Benzothiazole derivatives useful as agonists of the RXFP1 receptor

Abstract

The present invention provides compounds of formula (I): formula (I), wherein rings A, R1, R2 and R3 are as described herein, pharmaceutically acceptable salts thereof, and methods of using these compounds and their pharmaceutically acceptable salts to treat cardiovascular, pulmonary and / or renal symptoms, diseases and / or conditions in patients.

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 short-acting recombinant relaxin (serelaxin) have shown promise as a therapeutic agent for the treatment of 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, peptide agonists of the relaxin family peptide receptor-1 (RXFP1) require subcutaneous / intravenous administration.

[0004] Non-peptide small molecule modulators of RXFP1 have also been sought. For example, McBride A et al. (2017) Scientific Reports 7:10806 discussed small molecule orthoallosteric modulators of RXFP1. WO2023 / 076626, WO2023 / 077040 and WO2023 / 077070 each disclose small molecule analogs that can be used as RXFP1 receptor agonists.

[0005] There remains a need to provide alternative small-molecule RXFP1 agonists. Specifically, there is a need to provide additional orally deliverable RXFP1 agonists for the treatment of cardiovascular, pulmonary, and / or renal symptoms, diseases, and / or conditions. Furthermore, there is a desire to provide RXFP1 receptor agonists exhibiting better pharmacokinetic / pharmacodynamic properties. Additionally, there is a need to provide RXFP1 receptor agonists that demonstrate efficacy while reducing or minimizing adverse or undesirable effects. More specifically, there is a need to provide small-molecule RXFP1 receptor agonists that are selective for RXFP1 compared to RXFP2. This invention addresses one or more of these needs by providing novel small-molecule RXFP1 agonists. Summary of the Invention

[0006] This article discloses compounds of formula I. A compound of the following formula, or a pharmaceutically acceptable salt thereof: in: Ring A is a group of the following formula , , , , , , , or , in , , and Each of them may optionally be selected from one or more halogens, -CN, C 1-4 Alkyl, -SC 1-3 Alkyl and C 1-3 Alkyl substituents, wherein each C 1-4 Alkyl and C 1-3 The alkoxy group is independently and optionally substituted by one or more substituents selected from halogens and -CN; -Y- is C 1-3 Alkylene; -G6- is either -C(R1)- or -N-; R1 is C 1-3 Alkoxy; R2 is a -OCH2COOH or N-linked 4-7-membered heterocycle; wherein the N-linked 4-7-membered heterocycle is selected from aziridine, pyrrolidine, morpholine, piperazine, piperidine, and oxazine-heptanidine; wherein the heterocycle is optionally connected via C 1-4 Alkylene or 1-5-membered heteroalkyl groups are bridged, fused with, or spirolinked to them; wherein the heterocyclic ring, the C 1-4 The alkylene group and the 1-5 heteroalkyl group are each optionally surrounded by 1-3 groups independently selected from halogen, oxo group, C. 1-4 Alkyl, C 1-4 Substitution with haloalkyl groups, -OH and -COOH groups; R3 can be selected from the following groups: , , , , , and , in It can be optionally replaced by one to three halogens; -G4- is either -CH- or -N-; -G5- is either -CH2- or -O-; R 3a Each occurrence is independent of -H, one or two halogens, -SF5, -SO2CF3, -SCF3, -CN, or C. 1-4 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3The alkoxy group may optionally be replaced by one, two, or three 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 either -H or halogen each time it appears; R 3d It is -H, halogen, -CN, C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3 The alkoxy group may be optionally replaced by one, two, or three halogens.

[0007] The following are further numbered aspects of the invention: 1. A compound of the following formula, or a pharmaceutically acceptable salt thereof: in: Ring A is a group of the following formula , , , , , , , or , in , , and Each of them may optionally be selected from one or more halogens, -CN, C 1-4 Alkyl and C 1-3 Alkyl substituents, wherein each C 1-4 Alkyl and C 1-3 The alkoxy group is independently and optionally substituted by one or more substituents selected from halogens and -CN; -Y- is C 1-3 Alkylene; -G6- is either -C(R1)- or -N-; R1 is C 1-3 Alkoxy; R2 is a -OCH2COOH or N-linked 4-7-membered heterocycle; wherein the N-linked 4-7-membered heterocycle is selected from aziridine, pyrrolidine, morpholine, piperazine, piperidine, and oxazine-heptanidine; wherein the heterocycle is optionally connected via C 1-4Alkylene or 1-5-membered heteroalkyl groups are bridged, fused with, or spirolinked to them; wherein the heterocyclic ring, the C 1-4 The alkylene group and the 1-5 heteroalkyl group are each optionally surrounded by 1-3 groups independently selected from halogen, oxo group, C. 1-4 Alkyl, C 1-4 Substitution with haloalkyl groups, -OH and -COOH groups; R3 can be selected from the following groups: , , , , , and , in It can be optionally replaced by one to three halogens; -G4- is either -CH- or -N-; -G5- is either -CH2- or -O-; R 3a Each occurrence is independent of -H, halogen, -SF5, -SO2CF3, -SCF3, -CN, or C. 1-4 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl groups and the C 1-3 The alkoxy group may optionally be replaced by one, two, or three halogens; R 3b Independently -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN, or C 1-4 alkyl; R 3c It is either -H or halogen each time it appears; R 3d It is -H, halogen, -CN, C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl groups and the C 1-3 The alkoxy group may be optionally replaced by one, two, or three halogens.

[0008] This article discloses compounds of Formula I or pharmaceutically acceptable salts thereof, and methods of using compounds of Formula I or pharmaceutically acceptable salts thereof to treat cardiovascular, pulmonary and / or renal symptoms, diseases and / or conditions in patients.

[0009] This article also provides methods for treating cardiovascular, pulmonary, and / or renal symptoms, diseases, and / or conditions using compounds of Formula I, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. These methods include administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need.

[0010] This document further provides compounds of Formula I and their pharmaceutically acceptable salts for use in therapeutics. This document also provides compounds of Formula I and their pharmaceutically acceptable salts for use in the treatment of cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders. This document also provides the use of compounds of Formula I or their pharmaceutically acceptable salts in the manufacture of medicaments for the treatment of cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders. Detailed Implementation

[0011] This article describes novel RXFP1 receptor agonists. These new compounds address some or all of the needs mentioned above regarding novel RXFP1 receptor agonists for the treatment of cardiovascular, pulmonary, and / or renal symptoms, diseases, and / or conditions.

[0012] The following are further numbered aspects of the invention: 1. A compound of the following formula, or a pharmaceutically acceptable salt thereof: in: Ring A is a group of the following formula , , , , , , , or , in , , and Each of them may optionally be selected from one or more halogens, -CN, C 1-4 Alkyl and C 1-3 Alkyl substituents, wherein each C 1-4 Alkyl and C 1-3 The alkoxy group is independently and optionally substituted by one or more substituents selected from halogens and -CN; -Y- is C 1-3 Alkylene; -G6- is either -C(R1)- or -N-; R1 is C 1-3 Alkoxy; R2 is a -OCH2COOH or N-linked 4-7-membered heterocycle; wherein the N-linked 4-7-membered heterocycle is selected from aziridine, pyrrolidine, morpholine, piperazine, piperidine, and oxazine-heptanidine; wherein the heterocycle is optionally connected via C 1-4 Alkylene or 1-5-membered heteroalkyl groups are bridged, fused with, or spirolinked to them; wherein the heterocyclic ring, the C 1-4 The alkylene group and the 1-5 heteroalkyl group are each optionally surrounded by 1-3 groups independently selected from halogen, oxo group, C. 1-4 Alkyl, C 1-4 Substitution with haloalkyl groups, -OH and -COOH groups; R3 can be selected from the following groups: , , , , , and , in It can be optionally replaced by one to three halogens; -G4- is either -CH- or -N-; -G5- is either -CH2- or -O-; R 3a Each occurrence is independent of -H, halogen, -SF5, -SO2CF3, -SCF3, -CN, or C. 1-4 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl groups and the C 1-3 The alkoxy group may optionally be replaced by one, two, or three halogens; R 3b Independently -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN, or C 1-4 alkyl; R 3c It is either -H or halogen each time it appears; R 3d It is -H, halogen, -CN, C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl groups and the C 1-3 The alkoxy group may be optionally replaced by one, two, or three halogens.

[0013] 2. The compound according to aspect 1, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a group of the following formula , , , , , , or , in or Each of them is optionally controlled by one or two halogens, C 1-4 Alkyl or C 1-3 Alkoxy substitution, wherein each C 1-4 Alkyl or C 1-3 The alkoxy group is independently and optionally substituted with one or more halogens or -CN; R2 is a group in the following formula. , , , , , , , , , , , , , , , , , , , , , , , or , in Optionally replaced by one or two halogens, wherein It may be optionally replaced by one or two oxygen groups; R3 is selected from the following groups: , , , , and ; R 3a Each occurrence is independent of -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl groups and the C 1-3 The alkoxy group may optionally be replaced by one or two halogens; R 3d It is -H, halogen, -CN, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3 The alkoxy group is optionally substituted with one or two halogens; and -G6- is -C(R1)-.

[0014] 3. The compound according to aspect 1, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a group of the following formula , , , , , , or , in or Each of them is optionally controlled by one or two halogens, C 1-4 Alkyl or C 1-3 Alkoxy substitution, wherein each C 1-4 Alkyl or C 1-3 The alkoxy group is independently and optionally substituted by one or more of a halogen or -CN; R2 is a group in the following formula. , , , , , , , , , , , , , , , , , , , , , , , , or , in Optionally replaced by one or two halogens, wherein It may be optionally replaced by one or two oxygen groups; R3 is selected from the following groups: , , , , and ; R 3a Each occurrence is independent of -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3 The alkoxy group may optionally be replaced by one or two halogens; R 3d It is -H, halogen, -CN, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3 The alkoxy group is optionally substituted with one or two halogens; and -G6- is -C(R1)-.

[0015] 4. The compound according to aspect 1, or a pharmaceutically acceptable salt thereof, wherein ring A is a group of the following formula: , , or ; R2 is a -OCH2COOH or an N-linked 4-7-membered heterocycle; wherein the N-linked 4-7-membered heterocycle is selected from aziridine, pyrrolidine, morpholine, piperazine, piperidine, or oxazine-heptanidine; wherein the heterocycle is optionally connected via C 1-4 Alkylene or 1-5-membered heteroalkyl groups are bridged, fused with, or spirolinked to them; wherein the heterocyclic ring, the C 1-4 The alkylene group and the 1-5 heteroalkyl group are each optionally surrounded by 1-3 elements, each independently selected from halogens, C 1-4 Alkyl, C 1-4 Substitution with haloalkyl groups and -COOH groups; R3 is a group in the following formula: , , or ; R 3a It is -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3The alkoxy group may optionally be replaced by one or more halogens; Each R 3c It can be either -H or -F independently; R 3d It is -H, halogen, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3 The alkoxy group is optionally substituted with one or more halogens; and -G6- is -C(R1)-.

[0016] 5. The compound according to any one of aspects 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is a group of the following formula. , in Optionally by one or two halogens, C 1-4 Alkyl or C 1-3 Alkoxy substitution, wherein each C 1-4 Alkyl and C 1-3 The alkoxy group is independently and optionally substituted by one or more of a halogen and -CN.

[0017] 6. The compound according to any one of aspects 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is a group of the following formula. or , in Optionally by one or two halogens, C 1-4 Alkyl or C 1-3 Alkoxy substitution, wherein each C 1-4 Alkyl and C 1-3 The alkoxy group is independently and optionally substituted by one or more substituents selected from halogens and -CN.

[0018] 7. The compound according to aspect 1, or a pharmaceutically acceptable salt thereof, wherein ring A is a group of the following formula. , , , , , , or , in , , or Each of them may optionally be selected from one or more halogens, -CN, C 1-4 Alkyl, -SC 1-3Alkyl and C 1-3 Alkyl substituents, wherein each C 1-4 Alkyl and C 1-3 The alkoxy group is independently and optionally substituted by one or more substituents selected from halogens and -CN.

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

[0020] 9. A compound according to any one of aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring A is a group of the following formula. or .

[0021] 10. The compound according to aspect 9, or a pharmaceutically acceptable salt thereof, said compound having the following formula: .

[0022] 11. The compound according to aspect 9, or a pharmaceutically acceptable salt thereof, said compound having the following formula: .

[0023] 12. The compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 11, wherein -G6- is -C(R1)-.

[0024] 13. The compound according to aspect 12 or a pharmaceutically acceptable salt thereof, wherein R1 is methoxy, ethoxy or isopropoxy.

[0025] 14. The compound according to aspect 13 or a pharmaceutically acceptable salt thereof, wherein R1 is a methoxy group.

[0026] 15. A compound according to any one of aspects 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R3 is a group of the following formula. , , , or .

[0027] 16. The compound according to aspect 15, or a pharmaceutically acceptable salt thereof, wherein R 3d It is trifluoromethyl.

[0028] 17. The compound according to aspect 15, or a pharmaceutically acceptable salt thereof, wherein R3 is a group of the following formula. .

[0029] 18. The compound according to aspect 16 or a pharmaceutically acceptable salt thereof, 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.

[0030] 19. The compound according to aspect 18, or a pharmaceutically acceptable salt thereof, wherein R3 is a group of the following formula. , ,or .

[0031] 20. The compound according to aspect 19, or a pharmaceutically acceptable salt thereof, wherein R3 is a group of the following formula. .

[0032] 21. The compound according to aspect 20, or a pharmaceutically acceptable salt thereof, said compound having the following formula: .

[0033] 22. A compound according to any one of aspects 1, 3, 5 to 21, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the following formula , , , , , , , or .

[0034] 23. The compound according to any one of aspects 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the following formula , , or .

[0035] 24. A compound according to any one of aspects 1 to 3, 5 to 21, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the following formula , , , , or .

[0036] 25. A compound according to any one of aspects 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the following formula .

[0037] 26. The compound according to aspect 1, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; Or their pharmaceutically acceptable salts.

[0038] 27. The compound according to aspect 1, wherein the compound is selected from... , , , , , , , , , , , , , , , , , , , , , , , or ; or their pharmaceutically acceptable salts.

[0039] 28. The compound according to aspect 1, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , and .

[0040] 28. The compound according to aspect 1, wherein the compound is selected from... , , , , , , and Or their pharmaceutically acceptable salts.

[0041] 29. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 28 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0042] 30. A method of treating an individual with cardiovascular, pulmonary and / or renal symptoms, diseases and / or conditions, the method comprising administering to the individual an effective amount of a compound according to any one of aspects 1 to 28 or a pharmaceutical composition according to aspect 29.

[0043] 31. The compound according to any one of aspects 1 to 28, wherein the compound is used in a therapeutic manner.

[0044] 32. The compound according to any one of aspects 1 to 28 is used in the treatment of cardiovascular, pulmonary and / or renal symptoms, diseases and / or conditions.

[0045] 33. The use of any compound of any one of aspects 1 to 28 in the manufacture of a medicament for treating cardiovascular, pulmonary and / or renal symptoms, diseases and / or conditions.

[0046] 34. The method according to aspect 30, the compound used according to aspect 32, or the use according to aspect 33, wherein the disease or condition to be treated is selected from cardiovascular symptoms, diseases, or conditions such as acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.

[0047] 35. The method according to aspect 30, the compound used according to aspect 32, or the use according to aspect 33, wherein the disease or condition to be treated is a lung symptom, disease, or condition selected from pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

[0048] 36. The method according to aspect 30, the compound used according to aspect 32, or the use according to aspect 33, wherein the disease or symptom to be treated is a kidney symptom, disease, or symptom selected from acute kidney disease, chronic kidney disease, or diabetic nephropathy.

[0049] This invention provides compounds of the following formula or pharmaceutically acceptable salts thereof: G6, R2, ring A, and R3 are defined as above.

[0050] In one embodiment, ring A is a group of the following formula: , , , , , , or ,in or Each of them is optionally controlled by one or two halogens, C 1-4 Alkyl or C 1-3 Alkoxy substitution, wherein each C 1-4 Alkyl or C 1-3 The alkoxy group is independently and optionally substituted with one or more halogens or -CN; R2 is a group in the following formula. , , , , , , , , , , , , , , , , , , , , , , , or , in Optionally replaced by one or two halogens, wherein It may be optionally replaced by one or two oxygen groups; R3 is selected from the following groups: , , , , and ; R 3a Each occurrence is independent of -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3 The alkoxy group may optionally be replaced by one or two halogens; R 3d It is -H, halogen, -CN, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3 The alkoxy group is optionally substituted with one or two halogens; and -G6- is -C(R1)-; or a pharmaceutically acceptable salt thereof.

[0051] In another embodiment, ring A is a group of the following formula , , or ; R2 is a -OCH2COOH or an N-linked 4-7-membered heterocycle; wherein the N-linked 4-7-membered heterocycle is selected from aziridine, pyrrolidine, morpholine, piperazine, piperidine, or oxazine-heptanidine; wherein the heterocycle is optionally connected via C 1-4 Alkylene or 1-5-membered heteroalkyl groups are bridged, fused with, or spirolinked to them; wherein the heterocyclic ring, the C 1-4 The alkylene group and the 1-5 heteroalkyl group are each optionally surrounded by 1-3 elements, each independently selected from halogens, C 1-4 Alkyl, C1-4 Substitution with haloalkyl groups and -COOH groups; R3 is a group in the following formula: , , or ; R 3a It is -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3 The alkoxy group may optionally be replaced by one or more halogens; Each R 3c Independently, it is either -H or -F; and R 3d It is -H, halogen, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3 The alkoxy group is optionally substituted with one or more halogens; and -G6- is -C(R1)-; or a pharmaceutically acceptable salt thereof.

[0052] In another embodiment, ring A is a group of the following formula , or , in or Each of them is optionally selected from halogen, C 1-4 Alkyl and C 1-3 One or more alkoxy groups are substituted, wherein each C0 is a C2. 1-4 Alkyl or C 1-3 The alkoxy group is independently and optionally substituted by one or more of a halogen and -CN; Or its pharmaceutically acceptable salt.

[0053] In another embodiment, ring A is a group of the following formula , in Optionally selected from halogen, C 1-4 Alkyl and C 1-3 One or more alkoxy groups are substituted, wherein each C0 is a C2. 1-4 Alkyl or C 1-3 The alkoxy group is independently and optionally substituted by one or more of a halogen and -CN; Or its pharmaceutically acceptable salt.

[0054] In another embodiment, ring A is a group of the following formula or , in Optionally selected from halogen, C 1-4 Alkyl and C 1-3 One or more alkoxy groups are substituted, wherein each C0 is a C2. 1-4 Alkyl or C 1-3 The alkoxy group is independently and optionally substituted by one or more of a halogen and -CN; Or its pharmaceutically acceptable salt.

[0055] In another embodiment, ring A is a group of the following formula , Or its pharmaceutically acceptable salt.

[0056] In one implementation, ring A is selected from the group consisting of: and ; Or its pharmaceutically acceptable salt.

[0057] In another embodiment, -G6- is -C(R1)-; or a pharmaceutically acceptable salt thereof.

[0058] In another embodiment, the compound has the following formula: , Or its pharmaceutically acceptable salt.

[0059] In another embodiment, the compound has the following formula: , Or its pharmaceutically acceptable salt.

[0060] In another embodiment, R1 is methoxy, ethoxy, or isopropoxy; or a pharmaceutically acceptable salt thereof.

[0061] In another embodiment, R1 is a methoxy group; or a pharmaceutically acceptable salt thereof.

[0062] In another implementation, R3 is selected from the group consisting of: , , , and ; Or its pharmaceutically acceptable salt.

[0063] In another implementation, R 3d It is trifluoromethyl; or a pharmaceutically acceptable salt thereof.

[0064] In another implementation, R3 is , Or its pharmaceutically acceptable salt.

[0065] 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.

[0066] In another implementation, R3 is selected from the group consisting of: , and ; Or its pharmaceutically acceptable salt.

[0067] In another implementation, R3 is , Or its pharmaceutically acceptable salt.

[0068] In another embodiment, the compound has the following formula: , Or its pharmaceutically acceptable salt.

[0069] In another implementation, R2 is selected from the group consisting of: , , , , , , , , , and ; Or its pharmaceutically acceptable salt.

[0070] In another embodiment, R2 is a group of the following formula , , , , , , , or or its pharmaceutically acceptable salt.

[0071] In another embodiment, R2 is a group of the following formula , Or its pharmaceutically acceptable salt.

[0072] In another implementation, R2 is selected from the group consisting of: , , and ; Or its pharmaceutically acceptable salt.

[0073] In another implementation, R2 is selected from the group consisting of: , , , , and ; Or its pharmaceutically acceptable salt.

[0074] In another implementation, R2 is , Or its pharmaceutically acceptable salt.

[0075] In another embodiment, the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , Or their pharmaceutically acceptable salts.

[0076] In another embodiment, the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , Or their pharmaceutically acceptable salts.

[0077] In another embodiment, the compound is selected from... , , , , , , , , , , , , , , , , , , , , , , , or , or their pharmaceutically acceptable salts.

[0078] In another embodiment, a pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0079] In another embodiment, a method of treating an individual for cardiovascular, pulmonary, and / or renal symptoms, diseases, and / or conditions includes administering to the individual an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0080] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is used in a therapeutic manner.

[0081] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is used in the treatment of cardiovascular, pulmonary and / or renal symptoms, diseases and / or conditions.

[0082] In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is used to manufacture a medicament for treating cardiovascular, pulmonary and / or renal symptoms, diseases and / or conditions.

[0083] In another embodiment, a method of using a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the disease or condition to be treated is selected from cardiovascular symptoms, diseases, or conditions such as acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, local ischemia, vasoconstriction, or ventricular hypertrophy.

[0084] In another embodiment, a method of using a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the disease or condition to be treated is a lung symptom, disease, or condition selected from pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

[0085] In another embodiment, a method of using a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the disease or condition to be treated is a kidney symptom, disease, or condition selected from acute kidney disease, chronic kidney disease, or diabetic nephropathy.

[0086] In the above embodiments of the compounds of Formula I or their pharmaceutically acceptable salts, the chemical diagrams are shown in planar form without chiral information. These compounds typically have multiple chiral centers and are expected to exist in various forms with various combinations of chiral centers. Furthermore, these compounds have various enantiomers, diastereomers, and transisomers that may exist and are included herein.

[0087] 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.

[0088] It should be understood that isotope derivatives can be prepared using any of the various techniques recognized in the art. For example, isotope derivatives or pharmaceutically acceptable salts thereof can generally 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.

[0089] In one embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, the compound is a deuterated derivative of any of the compounds described herein or a pharmaceutically acceptable salt thereof.

[0090] 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", it should be understood as having hydrogen in its natural abundance isotopic composition. Additionally, unless otherwise stated, when an atom is specifically designated as "D" or "deuterium", it should be understood as having deuterium in an abundance significantly greater than the natural abundance of deuterium (which is 0.015%).

[0091] A compound of formula I or a pharmaceutically acceptable salt thereof, the compound being selected from... , , , , , , , , , , , , , , , , , , , , , , , or , or their pharmaceutically acceptable salts.

[0092] 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.

[0093] This article further provides methods for treating cardiovascular, pulmonary, and / or renal symptoms, diseases, and / or conditions, 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 symptoms, diseases, and / or conditions, 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 symptoms, diseases, and / or conditions, 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 symptoms, diseases, and / or conditions, comprising administering to a patient in need an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.

[0094] This document further provides compounds according to Formula I or pharmaceutically acceptable salts thereof for use in therapies. This document further provides compounds according to Formula I or pharmaceutically acceptable salts thereof for use in the treatment of cardiovascular, pulmonary, and / or renal symptoms, diseases, and / or conditions. This document further provides compounds according to Formula I or pharmaceutically acceptable salts thereof for use in therapies. This document further provides compounds according to Formula I or pharmaceutically acceptable salts thereof for use in the treatment of cardiovascular symptoms, diseases, and / or conditions. This document further provides compounds according to Formula I or pharmaceutically acceptable salts thereof for use in therapies. This document further provides compounds according to Formula I or pharmaceutically acceptable salts thereof for use in the treatment of pulmonary symptoms, diseases, and / or conditions. This document further provides compounds according to Formula I or pharmaceutically acceptable salts thereof for use in therapies. This document further provides compounds according to Formula I or pharmaceutically acceptable salts thereof for use in the treatment of renal symptoms, diseases, and / or conditions.

[0095] In the methods or uses described herein, cardiovascular symptoms, diseases, and conditions 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 symptoms, diseases, and conditions include, but are not limited to, pulmonary hypertension and chronic obstructive pulmonary disease (COPD). In the methods or uses described herein, renal symptoms, diseases, and conditions include, but are not limited to, acute kidney disease, chronic kidney disease, and diabetic nephropathy.

[0096] These methods 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 adjunctive therapeutic agent. In short, the standards of care for many symptoms / diseases / conditions described herein include 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 controlling comorbidities, including but not limited to high cholesterol, high blood pressure, atrial fibrillation, diabetes, and obesity. In some cases, the adjunctive therapeutic agent may be administered simultaneously, separately, or sequentially with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0097] This document further provides compounds of Formula I or pharmaceutically acceptable salts thereof for use in the treatment of cardiovascular, pulmonary, and / or renal symptoms, diseases, and / or conditions, concurrently, separately, or sequentially with at least one adjunctive therapeutic agent. Adjunctive 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, as well as other therapeutic agents for the control of comorbidities, including but not limited to high cholesterol, high blood pressure, atrial fibrillation, and diabetes.

[0098] The methods and uses described herein may include the steps described herein, and these steps may, but must, be performed in the order described. However, other orders are also contemplated. Furthermore, single or multiple steps may be performed in parallel and / or overlap in time and / or individually or as repeated steps. In addition, these methods may include additional, unspecified steps.

[0099] Therefore, such methods or uses may include selecting individuals who have or are susceptible to cardiovascular symptoms, diseases, or conditions. Alternatively, these methods may include selecting individuals who have or are susceptible to pulmonary symptoms, diseases, or conditions. Alternatively, these methods may include selecting individuals who have or are susceptible to kidney symptoms, diseases, or conditions. In some cases, these methods may include selecting individuals who have diabetes, hypertension with impaired kidney function, and / or obesity.

[0100] In some cases, individuals in need may have diabetes, hypertension with impaired kidney function, and / or obesity.

[0101] These methods or uses can also be combined with diet and exercise and / or with additional therapeutic agents other than those discussed above.

[0102] 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 for 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 SMBerge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.

[0103] Pharmaceutical compositions containing compounds of Formula I as described herein or their pharmaceutically acceptable salts may be prepared using pharmaceutically acceptable additives. As used herein, the term "pharmaceutically acceptable additive" 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, sugar, mannitol, and silica derivatives; binders such as carboxymethyl cellulose, alginate, gelatin, and polyvinylpyrrolidone; kaolin and bentonite; and polyethylene glycols.

[0104] As used herein, "effective amount" means the amount or dose of a compound of formula I or a pharmaceutically acceptable salt thereof, which, when administered to an individual in need in a single or multiple doses, provides the desired effect in the individual receiving diagnosis or treatment (i.e., can produce clinically measurable differences in the individual's condition, such as, 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) cardiac, renal, hepatic or pulmonary fibrosis). 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 the effective dose for an individual, many factors are considered, including but not limited to the mammal species, its size, age and general health condition, the specific disease or condition involved, the extent or severity of the disease or condition, the individual’s response, the specific Formula I compound administered or its pharmaceutically acceptable salt, the mode of administration, the bioavailability characteristics of the administered formulation, the chosen dosing regimen, the use of concomitant medications and other relevant circumstances.

[0105] As used herein, “treating” or “to treat” means the management and care of an individual suffering from a symptom, disease, condition, or ailment, the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof to that symptom, disease, condition, or ailment for the purpose of reducing, inhibiting, reversing, slowing, or stopping the progression or severity of the symptom, disease, condition, and / or ailment. Treatment includes administering to an individual a compound of Formula I or a pharmaceutically acceptable salt thereof, or a composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof, to prevent the onset of symptoms or complications, thereby reducing or eliminating symptoms or complications, or symptom, disease, condition, or ailment. Treatment comprises administering to an individual a compound of formula I herein or a pharmaceutically acceptable salt thereof, or a composition containing a compound of formula I herein or a pharmaceutically acceptable salt thereof, to produce effects such as, 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) cardiac, renal, hepatic, or pulmonary fibrosis. The individual to be treated is a mammal, particularly a human.

[0106] As used herein, “individual,” “patient,” and “subject” are used interchangeably and refer to mammals, especially humans. In some cases, an individual is further characterized by symptoms, diseases, conditions, and / or signs that would benefit from administration of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0107] As used herein, the term halogen means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). As used herein, the term alkyl means a saturated straight-chain or branched monovalent hydrocarbon group of one to a specified number of carbon atoms, such as "C". 1-4 Alkyl or C 1-3 Alkyl. 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 (alkylenyl) means a saturated straight-chain or branched divalent hydrocarbon group of 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 means a saturated straight-chain or branched monovalent hydrocarbon group containing a specified number of atoms, including carbon atoms and one or more oxygen atoms, such as "C". 1-3 "Alkoxy". For example, C 1-3 An alkoxy group refers to a saturated straight-chain or branched monovalent hydrocarbon group containing at least one carbon atom or at least one oxygen atom, wherein the total number of carbon and oxygen atoms is 1, 2, or 3. C 1-3Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 1-propoxy, and isopropoxy.

[0108] As used herein, the term heteroalkyl means a saturated straight-chain or branched divalent hydrocarbon group containing a specified number of atoms, including carbon atoms and one or more heteroatoms, such as "1-5-membered heteroalkyl". For example, a 4-membered heteroalkyl means a saturated straight-chain or branched monovalent hydrocarbon group containing at least one carbon atom or at least one heteroatom, wherein the total number of carbon atoms and heteroatoms is 4 atoms. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur. Examples of 1-5-membered heteroalkyls include, but are not limited to, -O-CH2-, -CH2-O-CH2-, -O-CH2-CH2-, -CH2-CH2-O-, -CH2-CH2-O-, -CH2-CH2-O-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2- CH2-O-CH2-, -CH2-O-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-O-, -O-CH2-CH2-CH2-CH2-, -CH 2-SO2-CH2-, -CH2-CH2-SO2-, -SO2-CH2-CH2-, -CH2-S-CH2-, -CH2-CH2-S-, and -S-CH2-CH2-.

[0109] 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 "C" 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group having three, four, five, or six carbon atoms. Examples of 3- to 6-membered cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0110] As used herein, the term heterocyclic alkyl means a saturated cyclic heteroalkyl group containing a specified number of atoms, including carbon atoms and one or more heteroatoms, such as "4-7 membered heterocycle". For example, a 7-membered heterocycle means a saturated cyclic hydrocarbon group containing at least one carbon atom and at least one heteroatom, wherein the total number of carbon atoms and heteroatoms is 7 atoms. Examples of 4-7 membered heterocycles include, but are not limited to, aziridine, pyrrolidine, morpholine, piperazine, piperidine, and oxaziridine.

[0111] Some abbreviations are defined as follows: "ACN" refers to acetonitrile; "DiPEA" refers to N,N-diisopropylethylamine; "DCM" refers to dichloromethane; "DMF" refers to N,N-dimethylformamide; "ES-MS" refers to electrospray mass spectrometry; "Et2O" refers to diethyl ether; "EtOAc" refers to ethyl acetate; "h" refers to hours; "HATU" refers to azirmonotriazole tetramethylureaium hexafluorophosphate; "HPLC" refers to high-performance liquid chromatography; "MeO" refers to... "H" refers to methanol; "min" refers to minutes; "NMI" refers to N-methylimidazole; "NMP" refers to N-methyl-2-pyrrolidone; "PG" refers to a protecting group; "RT" refers to room temperature; "TBD" refers to triazabicyclodecene; "TCFH" refers to chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; "T3P" refers to propanephosphonic anhydride; "Wt" refers to weight.

[0112] Individual isomers, enantiomers, diastereomers, and transisomers may be separated or resolved at any convenient point in the synthesis of the compounds listed below by methods such as selective crystallization or chiral chromatography (see, for example, J. Jacques et al., “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981, and E.L. Leeel and S.H. Wilen, “Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994). This specification is intended to include all isomers, enantiomers, diastereomers, and transisomers that are possible with respect to the compounds disclosed herein or that can be prepared using the compounds disclosed herein. Among the molecules described herein, only those in which the absolute conformation (or transisomer conformation) of the chiral center is known are given the nomenclature or chemical formula that is drawn to indicate chirality or transisomerism. 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.

[0113] Compounds of any one of the elements of Formula I that are chemically capable of forming salts are readily converted into pharmaceutically acceptable salts and can be isolated as pharmaceutically acceptable salts. Salt formation can occur upon addition of a pharmaceutically acceptable acid to form an acid addition salt. Salt formation can also occur simultaneously upon nitrogen or oxygen deprotection, i.e., removal of the protecting group. Examples, reactions, and conditions of salt formation can be found in Gould, PL, “Salt selection for basic drugs,” International Journal of Pharmaceutics.33 : 201-217 (1986); Bastin, RJ et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4 : 427-435 (2000); and Berge, SM et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66 : 1-19, (1977).

[0114] The compounds of the present invention or their salts can be prepared by various procedures, some of which are illustrated in the following schemes, preparations, and examples. The specific synthetic steps of each route 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 following preparations can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, preparation, and crystallization.

[0115] Additionally, some intermediates described in the following preparations may contain one or more nitrogen protecting groups. It should be understood that, as those skilled in the art will appreciate, protecting groups can vary depending on the specific reaction conditions and the specific transformation to be performed. 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, edited by Peter GMWuts and Theodora W. Greene, John Wiley and Sons, Inc. 2014).

[0116] Examples of known procedures and methods include those described in the 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.

[0117] Option 1 Scheme 1 describes the preparation of the compounds of the present invention starting from a suitable carboxylic acid 1 and an amine 2. The PG moiety on the amine of carboxylic acid 1 is a standard amine protecting group well known to those skilled in the art, including urethane and amide protecting groups. In step 1, carboxylic acid 1 is reacted with amine 2 under standard amide coupling conditions to prepare amide 3. Suitable amide coupling conditions are well known to those skilled in the art and include reacting a solution of carboxylic acid 1 and the desired amine 2 in a suitable solvent (such as DCM or DMF) at room temperature with stirring in the presence of a suitable organic base (such as DiPEA) with a suitable coupling agent (such as T3P or HATU). Removal of the PG moiety on the amine of amide 3 is achieved under standard acidic conditions in the art. Intermediate amide 4 is obtained by reacting a suitable acid (such as an Et2O solution of TFA or HCl) with a stirred solution of amide 3 in a suitable solvent (such as DCM) at room temperature for at least 12 hours. The intermediate amine is reacted with a suitable carboxylic acid under amide coupling conditions known to those skilled in the art. At room temperature, a suitable coupling agent (such as TCFH or HATU) and a suitable organic base (such as NMI or DiPEA) are introduced into a stirred solution of the desired carboxylic acid and intermediate amine in a suitable solvent (such as DMF or ACN).

[0118] In step 3, intermediate 4 is reacted under nucleophilic aromatic substitution conditions known to those skilled in the art to yield 5. Suitable nucleophilic aromatic substitution conditions involve reacting a compound with a suitable halogen (such as chlorine) on its aromatic moiety with a suitable nucleophilic reactant (such as an amine or alcohol). The reaction is carried out in a suitable organic solvent (such as NMP or DMF) in the presence of a suitable organic base (such as K₂CO₃ or NaH) at at least 80°C. Optionally, CuI may be added to catalyze the nucleophilic aromatic substitution reaction.

[0119] Option 2 Scheme 2 describes the preparation of the compound of the present invention starting from a suitable carboxylic acid 6. In step 1, carboxylic acid 6 is reacted with the desired amine under nucleophilic aromatic substitution conditions well known to those skilled in the art to give 7. The reaction is carried out at at least 80°C in a suitable organic solvent (such as NMP) in the presence of a suitable organic base (such as K2CO3). The resulting carboxylic acid 7 is reacted with the desired amine 8 under standard amide coupling conditions. Suitable amide coupling conditions are well known to those skilled in the art and include reacting a solution of carboxylic acid 7 and amine 8 in a suitable solvent (such as ACN or DCM) at room temperature with stirring in the presence of a suitable organic base (such as NMI or DiPEA) with a suitable coupling agent (such as TCFH or oxalyl chloride and DMF) for at least 18 hours. The ester of the intermediate amide is hydrolyzed under standard saponification conditions with a suitable base (such as LiOH or TBD) at at least room temperature with stirring in a mixture of a suitable organic solvent (such as THF) and H2O for at least 48 hours.

[0120] In step 3, the resulting carboxylic acid 9 is reacted with a suitable amine 2 under standard amide coupling conditions and includes reacting a solution of carboxylic acid 9 and amine 2 in a suitable solvent (such as ACN or NMP) at room temperature with stirring in the presence of a suitable organic base (such as NMI or DiPEA) with a suitable coupling agent (such as TCFH or T3P) for at least 48 hours.

[0121] Option 3 Scheme 3 describes the preparation of the compounds of the present invention starting from a suitable carboxylic acid 6 and an amine 11. In step 1, carboxylic acid 6 is reacted with amine 11 under standard amide coupling conditions to prepare amide 12. Suitable amide coupling conditions are well known to those skilled in the art and include reacting a solution of carboxylic acid 6 and the desired amine 11 in a suitable solvent (such as ACN) at room temperature with stirring in the presence of a suitable organic base (such as NMI) with a suitable coupling agent (such as TCFH) for at least 18 hours. The ester of amide 12 is hydrolyzed under standard saponification conditions using a suitable strong inorganic base (such as LiOH) at room temperature with stirring in a mixture of a suitable organic solvent (such as THF) and H2O for at least 18 hours. The intermediate carboxylic acid is then reacted with a suitable amine under standard amide coupling conditions and includes reacting a solution of carboxylic acid and the desired amine in a suitable solvent (such as ACN) at room temperature with stirring in the presence of a suitable organic base (such as NMI) with a suitable coupling agent (such as TCFH).

[0122] In step 3, intermediate amide 13 is reacted under nucleophilic aromatic substitution conditions known to those skilled in the art to yield 5. The reaction is carried out in a suitable organic solvent (such as NMP) at at least 80°C in the presence of a suitable organic base (such as K2CO3).

[0123] In Schemes 1-3, if the R2- group contains a carboxylic acid ester, it can be treated at room temperature with a suitable strong inorganic base (such as LiOH or TBD) under stirring in a mixture of a suitable organic solvent (such as THF) and H2O for at least 30 minutes under standard saponification conditions.

[0124] Preparation 1 2-(3-oxa-7-azabicyclo[3.3.1]non-7-yl)-6-methoxybenzo[d]thiazolyl-7-carboxylic acid A solution of 3-oxa-7-azabicyclo[3.3.1]nonane (1.566 g, 12.31 mmol), 2-chloro-6-methoxybenzo[d]thiazolyl-7-carboxylic acid (1.0 g, 4.104 mmol), and K₂CO₃ (1.702 g, 12.31 mmol) in NMP (20 mL) was stirred at 80 °C for 48 h. After 48 h, a small fraction of the material was directly purified by reversed-phase column chromatography (C18, gradient of 0%-100% (5% MeOH / ACN) / 10 mM NH₄HCO₃ aqueous solution (pH 10)) to give an impure product. The impure fraction and the reaction mixture were combined. Heptane (100 mL) was added, and the mixture was filtered. The filter cake was washed with heptane (50 mL) and dried under high vacuum to give the title compound (1.1 g, 3.3 mmol, 80%). ES-MS m / z 335 (M+H).

[0125] Preparation 2 (1R,2S,3R,4S)-3-(2-chloro-6-methoxybenzo[d]thiazolyl-7-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester TCFH (2.764 g, 4.925 mmol, 3 mL) and NMI (808.7 mg, 9.850 mmol, 0.8 mL) were added to a stirred solution of 2-chloro-6-methoxybenzo[d]thiazolyl-7-carboxylic acid (1000 mg, 4.104 mmol) and (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid (833.4 mg, 4.925 mmol). The reaction mixture was stirred at room temperature for 18 hours. After 18 hours, H2O (30 mL) and EtOAc (50 mL) were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by silica gel chromatography (0%-80% EtOAc / heptane) to give the title compound (1025 mg, 2.596 mmol, 63%). ES-MS m / z 395 (M+H).

[0126] Preparation 3 (1R,2S,3R,4S)-3-(2-chloro-6-methoxybenzo[d]thiazolyl-7-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid A solution of LiOH (296 mg, 12.3 mmol) in H₂O (5 mL) was added to a stirred solution of (1R,2S,3R,4S)-3-(2-chloro-6-methoxybenzo[d]thiazolyl-7-carboxamido)bicyclo[2.2.1]heptane-2-carboxylate (975 mg, 2.47 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (50 mL) and acidified with 2 M HCl to approximately pH 4. The organic layers were separated. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated to give the title compound (800 mg, 2.10 mmol, 85%). ES-MS m / z 381 (M+H).

[0127] Preparation 4 ((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)tert-butyl carbamate T3P (26 g, 41 mmol, 24 mL) and DIPEA (3.5 g, 27 mmol, 4.8 mL) were added to (1R,2S,3R,4S)-3-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptane-2-carboxylic acid (3.5 g, 14 mmol) and 4-fluoro-3-(trifluoromethyl)aniline (4.9 g, 27 mmol, 5 mL) in a stirred solution of DCM (100 mL). The reaction mixture was stirred at room temperature for 48 hours. After 48 hours, the reaction mixture was concentrated and purified by reversed-phase column chromatography (C18, 0%-100% (5% MeOH / ACN) / 10 mMNH4HCO3 aqueous solution (pH 10) gradient) to give the title compound (5.7 g, 14 mmol, 100%). ES-MS m / z 416 (M+H).

[0128] Preparation 5 (1R,2S,3R,4S)-3-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide TFA (52.9 mL) was added to a solution of ((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamate (317 mL). The reaction mixture was stirred at 25 °C. After 2 hours, the mixture was concentrated, and EtOAc (6 mL) was added to dissolve the residue, followed by the addition of pentane (200 mL). The resulting mixture was stirred vigorously for 12 hours to precipitate the product. After stirring for 12 hours, the product was separated by filtration and washed with pentane, and dried under vacuum to give the title compound (14.0 g, 44.3 mmol, >99%) as a white solid. ES-MS m / z 317 (M+H).

[0129] Preparation of 6 2-Chloro-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-6-methoxybenzo[d]thiazol-7-carboxamide TCFH (2.49 g, 4.43 mmol, 2 mL) and NMI (728 mg, 8.86 mmol, 0.7 mL) were added to a stirred solution of 2-chloro-6-methoxybenzo[d]thiazolyl-7-carboxylic acid (900 mg, 3.69 mmol) in ACN (30 mL), followed by (1R,2S,3R,4S)-3-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide (1.40 g, 4.43 mmol). The reaction mixture was stirred at room temperature for 1 hour. After 1 hour, H2O (30 mL) and EtOAc (50 mL) were added to the reaction mixture. The organic layer was separated. The aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by silica gel chromatography (0%-80% EtOAc / heptane) to give the title compound (1 g, 2 mmol, 50%). ES-MS m / z 542 (M+H).

[0130] The following items are prepared essentially as described in Preparation 6 using appropriate amines and carboxylic acids: a. Starting materials: 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine and (1R,2S,3R,4S)-3-(2-chloro-6-methoxybenzo[d]thiazolyl-7-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid b. Starting materials: 1-(trifluoromethyl)-2-oxabicyclo[2.2.2]octyl-4-amine and (1R,2S,3R,4S)-3-(2-chloro-6-methoxybenzo[d]thiazolyl-7-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid.

[0131] Preparation 10 3-(2-(3-oxa-7-azabicyclo[3.3.1]non-7-yl)-6-methoxybenzo[d]thiazolyl-7-carbamate)isonicotinic acid A solution of methyl 3-(2-(3-oxa-7-azabicyclo[3.3.1]non-7-yl)-6-methoxybenzo[d]thiazolyl-7-carbamate) isonicotinic acid (60 mg, 0.13 mmol) in THF (2 mL) with stirring was added to a solution of LiOH (50 mg, 2.1 mmol) in H2O (0.7 mL). The reaction mixture was stirred at room temperature for 48 hours. After 48 hours, the reaction mixture was purified directly by reversed-phase column chromatography (C18, gradient of 0%-100% (5% MeOH / ACN) / 10 mM NH4HCO3 aqueous solution (pH 10)) to give the title compound (60 mg, 0.12 mmol, 93%). ES-MS m / z 455 (M+H).

[0132] Preparation 11 7-(7-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-6-methoxybenzo[d]thiazolyl)-7-azaspiro[3.5]nonane-2-carboxylic acid methyl ester A solution of methyl 7-azaspiro[3.5]nonane-2-carboxylate (51 mg, 0.28 mmol), 2-chloro-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-6-methoxybenzo[d]thiazol-7-carboxamide (50 mg, 92 μmol), and K₂CO₃ (38 mg, 0.28 mmol) in DMF (1 mL) was stirred at 80 °C for 18 h. The reaction mixture was then purified directly by silica gel chromatography (0%–100% EtOAc / heptane) to give the title product (64 mg, 84 µmol, 91%). ES-MS m / z 689 (M+H).

[0133] Preparation 12 2-((7-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-6-methoxybenzo[d]thiazolyl)oxy)methyl acetate NaH (5.3 mg, 0.22 mmol) was added to a solution of methyl 2-hydroxyacetate (20 mg, 0.22 mmol, 0.02 mL) and 2-chloro-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-6-methoxybenzo[d]thiazol-7-carboxamide (40 mg, 74 μmol) in DMF (1 mL). The reaction mixture was stirred at 50 °C for 6 hours. The reaction mixture was then purified directly by silica gel chromatography to give the title compound (44 mg, 74 μmol, 100%). ES-MS m / z 596 (M+H).

[0134] Preparation 13 (5-Fluoro-4-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)pyridin-3-yl)tert-butyl carbamate A solution of 4-fluoro-3-(trifluoromethyl)aniline (271 mg, 2 mmol), 3-((tert-butoxycarbonyl)amino)-5-fluoroisonicotinic acid (400 mg, 2 mmol), DiPEA (780 µL, 5 mmol), and HATU (1.27 g, 3.27 mmol) in anhydrous DMF (14.5 mL) was stirred at 50 °C for 65 min. The reaction mixture was quenched with H₂O (75 mL) and EtOAc (75 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (3 × 75 mL). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (1%–50% EtOAc / n-heptane). The desired fractions were combined and concentrated to give the title compound (350.9 mg, 54%) as a grayish-white powder. ES-MS m / z 418 (M+H).

[0135] Preparation 14 3-Amino-5-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)isonicotinamide; hydrochloride A solution of tert-butyl (5-fluoro-4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)pyridin-3-yl)carbamate (351 mg, 1 mmol) and Et₂O (8.20 mL, 16.4 mmol) containing 2 M HCl in DCM (3.0 mL) / MeOH (1.0 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and then ground in Et₂O to give the title compound (294.7 mg, 91%) as a yellow solid. ES-MS m / z 318 (M+H).

[0136] Preparation 15 (1S,2R)-2-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopentane-1-carboxamide hydrochloride TCFH (2.45 g, 8.724 mmol) and NMI (0.90 g, 10.905 mmol) were added to a mixture of (1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclopentane-1-carboxylic acid (500 mg, 2.181 mmol) and 4-fluoro-3-(trifluoromethyl)aniline (470 mg, 2.617 mmol) in ACN (10 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated aqueous NaCl solution (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 1:3 solution of EtOAc in petroleum ether. HCl (4 M EtOAc solution, 5 mL) was added to the product at 0 °C, and the mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to give the title compound. ES-MS m / z 291 (M+H) Preparation of 16 Methyl 2-(2-chloro-6-methoxybenzo[d]thiazolyl-7-carbamate)-4-fluorobenzoate Oxaloyl chloride (1.50 g, 5.90 mL, 11.8 mmol) was added to a solution of 2-chloro-6-methoxybenzo[d]thiazolyl-7-carboxylic acid (1.15 g, 4.72 mmol) in DCM (20 mL), followed by the addition of DMF (0.25 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL). Methyl 2-amino-4-fluorobenzoate (958 mg, 6 mmol) and DiPEA (2.44 g, 3.25 mL, 18.9 mmol) were added to this solution. After stirring for 2 hours, the reaction mixture was diluted with DCM (200 mL) and washed with H2O (3 × 100 mL) and a saturated aqueous solution of NaCl (100 mL). The organic matter was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in MeOH (100 mL), and the resulting precipitate was collected and dried under vacuum to give the title compound (1.6 g, 86%) as a grayish-white solid. ES-MS m / z 395 (M+H).

[0137] The compounds in the table below are prepared essentially as described in Preparation 16 using appropriate amines and carboxylic acids.

[0138] The compounds in the table below are prepared essentially as described in Preparation 1 using appropriate amines and 2-chlorobenzothiazole derivatives.

[0139] Preparation 23 2-(2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazolyl-7-carbamate)-4-fluorobenzoic acid TBD (0.55 g, 3.9 mmol) was added to a solution of methyl 2-(2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazolyl-7-carbamate)-4-fluorobenzoate (0.60 g, 1.3 mmol) in THF (20 mL) and H2O (2 mL). The reaction mixture was stirred at 40 °C for 30 min. The reaction mixture was neutralized with aqueous citric acid, and a precipitate formed. The mixture was further diluted with H2O, and the precipitate was collected and dried under vacuum to give the title compound (0.5 g, 90%). ES-MS m / z 444 (M+H).

[0140] The compounds in the table below are prepared essentially using appropriate esters as described in Preparation 23.

[0141] The compounds in the table below are prepared essentially as described in Preparation 6 using appropriate amines and carboxylic acids.

[0142] The compounds in the table below are prepared essentially using appropriate esters as described in Preparation 10.

[0143] Preparation 28 2-(2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazolyl-7-carbamate)-4-chlorobenzoic acid Methyl 2-amino-4-chlorobenzoate (0.23 g, 1.2 mmol), T3P (1.6 g, 1.4 mL, 2.4 mmol), and DiPEA (0.42 g, 0.57 mL, 3.3 mmol) were added to a solution of 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazo-7-carboxylic acid (0.25 g, 0.82 mmol) in NMP (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (3 × 50 mL), followed by washing with a saturated aqueous solution of NaCl (50 mL). The organic matter was dried over Na2SO4, filtered, and concentrated. The residue was then dissolved in THF (10 mL) and H2O (2 mL) and treated with TBD (0.34 g, 2.4 mmol). The reaction mixture was stirred at 45°C for 1 hour, then neutralized with citric acid solution. Aqueous post-treatment gave the title compound (181 mg, 48%) as a grayish-white solid. ES-MS m / z 460 (M+H).

[0144] The compounds in the table below are prepared essentially as described in Preparation 28 using appropriate amines.

[0145] The compounds in the table below are prepared essentially as described in Preparation 4 using (1S,2R)-2-(2-chloro-6-methoxybenzo[d]thiazolyl-7-carbamate)cyclobutane-1-carboxylic acid and 2,2-difluorobenzo[d][1,3]dioxacyclopentene-5-amine.

[0146] Example 1 2-(9,9-difluoro-3,3-dioxo-3-thia-7-azabicyclo[3.3.1]non-7-yl)-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-6-methoxybenzo[d]thiazol-7-carboxamide A solution of 9,9-difluoro-3-thia-7-azabicyclo[3.3.1]nonane 3,3-dioxide (71 mg, 0.36 mmol), 2-chloro-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-6-methoxybenzo[d]thiazol-7-carboxamide (65 mg, 0.12 mmol) and K₂CO₃ (50 mg, 0.36 mmol) in NMP (1 mL) was stirred at 80 °C for 18 h. Copper(I) iodide (23 mg, 0.12 mmol) was added, and the reaction mixture was stirred at 105 °C for 48 h. The reaction mixture was cooled to room temperature and purified directly by reversed-phase column chromatography (C18, gradient of 0%–100% (5% MeOH / ACN) / 10 mM NH4HCO3 aqueous solution (pH 10)) to give the title compound (5 mg, 7 μmol, 6%). ES-MS m / z 717 (M+H).

[0147] The following items are prepared using appropriate amines, essentially as described in Example 1: a. Example 9 was separated as an isomer mixture using a racemic mixture of (5aR,8aR)-octahydro-2H-cyclopentadien[b][1,4]oxazatecycloheptane and (5aS,8aS)-octahydro-2H-cyclopentadien[b][1,4]oxazatecycloheptane as the starting amine.

[0148] b. Example 14 was separated as a mixture of isomers using a racemic mixture of (3aR,7aS)-octahydrofurano[3,2-c]pyridine hydrochloride and (3aS,7aR)-octahydrofurano[3,2-c]pyridine hydrochloride as the starting amine.

[0149] Example 24 7-(7-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-6-methoxybenzo[d]thiazolyl)-7-azaspiro[3.5]nonane-2-carboxylic acid A solution of methyl 7-(7-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-6-methoxybenzo[d]thiazolyl)-7-azaspiro[3.5]nonane-2-carboxylate (64 mg, 93 μmol) in THF (0.7 mL) with LiOH (11 mg, 0.46 mmol) in H2O (0.3 mL) was added. After 30 minutes, the reaction mixture was directly purified by reversed-phase column chromatography (C18, gradient of 0%-100% (5% MeOH / ACN) / 10 mM NH4HCO3 aqueous solution (pH 10)) to give the title compound (33.3 mg, 49.4 μmol, 53%). ES-MSm / z 675 (M+H).

[0150] The following items are prepared using appropriate esters, essentially as described in Example 24: .

[0151] Example 26 2-(3-oxa-7-azabicyclo[3.3.1]non-7-yl)-N-(4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)pyridin-3-yl)-6-methoxybenzo[d]thiazolyl-7-carboxamide A solution of 4-fluoro-3-(trifluoromethyl)aniline (24 mg, 0.13 mmol, 17 μL), 3-(2-(3-oxa-7-azabicyclo[3.3.1]non-7-yl)-6-methoxybenzo[d]thiazolyl-7-carboxamido)isonicotinic acid (60 mg, 0.13 mmol), TCFH (89 mg, 0.32 mmol), and NMI (13 mg, 0.16 mmol, 12 μL) in ACN (1 mL) was stirred at room temperature for 48 hours. The reaction mixture was then purified three times by silica gel chromatography (0%–20% MeOH / DCM) to give the title compound (6.6 mg, 0.13 mmol, 8%). ES-MS m / z 616 (M+H).

[0152] Example 27 2-(3-oxa-7-azabicyclo[3.3.1]non-7-yl)-N-(5-fluoro-4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)pyridin-3-yl)-6-methoxybenzo[d]thiazolyl-7-carboxamide A solution of 2-(3-oxa-7-azabicyclo[3.3.1]non-7-yl)-6-methoxybenzo[d]thiazolyl-7-carboxylic acid (65.0 mg, 0.2 mmol), 3-amino-5-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)isonicotinamide hydrochloride (74.7 mg, 0.2 mmol), and DiPEA (68.0 µL, 0.4 mmol) in ACN (1.0 mL) was stirred at 100 °C for 2 min. A solution of NMI (62.0 µL, 0.8 mmol) and TCFH (111 mg) in ACN (1 mL) was added to the reaction mixture and stirred at 100 °C for 45 min. The reaction mixture was quenched with H2O (20 mL) and EtOAc (20 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0%–10% MeOH / EtOAc). The desired fractions were combined and concentrated. The residue was dissolved in 1 mL of DCM, and the resulting precipitate was filtered and washed with 1 mL of DCM. The precipitate was dried under vacuum overnight to give the title compound (21.8 mg, 17%) as a white solid. ES-MS m / z 634 (M+H).

[0153] The compounds in the table below are prepared essentially using appropriate amines and carboxylic acids as described in Example 27.

[0154] Example 29 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-N-(5-fluoro-2-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)carbamoyl)phenyl)-6-methoxybenzo[d]thiazolyl-7-carboxamide NMP (5.0 mL), 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (0.17 g, 0.90 mmol), T3P (0.57 g, 0.53 mL, 0.90 mmol), and DiPEA (0.17 g, 0.24 mL, 1.4 mmol) were added to 2-(2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazo-7-carbamate)-4-fluorobenzoic acid (0.20 g, 0.45 mmol). The reaction mixture was stirred overnight at 50 °C. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (3 × 50 mL), followed by washing with a saturated aqueous solution of NaCl (50 mL). The organic matter was dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase rapid chromatography using a high-pH mobile phase to give the title compound (143 mg, 55%) as a grayish-white solid. ES-MS m / z 577 (M+H).

[0155] The compounds in the table below are prepared essentially as described in Example 29 using appropriate amines and carboxylic acids.

[0156] Example 63 N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)-2-((1R,3S,5S)-3-hydroxy-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazol-7-carboxamide A solution of (1R,3S,5S)-6-azabicyclo[3.1.1]hepta-3-ol (41 mg, 0.36 mmol), 2-chloro-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]hepta-2-yl)-6-methoxybenzo[d]thiazolyl-7-carboxamide (65 mg, 0.12 mmol), and K2CO3 (50 mg, 0.36 mmol) in NMP (1 mL) was stirred at 80 °C for 18 hours. After 18 hours, the reaction mixture was directly purified by reversed-phase column chromatography using a gradient of 0% to 100% (ACN + 5% MeOH) / 10 mM NH4HCO3 aqueous solution to give the title compound (38 mg, 51%). ES-MS m / z 619 (M+H).

[0157] The compounds in the table below are prepared essentially using appropriate amines as described in Example 63.

[0158] Example 68 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-N-(2-((3-cyanobicyclo[1.1.1]pent-1-yl)carbamoyl)-5-(difluoromethoxy)phenyl)-6-methoxybenzo[d]thiazolyl-7-carboxamide To a solution of 2-(2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazolyl-7-carbamate)-4-(difluoromethoxy)benzoic acid (50 mg, 0.10 mmol) and 3-aminobicyclo[1.1.1]pentane-1-carboxynitrile (22 mg, 0.20 mmol) in NMP (1 mL), PPACA (50% EtOAc solution) (0.19 g, 0.31 mmol, 0.18 mL) was added, followed by DiPEA (53 mg, 0.41 mmol, 70 μL). The reaction mixture was stirred at 45 °C for 3 days. The reaction mixture was diluted with EtOAc and washed with H2O (3 times). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase chromatography to give the title product (14.4 mg, 24.8 µmol, 24%). ES-MS m / z 580 (MH) The compounds in the table below are prepared essentially as described in Example 68 using appropriate amines and carboxylic acids.

[0159] Example 90 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-N-(4-((4-cyanophenyl)carbamoyl)-6-methoxypyridin-3-yl)-6-methoxybenzo[d]thiazolyl-7-carboxamide To a solution of 5-(2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazolyl-7-carbamate)-2-methoxyisonicotinic acid (100 mg, 219 μmol), 4-aminobenzylnitrile (51.8 mg, 438 μmol), DMAP (40.1 mg, 329 μmol), PPACA (418 mg, 657 μmol, 387 μL), and DiPEA (113 mg, 876 μmol, 153 μL) in NMP (5 mL), 4-aminobenzylnitrile (51.8 mg, 438 μmol), DMAP (40.1 mg, 329 μmol), PPACA (418 mg, 657 μmol, 387 μL), and DiPEA (113 mg, 876 μmol, 153 μL) were added. The reaction mixture was stirred at 85 °C for two days. The residue was purified by high-pH rapid chromatography (C18 column). The desired fractions were combined, concentrated, and dried under reduced pressure to give the title product (54 mg, 97 μmol, 44%) as a light brown solid. ES-MS m / z 557 (M+H).

[0160] The compounds in the table below are prepared essentially as described in Example 90 using appropriate amines and carboxylic acids.

[0161] a. Examples 109 and 110 were prepared from 5-(2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazolyl-7-carbamoyl)-2-methoxyisonicotinic acid and 1-methyl-3-(trifluoromethyl)cyclobut-1-amine hydrochloride (a mixture of isomers), and the products were purified by reversed-phase rapid chromatography using a gradient of 10% to 90% ACN / 10mMNH4HCO3 aqueous solution to give isomer 1 (first eluting isomer, Example 109) and isomer 2 (second eluting isomer, Example 110).

[0162] Example 118 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-isopropoxy-N-(6-methoxy-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)pyridin-3-yl)benzo[d]thiazolyl-7-carboxamide To a solution of 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-isopropoxybenzo[d]thiazolyl-7-carboxylic acid (0.060 g, 0.18 mmol) in ACN (1 mL), 5-amino-2-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)isonicotinamide (0.096 g, 0.26 mmol), NMI (52 mg, 0.63 mmol, 0.050 mL), and TCFH (0.070 g, 0.25 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 and saturated aqueous NaCl solutions. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was absorbed into ACN and the solid was precipitated. The solid was collected and washed with ACN. The residue was dried under reduced pressure over the weekend to give the title product as a white solid (0.072 g, 0.10 mmol, 58%). LC / MS m / z: 692 (M+H).

[0163] The following implementations, for example, as described in Example 118, use appropriate amines and carboxylic acids to prepare the product.

[0164] a. The product was purified by reversed-phase rapid chromatography using a gradient of 10% to 100% ACN / 10mM NH4HCO3 aqueous solution.

[0165] Example 126 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxy-N-(2-methoxy-5-((3(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)carbamoyl)pyridin-4-yl)benzo[d]thiazolyl-7-carboxamide 4-(2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazolyl-7-carbamate)-6-methoxynicotinic acid (55.4 mg, 121 μmol) and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (29 mg, 0.15 mmol) were dissolved in NMP (5 mL). PPACA (154 mg, 150 μL, 50 wt%, 243 μmol) and Et3N (73.7 mg, 0.10 mL, 728 μmol) were added, and the reaction mixture was stirred at 20 °C for 30 min. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase HPLC using a gradient of 56% to 81% ACN / 0.1% aqueous formic acid. ES-MS m / z 590 (M+H).

[0166] Example 127 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-N-(5-((4-fluoro-3(trifluoromethyl)phenyl)carbamoyl)-2-methoxypyridin-4-yl)-6-methoxybenzo[d]thiazolyl-7-carboxamide A mixture of 4-(2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazolyl-7-carbamate)-6-methoxynicotinic acid (28.4 mg, 62.2 μmol) and 4-fluoro-3-(trifluoromethyl)aniline (100 mg, 558 μmol) was dissolved in NMP (2 mL). PPACA (79.2 mg, 100 μL, 50 wt%, 124 μmol) and Et3N (73 mg, 100 μL, 0.72 mmol) were added, and the reaction mixture was stirred at 60 °C for 30 min. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with a saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase HPLC using a gradient of 53% to 78% ACN / 10 mM NH4HCO3 aqueous solution + 5% MeOH. ES-MS m / z 618 (M+H).

[0167] Example 128 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxy-N-(5-methoxy-2-((1(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)carbamoyl)phenyl)benzo[d]thiazol-7-carboxamide A mixture of 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazolyl-7-carboxylic acid (184 mg, 601 μmol) and 2-amino-4-methoxy-N-(1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)benzamide (190 mg, 601 μmol) was dissolved in NMP (3 mL). PPACA (1.15 g, 1 mL, 50 wt%, 1.80 mmol) and Et3N (243 mg, 0.33 mL, 2.40 mmol) were added, and the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was purified by reversed-phase HPLC using a gradient of 50% to 75% ACN / 0.1% formic acid aqueous solution. ES-MS m / z 605 (M+H).

[0168] Example 129 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxy-N-(5-methoxy-2-((3-methoxybicyclo[1.1.1]pent-1-yl)carbamoyl)phenyl)benzo[d]thiazolyl-7-carboxamide 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazolyl-7-carboxylic acid (142 mg, 465 μmol) and 2-amino-4-methoxy-N-(3-methoxybicyclo[1.1.1]pent-1-yl)benzamide (122 mg, 465 μmol) were dissolved in NMP (3 mL). PPACA (888 mg, 1 mL, 50 wt% 1.40 mmol) and Et3N (188 mg, 0.26 mL, 1.86 mmol) were added, and the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by reversed-phase HPLC using a gradient of 39% to 64% ACN / 10 mM NH4HCO3 aqueous solution + 5% MeOH. ES-MS m / z 551 (M+H).

[0169] Example 130 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxy-N-(4-((3-methoxybicyclo[1.1.1]pent-1-yl)carbamoyl)-6-(methylthio)pyridin-3-yl)benzo[d]thiazolyl-7-carboxamide A mixture of 5-amino-N-(3-methoxybicyclo[1.1.1]pent-1-yl)-2-(methylthio)isonicotinamide (20 mg, 72 μmol), 2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6-methoxybenzo[d]thiazolyl-7-carboxylic acid (26 mg, 86 μmol), EtOAc (0.72 mL), DiPEA (28 mg, 37 μL, 0.21 mmol), 4-(pyrrolidone-1-yl)pyridine (6.4 mg, 43 μmol), and PPACA (50 wt%, 68 mg, 62 μL, 0.11 mmol) was heated to 50 °C for 90 minutes, and then additional PPACA (50 wt%, 23 mg, 21 μL, 0.037 mmol) was added. The reactants were heated to 50°C overnight, then cooled to room temperature and diluted with EtOAc and a 1:1 saturated K₂CO₃ aqueous solution:water. The mixture was filtered, the layers were separated, and the organic layer was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography using a gradient of 20% to 100% ACN / 10mM NH₄HCO₃ aqueous solution + 5% MeOH to give the title compound (15 mg, 37%). ES-MS m / z 568 (M+H).

[0170] Bioassay The following assays demonstrate that the exemplary compound is an RXFP1 receptor agonist.

[0171] Human RXFP1 cell cAMP HTRF assay Cells expressing the relaxin family peptide receptor 1 (RXFP1) were generated 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 (catalog number H-6784.0200, Bachem, Torrance, CA). Cells expressing RXFP1 were treated with 1 µg / mL doxycycline for 24 hours prior to compound administration to induce RXFP1 expression. At cell administration, the compound was acoustically transferred to 384-well plates (ProxiPlate, 384 wells, catalog number 6008289, Revvity, Waltham, MA) using an ECHO acoustic liquid processor (Beckman, Brea, CA). Cells were administered 1 hour at 37°C with a 10-point dose-response curve (3-fold dilution). The final DMSO concentration was 0.6% in a 10 µL assay volume.

[0172] The assay buffer used for processing was a 1X stimulation buffer (provided by the Gs cAMP HighRange Kit, catalog number 62AM6PEJ, Revvity) diluted in distilled water and ultimately containing 500 µM 3-isobutyl-1-methylxanthine (catalog number I5879250MG, Sigma-Aldrich, St. Louis, MO). After a 1-hour incubation, cAMP levels were assessed using the CisBio Gs cAMP HighRange Kit (catalog number 62AM6PEJ) according to the manufacturer's instructions (Revvity). In short, 5 µL of D2-labeled cAMP diluted in the (kit-provided) lysis buffer and 5 µL of Eu... 3+ - Anti-cAMP antibodies labeled with a cavitation compound were added to each well. Cell lysis solutions were incubated at room temperature for 1 hour and then detected on a PHERAstar FSX microplate reader (BMG, Ortenberg, Germany). The HTRF ratio (emission 665 nm / emission 620 nm × 10,000) was converted to cAMP units using a cAMP standard curve. (Relative EC) 50 It is calculated relative to the top and bottom of the response curves for each concentration, and is determined using Genedata version 18.0.8 (Genedata, Basel, Switzerland) via nonlinear regression with four-parameter logistic fitting.

[0173] In the above assays, the compounds of Examples 1-130 exhibited agonist activity in the RXFP1 receptor, relative to EC50. 50 <50 nM. This data indicates that the compound of formula I, as described herein, is an RXFP1 agonist in these individuals' HEK293 cells.

Claims

1. A compound of the following formula, or a pharmaceutically acceptable salt thereof: in: Ring A is a group of the following formula , , , , , , , or , in , , and Each of them may optionally be selected from one or more halogens, -CN, C 1-4 Alkyl, -SC 1-3 Alkyl and C 1-3 Alkyl substituents, wherein each C 1-4 Alkyl and C 1-3 The alkoxy group is independently and optionally substituted by one or more substituents selected from halogens and -CN; -Y- is C 1-3 alkylene; -G6- is either -C(R1)- or -N-; R1is C 1-3 alkoxy; R2 is a -OCH2COOH or N-linked 4-7-membered heterocycle; wherein the N-linked 4-7-membered heterocycle is selected from aziridine, pyrrolidine, morpholine, piperazine, piperidine, and oxazine-heptanidine; wherein the heterocycle is optionally connected via C 1-4 Alkylene or 1-5-membered heteroalkyl groups are bridged, fused with, or spirolinked to them; wherein the heterocyclic ring, the C 1-4 The alkylene group and the 1-5 heteroalkyl group are each optionally surrounded by 1-3 groups, each independently selected from halogen, oxo group, C... 1-4 Alkyl, C 1-4 Substitution with haloalkyl groups, -OH and -COOH groups; R3 can be selected from the following groups: , , , , , and , in It can be optionally replaced by one to three halogens; -G4- is either -CH- or -N-; -G5- is either -CH2- or -O-; R 3a Each occurrence is independent of -H, halogen, -SF5, -SO2CF3, -SCF3, -CN, or C. 1-4 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl groups and the C 1-3 The alkoxy group may optionally be replaced by one, two, or three halogens; R 3b independently -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN, or C 1-4 alkyl; R 3c independently at each occurrence -H or halogen; R 3d It is -H, halogen, -CN, C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl groups and the C 1-3 The alkoxy group may be optionally replaced by one, two, or three halogens.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a group of the following formula , , , , , , or , in or Each of them is optionally controlled by one or two halogens, C 1-4 Alkyl or C 1-3 Alkoxy substitution, wherein each C 1-4 Alkyl or C 1-3 The alkoxy group is independently and optionally substituted by one or more of a halogen or -CN; R2 is a group in the following formula , , , , , , , , , , , , , , , , , , , , , , , or , in Optionally replaced by one or two halogens, wherein It may be optionally replaced by one or two oxygen groups; R3 is selected from the following groups: , , , , and ; R 3a Each occurrence is independent of -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3 The alkoxy group may optionally be replaced by one or two halogens; R 3d is -H, halogen, -CN, C 1-4 alkyl or C 1-3 alkoxy, wherein said C 1-4 alkyl or said C 1-3 alkoxy is optionally substituted with one or two halogens; and -G6- is -C(R1)-.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a group of the following formula , , , , , , or , in or Each of them is optionally controlled by one or two halogens, C 1-4 Alkyl or C 1-3 Alkoxy substitution, wherein each C 1-4 Alkyl or C 1-3 The alkoxy group is independently and optionally substituted by one or more of a halogen or -CN; R2 is a group in the following formula. , , , , , , , , , , , , , , , , , , , , , , , , or , in Optionally replaced by one or two halogens, wherein It may be optionally replaced by one or two oxygen groups; R3 is selected from the following groups: , , , , and ; R 3a independently at each occurrence is -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 alkyl or C 1-3 alkoxy, wherein said C 1-4 alkyl and said C 1-3 alkoxy are optionally substituted with one or two halogens; R 3d is -H, halogen, -CN, C 1-4 alkyl or C 1-3 alkoxy, wherein said C 1-4 alkyl or said C 1-3 alkoxy is optionally substituted with one or two halogens; and -G6- is -C(R1)-.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is a group of the following formula: , , or ; R2 is a -OCH2COOH or an N-linked 4-7-membered heterocycle; wherein the N-linked 4-7-membered heterocycle is selected from aziridine, pyrrolidine, morpholine, piperazine, piperidine, or oxazine-heptanidine; wherein the heterocycle is optionally connected via C 1-4 Alkylene or 1-5-membered heteroalkyl groups are bridged, fused with, or spirolinked to them; wherein the heterocyclic ring, the C 1-4 The alkylene group and the 1-5 heteroalkyl group are each optionally surrounded by 1-3 elements, each independently selected from halogens, C 1-4 Alkyl, C 1-4 Substitution with haloalkyl groups and -COOH groups; R3 is a group in the following formula: , , or ; R 3a It is -H, halogen, -SF5, -SO2CF3, -SCF3, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3 The alkoxy group may optionally be replaced by one or more halogens; Each R 3c It can be either -H or -F independently; R 3d It is -H, halogen, C 1-4 Alkyl or C 1-3 Alkoxy, wherein the C 1-4 alkyl or the C 1-3 The alkoxy group is optionally substituted with one or more halogens; and -G6- is -C(R1)-.

5. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is a group of the following formula: ， in Optionally by one or two halogens, C 1-4 Alkyl or C 1-3 Alkoxy substitution, wherein each C 1-4 Alkyl or C 1-3 The alkoxy group is independently and optionally substituted by one or more of a halogen and -CN.

6. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is a group of the following formula: or , in Optionally by one or two halogens, C 1-4 Alkyl or C 1-3 Alkoxy substitution, wherein each C 1-4 Alkyl or C 1-3 The alkoxy group is independently and optionally substituted by one or more substituents selected from halogens and -CN.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is a group of the following formula: , , , , , , or , in , , and Each of them may optionally be selected from one or more halogens, -CN, C 1-4 Alkyl, -SC 1-3 Alkyl and C 1-3 Alkyl substituents, wherein each C 1-4 Alkyl and C 1-3 The alkoxy group is independently and optionally substituted by one or more substituents selected from halogens and -CN; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein ring A is a group of the following formula: 。 9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein -G6- is -C(R1)-.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R1 is methoxy, ethoxy, or isopropoxy.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R1 is a methoxy group.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of: , , , and .

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 3d It is trifluoromethyl.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula: 。 15. The compound according to any one of claims 1, 3, 5 to 14, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of: , , , , , , , , , and .

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the following formula: , , , , , , , or .

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the following formula: 。 18. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of: , , and .

19. The compound according to any one of claims 1 to 3, 5 to 13, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of: , , , , and .

20. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R2 is 。 21. The compound according to claim 1, wherein the compound is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; or their pharmaceutically acceptable salts.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

23. A method of treating an individual with cardiovascular, pulmonary and / or renal symptoms, diseases and / or conditions, the method comprising administering to the individual an effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22.

24. The compound according to any one of claims 1 to 21, wherein the compound is used in a therapeutic manner.

25. The compound according to any one of claims 1 to 21, wherein the compound is used in the treatment of cardiovascular, pulmonary and / or renal symptoms, diseases and / or conditions.

26. Use of the compound of any one of claims 1 to 21 in the manufacture of a medicament for treating cardiovascular, pulmonary and / or renal symptoms, diseases and / or conditions.

27. The method of claim 23, the compound of claim 25, or the use of claim 26, wherein the disease or condition to be treated is selected from cardiovascular symptoms, diseases, or conditions such as acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.

28. The method of claim 23, the compound of claim 25, or the use of claim 26, wherein the disease or condition to be treated is a lung symptom, disease, or condition selected from pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

29. The method of claim 23, the compound of claim 25, or the use of claim 26, wherein the disease or condition to be treated is a kidney symptom, disease, or condition selected from acute kidney disease, chronic kidney disease, or diabetic nephropathy.

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