RXFP1 receptor agonists

Abstract

To provide small molecule relaxin family peptide receptor-1 (RXFP1) agonists and uses thereof.SOLUTION: The present invention provides a compound of the following formula, and a method of using the compound and a pharmaceutically acceptable salt thereof for treating a patient for cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to small molecule RXFPl agonists and their use.

Background Art

[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 serelaxin, a short-acting recombinant relaxin, have shown the promise of recombinant relaxin as a therapeutic agent in the treatment of cardiovascular diseases and fibrotic diseases.

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

[0004] Non-peptide small molecule modulators of RXFPl are also being explored. For example, McBride A et al. (2017) Scientific Reports 7:10806 discusses small molecule positive allosteric modulators of RXFPl. International Publication No. WO 2023 / 076626, International Publication No. WO 2023 / 077040, and International Publication No. WO 2023 / 077070 each disclose small molecule analogs useful as RXFPl receptor agonists.

[0005] There remains a need to provide alternative small molecule RXFP1 agonists. In particular, there is a need to provide additional orally deliverable RXFP1 agonists that are useful for treating cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders. Further, there is a need to provide RXFP1 receptors that exhibit better pharmacokinetic / pharmacodynamic properties. There is also a need to provide RXFP1 receptor agonists that exhibit efficacy with reduced or minimized adverse or undesirable effects. More particularly, there is a need to provide small molecule RXFP1 receptor agonists that are more selective for RXFP1 than RXFP2. The present invention addresses one or more of these needs by providing novel RXFP1 agonists. SUMMARY OF THE INVENTION

[0006] Disclosed herein are compounds of Formula I

[0007] Compounds of the following formula,

[0008]

Chemical formula

[0009]

Chemical formula

[0010]

Chemical formula

[0011]

Chemical formula

[0012]

Chemical formula

[0013] The following are further numbered embodiments of the present invention: 1. A compound of the following formula,

[0014]

Chemical formula

[0015]

Chemical formula

[0016]

Chemical formula

[0017]

Chemical formula

[0018]

Chemical formula

[0019] Disclosed herein are a compound of formula I or a pharmaceutically acceptable salt thereof, and a method of using a compound of formula I or a pharmaceutically acceptable salt thereof to treat a patient for a cardiovascular, pulmonary, and / or renal condition, disease, and / or disorder.

[0020] Also provided herein is a method of using a compound of formula I, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof for treating a cardiovascular, pulmonary, and / or renal condition, disease, and / or disorder. The method includes administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0021] Further provided herein are a compound of formula I, and a pharmaceutically acceptable salt thereof for use in therapy. In addition, provided herein are a compound of formula I and a pharmaceutically acceptable salt thereof for use in treating a cardiovascular, pulmonary, and / or renal condition, disease, and / or disorder. Also in addition, provided herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cardiovascular, pulmonary, and / or renal condition, disease, and / or disorder.

DETAILED DESCRIPTION OF THE INVENTION

[0022] Novel RXFP1 receptor agonists are described herein. These novel compounds can address some or all of the above - mentioned needs for novel RXFP1 receptor agonists in the treatment of cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders.

[0023] The following are further numbered aspects of the present invention: 1. A compound of the following formula,

[0024]

Chemical formula

[0025]

Chemical formula

[0026]

Chemical formula

[0027]

Chem.

[0028]

Chem.

[0029]

Chem.

[0030] [Chemical formula] each of which is optionally substituted with one or two halogens, C 1~4 alkyl, or C 1~3 alkoxy, and each C 1~4 alkyl or C 1~3 alkoxy is independently optionally substituted with one or more halogens or -CN, R2 is a group of the formula

[0031] [Chemical formula] wherein

[0032] [Chemical formula] is optionally substituted with one or two halogens,

[0033] [Chemical formula] is optionally substituted with one or two oxo groups, R3 is

[0034] [Chemical formula] selected from the group consisting of R 3a is, in each occurrence, independently -H, halogen, -SF5, -SO2CF3, -SCF3, C 1~4 alkyl, or C 1~3 alkoxy, and C 1~4 alkyl and 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, and C 1~4 alkyl or C 1~3 alkoxy are optionally substituted with one or two halogens, The compound according to embodiment 1, wherein -G6- is -C(R1)-, or a pharmaceutically acceptable salt thereof. 3. Ring A is of the formula

[0035]

Chemical formula

[0036]

Chemical formula

[0037]

Chemical formula

[0038]

Chemical formula

[0039]

Chemical formula

[0040]

Chemical formula

[0041]

Chemical formula

[0042]

Chemical formula

[0043]

Chemical formula

[0044]

Chemical formula

[0045]

Chemical formula

[0046]

Chemical formula

[0047]

Chem.

[0048]

Chem.

[0049]

Chem.

[0050]

Chem.

[0051]

Chem.

[0052]

Chem.

[0053]

Chemical formula

[0054]

Chemical formula

[0055]

Chemical formula

[0056]

Chem.

[0057]

Chem.

[0058]

Chem.

[0059]

Chem.

[0060]

Chem.

[0061]

Chem.

[0062]

Chem.

[0063]

Chem.

[0064]

Chem.

[0065]

Chem.

[0066]

Chem.

[0067]

Chem.

[0068]

Chem.

[0069]

Chem.

[0070]

Chem.

[0071]

Chem.

[0072] [Chemistry]

[0073] [Chemistry]

[0074] [Chemistry]

[0075] [Chemistry]

[0076] [Chemistry] The compound according to embodiment 1, selected from the group consisting of 28.

[0077] [Chemistry] The compound according to embodiment 1, selected from or a pharmaceutically acceptable salt thereof. 29. A pharmaceutical composition comprising the compound defined in any one of embodiments 1 to 28 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 30. A method for treating a cardiovascular, pulmonary, and / or renal condition, disease, and / or disorder in an individual, comprising administering to the individual an effective amount of the compound according to any one of embodiments 1 to 28 or the pharmaceutical composition according to embodiment 29. 31. The compound according to any one of embodiments 1 to 28 for use in therapy. 32. The compound according to any one of embodiments 1 to 28 for use in the treatment of a cardiovascular, pulmonary, and / or renal condition, disease, and / or disorder. 33. Use of a compound according to any one of aspects 1 to 28 for the manufacture of a medicament for the treatment of cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders. 34. The method according to aspect 30, the compound for use according to aspect 32, or the use according to aspect 33, wherein the disease or disorder to be treated is a cardiovascular condition, disease, or disorder selected from acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vascular stenosis, or ventricular hypertrophy. 35. The method according to aspect 30, the compound for use according to aspect 32, or the use according to aspect 33, wherein the disease or disorder to be treated is a pulmonary condition, disease, or disorder selected from pulmonary hypertension or chronic obstructive pulmonary disease (COPD). 36. The method according to aspect 30, the compound for use according to aspect 32, or the use according to aspect 33, wherein the disease or disorder to be treated is a renal condition, disease, or disorder selected from acute kidney disease, chronic kidney disease, or diabetic nephropathy.

[0078] The present invention provides a compound of the following formula,

[0079]

Chemical formula

[0080] In one embodiment, ring A is a group of the formula

[0081]

Chemical formula

[0082]

Chemical formula

[0083]

Chemical formula

[0084]

Chemical formula

[0085]

Chemical formula

[0086]

Chemical formula

[0087] In another embodiment, ring A is of the formula

[0088]

Chem.

[0089]

Chem.

[0090] In another embodiment, ring A is of the formula

[0091] [Chemistry] is a group of

[0092] [Chemistry] each of which is optionally substituted with one or more selected from halogen, C 1~4 alkyl, and C 1~3 alkoxy, and each C 1~4 alkyl or C 1~3 alkoxy is independently optionally substituted with one or more selected from halogen and -CN, or is a pharmaceutically acceptable salt thereof.

[0093] In another embodiment, ring A is a group of the formula

[0094] [Chemistry] is a group of

[0095] [Chemistry] is optionally substituted with one or more selected from halogen, C 1~4 alkyl, and C 1~3 alkoxy, and each C 1~4 alkyl or C 1~3 alkoxy is independently optionally substituted with one or more selected from halogen and -CN, or is a pharmaceutically acceptable salt thereof.

[0096] In another embodiment, ring A is a group of the formula

[0097] [Chemistry] is a group of

[0098] [Chemistry] is selected from halogen, C 1~4 alkyl, and C 1~3 alkoxy, is optionally substituted with one or more selected therefrom, and each C 1~4 alkyl or C 1~3 alkoxy is independently optionally substituted with one or more selected from halogen and -CN, or is a pharmaceutically acceptable salt thereof.

[0099] In another embodiment, ring A is of the formula

[0100]

Chemical formula

[0101] In one embodiment, ring A is

[0102]

Chemical formula

[0103] In another embodiment, -G6- is -C(R1)- or is a pharmaceutically acceptable salt thereof.

[0104] In another embodiment, the compound is a compound of the following formula, or

[0105]

Chemical formula

[0106] In another embodiment, the compound is a compound of the following formula, or

[0107]

Chemical formula

[0108] In another embodiment, R1 is methoxy, ethoxy, or isopropoxy, or a pharmaceutically acceptable salt thereof.

[0109] In another embodiment, R1 is methoxy or a pharmaceutically acceptable salt thereof.

[0110] In another embodiment, R3 is

[0111]

Chemical formula

[0112] In another embodiment, R 3d is trifluoromethyl or a pharmaceutically acceptable salt thereof.

[0113] In another embodiment, R3 is

[0114]

Chemical formula

[0115] In another embodiment, R 3a is -F, -Cl, -Br, difluoromethyl, difluorochloromethyl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy, and R 3b is -H, -F, -Cl, -Br, trifluoromethyl, -CN, or methyl, or a pharmaceutically acceptable salt thereof.

[0116] In another embodiment, R3 is

[0117]

Chemical formula

[0118] In another embodiment, R3 is:

[0119] [ka] or a pharma- ceutically acceptable salt thereof.

[0120] In another embodiment, the compound is a compound of the following formula:

[0121] [ka] or a pharma- ceutically acceptable salt thereof.

[0122] In another embodiment, R2 is

[0123] [ka] or selected from the group consisting of or a pharma- ceutically acceptable salt thereof.

[0124] In another embodiment, R2 is of the formula

[0125] [ka] or a pharma- ceutically acceptable salt thereof.

[0126] In another embodiment, R2 is of the formula

[0127] [ka] Is it a group of or a pharma- ceutically acceptable salt thereof.

[0128] In another embodiment, R2 is

[0129]

Chemical formula

[0130] In another embodiment, R2 is

[0131]

Chemical formula

[0132] In another embodiment, R2 is

[0133]

Chemical formula

[0134] In another embodiment, the compound is

[0135]

Chemical formula

[0136]

Chemical formula

[0137]

Chemical formula

[0138]

Chemical formula

[0139] [Chemical]

[0140] [Chemical]

[0141] [Chemical]

[0142] [Chemical]

[0143] [Chemical]

[0144] [Chemical] selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0145] In another embodiment, the compound is

[0146] [Chemical]

[0147] [Chemical]

[0148] [Chemical]

[0149] [Chemical]

[0150]

Chem.

[0151]

Chem.

[0152] In another embodiment, the compound is

[0153]

Chem.

[0154]

Chem.

[0155] In another embodiment, the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient.

[0156] In another embodiment, a method of treating a cardiovascular, pulmonary, and / or renal condition, disease, and / or disorder in an individual, the method comprising 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.

[0157] In another embodiment, a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0158] In another embodiment, a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a cardiovascular, pulmonary, and / or renal condition, disease, and / or disorder.

[0159] In another embodiment, it is the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders.

[0160] In another embodiment, it is a method of using a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder to be treated is a cardiovascular condition, disease, or disorder selected from acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vascular stenosis, or ventricular hypertrophy.

[0161] In another embodiment, it is a method of using a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder to be treated is a pulmonary condition, disease, or disorder selected from pulmonary hypertension or chronic obstructive pulmonary disease (COPD).

[0162] In another embodiment, it is a method of using a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder to be treated is a renal condition, disease, or disorder selected from acute kidney disease, chronic kidney disease, or diabetic nephropathy.

[0163] In the above embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, the chemical diagrams are shown monotonously without chiral information. These compounds often have multiple chiral centers and are contemplated to exist in various forms with various combinations of chiral centers. In addition, these compounds may have various enantiomers, diastereomers, and atropisomers that may exist and are included herein.

[0164] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound is an isotope derivative of any one of the compounds described herein or a pharmaceutically acceptable salt thereof.

[0165] It is understood that isotopic derivatives can be prepared using any of the various techniques known in the art. For example, isotopic derivatives can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein using an isotopically labeled reagent or a pharmaceutically acceptable salt thereof in place of a non-isotopically labeled reagent.

[0166] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound is a deuterated derivative of any one of the compounds described herein or a pharmaceutically acceptable salt thereof.

[0167] In the compounds of the present invention, any atom not specifically designated as a particular isotope is meant to represent a stable isotope of that atom. Unless otherwise specified, when an atom is specifically designated as "H" or "hydrogen", that atom is understood to have hydrogen in its natural abundance isotopic composition. Also, unless otherwise specified, when an atom is specifically shown as "D" or "deuterium", the atom is understood to have deuterium in an abundance substantially greater than the natural abundance of deuterium, which is 0.015%.

[0168] The compound of formula I, or a pharmaceutically acceptable salt thereof, the compound is

[0169]

Chemical formula

[0170]

Chemical formula

[0171] Also provided herein is a pharmaceutical composition comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof (examples include, but are not limited to, the compounds disclosed herein), and a pharmaceutically acceptable carrier, diluent, or excipient.

[0172] Further provided herein is a method for treating a cardiovascular, pulmonary, and / or renal condition, disease, and / or disorder, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. Further provided herein is a method for treating a cardiovascular condition, disease, and / or disorder, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. Further provided herein is a method for treating a pulmonary condition, disease, and / or disorder, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. Further provided herein is a method for treating a renal condition, disease, and / or disorder, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0173] Further provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy. Further provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a cardiovascular, pulmonary, and / or renal condition, disease, and / or disorder. Further provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy. Further provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a cardiovascular condition, disease, and / or disorder. Further provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy. Further provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a pulmonary condition, disease, and / or disorder. Further provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy. Further provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a renal condition, disease, and / or disorder.

[0174] In the methods or uses herein, cardiovascular conditions, diseases, and disorders include, but are not limited to, acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, and ventricular hypertrophy. In the methods or uses herein, pulmonary conditions, diseases, and disorders include, but are not limited to, pulmonary hypertension and chronic obstructive pulmonary disease (COPD). In the methods or uses herein, renal conditions, diseases, and disorders include, but are not limited to, acute kidney disease, chronic kidney disease, and diabetic nephropathy.

[0175] The method may also include administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of at least one additional therapeutic agent. Briefly, standard treatments for many of the conditions / diseases / disorders herein include anticoagulants, ACE inhibitors, ARBs, ARNIs, β-blockers, diuretics, digitalis, digoxin, hydralazine nitrate / isosorbide, MRAs or other aldosterone antagonists, SGLT2 inhibitors, statins, and / or antihyperglycemic agents, and other therapeutic agents for controlling comorbidities including, but not limited to, hypercholesterolemia, hypertension, atrial fibrillation, diabetes, and obesity. In some cases, the additional therapeutic agent may be administered simultaneously with, separately from, or sequentially to the compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0176] Furthermore, provided herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of cardiovascular, pulmonary, and / or renal conditions, diseases, and / or disorders, either simultaneously, separately, or sequentially in combination with at least one additional therapeutic agent. Additional therapeutic agents include, but are not limited to, anticoagulants, ACE inhibitors, ARBs, ARNIs, β-blockers, diuretics, digitalis, digoxin, hydralazine nitrate / isosorbide, MRAs or other aldosterone antagonists, SGLT2 inhibitors, statins, and / or antihyperglycemic agents, and other therapeutic agents for controlling comorbidities including, but not limited to, hypercholesterolemia, hypertension, atrial fibrillation, and diabetes.

[0177] The methods or uses herein may include the steps described herein, which may be performed, but are not necessarily limited to, the order described. However, other orders are contemplated. Further, the individual or multiple steps may be performed in steps that are time-parallel and / or overlapping, and / or separately, or repeated multiple times. Further, the method may include additional unspecified steps.

[0178] Accordingly, such methods or uses may include selecting an individual having or at risk of having a cardiovascular condition, disease, or disorder. Alternatively, the method may include selecting an individual having or at risk of having a pulmonary abnormality, disease, or disorder. Alternatively, the method may include selecting an individual having or at risk of having a renal abnormality, disease, or disorder. In certain instances, the method may include selecting an individual who is diabetic, has hypertension with renal dysfunction, and / or is obese.

[0179] In some instances, the individual in need is a patient with diabetic hypertension with renal dysfunction and / or obesity.

[0180] These methods or uses may also be combined with diet and exercise and / or in combination with additional therapeutic agents other than those discussed above.

[0181] As used herein, the term "pharmaceutically acceptable salt" refers to salts of compounds that are considered acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and general methodologies 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 S.M. Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.

[0182] The pharmaceutical compositions comprising the compounds of formula I described herein, or pharmaceutically acceptable salts thereof, may be prepared using pharmaceutically acceptable additives. As used herein, the term "pharmaceutically acceptable additives" for pharmaceutical compositions refers to one or more carriers, diluents, and excipients that are compatible with other additives in the composition or formulation and are not harmful to the patient. Examples of pharmaceutical compositions and processes for their preparation can be found in "Remington: The Science and Practice of Pharmacy", Loyd, V., et al. Eds., 22nd Ed., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include physiological saline, water, starch, sugar, mannitol, and silica derivatives; binders such as carboxymethylcellulose, alginates, gelatin, and polyvinylpyrrolidone; kaolin and bentonite; and polyethylene glycol.

[0183] As used herein, "effective amount" means an amount or dosage of a compound of Formula I or a pharmaceutically acceptable salt thereof that, upon single or multiple administration to an individual in need thereof, provides a desired effect (i.e., for example, an increase in angiogenesis, an increase in vascular compliance, an increase in cardiovascular blood flow, an increase in hepatic blood flow, an increase in pulmonary blood flow, an increase in renal blood, an increase in glomerular filtration rate, a decrease in blood pressure, a decrease (or prevention) of inflammation, and / or a decrease (or prevention) of fibrosis of the heart, kidney, liver, or lung, etc., a clinically measurable difference in the condition of the individual) in such an individual being diagnosed or treated. The effective amount can be readily determined by one of ordinary skill in the art by use of known techniques and by observing results obtained under similar circumstances. In determining the effective amount for an individual, numerous factors are considered including, but not limited to, the mammalian species, its size, age, and general health, the particular disease or disorder involved, the degree or involvement or severity of the disease or disorder, the individual's response, the particular compound of Formula I administered, or a pharmaceutically acceptable salt thereof, the mode of administration, the bioavailability characteristics of the preparation administered, the selected dosage regimen, the use of concomitant medications, and other relevant circumstances.

[0184] As used herein, "treating" (or "to treat") means administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to an individual having a condition, disease, disorder, or symptom for the purpose of reducing, suppressing, reversing, slowing, or stopping the progression or severity of the condition, disease, disorder, or symptom. Treating includes administering to an individual a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, to prevent the onset of symptoms or complications, relieve symptoms or complications, or eliminate a condition, disease, disorder, or symptom. Treating includes administering to an individual a compound of formula I, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, to cause, for example, an increase in angiogenesis, an increase in vascular compliance, an increase in cardiovascular blood flow, an increase in hepatic blood flow, an increase in pulmonary blood flow, an increase in renal blood, an increase in glomerular filtration rate, a decrease in blood pressure, a decrease (or prevention) of inflammation, and / or a decrease (or prevention) of fibrosis of the heart, kidney, liver, or lung. The individual to be treated is a mammal, particularly a human.

[0185] As used herein, the terms "individual", "patient", and "subject" are used synonymously and mean a mammal, particularly a human. In certain instances, the individual is further characterized by a condition, disease, disorder, and / or symptom that would benefit from administration of a compound of formula I described herein, or a pharmaceutically acceptable salt thereof.

[0186] As used herein, the term halogen means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). As used herein, the term alkyl means a saturated straight-chain or branched-chain monovalent hydrocarbon radical of one to a specific number of carbon atoms, e.g., "C 1~4 alkyl" or "C 1~3means "alkyl". Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, and iso-butyl. As used herein, the terms "alkylene" or "alkylenyl" mean a saturated straight-chain or branched-chain divalent hydrocarbon radical of 1 to a specific number of carbon atoms, for example, "C 1~3 means "alkylene". Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, 1-propylene, and isopropyl. As used herein, the term "alkoxy" means a saturated straight-chain or branched-chain monovalent hydrocarbon radical containing a specific number of atoms including both carbon atoms and one or more oxygen atoms, for example, "C 1~3 means "alkoxy". For example, C 1~3 alkoxy means a saturated straight-chain or branched-chain monovalent hydrocarbon radical containing at least one carbon atom or at least one oxygen, and the total number of carbon and oxygen atoms is 1, 2, or 3 atoms in total. C 1~3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 1-propoxy, and isopropoxy.

[0187] As used herein, the term "heteroalkyl" means a saturated straight or branched chain divalent hydrocarbon radical containing a specified number of atoms including both carbon atoms and one or more heteroatoms, e.g., "1-5 membered heteroalkyl". For example, 4-membered heteroalkyl means a saturated straight or branched chain monovalent hydrocarbon radical containing at least one carbon atom or at least one heteroatom, and the total number of carbon and heteroatoms is a total of 4 atoms. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur. Examples of 1-5 membered heteroalkyl include, but are not limited to, -O-CH2-, -CH2-O-CH2-, -O-CH2-CH2-, -CH2-CH2-O-, -CH2-SO2-CH2-, -O-CH2-CH2-CH2-, -CH2-CH2-CH2-O-, -CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-CH2-CH2-O-CH2-, -CH2-O-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-O-, -O-CH2-CH2-CH2-CH2-, -CH2-SO2-CH2-, -CH2-CH2-SO2-, -SO2-CH2-CH2-, -CH2-S-CH2-, -CH2-CH2-S-, and -S-CH2-CH2-.

[0188] As used herein, the term "cycloalkyl" means a saturated cyclic hydrocarbon group containing the specified number of carbon atoms. For example, the term "C 3~6 cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon group having 3, 4, 5, or 6 carbon atoms. Examples of 3-6 membered cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0189] As used herein, the term heterocycloalkyl means a saturated cyclic heteroalkyl group containing a specific number of atoms including both carbon atoms and one or more heteroatoms, for example, a "4- to 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, and the total number of carbon and heteroatoms is a total of 7 atoms. Examples of 4- to 7-membered heterocycles include, but are not limited to, azetidine, pyrrolidine, morpholine, piperazine, piperidine, and oxazepane.

[0190] Certain 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 hour, "HATU" refers to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, "HPLC" refers to high performance liquid chromatography, "MeOH" refers to methanol, "min" refers to minute, "NMI" refers to N-methylimidazole, "NMP" refers to N-methyl-2-pyrrolidone, "PG" refers to protecting group, "RT" refers to room temperature, "TBD" refers to 1,5,7-triazabicyclo[4.4.0]dec-5-ene, "TCFH" refers to chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, "T3P" refers to propanesulfonic anhydride, and "Wt" refers to weight.

[0191] Individual isomers, enantiomers, diastereomers, and atropisomers can be separated or resolved at any convenient point in the synthesis of the compounds listed below by methods such as selective crystallization techniques or chiral chromatography (see, e.g., J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). This specification is intended to include all isomers, enantiomers, diastereomers, and atropisomers possible for the compounds disclosed herein or that can be made using the compounds disclosed herein. In the molecules described herein, only those molecules for which the absolute configuration (or atropisomer configuration) of the chiral center is known are depicted using the nomenclature rules or chemical formulas shown to indicate chirality or atropisomerism. One of ordinary skill in the art will readily understand and be able to identify when other chiral centers are present in the molecules described herein.

[0192] Any one of the compounds of Formula I that can form a salt chemically can be readily converted to a pharmaceutically acceptable salt and isolated as a pharmaceutically acceptable salt. Salt formation can occur upon addition of a pharmaceutically acceptable acid to form an acid addition salt. The salt can also be formed simultaneously upon deprotection of nitrogen or oxygen, i.e., upon removal of a protecting group. Examples of reactions and conditions for salt formation can be found in Gould, P.L., "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986), Bastin, R.J., et al. "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000), and Berge, S.M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19, (1977).

[0193] The compounds of the present invention, or salts thereof, can be prepared by various procedures, some of which are described in the following schemes, preparations, and examples. The specific synthetic steps for each described route 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, trituration, and crystallization.

[0194] In addition, the specific intermediates described in the following preparations may contain one or more nitrogen protecting groups. It is understood that the protecting groups can vary depending on the specific reaction conditions and the specific transformations being carried out, as will be understood by those skilled in the art. The conditions for protection and deprotection 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", Fifth Edition, Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2014).

[0195] Examples of known procedures and methods include 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, 5 th 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 those described in general reference books such as the references cited therein.

[0196]

Chemical formula

[0197] Scheme 1 shows the preparation of the compounds of the present invention starting from suitable carboxylic acid 1 and 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 carbamate 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 involve reacting a solution of carboxylic acid 1 and the desired amine 2 in a suitable solvent such as DCM or DMF with a suitable coupling reagent such as T3P or HATU in the presence of a suitable organic base such as DiPEA with stirring at room temperature. Removal of the PG moiety on the amine of amide 3 is achieved under acidic conditions standard in the art. Intermediate amide 4 is obtained by reacting a suitable acid such as TFA or HCl in Et2O 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. A suitable coupling reagent 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 the intermediate amine in a suitable solvent such as DMF or ACN at room temperature.

[0198] In step 3, intermediate 4 is reacted under nucleophilic aromatic substitution conditions well known to those skilled in the art to obtain 5. Suitable nucleophilic aromatic substitution conditions involve reacting a compound having a suitable halogen such as chlorine on the aromatic moiety with a suitable nucleophilic reactant such as an amine or an alcohol. The reaction occurs at at least 80 °C in a suitable organic solvent such as NMP or DMF in the presence of a suitable organic base such as K2CO3 or NaH. Optionally, CuI can be added to catalyze the nucleophilic aromatic substitution reaction.

[0199]

Chemical formula

[0200] Scheme 2 shows the preparation of the compounds of the present invention starting from the 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 obtain 7. The reaction occurs 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 with a suitable coupling reagent such as TCFH or oxalyl chloride and DMF in the presence of a suitable organic base such as NMI or DiPEA with stirring at room temperature for at least 18 hours. The ester of the intermediate amide is hydrolyzed under standard saponification conditions using a suitable base such as LiOH or TBD in a mixture of suitable organic solvents such as THF and H2O with stirring at at least room temperature for at least 48 hours.

[0201] In step 3, the resulting carboxylic acid 9 is reacted with the appropriate amine 2 under standard amide coupling conditions, including reacting a solution of carboxylic acid 9 and amine 2 in a suitable solvent such as ACN or NMP with a suitable coupling reagent such as TCFH or T3P in the presence of a suitable organic base such as NMI or DiPEA with stirring at room temperature for at least 48 hours.

[0202]

Chemical formula

[0203] Scheme 3 shows the preparation of the compounds of the present invention starting from suitable carboxylic acid 6 and 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 involve reacting a solution of carboxylic acid 6 and the desired amine 11 in a suitable solvent such as ACN with a suitable coupling reagent such as TCFH in the presence of a suitable organic base such as NMI with stirring at room temperature 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 in a mixture of suitable organic solvents such as THF and H2O with stirring at room temperature for at least 18 hours. The intermediate carboxylic acid is then reacted with a suitable amine under standard amide coupling conditions, involving reacting a solution of the carboxylic acid and the desired amine in a suitable solvent such as ACN with a suitable coupling agent such as TCFH in the presence of a suitable organic base such as NMI with stirring at room temperature.

[0204] In step 3, intermediate amide 13 is reacted under nucleophilic aromatic substitution conditions well known to those skilled in the art to obtain 5. The reaction occurs at at least 80 °C in a suitable organic solvent such as NMP in the presence of a suitable organic base such as K2CO3.

[0205] In Schemes 1 - 3, when the R2 - group contains a carboxylic acid ester, it can be treated under standard saponification conditions using a suitable strong inorganic base such as LiOH or TBD in a mixture of suitable organic solvents such as THF and H2O with stirring at room temperature for at least 30 minutes.

[0206] Preparation 1 2-(3 - oxa - 7 - azabicyclo[3.3.1]nonan - 7 - yl)-6 - methoxybenzo[d]thiazole - 7 - carboxylic acid

[0207]

Chemical Structure

[0208] A solution of 3-oxa-7-azabicyclo[3.3.1]nonane (1.566 g, 12.31 mmol), 2-chloro-6-methoxybenzo[d]thiazole-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 amount of this material was directly purified by reverse-phase column chromatography (C18, 0–100% gradient (5% MeOH / ACN) in 10 mM aqueous NH4HCO3, pH 10) to give an impure product. The impure fractions 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).

[0209] Preparation 2 Methyl (1R,2S,3R,4S)-3-(2-chloro-6-methoxybenzo[d]thiazole-7-carboxamido)bicyclo[2.2.1]heptane-2-carboxylate

[0210] [Chemical formula]

[0211] To a stirred solution of 2-chloro-6-methoxybenzo[d]thiazole-7-carboxylic acid (1000 mg, 4.104 mmol) and methyl (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]heptane-2-carboxylate (833.4 mg, 4.925 mmol) in THF (20 mL), TCFH (2.764 g, 4.925 mmol, 3 mL) and NMI (808.7 mg, 9.850 mmol, 0.8 mL) were added. The reaction mixture was stirred at room temperature for 18 h. After 18 h, 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% ethyl acetate in heptane) to afford the title compound (1025 mg, 2.596 mmol, 63%). ES-MS m / z 395 (M+H).

[0212] Preparation 3 (1R,2S,3R,4S)-3-(2-Chloro-6-methoxybenzo[d]thiazole-7-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid

[0213]

Chemical formula

[0214] To a stirred solution of methyl (1R,2S,3R,4S)-3-(2-chloro-6-methoxybenzo[d]thiazole-7-carboxamido)bicyclo[2.2.1]heptane-2-carboxylate (975 mg, 2.47 mmol) in THF (20 mL), a solution of LiOH (296 mg, 12.3 mmol) in H2O (5 mL) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and acidified to about pH 4 with 2 M HCl. The organic layer was separated. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over Na2SO4, concentrated to afford the title compound (800 mg, 2.10 mmol, 85%). ES-MS m / z 381 (M+H).

[0215] Preparation 4 tert-Butyl ((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate

[0216]

Chemical formula

[0217] T3P (26 g, 41 mmol, 24 mL) and DIPEA (3.5 g, 27 mmol, 4.8 mL) were added to a stirred solution of (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 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 reverse-phase column chromatography (C18, gradient of 0 - 100% (5% MeOH / ACN) in 10 mM aqueous NH4HCO3, pH 10) to give the title compound (5.7 g, 14 mmol, 100%). ES-MS m / z 416 (M+H).

[0218] Preparation 5 (1R,2S,3R,4S)-3-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide

[0219]

Chemical formula

[0220] To a solution of tert-butyl ((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate (18.5 g, 44.4 mmol) in DCM (317 mL) was added TFA (52.9 mL). The reaction mixture was stirred at 25 °C. After 2 h, the reaction mixture was concentrated, then EtOAc (6 mL) was added to dissolve the residue, followed by pentane (200 mL). The resulting mixture was stirred vigorously for 12 h to precipitate the product. After stirring for 12 h, the product was isolated by filtration, 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).

[0221] Preparation 6 2-Chloro-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-6-methoxybenzo[d]thiazole-7-carboxamide

[0222] [Chemical Structure]

[0223] To a stirred solution of 2-chloro-6-methoxybenzo[d]thiazole-7-carboxylic acid (900 mg, 3.69 mmol) in ACN (30 mL) were added TCFH (2.49 g, 4.43 mmol, 2 mL) and NMI (728 mg, 8.86 mmol, 0.7 mL), followed by addition of (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% ethyl acetate in heptane) to afford the title compound (1 g, 2 mmol, 50%). ES-MS m / z 542 (M+H).

[0224] The following were prepared essentially as described in Preparation 6 using the appropriate amine and carboxylic acid:

[0225] [Table 1] a. Starting materials: 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine and (1R,2S,3R,4S)-3-(2-chloro-6-methoxybenzo[d]thiazole-7-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid b. Starting materials: 1-(trifluoromethyl)-2-oxabicyclo[2.2.2]octan-4-amine and (1R,2S,3R,4S)-3-(2-chloro-6-methoxybenzo[d]thiazole-7-carboxamido)bicyclo[2.2.1]heptane-2-carboxylic acid

[0226] Preparation 10 3-(2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)-6-methoxybenzo[d]thiazole-7-carboxamido)isonicotinic acid

[0227] [Chem.]

[0228] To a stirred solution of methyl 3-(2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)-6-methoxybenzo[d]thiazole-7-carboxamide)isonicotinate (60 mg, 0.13 mmol) in THF (2 mL) was added a solution of LiOH (50 mg, 2.1 mmol) in H2O (0.7 mL). The reaction mixture was stirred at room temperature for 48 h. After 48 h, the reaction mixture was purified directly by reverse-phase column chromatography (C18, gradient of 0–100% (5% MeOH / ACN) in 10 mM aqueous NH4HCO3, pH 10) to afford the title compound (60 mg, 0.12 mmol, 93%). ES-MS m / z 455 (M+H).

[0229] Preparation 11 Methyl 7-(7-(((1S,2R,3S,4R)-3-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-methoxybenzo[d]thiazol-2-yl)-7-azaspiro[3.5]nonane-2-carboxylate

[0230] [Chem.]

[0231] 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]heptan-2-yl)-6-methoxybenzo[d]thiazole-7-carboxamide (50 mg, 92 μmol), and K2CO3 (38 mg, 0.28 mmol) was stirred at 80 °C in DMF (1 mL) for 18 h. The reaction mixture was then purified directly by silica gel chromatography (0 - 100% ethyl acetate in heptane) to afford the title product (64 mg, 84 μmol, 91%). ES-MS m / z 689 (M+H).

[0232] Preparation 12 Methyl 2-((7-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-methoxybenzo[d]thiazol-2-yl)oxy)acetate

[0233] [Chemical formula]

[0234] 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]heptan-2-yl)-6-methoxybenzo[d]thiazole-7-carboxamide (40 mg, 74 μmol) in DMF (1 mL) was added NaH (5.3 mg, 0.22 mmol). The reaction mixture was stirred at 50 °C for 6 h. The reaction mixture was then purified directly by silica gel chromatography to afford the title compound (44 mg, 74 μmol, 100%). ES-MS m / z 596 (M+H).

[0235] Preparation 13 tert-Butyl (5-fluoro-4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)pyridin-3-yl)carbamate

[0236] [Chemical Formula]

[0237] 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 minutes. 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 saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (1 - 50% ethyl acetate in n-heptane). The desired fractions were combined and concentrated to give the title compound (350.9 mg, 54%) as an off-white powder. ES-MS m / z 418 (M + H).

[0238] Preparation 14 3-Amino-5-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)isonicotinamide; Hydrochloride

[0239] [Chemical Formula]

[0240] tert-Butyl (5-fluoro-4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)pyridin-3-yl)carbamate (351 mg, 1 mmol) in DCM (3.0 mL) / MeOH (1.0 mL) and a solution of 2 M HCl in Et2O (8.20 mL, 16.4 mmol) were stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and triturated with Et2O to afford the title compound (294.7 mg, 91%) as a yellow solid. ES-MS m / z 318 (M+H).

[0241] Preparation 15 (1S,2R)-2-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopentane-1-carboxamide hydrochloride

[0242] [Chemical formula]

[0243] 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), TCFH (2.45 g, 8.724 mmol) and NMI (0.90 g, 10.905 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 h. 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 (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 1:3 EtOAc in petroleum ether. HCl (4 M in EtOAc, 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 afford the title compound. ES-MS m / z 291 (M+H)

[0244] Preparation 16 Methyl 2-(2-chloro-6-methoxybenzo[d]thiazole-7-carboxamido)-4-fluorobenzoate

[0245]

Chem.

[0246] To a solution of 2-chloro-6-methoxybenzo[d]thiazole-7-carboxylic acid (1.15 g, 4.72 mmol) in DCM (20 mL) was added oxalyl chloride (1.50 g, 5.90 mL, 11.8 mmol), followed by DMF (0.25 mL). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL). To this solution were added methyl 2-amino-4-fluorobenzoate (958 mg, 6 mmol) and DiPEA (2.44 g, 3.25 mL, 18.9 mmol). After stirring for 2 h, the reaction mixture was diluted with DCM (200 mL) and washed with H2O (3 × 100 mL) and saturated aqueous NaCl (100 mL). The organic layer 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 an off-white solid. ES-MS m / z 395 (M+H).

[0247] The compounds in the following table were prepared basically as described in Preparation 16 using appropriate amines and carboxylic acids.

[0248]

Table 2

[0249] The compounds in the following table were prepared basically as described in Preparation 1 using appropriate amines and 2-chlorobenzothiazole derivatives.

[0250]

Table 3

[0251] Modulation 23 2-(2-(3-Oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzo[d]thiazole-7-carboxamide)-4-fluorobenzoic acid

[0252]

Chemical formula

[0253] To a solution of methyl 2-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzo[d]thiazole-7-carboxamide)-4-fluorobenzoate (0.60 g, 1.3 mmol) in THF (20 mL) and H2O (2 mL) was added TBD (0.55 g, 3.9 mmol). The reaction mixture was stirred at 40 °C for 30 minutes. Neutralization of the reaction mixture with aqueous citric acid formed a precipitate. 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).

[0254] The compounds in the following table were prepared essentially as described for Modulation 23 using the appropriate ester.

[0255]

Table 4

[0256] The compounds in the following table were prepared essentially as described for Modulation 6 using the appropriate amine and carboxylic acid.

[0257]

Table 5

[0258] The compounds in the following table were prepared essentially as described for Modulation 10 using the appropriate ester.

[0259]

Table 6

[0260] Formulation 28 2-(2-(3-Oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzo[d]thiazole-7-carboxamide)-4-chlorobenzoic acid

[0261]

Chem.

[0262] To a solution of 2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzo[d]thiazole-7-carboxylic acid (0.25 g, 0.82 mmol) in NMP (5 mL) were added 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). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with H2O (3 × 50 mL), and then washed with saturated aqueous NaCl (50 mL). The organic layer 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 h and then neutralized with citric acid solution. After aqueous workup, the title compound (181 mg, 48%) was obtained as an off-white solid. ES-MS m / z 460 (M+H).

[0263] The compounds in the following table were prepared basically as described for Formulation 28 using the appropriate amine.

[0264]

Table 7-1

[0265]

Table 7-2

[0266]

Table 7-3

[0267]

Table 7-4

[0268] The compounds in the following table were prepared basically as described in Preparation 4 using (1S,2R)-2-(2-chloro-6-methoxybenzo[d]thiazole-7-carboxamide)cyclobutane-1-carboxylic acid and 2,2-difluorobenzo[d][1,3]dioxol-5-amine.

[0269]

Table 8

[0270] Example 1 2-(9,9-difluoro-3,3-dioxide-3-thia-7-azabicyclo[3.3.1]nonan-7-yl)-N-((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-6-methoxybenzo[d]thiazole-7-carboxamide

[0271]

Chemical formula

[0272] 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]heptan-2-yl)-6-methoxybenzo[d]thiazole-7-carboxamide (65 mg, 0.12 mmol), and K2CO3 (50 mg, 0.36 mmol) was stirred at 80 °C for 18 h in NMP (1 mL). 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 reverse-phase column chromatography (C18, gradient of 0 - 100% (5% MeOH / ACN) in 10 mM aqueous NH4HCO3, pH 10) to give the title compound (5 mg, 7 μmol, 6%). ES-MS m / z 717 (M+H).

[0273] The following was prepared basically as described in Example 1 using the appropriate amine:

[0274] [Table 9-1]

[0275] [Table 9-2]

[0276] [Table 9-3]

[0277] [Table 9-4]

[0278] [Table 9-5]

[0279]

Table 9-6

[0280]

Table 9-7

[0281]

Table 9-8

[0282] Example 24 7-(7-(((1S,2R,3S,4R)-3-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-methoxybenzo[d]thiazol-2-yl)-7-azaspiro[3.5]nonane-2-carboxylic acid

[0283]

Chemical formula

[0284] A solution of lithium hydroxide (11 mg, 0.46 mmol) in H2O (0.3 mL) was added to a stirred solution of methyl 7-(7-(((1S,2R,3S,4R)-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-methoxybenzo[d]thiazol-2-yl)-7-azaspiro[3.5]nonane-2-carboxylate (64 mg, 93 μmol) in THF (0.7 mL). After 30 minutes, the reaction mixture was purified directly by reverse-phase column chromatography (C18, gradient of 0 - 100% (5% MeOH / ACN) in 10 mM aqueous NH4HCO3, pH 10) to afford the title compound (33.3 mg, 49.4 μmol, 53%). ES-MS m / z 675 (M+H).

[0285] The following was prepared basically as described in Example 24 using the appropriate ester:

[0286] [Table 10]

[0287] Example 26 2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)-N-(4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)pyridin-3-yl)-6-methoxybenzo[d]thiazole-7-carboxamide

[0288] [Chemical formula]

[0289] A solution of 4-fluoro-3-(trifluoromethyl)benzenamine (24 mg, 0.13 mmol, 17 μL), 3-(2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)-6-methoxybenzo[d]thiazole-7-carboxamide)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 h. The reaction mixture was then purified three times by silica gel chromatography (0 - 20% MeOH in DCM) to afford the title compound (6.6 mg, 0.13 mmol, 8%). ES-MS m / z 616 (M+H).

[0290] Example 27 2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)-N-(5-fluoro-4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)pyridin-3-yl)-6-methoxybenzo[d]thiazole-7-carboxamide

[0291]

Chem.

[0292] A solution of 2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)-6-methoxybenzo[d]thiazole-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 minutes. 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 the mixture was stirred at 100 °C for 45 minutes. 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 aqueous NaCl, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0 - 10% MeOH in EtOAc). The desired fractions were combined and concentrated. The residue was dissolved in 1 mL of DCM, the formed 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).

[0293] The compounds in the following table were prepared basically as described in Example 27 using the appropriate amines and carboxylic acids.

[0294]

Table 11

[0295] Example 29 2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-N-(5-fluoro-2-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)carbamoyl)phenyl)-6-methoxybenzo[d]thiazole-7-carboxamide

[0296]

Chem.

[0297] To 2-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzo[d]thiazole-7-carboxamide)-4-fluorobenzoic acid (0.20 g, 0.45 mmol) were added 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). The reaction mixture was stirred at 50 °C overnight. The reaction mixture was diluted with EtOAc (100 mL), washed with H2O (3 × 50 mL), and then with saturated aqueous NaCl (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography using a high pH mobile phase to afford the title compound (143 mg, 55%) as an off-white solid. ES-MS m / z 577 (M+H).

[0298] The compounds in the following table were prepared essentially as described in Example 29 using the appropriate amines and carboxylic acids.

[0299]

Table 12-1

[0300]

Table 12-2

[0301]

Table 12-3

[0302]

Table 12-4

[0303]

Table 12-5

[0304]

Table 12-6

[0305]

Table 12-7

[0306]

Table 12-8

[0307]

Table 12-9

[0308]

Table 12-10

[0309]

Table 12-11

[0310] Example 63 N-((1S,2R,3S,4R)-3-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-2-((1R,3S,5S)-3-hydroxy-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzo[d]thiazole-7-carboxamide

[0311]

Chemical formula

[0312] A solution of (1R,3S,5S)-6-azabicyclo[3.1.1]heptan-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]heptan-2-yl)-6-methoxybenzo[d]thiazole-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. After 18 h, the reaction mixture was purified directly by reverse-phase column chromatography using a gradient of 0–100% (ACN + 5% MeOH) in 10 mM aqueous NH4HCO3 to give the title compound (38 mg, 51%). ES-MS m / z 619 (M+H).

[0313] The compounds in the following table were prepared essentially as described in Example 63 using the appropriate amine.

[0314]

Table 13

[0315] Example 68 2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-N-(2-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)-5-(difluoromethoxy)phenyl)-6-methoxybenzo[d]thiazole-7-carboxamide

[0316] A solution of 2-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzo[d]thiazole-7-carboxamide)-4-(difluoromethoxy)benzoic acid (50 mg, 0.10 mmol) and 3-aminobicyclo[1.1.1]pentane-1-carbonitrile (22 mg, 0.20 mmol) in NMP (1 mL) was added with PPACA (50% in EtOAc) (0.19 g, 0.31 mmol, 0.18 mL), followed by addition of 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 3 times with H2O. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase chromatography to obtain the title product (14.4 mg, 24.8 μmol, 24%). ES-MS m / z 580 (M-H)

[0317] The compounds in the following table were prepared basically as described in Example 68 using the appropriate amines and carboxylic acids.

[0318]

Table 14-1

[0319]

Table 14-2

[0320]

Table 14-3

[0321]

Table 14-4

[0322]

Table 14-5

[0323]

Table 14-6

[0324]

Table 14-7

[0325] Example 90 2-(3-Oxa-6-azabicyclo[3.1.1]heptan-6-yl)-N-(4-((4-cyanophenyl)carbamoyl)-6-methoxypyridin-3-yl)-6-methoxybenzo[d]thiazole-7-carboxamide

[0326]

Chemical formula

[0327] To a solution of 5-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzo[d]thiazole-7-carboxamide)-2-methoxyisonicotinic acid (100 mg, 219 μmol) in NMP (5 mL) were added 4-aminobenzonitrile (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). The reaction mixture was stirred at 85 °C for 2 days. The residue was purified by high pH flash 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 pale yellowish brown solid. ES-MS m / z 557 (M+H).

[0328] The compounds in the following table were prepared basically as described in Example 90 using the appropriate amines and carboxylic acids.

[0329]

Table 15-1

[0330]

Table 15-2

[0331]

Table 15-3

[0332]

Table 15-4

[0333]

Table 15-5

[0334]

Table 15-6

[0335]

Table 15-7

[0336]

Table 15-8

[0337]

Table 15-9

[0338] Example 118 2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-isopropoxy-N-(6-methoxy-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)pyridin-3-yl)benzo[d]thiazole-7-carboxamide

[0339]

Chemical formula

[0340] A solution of 2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-isopropoxybenzo[d]thiazole-7-carboxylic acid (0.060 g, 0.18 mmol) in ACN (1 mL) was added with 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). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The combined organic layers were dried over MgSO4, filtered, and concentrated. When the residue was taken up in ACN, a solid precipitated. The solid was collected and washed with ACN. The residue was dried under reduced pressure over the weekend to give the title product (0.072 g, 0.10 mmol, 58%) as a white solid. LC / MS m / z: 692 (M+H).

[0341] The following examples were prepared as described in Example 118 using the appropriate amines and carboxylic acids.

[0342]

Table 16-1

[0343]

Table 16-2

[0344]

Table 16-3

[0345] Example 126 2-(3-Oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxy-N-(2-methoxy-5-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-4-yl)benzo[d]thiazole-7-carboxamide

[0346]

Chem.

[0347] 4-(2-(3-Oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzo[d]thiazole-7-carboxamide)-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 was stirred at 20 °C for 30 minutes. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse phase HPLC using a gradient of 56 - 81% ACN in 0.1% aqueous formic acid. ES-MS m / z 590 (M+H).

[0348] Example 127 2-(3-Oxa-6-azabicyclo[3.1.1]heptan-6-yl)-N-(5-((4-fluoro-3(trifluoromethyl)phenyl)carbamoyl)-2-methoxypyridin-4-yl)-6-methoxybenzo[d]thiazole-7-carboxamide

[0349]

Chem.

[0350] A mixture of 4-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzo[d]thiazole-7-carboxamide)-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 was stirred at 60 °C for 30 minutes. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC using a gradient of 53 - 78% ACN in 10 mM aqueous NH4HCO3 + 5% MeOH. ES-MS m / z 618(M+H).

[0351] Example 128 2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxy-N-(5-methoxy-2-((1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)carbamoyl)phenyl)benzo[d]thiazole-7-carboxamide

[0352] [Chemical formula]

[0353] A mixture of 2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzo[d]thiazole-7-carboxylic acid (184 mg, 601 μmol) and 2-amino-4-methoxy-N-(1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hexan-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 was stirred at 60 °C for 16 h. The reaction mixture was purified by reverse phase HPLC using a gradient of 50 - 75% ACN in 0.1% aqueous formic acid. ES-MS m / z 605 (M+H).

[0354] Example 129 2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxy-N-(5-methoxy-2-((3-methoxybicyclo[1.1.1]pentan-1-yl)carbamoyl)phenyl)benzo[d]thiazole-7-carboxamide

[0355] [Chemical formula]

[0356] A mixture of 2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzo[d]thiazole-7-carboxylic acid (142 mg, 465 μmol) and 2-amino-4-methoxy-N-(3-methoxybicyclo[1.1.1]pentan-1-yl)benzamide (122 mg, 465 μmol) was 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 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 reverse phase HPLC using a gradient of 39 - 64% ACN in 10 mM aqueous NH4HCO3 + 5% MeOH. ES-MS m / z 551 (M+H).

[0357] Example 130 2-(3-Oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxy-N-(4-((3-methoxybicyclo[1.1.1]pentan-1-yl)carbamoyl)-6-(methylthio)pyridin-3-yl)benzothiazole-7-carboxamide

[0358]

Chemical formula

[0359] A mixture of 5-amino-N-(3-methoxybicyclo[1.1.1]pentan-1-yl)-2-(methylthio)isonicotinamide (20 mg, 72 μmol), 2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6-methoxybenzothiazole-7-carboxylic acid (26 mg, 86 μmol), EtOAc (0.72 mL), DiPEA (28 mg, 37 μL, 0.21 mmol), 4-(pyrrolidin-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, then additional PPACA (50 wt%, 23 mg, 21 μL, 0.037 mmol) was added. The reaction was heated at 50 °C overnight and then cooled to room temperature and diluted with EtOAc and 1:1 saturated aqueous K2CO3:water. The mixture was filtered, the layers were separated, and the organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using a gradient of 20 - 100% ACN in 10 mM aqueous NH4HCO3 + 5% MeOH to afford the title compound (15 mg, 37%). ES-MS m / z 568 (M+H).

[0360] Biological assay: The following assay demonstrates that the exemplified compounds are RXFP1 receptor agonists.

[0361] Human RXFP1 Cell cAMP HTRF Assay: Relaxin family peptide receptor 1 (RXFP1)-expressing cells were generated by transfecting HEK293 cells with a tetracycline-inducible RXFP1 expression cassette (accession number NM_021634.4), and single cell clones responsive to human relaxin 2 (catalog number H-6784.0200, Bachem, Torrance, CA) were selected. RXFP1-expressing cells were treated with 1 μg / mL doxycycline 24 hours prior to compound administration to induce RXFP1 expression. At the time of cell seeding, compounds were acoustically transferred into 384-well plates (ProxiPlate, 384 well, catalog number 6008289, Revvity, Waltham, MA) using an ECHO ultrasonic liquid handler (Beckman, Brea, CA). Cells were dosed with a 10-point dose response curve (3-fold dilutions) starting at 10 μM for 1 hour at 37°C. The final DMSO concentration was 0.6% in a 10 μL assay volume.

[0362] The assay buffer used for the treatment was 1X stimulation buffer (provided by Gs cAMP HighRange kit, catalog number 62AM6PEJ, Revvity) diluted with distilled water and containing 500 μM 3-isobutyl-1-methylxanthine final (catalog number I5879250MG, Sigma-Aldrich, St. Louis, MO). After 1 hour of incubation, cAMP levels were evaluated using the CisBio Gs cAMP HighRange Kit (catalog number 62AM6PEJ) according to the manufacturer's (Revvity) instructions. Briefly, 5 μL of D2-labeled cAMP and 5 μL of Eu 3+ -cryptate-labeled anti-cAMP antibody were added to each well. After incubating the cell lysis solution for 1 hour at room temperature, detection was performed using a PHERAstar FSX microplate reader (BMG, Ortenberg, Germany). The HTRF ratio (luminescence at 665 nm / luminescence at 620 nm × 10,000) was converted to cAMP units using a cAMP standard curve. Relative EC 50It was calculated for the upper and lower limits of the individual concentration-response curves and determined via non-linear regression using a four-parameter logistic fit with Genedata version 18.0.8 (Genedata, Basel, Switzerland).

[0363] In the above assay, the compounds of Examples 1 to 130 showed agonist activity at the RXFP1 receptor with an <50 nM relative EC 50 This data indicates that the compounds of Formula I described herein are RXFP1 agonists in these human HEK293 cells.

Claims

1. A compound of the formula: 【Chemistry 1】 During the ceremony, Ring A is of the formula 【Chemistry 2】 Based on 【Chemistry 3】 Each of the groups is selected from the group consisting of halogen, —CN, C １～４ Alkyl, -S-C １～３ Alkyl, and C １～３ alkoxy; each C １～４ Alkyl and C １～３ the alkoxy is optionally substituted with one or more substituents independently selected from halogen and -CN; -Y- is C １～３ is alkylene, -G ６ - is -C(R １ )- or -N-; R １ But, C １～３ is an alkoxy; R ２ But, -OCH ２ COOH or an N-linked 4- to 7-membered heterocycle, said N-linked 4- to 7-membered heterocycle being selected from azetidine, pyrrolidine, morpholine, piperazine, piperidine, and oxazepane, said heterocycle being １～４ Optionally bridged, optionally fused, or optionally spiro-linked by an alkylenyl, or a 1- to 5-membered heteroalkyl; １～４ The alkylenyl and the 1- to 5-membered heteroalkyl are each independently selected from halogen, oxo, C １～４ Alkyl, C １～４ optionally substituted with 1 to 3 substituents selected from haloalkyl, -OH, and -COOH; R ３ but, 【Chemistry 4】 is selected from the group consisting of 【Chemistry 5】 is optionally substituted with 1 to 3 halogens; -G ４ - is -CH- or -N-, -G ５ -, -CH ２ - or -O-, R ３ａ is, in each occurrence, independently, -H, halogen, -SF ５ , -SO ２ CF ３ , -SCF ３ , -C.N., C. １～４ Alkyl, C ３～６ Cycloalkyl, or C １～３ Alkoxy, １～４ Alkyl and C １～３ the alkoxy is optionally substituted with 1, 2, or 3 halogens; R ３ｂ are independently -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN, or C １～４ is alkyl, R ３ｃ is independently at each occurrence -H or halogen; R ３ｄ -H, halogen, -CN, C １～４ Alkyl, C ３～６ Cycloalkyl, or C １～３ Alkoxy, １～４ Alkyl and C １～３ A compound, or a pharma- ceutically acceptable salt thereof, wherein alkoxy is optionally substituted with one, two, or three halogens.

2. Ring A is of the formula 【Chemistry 6】 Based on 【Chemistry 7】 Each of the groups is selected from the group consisting of 1 or 2 halogens, C １～４ Alkyl, or C １～３ Optionally substituted with alkoxy, each C １～４ Alkyl or C １～３ the alkoxy is optionally substituted independently with one or more of halogen or -CN; R ２ But, the formula 【Chemistry 8】 Based on 【Chemistry 9】 is optionally substituted with 1 or 2 halogens; 【Chemistry 10】 is optionally substituted with 1 or 2 oxo; R ３ but, 【Chemistry 11】 is selected from the group consisting of R ３ａ is, in each occurrence, independently, -H, halogen, -SF ５ , -SO ２ CF ３ , -SCF ３ , C １～４ Alkyl, or C １～３ Alkoxy, １～４ Alkyl or C １～３ the alkoxy is optionally substituted with 1 or 2 halogens; R ３ｄ -H, halogen, -CN, C １～４ Alkyl, or C １～３ Alkoxy, １～４ Alkyl or C １～３ the alkoxy is optionally substituted with 1 or 2 halogens; -G ６ - is -C(R １ 2. The compound of claim 1, wherein R 1 is -R 2 , or a pharma- ceutically acceptable salt thereof.

3. Ring A is of the formula 【Chemistry 12】 Based on 【Chemistry 13】 Each of the groups is selected from the group consisting of 1 or 2 halogens, C １～４ Alkyl, or C １～３ Optionally substituted with alkoxy, each C １～４ Alkyl or C １～３ the alkoxy is optionally substituted independently with one or more of halogen or -CN; R ２ But, the formula 【Chemistry 14】 Based on 【Chemistry 15】 is optionally substituted with 1 or 2 halogens; 【Chemistry 16】 is optionally substituted with 1 or 2 oxo; R ３ but, 【Chemistry 17】 is selected from the group consisting of R ３ａ is, in each occurrence, independently, -H, halogen, -SF ５ , -SO ２ CF ３ , -SCF ３ , C １～４ Alkyl, or C １～３ Alkoxy, １～４ Alkyl and C １～３ the alkoxy is optionally substituted with 1 or 2 halogens; R ３ｄ -H, halogen, -CN, C １～４ Alkyl, or C １～３ Alkoxy, １～４ Alkyl or C １～３ the alkoxy is optionally substituted with 1 or 2 halogens; -G ６ - is -C(R １ 2. The compound of claim 1, wherein R 1 is -R 2 , or a pharma- ceutically acceptable salt thereof.

4. Ring A is of the formula 【Chemistry 18】 Based on R ２ But, -OCH ２ COOH or an N-linked 4- to 7-membered heterocycle, said N-linked 4- to 7-membered heterocycle being selected from azetidine, pyrrolidine, morpholine, piperazine, piperidine, or oxazepane, said heterocycle being １～４ Optionally bridged, optionally fused, or optionally spiro-linked by an alkylenyl, or a 1- to 5-membered heteroalkyl; １～４ Alkylene and 1- to 5-membered heteroalkyl are each independently selected from halogen, C １～４ Alkyl, C １～４ optionally substituted with 1 to 3 substituents selected from haloalkyl, and —COOH; R ３ But the formula: 【Chemistry 19】 Based on R ３ａ is -H, halogen, -SF ５ , -SO ２ CF ３ , -SCF ３ , C １～４ Alkyl, or C １～３ Alkoxy, １～４ Alkyl or C １～３ the alkoxy is optionally substituted with one or more halogens; Each R ３ｃ is independently -H or -F; R ３ｄ is -H, halogen, C １～４ Alkyl, or C １～３ Alkoxy, １～４ Alkyl or C １～３ the alkoxy is optionally substituted with one or more halogens; -G ６ - is -C(R １ 2. The compound of claim 1, wherein R 1 is -R 2 , or a pharma- ceutically acceptable salt thereof.

5. Ring A is of the formula 【Chemistry 20】 Based on 【Chemistry 21】 is 1 or 2 halogens, C １～４ Alkyl, or C １～３ Optionally substituted with alkoxy, each C １～４ Alkyl or C １～３ the alkoxy is optionally substituted with one or more independently selected from halogen and -CN; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

6. Ring A is of the formula 【Chemical 22】 Based on 【Chemistry 23】 is 1 or 2 halogens, C １～４ Alkyl, or C １～３ Optionally substituted with alkoxy, each C １～４ Alkyl or C １～３ alkoxy is optionally substituted with one or more substituents independently selected from halogen and -CN; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

7. Ring A is of the formula 【Chemistry 24】 Based on 【Chemistry 25】 Each of the groups is selected from the group consisting of halogen, —CN, C １～４ Alkyl, -S-C １～３ Alkyl, and C １～３ alkoxy; each C １～４ Alkyl and C １～３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein said alkoxy is optionally substituted with one or more substituents independently selected from halogen and -CN.

8. Ring A is of the formula 【Chemistry 26】 Based on 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

9. -G ６ - is -C(R １ 9. The compound according to claim 1, wherein R is -R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R

10. R １ 10. The compound of claim 9, or a pharma- ceutically acceptable salt thereof, wherein is methoxy, ethoxy, or isopropoxy.

11. R １ The compound of claim 10, or a pharma- ceutically acceptable salt thereof, wherein is methoxy.

12. R ３ but, 【Chemistry 27】 Selected from the group consisting of:

2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

13. R ３ｄ is trifluoromethyl; or a pharma- ceutically acceptable salt thereof.

14. formula 【Chemistry 28】 A compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof.

15. R ２ but, 【Chemical Formula 29】 Selected from the group consisting of:

15. The compound according to any one of claims 1, 3, and 5 to 14, or a pharma- ceutically acceptable salt thereof.

16. R ２ But, the formula 【Chemistry 30】 16. The compound of claim 15, which is a group: or a pharma- ceutically acceptable salt thereof.

17. R ２ But, the formula 【Chemistry 31】 Based on 17. The compound of claim 16, or a pharma- ceutically acceptable salt thereof.

18. R ２ but, 【Chemistry 32】 A compound according to any one of claims 1 to 13, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

19. R ２ but, 【Chemical 33】 The compound according to any one of claims 1 to 3, 5 to 13, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

20. R ２ but, 【Chemical 34】 The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof.

21. 【Chemical 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 2. The compound of claim 1, selected from the group consisting of:

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

23. 23. A method of treating a cardiovascular, pulmonary and / or renal condition, disease and / or disorder in an individual, comprising administering to said 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. A compound according to any one of claims 1 to 21 for use in therapy.

25. A compound according to any one of claims 1 to 21 for use in the treatment of cardiovascular, pulmonary and / or renal conditions, diseases and / or disorders.

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

27. 27. The method of claim 23, the compound for use according to claim 25, or the use according to claim 26, wherein the disease or disorder to be treated is a cardiovascular condition, disease or disorder selected from acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vascular stenosis, or ventricular hypertrophy.

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

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

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