 243 (M+H).

[0213] Preparation of 63 (3-(thiazolyl-2-yl)bicyclo[1.1.1]pent-1-yl)tert-butyl carbamate Under a nitrogen atmosphere at room temperature, 2-bromo-1,1-dimethoxyethane (600 mg, 4 mmol) was added dropwise to a stirred solution of (3-thiocarbamoylbicyclo[1.1.1]pent-1-yl)carbamate (430 mg, 2 mmol) and TsOH (1070 mg, 6 mmol) in EtOH (3 mL). The reaction mixture was stirred at 80 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (3 mL), and Boc2O (504 mg, 2 mmol) and TEA (539 mg, 5 mmol) were added dropwise at room temperature. The reaction mixture was stirred again at room temperature for 2 hours. The resulting mixture was diluted with H2O (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with saturated aqueous NaCl solution (3 x 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (20-50% EtOAc in petroleum ether) to give the title product (140 mg, 30%) as a yellow solid. ES-MS 267 (M+H).

[0214] Preparation of 64 4-Fluoro-(4-fluoro-3-(trifluoromethyl)phenyl)-2-nitrobenzamide To a solution of 4-fluoro-2-nitrobenzoic acid (1.12 g, 6.05 mmol) in DCM (25 mL), add oxalyl chloride (960 mg, 662 μL, 8 mmol) and DMF (22.1 mg, 23 μL, 303 μmol). Stir the reaction mixture at room temperature for 90 minutes. Concentrate the reaction mixture under reduced pressure. Dissolve the residue in DCM (25 mL) and add a solution of 4-fluoro-3-(trifluoromethyl)aniline (1.08 g, 6.05 mmol) and DiPEA (1.56 g, 2.11 mL, 12.1 mmol) in DCM (25 mL) at room temperature. Stir the reaction mixture at room temperature overnight. Concentrate the reaction mixture under reduced pressure. Extract the reaction mixture with EtOAc (3 x 50 mL). Wash the combined organic layers with H₂O, saturated aqueous NaCl solution (3 x 10 mL), and dry over anhydrous MgSO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM, and the precipitate was filtered off and washed with DCM. The filtrate was purified by silica gel chromatography (0-50% EtOAc in cyclohexane) to give the title product (1.6 g, 76%) as a yellow crystalline solid. ES-MS 345 (M+H).

[0215] Preparation of 65 2-Amino-4-fluoro-(4-fluoro-3-(trifluoromethyl)phenyl)benzamide A solution of 4-fluoro-(4-fluoro-3-(trifluoromethyl)phenyl)-2-nitrobenzamide (1.60 g, 4.62 mmol) in EtOAc (30 mL) was added to a solution of Pd / C (197 mg, 924 μmol) in EtOAc (10 mL). The flask was then evacuated twice with N2 and then placed under 276 kPa of H2 (gas) (9.34 mg, 4.62 mmol). The reaction was stirred at room temperature for 6 hours. The reaction mixture was filtered through a diatomaceous earth pad and the solvent was removed under reduced pressure. The residue was diluted with EtOAc, heated, and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (0-20% EtOAc in cyclohexane) to give the title product (1.08 g, 65%) as a white solid. ES-MS 315 (M+H).

[0216] The following compounds were prepared essentially as described in Preparation 64: a. Starting materials used: 2-amino-4-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)benzamide and 2-fluoro-4-methoxynicotinic acid.

[0217] Preparation of 67 (R)-3-((3-((5-fluoro-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)carbamoyl)-4-methoxypyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester A solution of (R)-3-aminopiperidin-1-carboxylic acid tert-butyl ester (320.0 mg, 1.6 mmol), 2-fluoro-(5-fluoro-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-4-methoxynicotinamide (500.0 mg, 1.1 mmol), NMP (5 mL), and DiPEA (275.4 mg, 371 μL, 2.1 mmol) was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl solution, and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–30% EtOAc in DCM) to give the title product (480.0 mg, 69%) as a white solid. ES-MS 650 (M+H).

[0218] Preparation of 68 3-(1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentane-1-amine; hydrochloride A solution of tert-butyl (3-(1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pent-1-yl)carbamate (700 mg, 3 mmol) in HCl (4 M solution in 1,4-dioxane, 20 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (500 mg) as a white solid. ES-MS 152 (M+H).

[0219] The following compounds were prepared essentially as described in Preparation 68 using appropriate BOC-protected starting materials:

[0220] Preparation of 74 2,5-Difluoro-4-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinic acid methyl ester A solution of 3-morpholinobicyclo[1.1.1]pentane-1-amine (3.49 g, 14.45 mmol), methyl 4-chloro-2,5-difluoronicotinic acid (2 g, 10 mmol), and DiPEA (8.39 mL, 48.18 mmol) in NMP (200 mL) was stirred at 50 °C for 2 h. The reaction mixture was diluted with H2O (500 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with saturated aqueous NaCl solution (2 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (C18; ACN in H2O) to give the title compound (1.45 g, 42%) as a white solid. ES-MS 340 (M+H).

[0221] The following compounds are prepared essentially as described in Preparation 74 using appropriate aryl chlorides: a. Starting material used: 2-fluoro-4-methoxypyridine-3-carboxylic acid benzyl ester.

[0222] Preparation of 78 4-Methoxy-2-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinic acid A solution of 4-methoxy-2-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinic acid benzyl ester (15 g, 37 mmol) and Pd / C (15 g) in MeOH (250 mL) was stirred at room temperature under H2 atmosphere for 16 hours. The reaction mixture was filtered and the filter cake was washed with MeOH (2 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by grinding with EtOAc (50 mL). The precipitated solid was collected by filtration, washed with EtOAc (2 x 30 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-20% MeOH in DCM) to give the title product (4.3295 g) as an off-white solid. ES-MS 320 (M+H).

[0223] Preparation 79 5-Fluoro-2-methoxy-4-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinic acid methyl ester A solution of methyl 2,5-difluoro-4-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinic acid (500 mg, 2 mmol) in MeOH (50 mL) was stirred overnight at 80 °C. The reaction mixture was diluted with H₂O (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaCl solution (2 x 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% EtOAc in petroleum ether) to give the title compound (300 mg, 55%) as a white solid. ES-MS 352 (M+H).

[0224] The following compounds were prepared essentially as described in Preparation 79:

[0225] Preparation of 81 Methyl cis-3-(4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidin-5-carboxamido)bicyclo[2.2.2]octane-2-carboxylate (racemic mixture) A solution of 4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid (98.0 mg), cis-3-aminobicyclo[2.2.2]octane-2-carboxylic acid methyl ester; hydrochloride (racemic mixture) (60.8 mg), and DiPEA (120 μL, 0.687 mmol) in ACN (1.9 mL) was stirred at 100 °C for 3 min. A solution of TCFH (80.4 mg) and NMI (65.0 μL, 0.815 mmol) in ACN (1.9 mL) was added to the reaction mixture, and the mixture was stirred at 100 °C for 30 min. The reaction mixture was cooled to 25 °C, and then H2O (10 mL) and EtOAc (10 mL) were added. The phases were separated, and the aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were dried using a phase separator and concentrated under vacuum. The residue was purified by silica gel chromatography (1-50% EtOH / EtOAc (3:1) in n-heptane). The fractions were combined and concentrated under reduced pressure to give the title product (69.0 mg, 59%) as a pale yellow gel. ES-MS 486 (M+H).

[0226] Preparation of 82 Methyl 2-(4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidin-5-carbamate)benzoate DiPEA (968 mg, 1.31 mL, 8 mmol) was added to a solution of 4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid (400 mg, 1 mmol), methyl 2-aminobenzoate (283 mg, 242 μL, 2 mmol), and BOP-Cl (381 mg, 2 mmol) in NMP (12.5 mL). The reaction mixture was stirred at 50 °C for 12 hours. After 12 hours, the solvent was removed and the residue was purified directly by reversed-phase column chromatography (C18, 0.1% FA in H2O, 0.1% FA in ACN) to give the title product (335 mg, 53%) as a white solid. ES-MS 454 (M+H).

[0227] Preparation of 83 4-Methoxy-2-methyl-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid At 0 °C, LiOH·H₂O (28.90 mg, 0.69 mmol) in H₂O (10 mL) was added dropwise to a stirred solution of methyl 4-methoxy-2-methyl-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylate (120 mg) in THF (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the title product (100 mg) as a white solid. ES-MS 335 (M+H).

[0228] The following compounds are prepared essentially using appropriate esters as described in Preparation 83:

[0229] Preparation of 88 Methyl 4-methoxy-2-(methanesulfonyl)-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid The mixture was stirred overnight at room temperature under N2 atmosphere in a solution of methyl 4-methoxy-2-(methylthio)-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylate (1.2 g, 3.2 mmol) and -CPBA (1.31 g, 7.57 mmol) in DCM (30 mL). The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (8-10% MeOH in DCM) to give the title product (1.2 g, 92%) as a pale yellow solid. ES-MS 413 (M+H).

[0230] Preparation of 89 Methyl 2-cyano-4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid Under a nitrogen atmosphere at room temperature, KOBu (95.2 mg, 0.9 mmol) was added dropwise to a stirred mixture of methyl 4-methoxy-2-(methanesulfonyl)-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylate (700 mg, 2 mmol) and trimethylsilaneformonitrile (336.7 mg, 3.4 mmol) in ACN (20 mL). The reaction mixture was stirred at room temperature for another 3 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL), and bis(pinacol)diboron (2154.8 mg, 8.5 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for another 3 hours. The reaction mixture was diluted with 100 mL of H₂O and extracted with DCM (3 x 100 mL). The combined organic layers were washed with 100 mL of saturated aqueous NaCl solution and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (30-50% EtOAc in petroleum ether) to give the title product (350 mg, 57%) as a white solid. 1 H NMR (400 MHz, DMSO-6) δ 8.70 (s, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.58 (t, 4H), 2.38 (t, 4H), 2.09 (s, 6H).

[0231] Preparation of 90 -((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-2,5-dicarboxamide A solution of methyl 2-cyano-4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylate (300 mg) and LiOH·H2O (70.05 mg, 1.67 mmol) in THF (10 mL) / H2O (10 mL) was stirred overnight at 50 °C under a nitrogen atmosphere. The reaction mixture was diluted with H2O (50 mL). The mixture was acidified to pH 5 with concentrated HCl. The reaction mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with saturated aqueous NaCl solution (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Under a nitrogen atmosphere at room temperature, NMI (190.19 mg, 2.32 mmol) and TCFH (324.97 mg, 1.16 mmol) were added dropwise to a stirred solution of the residue (200 mg) in ACN (30 mL) and (1R,2S,3R,4S)-3-amino-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (274.76 mg, 0.87 mmol). The reaction mixture was diluted with H2O (50 mL). The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with saturated aqueous NaCl solution (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (C18; mobile phase, 20-30% ACN (0.1% FA) in H2O). The resulting mixture was concentrated under reduced pressure to give the title product (130 mg, 36%) as a pale yellow solid. ES-MS 662 (M+H).

[0232] Preparation of 91 2-Amino-4-methoxy-n-(1-(trifluoromethyl)-2-oxabicyclo[2.2.2]oct-4-yl)benzamide 1-(trifluoromethyl)-2-oxabicyclo[2.2.2]octyl-4-amine hydrochloride (2.77 g, 12.0 mmol), 2-amino-4-methoxybenzoic acid (2.00, 12.0 mmol), PyBOP (9.34 g, 18.0 mmol), and EtOAc (20 mL) were added to the reaction vessel, followed by DIPEA (4.64 g, 6.26 mL, 35.9 mmol). The reaction was heated to 30 °C and maintained for 18 hours, after which EtOAc was added. The mixture was washed twice with HCl (1 M aqueous solution, 100 mL) and then with saturated NaCl aqueous solution. The organic matter was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane to give the title compound (2 g, 50%). ES-MS 345 (M+H).

[0233] Preparation of 92 6-Amino-2,2-difluoro-N-(1-(trifluoromethyl)-2-oxabicyclo[2.2.2]oct-4-yl)benzo[d][1,3]dioxacyclopentene-5-carboxamide The title compound was prepared essentially as described in Preparation 91 using 6-amino-2,2-difluorobenzo[d][1,3]dioxane-5-carboxylic acid. ES-MS 395 (M+H).

[0234] Preparation of 93 (4-((2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)carbamoyl)-6-methoxypyridin-3-yl)tert-butyl carbamate The title compound was prepared essentially as described in Preparation 91 using 5-((tert-butoxycarbonyl)amino)-2-methoxyisonicotinic acid and 2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-amine, with NMP as solvent and the reaction heated to 60 °C for 18 hours. ES-MS 424 (M+H).

[0235] Preparation of 94 2-Methoxy-5-(4-Methoxy-2-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinamide)methyl isonicotinic acid PPACA (15.4 g, 14.3 mL, 24.3 mmol) was added dropwise to a solution of 4-methoxy-2-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinic acid (1.55 g, 4.85 mmol), methyl 5-amino-2-methoxyisonicotinic acid (884 mg, 4.85 mmol), and TEA (1.47 g, 2.03 mL, 14.6 mmol) in NMP (15 mL), and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was allowed to cool to room temperature and washed with water, then extracted with DCM (4 x 15 mL) and purified by reversed-phase rapid chromatography with a gradient elution of 50 to 70% ACN (+0.1% FA) in 0.1% aqueous FA solution to give the title compound (1.25 g, 53%) as a solid. ES-MS 484 (M+H).

[0236] Preparation of 95 N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-methoxy-2-nitrobenzamide PPACA (2.92 g, 3 mL, 4.60 mmol) and TEA (930 mg, 1.3 mL, 9.19 mmol) were added to a solution of 4-methoxy-2-nitrobenzoic acid (302 mg, 1.53 mmol) and 4-fluoro-3-(trifluoromethyl)aniline hydrochloride (363 mg, 1.69 mmol) in NMP (5 mL), and the reaction was stirred at 60 °C for 16 h. The mixture was partitioned between EtOAc and water. The organic layer was washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered, and concentrated to give the title compound (549 mg, quantitative yield). ES-MS 359 (M+H).

[0237] Preparation of 96 (4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-methoxypyridin-3-yl)tert-butyl carbamate Acetonitrile (10 mL) was added to a mixture of 5-((tert-butoxycarbonyl)amino)-2-methoxyisonicotinic acid (0.500 g, 1.86 mmol), 4-fluoro-3-(trifluoromethyl)aniline (0.670 g, 3.74 mmol), 1-methylimidazole (0.37 g, 0.36 mL, 4.5 mmol), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (0.630 g, 2.25 mmol), and the mixture was stirred for 16 hours. The reaction mixture was concentrated, and the residue was dissolved and absorbed in ethyl acetate. The organic matter was washed with saturated aqueous NaHCO3 solution, saturated aqueous NH4Cl solution, and then with saturated aqueous NaCl solution. The organic matter was dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel using a gradient of 0 to 100% ethyl acetate in cyclohexane to give the title compound (0.725 g, 91%) as a yellow solid. ES-MS 330 (M+H).

[0238] The following compounds are prepared essentially as described in Preparation 96 using appropriate amines and carboxylic acids.

[0239] Prepare 100 (6-Methoxy-4-((1-(trifluoromethyl)-2-oxabicyclo[2.2.2]oct-4-yl)carbamoyl)pyridin-3-yl)tert-butyl carbamate A mixture of 5-((tert-butyloxycarbonyl)amino)-2-methoxyisonicotinic acid (2.0 g, 7.5 mmol), TCFH (2.5 g, 8.9 mmol), 1-(tert-butyl)-2-oxabicyclo[2.2.2]oct-4-amine (2.0 g, 11 mmol), and 1-methylimidazole (1.5 g, 1.5 mL, 19 mmol) in ACN (40 mL) was stirred overnight at room temperature. Water (75 mL) was added, and the reaction mixture was stirred for 45 minutes. The resulting solid was filtered, washed with water, and dried under reduced pressure at 40 °C for 1 hour. The solid was stirred in diethyl ether for 20 minutes, then filtered and dried under reduced pressure at 40 °C for 2 hours to give the title compound (1.5 g) as a pale yellow solid. ES-MS 446 (M+H).

[0240] Preparation 101 5-Amino-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-2-methoxyisonicotinamide TFA (721 mg, 487 μL, 7.36 mmol) was added to a solution of (4-((2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)carbamoyl)-6-methoxypyridin-3-yl)carbamate tert-butyl ester (623 mg, 1.47 mmol) in DCM (2 mL). After 20 min, the reaction mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (476 mg, quantitative yield). ES-MS 324 (M+H).

[0241] The following compounds were prepared essentially as described in Preparation 101 using appropriate Boc-protected amines.

[0242] a. The product was slurried and filtered in DCM, and the solids were purified by reversed-phase rapid chromatography using a gradient of 10% to 100% ACN in 10 mM NH4HCO3 aqueous solution.

[0243] The following compounds are prepared essentially as described in Preparation 8 using appropriate aryl or heteroaryl nitrates, with acetone and water as reaction solvents and the reaction stirred at 30°C for 1 hour.

[0244] Preparation of 107 2-Fluoro-N-(4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-methoxypyridin-3-yl)-4-methoxynicotinamide Oxaloyl chloride (0.29 g, 0.20 mL, 2.3 mmol) was added to a mixture of 2-fluoro-4-methoxynicotinic acid (0.400 g, 2.34 mmol) and DCM (10 mL), followed by dropwise addition of DMF (0.2 g, 0.2 mL, 3 mmol) and stirring for 30 min. A solution of 5-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methoxyisonicotinamide (0.93 g, 2.8 mmol) dissolved in THF (5 mL) was added at 0 °C, followed by addition of DIPEA (0.89 g, 1.2 mL, 6.9 mmol). The reaction mixture was stirred at ambient temperature for 16 h and then diluted with EtOAc. The mixture was washed with saturated NaHCO3 aqueous solution, water, and then with saturated NaCl aqueous solution. The organic phase was concentrated, and the residue was mixed with a minimum amount of EtOAc and sonicated. The solid was collected and washed with cold EtOAc. The solid was dried under reduced pressure to give the title compound (0.853 g, 76%) as a white solid. ES-MS 483 (M+H).

[0245] The following compounds are prepared essentially as described in Preparation 107 using appropriate acids and amines.

[0246] Preparation 111 (3-(2-(2-chloroethoxy)acetamido)bicyclo[1.1.1]pent-1-yl)carbamate tert-butyl To the reaction vessel, tert-butyl (3-aminobicyclo[1.1.1]pent-1-yl)carbamate (0.380 g, 1.92 mmol), DMF (8 mL), 2-(2-chloroethoxy)acetic acid (0.220 g, 1.59 mmol), and HATU (0.73 g, 1.9 mmol) were added. DIPEA (0.45 g, 0.60 mL, 3.4 mmol) and the reaction mixture were stirred for 16 hours. The reaction mixture was diluted with EtOAc and washed three times with water, followed by washing with a saturated aqueous NaCl solution. The organic matter was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give the title compound (0.300 g, 60%). ES-MS 319 (M+H).

[0247] Preparation 112 (3-(3-oxomorpholino)bicyclo[1.1.1]pent-1-yl)tert-butyl carbamate A mixture of (3-(2-(2-chloroethoxy)acetamido)bicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (0.295 g, 925 μmol), DMF (5.0 mL), and K₂CO₃ (0.260 g, 1.88 mmol) was heated to 80 °C for 23 h, then cooled to room temperature. The mixture was filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound (0.295 g, quantitative yield). ES-MS 283 (M+H).

[0248] Preparation of 113 4-(3-aminobicyclo[1.1.1]pent-1-yl)morpholin-3-one A mixture of (3-(3-oxomorpholino)bicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (261 mg, 0.925 mmol), DCM (1.5 mL), and TFA (2.2 g, 1.5 mL, 19 mmol) was stirred for 3 hours and then concentrated under reduced pressure. The residue was purified by loading it as a MeOH solution onto an SCX resin, which was then washed with MeOH. The column was then eluted with a solution of NH3 in MeOH, and the eluent was concentrated under reduced pressure to give the title compound (0.180 g, quantitative yield). ES-MS 183 (M+H).

[0249] Preparation of 114 3-((3-((4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-methoxypyridin-3-yl)carbamoyl)-4-methoxypyridin-2-yl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid DIPEA (0.22 g, 460 μmol) was added to a mixture of 2-fluoro-N-(4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-methoxypyridin-3-yl)-4-methoxynicotinamide (0.222 g, 460 μmol) and methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate (0.134 g, 949 μmol) in NMP (2.0 mL). The reaction vessel was sealed and heated at 80 °C for 18 h, followed by the addition of 1,3,4,6,7,8-hexahydro-2H-pyrimidino[1,2-a]pyrimidinium (0.200 g, 1.44 mmol), and then THF (1 mL). The reaction mixture was heated at 80 °C for 20 h and then combined with a reaction mixture operated on a 100 μmol scale in the same manner. The mixture was purified by reversed-phase rapid chromatography using a gradient of 10 to 100% ACN in 10 mM NH4HCO3 aqueous solution to give the title compound as a solid (0.135 mg, 46%). ES-MS 590 (M+H).

[0250] Preparation 115 5-(2-fluoro-4-methoxynicotinamide)-2-methoxyisonicotinic acid methyl ester A mixture of 2-fluoro-4-methoxynicotinic acid (1.35 g, 7.89 mmol), DCM (60.0 mL), oxaloyl dichloride (1.44 g, 960 μL, 11.3 mmol), and DMF (23.6 mg, 25.0 μL, 323 μmol) was stirred at room temperature under nitrogen for 68 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in DCM (30 mL). The resulting solution was added dropwise to a solution of methyl 5-amino-2-methoxyisonicotinic acid (1.18 g, 6.48 mmol) and DIPEA (2.52 g, 3.40 mL, 19.5 mmol) in DCM (30 mL). The mixture was stirred for 2 hours, then washed with HCl (0.5 N aqueous solution), saturated NaHCO3 aqueous solution, and then with saturated NaCl aqueous solution. The organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in DCM to give the title compound as a solid (2.00 g, 92%). ES-MS 336 (M+H).

[0251] Preparation of 116 2-Methoxy-5-(4-Methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carbamate)methyl isonicotinamide Hydroxybenzotriazole (2.84 g, 21 mmol) and methyl 5-amino-2-methoxyisonicotinamide (3.82 g, 21 mmol) were added to a stirred solution of 4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid (5.60 g, 17.5 mmol) in DMF (56 mL). The mixture was stirred at 20–30 °C for 5 min, followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (4.03 g, 21 mmol). The reaction mixture was stirred at 20–30 °C for 15 h, followed by the dropwise addition of water (112 mL). The resulting solid was then collected by filtration, washed with water (30 mL), and dried at 45 °C for 16 h to give the title compound (8.33 g, 98%) as a solid. ES-MS 485 (M+H).

[0252] Preparation of 117 (R)-5-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-4-methoxynicotinamide)-2-methoxyisonicotinic acid methyl ester A mixture of methyl 5-(2-fluoro-4-methoxynicotinamide)-2-methoxyisonicotinic acid (500.0 mg, 1.491 mmol), (R)-3-aminopiperidin-1-carboxylic acid tert-butyl ester (525.0 mg, 2.621 mmol), DIPEA (579 mg, 780 μL, 4.48 mmol), and NMP (6.0 mL) was stirred at 80 °C for 22 h. Water was added, and the reaction mixture was extracted three times with EtOAc. The combined organic matter was washed three times with water and once with a saturated aqueous solution of NaCl, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in DCM to give the title compound (525 mg, 69%) as a solid. ES-MS 516 (M+H).

[0253] Preparation of 118 (R)-2-methoxy-5-(4-methoxy-2-(piperidin-3-ylamino)nicotinamide)methyl isonicotinate The title compound was prepared essentially as described in Preparation 101 using (R)-5-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-4-methoxynicotinamide)-2-methoxyisonicotinic acid methyl ester. The reaction mixture was loaded onto an SCX resin, washed with MeOH, eluted with a solution of NH3 in MeOH, collected, and concentrated to give the title compound. ES-MS416 (M+H).

[0254] Preparation of 119 (R)-2-methoxy-5-(4-methoxy-2-((1-(oxecyclobutan-3-yl)piperidin-3-yl)amino)nicotinamide)methyl isonicotinamide Acetic acid (52.45 mg, 50.00 μL, 873.4 μmol) and oxetane-3-one (190.0 mg, 2.637 mmol) were added to a solution of (R)-2-methoxy-5-(4-methoxy-2-(piperidin-3-ylamino)nicotinamide) isonicotinic acid methyl ester (450.0 mg, 82 wt%, 888.2 μmol) in MeOH (4.50 mL). The mixture was stirred for 20 min, and then sodium cyanoborohydride (220 mg, 3.50 mmol) was added. The reaction was stirred at room temperature for 3 h, and then concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic matter was washed twice with saturated aqueous NaHCO3 solution, and then washed with saturated aqueous NaCl solution. The organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography using a gradient of 10 to 100% ACN in water + 0.1% formic acid to obtain the title compound (250 mg, 60%) as a solid. 1H-NMR (400 MHz, DMSO-6) δ 11.06 (s, 1H), 9.05 (d, J= 7.0 Hz,1H), 8.77-8.67 (m, 1H), 8.11 (d, J= 5.7 Hz, 1H), 7.20 (s, 1H), 6.47 (d, J=5.8 Hz, 1H), 4.51 (td, J= 6.5, 2.5 Hz, 2H), 4.42 (dt, J= 9.9, 6.1 Hz, 2H), 4.24-4.18 (m, 1H), 4.01 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.42 (quintet, J= 6.4 Hz, 1H), 2.62-2.57 (m, 1H), 2.34-2.29 (m, 1H), 2.17-2.15 (m, 1H), 2.01-1.97 (m, 1H), 1.81-1.76 (m, 2H), 1.57-1.49 (m, 2H).

[0255] Preparation 120 (R)-2-methoxy-5-(4-methoxy-2-((1-(oxecyclobutan-3-yl)piperidin-3-yl)amino)nicotinamide)isonicotinic acid A mixture of (R)-2-methoxy-5-(4-methoxy-2-((1-(oxecyclobut-3-yl)piperidin-3-yl)amino)nicotinamide)isonicotinic acid methyl ester (250.0 mg, 530.2 μmol), THF (4.50 mL), water (0.500 mL), and 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (151.3 mg, 1.087 mmol) was heated to 60 °C for 18 hours, then acidified to pH 4–5, and volatile solvents were removed by passing a nitrogen stream through the mixture at 45 °C. The remaining aqueous solution was purified by reversed-phase rapid chromatography using a gradient of 5–95% ACN in 10 mM NH4HCO3 aqueous solution + 5% MeOH to give the title compound as a solid (217 mg, 89%). ES-MS 458 (M+H).

[0256] Preparation 121 2-Methoxy-5-(4-Methoxy-2-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinamide)isonicotinic acid To a solution of methyl 2-methoxy-5-(4-methoxy-2-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinamide)isonicotinic acid (146 mg, 302 μmol) in THF (1 mL), LiOH (2 M aqueous solution, 72.3 mg, 1.51 mL, 3.02 mmol) and EtOH (0.2 mL) were added. The reaction mixture was stirred overnight. 1 M HCl aqueous solution was added to adjust the pH to 2, and the mixture was then extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated to dryness to give the title compound as a solid (119.9 mg, 85%). ES-MS 458 (M+H).

[0257] Preparation 122 2-Methoxy-5-(4-Methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carbamate)isonicotinic acid The title compound was prepared essentially as described in Preparation 121 using methyl 2-methoxy-5-(4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidin-5-carbamate)isonicotinic acid. ES-MS 471 (M+H).

[0258] Preparation 123 5-Amino-N-(2,2-difluoro-1,3-benzodioxane-5-yl)-3-fluoro-2-methoxypyridine-4-carboxamide Under a nitrogen atmosphere at 0°C, CuI (47.01 mg, 0.247 mmol) and ammonium hydroxide (25%, 3.46 g, 24.7 mmol) were added to a stirred mixture of 5-bromo-N-(2,2-difluoro-1,3-benzodioxane-5-yl)-3-fluoro-2-methoxypyridine-4-carboxamide (500 mg, 1.24 mmol) and L-proline (42.63 mg, 0.370 mmol) in DMSO (3 mL). The resulting mixture was stirred at 100°C for 5 hours under a nitrogen atmosphere and then diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaCl solution (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography using a gradient of 65 to 70% ACN in 10 mM NH4HCO3 to give the title compound (200 mg, 47%) as a yellow solid. ES-MS 342 (M+H).

[0259] Preparation 124 methyl 4-chloro-6-isopropoxypyrimidine-5-carboxylate Under a nitrogen atmosphere, 2-propanol (1.60 g, 2.03 mL, 26.6 mmol) and THF (50 mL) were added to a 250 mL round-bottom flask equipped with a stir bar. The solution was cooled to 0 °C, and NaH (60 wt% in mineral oil, 1.06 g, 26.6 mmol) was added in portions. The reaction mixture was stirred in an ice bath for 30 min, followed by the addition of methyl 4,6-dichloropyrimidine-5-carboxylate (5.00 g, 24.2 mmol) in a single batch, and the reaction was continued to be stirred in an ice bath. The reaction was slowly heated to ambient temperature with stirring, and then stirred for 22 h. The reaction was quenched with a saturated aqueous NH4Cl solution and stirred for 5 min, then diluted with a minimal amount of water and EtOAc. The organic phase was washed with a saturated aqueous NaHCO3 solution, followed by a saturated aqueous NaCl solution. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give the title compound (1.91 g, 27%) as an oil. ES-MS 231 (M+H).

[0260] The following compounds were prepared using appropriate alcohols as described in Preparation 124.

[0261] a. Silica gel chromatography gradient: 0 to 25% EtOAc in hexane.

[0262] Preparation 128 4-Isopropoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid NMP (10 mL) was added to a mixture of methyl 4-chloro-6-isopropoxypyrimidin-5-carboxylate (0.835 g, 3.62 mmol) and 3-morpholinobicyclo[1.1.1]pentan-1-amine (1.05 g, 6.24 mmol), followed by DIPEA (1.3 g, 1.8 mL, 10 mmol). The reaction vessel was sealed and heated at 80 °C for 16 hours, then cooled to ambient temperature and diluted with water and EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution, water, and then with saturated aqueous NaCl solution. The organic phase was dried over MgSO4, filtered, and concentrated. 1,3,4,6,7,8-hexahydro-2H-pyrimidino[1,2-a]pyrimidinium (1.51 g, 10.8 mmol), THF (5 mL), and water (1 mL) were added to the residue. The solution was heated to 50 °C and stirred for 90 minutes, then concentrated under a nitrogen stream and 10% citric acid aqueous solution (2 mL) was added. The solution was purified by reversed-phase rapid chromatography using a gradient of 10 to 100% ACN in 10 mM NH4HCO3 aqueous solution to give the title compound (1.26 g, 48%). ES-MS 349 (M+H).

[0263] The following compounds were prepared using appropriate heteroaryl halides as described in Preparation 128.

[0264] a. No 10% citric acid aqueous solution was added before purification.

[0265] b. The product was further purified by slurrying in EtOAc and EtOH, and the solid was filtered and dried under reduced pressure.

[0266] Preparation of 131 4-Ethoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid A mixture of methyl 4-chloro-6-ethoxypyrimidine-5-carboxylate (0.600 g, 2.77 mmol), 3-morpholinobicyclo[1.1.1]pentan-1-amine (0.660 g, 3.92 mmol), and DIPEA (0.74 g, 1.0 mL, 5.7 mmol) in NMP (10 mL) was heated to 80 °C for 4 days, then cooled to room temperature and diluted with water and EtOAc. The organic phase was washed with saturated NaHCO3 aqueous solution, water, and then with saturated NaCl aqueous solution. The organic matter was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give methyl 4-ethoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylate, which was mixed with 1,3,4,6,7,8-hexahydro-2H-pyrimidino[1,2-a]pyrimidine (0.280 g, 2.01 mmol), THF (3 mL), and water (0.5 mL). The mixture was heated to 50 °C for 2 hours, then cooled to room temperature and adjusted to pH 5 with 10% citric acid aqueous solution. The mixture was concentrated under a nitrogen stream to reduce the volume of THF, and then purified by reversed-phase rapid chromatography using a gradient of 10 to 100% ACN in 10 mM NH4HCO3 aqueous solution to give the title compound (0.151 g, 68%). ES-MS 335 (M+H).

[0267] Preparation of 132 2-((3-((tert-Butoxycarbonyl)amino)bicyclo[1.1.1]pent-1-yl)amino)-4-methoxynicotinic acid benzyl ester Under a nitrogen atmosphere, a solution of N-{3-aminobicyclo[1.1.1]pent-1-yl}carbamate tert-butyl ester (5.69 g, 28.709 mmol) and DIPEA (7.42 g, 57.417 mmol) in DMSO (20 mL) was stirred at room temperature for 20 min. 2-Fluoro-4-methoxypyridine-3-carboxylate benzyl ester (5 g, 19.139 mmol) was added dropwise to the reaction mixture at room temperature. The resulting mixture was stirred at 90 °C for another 16 h. The resulting mixture was diluted with H₂O (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with H₂O (2 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give the title product (10 g) as a yellow oil. ES-MS 440 (M+H).

[0268] Preparation of 133 2-((3-aminobicyclo[1.1.1]pent-1-yl)amino)-4-methoxynicotinic acid benzyl ester hydrochloride HCl (in 25 mL of 4 M solution in 1,4-dioxane) was added dropwise to a solution of 2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pent-1-yl)amino)-4-methoxynicotinic acid benzyl ester (2.5 g, 5.68 mmol) in ACN (100 mL), and the resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give the title product (2 g, 72%) as a solid. ES-MS 340 (M+H).

[0269] Preparation of 134 2-((3-(3-hydroxypyrrolidone-1-yl)bicyclo[1.1.1]pent-1-yl)amino)-4-methoxynicotinic acid benzyl ester (isomer 1) At room temperature, Cs₂CO₃ (3.77 g, 11.60 mmol) and KI (0.962 g, 5.80 mmol) were added in portions to a stirred mixture of 2-((3-aminobicyclo[1.1.1]pent-1-yl)amino)-4-methoxynicotinic acid benzyl ester (2 g, 5.80 mmol) and 1,4-dichlorobut-2-ol (racemic mixture, 1.00 g, 7.05 mmol) in DMF (50 mL). The resulting mixture was stirred at 90 °C for 5 hours. The reaction was quenched at room temperature by adding water (150 mL) and then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography using a gradient of 10 to 80% ACN in 0.1% NH4OH aqueous solution to give the title compound (0.78 g, 33%) as a racemic mixture. The product was purified by chiral HPLC [column: CHIRALART Cellulose-SB, 3 × 25 cm, 5 μm; mobile phase: solvent A - hexane + 0.1% diethylamine, solvent B - IPA; gradient: isocratic in solvent A 10% solvent B] to give the title compound (76 mg) as the first eluting isomer (white solid). ES-MS 410 (M+H).

[0270] Preparation of 135 2-((3-(1,1-dioxothiomorpholino)bicyclo[1.1.1]pent-1-yl)amino)-4-methoxynicotinic acid benzyl ester The title compound was prepared using 1-chloro-2-(2-chloroethanesulfonyl)ethane as described in Preparation 134. DCM was used instead of EtOAc in the water extraction step, and the product was purified by reversed-phase rapid chromatography using a gradient of 70 to 75% ACN in 0.1% formic acid aqueous solution. ES-MS 458 (M+H).

[0271] Preparation of 136 2-((3-(3-hydroxypyrrolidone-1-yl)bicyclo[1.1.1]pent-1-yl)amino)-4-methoxynicotinic acid (isomer 1) At room temperature, 10% palladium on carbon (20 mg) was added to a stirred solution of 2-((3-(3-hydroxypyrrolidin-1-yl)bicyclo[1.1.1]pent-1-yl)amino)-4-methoxynicotinic acid benzyl ester (isomer 1, 76 mg, 0.185 mmol) in MeOH (20 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The resulting mixture was filtered, the filter cake was washed with methanol (3 × 10 mL), and the filtrate was concentrated under reduced pressure to give the title compound (40 mg, 68%) as a white solid. ES-MS 320 (M+H).

[0272] Preparation of 137 2-((3-(1,1-dioxothiomorpholino)bicyclo[1.1.1]pent-1-yl)amino)-4-methoxynicotinic acid The title compound was prepared as described in Preparation 136 using benzyl 2-((3-(1,1-dioxothiomorpholino)bicyclo[1.1.1]pent-1-yl)amino)-4-methoxynicotinic acid, with the reaction stirred for 3 hours under a hydrogen atmosphere. ES-MS m / z 368 (M+H).

[0273] Example Example 1 N-((1S,2R,3S,4R)-3-((4-cyano-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxamide A mixture of (1R,2S,3R,4S)-3-(4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidin-5-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid (50 mg, 0.11 mmol) and 4-amino-2-(trifluoromethyl)benzyl nitrile (22 mg, 0.12 mmol) was added to TCFH (34 mg, 0.12 mmol) and 1-methylimidazole (20 mg, 19 μL, 0.24 mmol) in ACN (1.1 mL). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was then concentrated and purified directly by reversed-phase column chromatography (C18, 0.1% FA in H2O, 0.1% FA in ACN) to give the title compound (14.0 mg, 21 μmol, 19%) as a white solid. ES-MS 626 (M+H).

[0274] The following preparations are essentially as described in Example 1, using appropriate carboxylic acids and aniline:

[0275] Example 12 N-((1S,2R,3S,4R)-3-((4-Fluoro-3-(pentafluoro-λ) 6 -thioalkyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxamide 4-chloro-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(pentafluoro-λ) 6A mixture of thioalkyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-6-methoxypyrimidine-5-carboxamide (64.1 mg, 118 μmol), 3-morpholinobicyclo[1.1.1]pentane-1-amine dihydrochloride (33.2 mg, 138 μmol), and DiPEA (89.0 mg, 688 μmol, 0.12 mL) was dissolved in DMF (4 mL). The reaction was stirred at 80 °C for 3 hours. After the reaction was complete, the reaction mixture was partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was washed with a saturated aqueous solution of NaCl (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel using a gradient of 0-100% EtOAc in heptane followed by 0-20% MeOH in DCM. The product was then repurified by reversed-phase chromatography using 0-100% ACN / H2O (with 0.1% FA modifier in both eluents) to give the title compound (14.4 mg, 21.3 μmol, 19%). ES-MS 677 (M+H).

[0276] The following preparations are essentially as described in Example 12, using appropriate aryl halides and amines:

[0277] Example 29 (1S,3R)-3-((6-methoxy-5-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)carbamoyl)pyrimidin-4-yl)amino)cyclohexane-1-carboxylic acid To a solution of methyl (1S,3R)-3-((6-methoxy-5-((2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)carbamoyl)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate (295 mg, 464 μmol) in THF (1 mL), LiOH (2 M aqueous solution, 111 mg, 2.32 mL, 4.64 mmol) and EtOH (0.2 mL) were added. The reaction mixture was heated to 60 °C and stirred for 45 min. 1 M HCl was added to bring the mixture to pH 2. The mixture was extracted with EtOAc (30 mL), and the combined organic layers were concentrated. The residue was purified by reversed-phase chromatography (C18) using a gradient elution of 45% to 85% aqueous solution of 0.1% FA in ACN to give the title compound (57.5 mg, 92.5 μmol, 20%) as an off-white solid. ES-MS 622 (M+H).

[0278] The following preparations were essentially made using suitable ester starting materials as described in Example 29: a. The product was purified by chiral chromatography as the second eluting isomer [column: Phenomenex® Lux® i-Amylose-1, 30 × 150 mm, 5 μm; mobile phase: 5-20% isopropanol in heptane].

[0279] b. The product was purified by chiral normal phase chromatography as the second eluting isomer [column: Phenomenex® Lux® i-Amylose-3, 30×150mm, 5μm; mobile phase: 23% MeOH / CO2].

[0280] c. The product was purified by chiral chromatography as the second eluting isomer [column: Phenomenex® Lux® i-Amylose-1, 30 × 150 mm, 5 μm; mobile phase: 10-20% isopropanol in heptane].

[0281] Example 36 N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-4-methoxy-6-((4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)amino)pyrimidine-5-carboxamide A mixture of 4-chloro-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-6-methoxypyrimidine-5-carboxamide (100 mg, 205 μmol) and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(4H)-one HCl (48.3 mg, 226 μmol) was added to p-toluenesulfonic acid monohydrate (39.1 mg, 205 μmol) in isopropanol (2 mL). The reaction mixture was stirred at 80 °C for 2 hours, then the reaction mixture was concentrated and the residue was purified directly by reversed-phase column chromatography (C18, 0.1% FA in water, 0.1% FA in ACN) to give the title compound (47.8 mg, 72 μmol, 35%) as a white solid.

[0282] Example 37 4-((4-(1,3,4-thiadiazol-2-yl)phenyl)amino)-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl))bicyclo[2.2.1]hept-2-yl)-6-methoxypyrimidine-5-carboxamide The title compound was prepared essentially as described in Example 36 using -(1,3,4-thiadiazol-2-yl)aniline. ES-MS 628 (M+H).

[0283] Example 38 N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-4-methoxy-6-((3-morpholino-1,2,4-thiadiazol-5-yl)amino)pyrimidine-5-carboxamide To a mixture of 4-chloro-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-6-methoxypyrimidin-5-carboxamide (48.9 mg, 100 μmol), morpholino-1,2,4-thiadiazol-5-amine (20.3 mg, 109 μmol), dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (76.9 mg, 107 μmol) and Na₂CO₃ (44.0 mg, 415 μmol) were added. The reaction vessel was sealed and purged with argon, and then anhydrous degassed 1,4-dioxane (1.00 mL) was added via syringe. Before stirring at 80 °C for 16 hours, the reaction was purged with argon for another 2 minutes. The mixture was then partitioned between EtOAc (50 mL) and water (10 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified on silica gel using a gradient of 0–100% EtOAc in heptane, and the product was then repurified by reversed-phase HPLC using ACN and 0.1% FA in water to give the title compound (32.8 mg, 51.5 μmol, 51%). ES-MS 637 (M+H).

[0284] The following preparation was essentially as described in Example 1, using a suitable carboxylic acid and (1R,2S,3R,4S)-3-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide:

[0285] The following compounds were prepared essentially as described in Example 12 using appropriate aryl halides and amines:

[0286] Example 51 -(2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxamide DiPEA (118 mg, 159 μmol) was added to a solution of 4-fluoro-3-(trifluoromethyl)aniline (42.8 mg, 239 μmol), 2-(4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidin-5-carbamate)benzoic acid (100 mg, 228 μmol), and PPACA (217 mg, 201 μL, 341 μmol) in DCM (2.28 mL), and the reaction mixture was stirred at 50 °C for 2 hours. After 2 hours, the reaction mixture was concentrated and then purified directly by reversed-phase column chromatography (C18, 0.1% FA in H2O, 0.1% FA in ACN) to give the title product (83 mg, 58%) as a white solid. ES-MS 601 (M+H).

[0287] Example 52 N-(cis-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.2]oct-2-yl)-4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxamide (racemic mixture) A solution of cis-3-(4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidin-5-carboxamido)bicyclo[2.2.2]octane-2-carboxylic acid (racemic mixture) (95.7 mg, 0.2 mmol), HATU (110 mg), and TEA (78 μL) in DMF (1.5 mL) was stirred at 25 °C for 5 min, followed by the addition of 4-fluoro-3-(trifluoromethyl)aniline (41.0 mg, 0.2 mmol). The reaction mixture was stirred at 65 °C for 100 min. The reaction mixture was cooled to 25 °C, quenched with H2O (20 mL), and EtOAc (20 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried using a phase separator and concentrated under vacuum. The residue was purified by silica gel chromatography (1-40% EtOAc / EtOH (3:1) in n-heptane). The fractions were combined and concentrated under reduced pressure. The product was further purified by preparative TLC (5% MeOH in DCM) to give the first isomer (26.0 mg, 21%) as a white foam. ES-MS 633 (M+H).

[0288] Example 53 -(2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-4-methoxy-2-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinamide Oxaloyl chloride (95.4 mg, 66 μL, 752 μmol) was added to a solution of 4-methoxy-2-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinic acid (200 mg, 626 μmol) in DCE (6.26 mL), followed by dropwise addition of DMF (114 mg, 121 μL, 2 mmol). After bubbling was stopped, 2-amino-(4-fluoro-3-(trifluoromethyl)phenyl)benzamide (224 mg, 752 μmol) was added, followed by DiPEA (243 mg, 327 μL, 2 mmol). The reaction mixture was stirred for 20 min, and then the mixture was purified directly by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane to give the title product (59 mg, 15%). ES-MS 600 (M+H).

[0289] Example 54 2-Cyano-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxamide TFAA (47.6 mg, 0.2 mmol) was added to a stirred mixture of -((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-2,5-dicarboxamide (100 mg) and pyridine (23.91 mg, 0.30 mmol) in toluene (20 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. A solution of the residue (80 mg) in DMF (2 mL) and TEA (43.7 mg, 0.4 mmol) was stirred at 50 °C for 3 hours under N2 atmosphere. The mixture was purified by preparative HPLC (column: RP18 OBD, 30). 150 mm, 5 μm; mobile phase A: H₂O (10 mmol / L NH₄HCO₃), mobile phase B: ACN). The pure fraction was lyophilized to give the title product (24.8 mg, 26%) as a white solid. ES-MS 644 [M+H]; [a] D 25 = +91.5 (c=1.0, in MeOH).

[0290] Example 55 (R)--(5-fluoro-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-4-methoxy-2-((1-(oxecyclobutan-3-yl)piperidin-3-yl)amino)nicotinamide To a solution of (R)-(5-fluoro-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-4-methoxy-2-(piperidin-3-ylamino)nicotinamide (50.0 mg, 91.0 μmol) in MeOH (0.750 mL), AcOH (5.46 mg, 91.0 μmol) and oxetane-3-one (19.7 mg, 273 μmol) were added. The reaction mixture was stirred at room temperature for 15 min and then treated with NaBH3CN (17.2 mg, 273 μmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under a stream of N2 at 40 °C. The residue was purified by reversed-phase HPLC using a gradient of 40 to 77% ACN in 10 mM NH4HCO3 aqueous solution + 5% MeOH to give the title product (41.1 mg, 75%). ES-MS 606 (M+H).

[0291] Examples 56 and 57 -(2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-4-((3-(3-hydroxypyrrolidone-1-yl)bicyclo[1.1.1]pent-1-yl)amino)-6-methoxypyrimidine-5-carboxamide (Isomer 1 - Example 56 and Isomer 2 - Example 57) Under a nitrogen atmosphere at room temperature, TEA (88.95 μL, 0.64 mmol) was added dropwise to a stirred solution of 1-(3-aminobicyclo[1.1.1]pent-1-yl)pyrrolidine-3-ol; hydrochloride (racemic mixture) (131.00 mg, 0.64 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. 4-chloro--(2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-6-methoxypyrimidine-5-carboxamide (200 mg) and CsF (12.96 mg, 0.09 mmol) were added in portions to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was then stirred at 50 °C under a nitrogen atmosphere for 2 days. The reaction mixture was quenched with H2O (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated NaCl aqueous solution (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (C18, ACN in H2O (0.1% NH3·H2O)) and preparative HPLC (RP18 OBD column, ACN in H2O) to give a racemic mixture (60 mg, 23%) of the title product as a white solid. The racemic mixture was then purified by chiral HPLC under the following conditions (column: Lux 5μ Cellulose-2, 30 °C). 250 mm, 5.0 μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MeOH)), to obtain isomer 1 (first eluting isomer, 21.8 mg, 35%) as a white solid with 100% ee, and isomer 2 (second eluting isomer, 26.5 mg, 44%) as a white solid with 99.22% ee. Both isomers: ES-MS 601 (M+H).

[0292] Example 58 4-Methoxy-N-(5-Methoxy-2-((1-(trifluoromethyl)-2-oxabicyclo[2.2.2]oct-4-yl)carbamoyl)phenyl)-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxamide To a mixture of 2-amino-4-methoxy-N-(1-(trifluoromethyl)-2-oxabicyclo[2.2.2]oct-4-yl)benzamide (100 mg, 290 μmol) and 4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid (93.0 mg, 290 μmol) dissolved in EtOAc (2 mL), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide (924 mg, 1 mL, 50 wt%, 1.45 mmol) and DIPEA (113 mg, 0.15 mL, 871 μmol) were added, and the reaction mixture was stirred at 60 °C for 18 hours. The reaction mixture was partitioned between EtOAc and water, and the organic layer was dried over Na2SO4, filtered, and concentrated. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using 0 to 100% EtOAc in heptane, followed by a gradient of 0 to 20% MeOH in EtOAc, to give the title compound (43 mg, 23%). ES-MS 647 (M+H).

[0293] The following examples are prepared essentially as described in Example 58 using appropriate carboxylic acids and amines: a. The product was purified by reversed-phase HPLC using a gradient of ACN (50-55% starting %B, 75-81% ending %B) in 10 mM NH4HCO3 aqueous solution + 5% MeOH.

[0294] Example 64 N-(4-((2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)carbamoyl)-6-methoxypyridin-3-yl)-4-methoxy-2-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinamide Add DIPEA (128 mg, 0.17 mL, 990 μmol) and N,N-dimethylpyridin-4-amine (36.3 mg, 297 μmol) to a mixture of 5-amino-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-2-methoxyisonicotinamide (80.0 mg, 247 μmol), DIPEA (128 mg, 0.17 mL, 990 μmol), and ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tris(pyrrolidine-1-yl)phosphonium hexafluorophosphate (V) (386 mg, 742 μmol) in EtOAc (2 mL). Stir the mixture at 60 °C for 1 hour, then cool to room temperature and partition between EtOAc (5 mL) and water (5 mL). The organic layer was washed with water (2 × 5 mL), concentrated, and the residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane to give the title compound (52 mg, 34%). ES-MS 623 (MH).

[0295] Example 65 N-(2,2-difluoro-1,3-benzodioxane-5-yl)-3-fluoro-2-methoxy-5-(4-methoxy-2-{[3-(morpholin-4-yl)bicyclo[1.1.1]pent-1-yl]amino}pyridine-3-amido)pyridine-4-carboxamide Under a nitrogen atmosphere at room temperature, TCFH (164.44 mg, 0.586 mmol) and 1-methyl-1H-imidazolium (96.24 mg, 1.172 mmol) were added to a stirred mixture of 5-amino-N-(2,2-difluoro-1,3-benzodioxane-5-yl)-3-fluoro-2-methoxypyridine-4-carboxamide (100 mg, 0.293 mmol, 1 equivalent) and 4-methoxy-2-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)nicotinic acid (102.95 mg, 0.322 mmol) in ACN (5 mL), and the mixture was stirred for 4 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated aqueous solution (3 × 100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC using a gradient of 45 to 55% ACN in 10 M NH₄HCO₃ + 0.05% NH₄OH to give the title compound as a solid (141.3 mg, 75%). ES-MS 643 (M+H).

[0296] Example 66 4-Isopropoxy-N-(6-methoxy-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)pyridin-3-yl)-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxamide The title compound was prepared essentially as described in Example 65 using 4-isopropoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid and 5-amino-2-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)isonicotinamide. ES-MS 706 (M+H).

[0297] The following examples are prepared essentially as described in Example 12 using suitable aryl halides and amines:

[0298] Example 77 N-(4-((2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)carbamoyl)-6-methoxypyridin-3-yl)-4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxamide PPACA (339.8 mg, 0.5 mL, 50 wt%, 533.9 μmol) and TEA (108.1 mg, 0.15 mL, 1.068 mmol) were added to a mixture of 2-methoxy-5-(4-methoxy-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidin-5-carbamate) in NMP (2 mL), and the reaction mixture was stirred at 20 °C for 1 hour. The mixture was partitioned between EtOAc and water, and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase HPLC using a gradient of 38 to 63% ACN in 0.1% aqueous formic acid to give the title compound (15.3 mg, 9%). ES-MS 626 (M+H).

[0299] The following practices, for example, are described in Example 77, using appropriate amines and carboxylic acids for preparation.

[0300] a. Add 1.07-1.9 equivalents of 4-dimethylaminopyridine to establish the reaction mixture and heat it to 80-85°C for 18 hours to 4 days. Purify the reaction mixture by reversed-phase rapid chromatography using a gradient of ACN (5-10% starting, 95-100% ending) in 10 mM NH4HCO3 aqueous solution (optionally with 5% MeOH) without post-treatment.

[0301] b. The product was purified by reversed-phase HPLC using a gradient of 46-71% ACN in 10 mM ammonium acetate aqueous solution + 5% MeOH.

[0302] Example 84 N-(4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-methoxypyridin-3-yl)-4-methoxy-2-((3-(morpholin-4-carbonyl)bicyclo[1.1.1]pentan-1-yl)amino)nicotinamide HATU (0.039 g, 0.10 mmol) and DIPEA (22 mg, 0.030 mL, 0.17 mmol) were added to a mixture of 3-((3-((4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-methoxypyridin-3-yl)carbamoyl)-4-methoxypyridin-2-yl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (0.049 g, 83 μmol) and morpholine (0.015 g, 0.17 mmol) in NMP (1.0 mL). The reaction mixture was stirred at room temperature for 3 days, then diluted with water and EtOAc. A saturated aqueous solution of NH4Cl was added to the mixture and the layers were separated. The organic matter was washed with a saturated aqueous solution of NaHCO3, water, and then with a saturated aqueous solution of NaCl. The organic matter was dried over MgSO4, filtered, and concentrated. The residue was purified by reversed-phase rapid chromatography using a gradient of 10 to 100% ACN in 10 mM NH4HCO3 aqueous solution. The fraction containing the product was concentrated, and the residue was then dissolved in EtOAc, with the organic matter washed with water and saturated NaCl aqueous solution. The organic matter was dried over MgSO4, filtered, and concentrated to give the title compound as a solid (0.024 g, 44%). ES-MS 659 (M+H).

[0303] Example 85 2-((3-(3-oxa-6-azabicyclo[3.1.1]heptane-6-carbonyl)bicyclo[1.1.1]pent-1-yl)amino)-N-(4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-methoxypyridin-3-yl)-4-methoxynicotinamide The title compound was prepared as described in Example 84 using 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride and 4 equivalents of DIPEA. ES-MS 671 (M+H).

[0304] Example 86 4-Methoxy-N-(6-methoxy-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)pyridin-3-yl)-2-((3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)bicyclo[1.1.1]pent-1-yl)amino)nicotinamide 2-Fluoro-4-methoxy-N-(6-methoxy-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)pyridin-3-yl)nicotinamide (83 mg, 0.16 mmol) and 3-(3-aminobicyclo[1.1.1]pent-1-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride (38 mg, 0.19 mmol) were combined in N,N-dimethylacetamide and treated with K2HPO4 (82 mg, 0.47 mmol), and the mixture was stirred overnight at 70 °C. The reaction mixture was purified by reversed-phase HPLC using a gradient of 48 to 73% ACN in 0.1% aqueous formic acid to give the title compound (3.2 mg, 3%). ES-MS 676 (M+H).

[0305] Example 87 4-(2,2-Difluoroethoxy)-N-(6-methoxy-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)pyridin-3-yl)-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxamide A mixture of 4-(2,2-difluoroethoxy)-6-((3-morpholinobicyclo[1.1.1]pent-1-yl)amino)pyrimidine-5-carboxylic acid (75 mg, 0.20 mmol), 5-amino-2-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)isonicotinamide (100 mg, 266 μmol), and TCFH (85 mg, 0.30 mmol) was mixed with ACN (1 mL) and 1-methylimidazole (67 mg, 0.82 mmol). The mixture was stirred overnight at room temperature and then purified by reversed-phase rapid chromatography using a gradient of 10 to 100% ACN in 10 mM NH4HCO3 aqueous solution to give the title compound (66 mg, 45%) as an off-white solid. ES-MS m / z 728 (M+H).

[0306] The following examples are prepared using appropriate amines and carboxylic acids, essentially as described in Example 87.

[0307] a. The reaction mixture was post-treated with an aqueous phase by adding EtOAc, and the organic matter was washed with water and a saturated NaCl aqueous solution.

[0308] b. The product was purified by reversed-phase HPLC using a gradient of 47 to 49% ACN in 10 mM NH4HCO3 aqueous solution + 0.05% NH4OH.

[0309] c. After rapid reverse-phase purification, the product was slurried in ACN, filtered, and dried under reduced pressure. The reaction mixture was post-treated with aqueous phase by adding water and extracting three times with DCM. The combined organic matter was washed with a saturated aqueous NaCl solution and then dried over Na2SO4.

[0310] Biological assays: The following assays demonstrate that the example compound is an RXFP1 receptor agonist.

[0311] We generated relaxin family peptide receptor 1 (RXFP1) expressing cells by transfecting HEK293 cells with a tetracycline-inducible RXFP1 expression cassette (accession number NM_021634.4) and selecting single-cell clones responsive to human relaxin 2 (cat# H-6784.0200, Bachem, Torrance, CA). RXFP1-expressing cells were induced by treatment with 1 μg / mL doxycycline for 24 hours prior to compound administration. At cell administration, the compound was acoustically transferred to 384-well plates (ProxiPlate, 384-well, cat#6008289, Revvity, Waltham, MA) using an ECHO acoustic liquid processor (Beckman, Brea, CA). Cells were administered a 10-point dose-response curve (3-fold dilution), starting at 10 μM and incubated at 37°C for 1 hour. The final DMSO concentration was 0.6% in a 10 μL assay volume.

[0312] The assay buffer used for processing was 1X stimulation buffer (supplied with the CisBio GscAMP HighRange Kit, cat#62AM6PEJ, Revvity) diluted in distilled water and containing 3-isobutyl-1-methylxanthine (cat# I5879250 MG, Sigma-Aldrich, St. Louis, MO) to a final concentration of 500 μM. After incubation for 1 hour, cAMP levels were assessed using the CisBio GscAMP HighRange Kit (cat#62AM6PEJ) according to the manufacturer's instructions (Revvity). In short, 5 μL of D2-labeled cAMP diluted in lysis buffer (supplied with the kit) and 5 μL of Eu were added to each well. 3+ - Anti-cAMP antibody labeled with cavitation compounds. Cell lysates were incubated at room temperature for 1 hour before detection on a Pherastar FSX microplate reader (BMG, Ortenberg, Germany). HTRF ratios (emission 665 nm / emission 620 nm x 10,000) were converted to cAMP units using a cAMP standard curve. (Relative EC50) 50 The top and bottom of each concentration response curve were calculated relative to the top and bottom, determined by nonlinear regression with a four-parameter logistic fit using Genedata Ver. 18.0.8 (Genedata, Basel, Switzerland).

[0313] In the above assays, the compounds of Examples 1-98 exhibited agonist activity in the RXFP1 receptor, relative to EC 50<50 nM. This data indicates that the compound of formula I described herein is an RXFP1 agonist in human HEK293 cells.

Claims

1. The following compound: in: G1 is -C(R) a - or -N-; G2 is -C(R) b - or -N-; Ring A is a group of the following formula , , , or , in , or For unsubstituted or by one or more halogens or C 1-3 Alkyl substitution; -X- is either -NH- or -S-; R a It is -H or halogen; R b It is -H or halogen; R1 is C 1-3 alkoxy or cyclopropoxy, wherein C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; R2 is a group in the following formula , , , , , , , , , , , or ; R 2a C 1-3 Alkyl, -OH, oxo, -N(R)2, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazolium, pyrimidine, piperazine, pyrrolidine, pyrazine, thiomorpholine 1,1-dioxide or , Wherein C 1-3 The alkyl group is unsubstituted or substituted with one or more -OH, oxo, or morpholine groups, wherein the morpholine group is unsubstituted or substituted with C. 1-3 Alkyl-bridged substitution, wherein the oxadiazole, thiadiazole, pyrimidine, piperazine, pyrazine, or morpholine is unsubstituted or substituted with an oxo group, wherein the pyrimidine, piperazine, and pyrazine are unsubstituted or substituted with an oxo group. 1-3 Alkyl substitution, wherein the pyrrolidine is unsubstituted or substituted with -OH, and wherein the pyrrole is unsubstituted or substituted with -OH; Each R is independently C 1-3 alkyl; -G 3a -for-CHR 2b -or -CH2-O-CH2-; -Y- is C 1-3 Alkylene; R 2b -COOH; R 2c It is -H or halogen; R3 is a group in the following formula: , , or ; -G4- is either -CH- or -N-; R 3a -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; R 3b -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN or C 1-4 alkyl; R 3c It is independently -H or halogen each time it appears; R 3d -H, halogen, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; R4 is -H, -CN, or C 1-3 Alkyl, wherein C 1-3 The alkyl group is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein: R1 is C 1-3 Alkyl groups; or pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 or 2, wherein: Ring A is a group of the following formula , , , or , in It is either unsubstituted or substituted with halogens; R1 is C 1-3 Alkoxy; R 2a For -OH, -N(R)2, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazolium, pyrimidine, pyrazine, thiomorpholine 1,1-dioxide, or , The pyrimidine, pyrazine, or morpholine therein is unsubstituted or substituted with an oxo group, wherein the pyrimidine and pyrazine are unsubstituted or substituted with an oxo group. 1-3 Alkyl substitution, wherein the pyrrole is unsubstituted or substituted with -OH; R 3a Each occurrence is independently -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; and R4 is -H or C 1-3 Alkyl, wherein C 1-3 The alkyl group is either unsubstituted or substituted with -CN; Or its pharmaceutically acceptable salt.

4. The compound according to claim 1 or 2, wherein: Ring A is a group of the following formula , , or ; R a -H or -F; R b -H or -F; R1 is C 1-3 Alkoxy; R2 is a group in the following formula , , , , , , or , Where R 2a The oxadiazole, thiadiazole, morpholine or thiomorpholine 1,1-dioxide is -OH, -N(R)2, oxadiazole, thiadiazole, morpholine or thiomorpholine, wherein the oxadiazole, thiadiazole or morpholine is unsubstituted or substituted with an oxo group; R 3a -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; Each R 3c Independently -H or -F; R 3d -H, halogen, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; and R4 is -H; or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1-4, wherein: Ring A is a group of the following formula , , or ; R a -H or -F; R b -H or -F; R1 is C 1-3 Alkoxy; R2 is a group in the following formula , , , , , , or ; R 2a The oxadiazole, thiadiazole, morpholine or thiomorpholine 1,1-dioxide is -OH, -N(R)2, oxadiazole, thiadiazole, morpholine or thiomorpholine, wherein the oxadiazole, thiadiazole or morpholine is unsubstituted or substituted with an oxo group; R3 is a group in the following formula: or ; R 3a -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 Alkyl or C 1-3 The alkoxy group is either unsubstituted or substituted with one or more halogens; Each R 3c Independently -H or -F; and R4 is -H; Or its pharmaceutically acceptable salt.

6. The compound according to any one of claims 1-5, wherein ring A is selected from the group consisting of: and Or, or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1-3, wherein ring A is a group of the following formula. or Or, or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1-3, wherein ring A is a group of the following formula. , , or Or, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8, wherein ring A is a group of the following formula. Or, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 or 2, wherein ring A is a group of the following formula. Or, or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 1-10, wherein R4 is -H, or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1-11, wherein G1 is -N- or a pharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 1-11, wherein G1 is -C(R a )-, or its pharmaceutically acceptable salt.

14. The compound according to claim 13, wherein R a It is -H, or a pharmaceutically acceptable salt thereof.

15. The compound according to any one of claims 1-14, wherein G2 is -N- or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1-14, wherein G2 is -C(R b )-, or its pharmaceutically acceptable salt.

17. The compound according to claim 16, wherein R b It is -H, or a pharmaceutically acceptable salt thereof.

18. The compound according to any one of claims 1, 6-17, wherein R1 is methoxy, difluoroethoxy, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18, wherein R1 is a methoxy group or a pharmaceutically acceptable salt thereof.

20. The compound according to any one of claims 1-19, wherein R3 is selected from the group consisting of: and Or, or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 20, wherein R 3a It is tert-butyl, -SF5, -SO2CF3 or -SCF3, and R 3b It is -H or -F, or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 20, wherein R 3a It is -F, -Cl, -Br, difluoromethyl, difluorochloromethyl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy, and R 3b It is -H, -F, -Cl, -Br, trifluoromethyl, -CN or methyl, or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 20, wherein R 3a and R 3b It is a methoxy group or a pharmaceutically acceptable salt thereof.

24. The compound according to any one of claims 1-23, wherein -X- is -NH- or a pharmaceutically acceptable salt thereof.

25. The compound according to any one of claims 1-24, wherein R2 is a group of the following formula. Or, or a pharmaceutically acceptable salt thereof.

26. The compound according to any one of claims 1-24, wherein R2 is a group of the following formula And R 2a Choose from the following groups: -OH, , , , , , , , , , , , , and Or, or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 26, wherein R 2a Choose from the following groups: , and Or, or a pharmaceutically acceptable salt thereof.

28. The compound according to any one of claims 1-24, wherein R2 is selected from the group consisting of: , , , and Or, or a pharmaceutically acceptable salt thereof.

29. The compound of claim 28, wherein R2 is selected from the group consisting of: , , , , , , , , and Or, or a pharmaceutically acceptable salt thereof.

30. The compound according to any one of claims 1-24, wherein R2 is selected from the group consisting of: and Or, or a pharmaceutically acceptable salt thereof.

31. The compound according to claim 30, wherein R2 is selected from the group consisting of: , and Or, or a pharmaceutically acceptable salt thereof.

32. The compound according to claim 1, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

33. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-32, and a pharmaceutically acceptable carrier, diluent or excipient.

34. A method for treating cardiovascular, pulmonary and / or renal conditions, diseases and / or disorders in an individual with such need, the method comprising administering to the individual a therapeutically effective amount of any one of claims 1-32 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 33.

35. The method of claim 34, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.

36. The method of claim 34, wherein the condition, disease, or disorder to be treated is a pulmonary condition, disease, or disorder, wherein the pulmonary condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

37. The method of claim 34, wherein the condition, disease, or disorder to be treated is a kidney condition, disease, or disorder, wherein the kidney condition, disease, or disorder is acute kidney disease, chronic kidney disease, or diabetic nephropathy.

38. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-32, used in a therapeutic manner.

39. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-32, for the treatment of cardiovascular, pulmonary and / or renal conditions, diseases and / or disorders.

40. The compound for use according to claim 39, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.

41. The compound for use according to claim 40, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.

42. The compound for use according to claim 39, wherein the condition, disease, or disorder to be treated is a lung condition, disease, or disorder.

43. The compound for use according to claim 42, wherein the lung condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

44. The compound for use according to claim 39, wherein the condition, disease, or disorder to be treated is a kidney condition, disease, or disorder.

45. The compound for use according to claim 44, wherein the kidney condition, disease, or disorder is acute kidney disease, chronic kidney disease, or diabetic nephropathy.

46. ​​A method of expressing agonist activity in the RXFP1 receptor in an individual with this need, comprising administering to said individual a therapeutically effective amount of any one of claims 1-33 or the pharmaceutical composition of claim 34.

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