Small molecule prostaglandin f receptor antagonists

Abstract

Disclosed herein are small molecule prostaglandin F (FP) receptor antagonists, methods of making them, and therapeutic methods using them.

Description

SMALL MOLECULE PROSTAGLANDIN F RECEPTOR ANTAGONISTS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 529,092, filed on July 26, 2023, and U.S. Provisional Patent Application No. 63 / 607,942, filed on December 8, 2023, the entire contents of each of which is incorporated by reference herein. FIELD

[0002] The present disclosure is in the field of pharmaceutical compounds and compositions and therapeutic methods of their use. In particular, the present disclosure is in the field of prostaglandin F (FP) receptor antagonists and their use. BACKGROUND

[0003] Prostaglandins are bioactive metabolites of arachidonic acid, which are principally involved in mediation of inflammation. Arachidonic acid is released from lipids in the cell membrane through the actions of phospholipases; the arachidonic acid is then metabolized by cyclooxygenase and various isomerases and prostaglandin synthases to form the different prostaglandins. The most predominant and biologically relevant prostaglandins are PGE2, PGI2, PGD2, PGF2αand TXA2.

[0004] Prostaglandin receptors are members of the seven transmembrane superfamily of G- protein coupled receptors (GPCR). The prostanoid receptor subfamily is comprised of at least eight members: EP1, EP2, EP3, and EP4 subtypes of the PGE receptor; DP1; FP; IP; and TP. The receptors are generally named for the prostaglandin that has the highest potency at the receptor; however, the receptors may effectively bind more than one prostaglandin. The FP receptor may be considered the least selective of the prostanoid receptors in binding the principal endogenous prostaglandins; in addition to PGF2α, both PGD2 and PGE2 activate the FP with EC50 values in the nanomolar range.

[0005] PGF2αand the FP receptor are associated with various diseases, conditions, and inflammatory disorders. During reproduction, PGF2α, derived mainly from COX-1 in the female reproductive system, plays an important role in ovulation, luteolysis, contraction of uterine smooth muscle and initiation of parturition. PGF2α has also been shown to play a significant role in renal function, contraction of arteries, myocardial dysfunction, brain injury and pain. The tachycardia induced in wild-type mice by injection of LPS is greatly attenuated in FP-deficient mice (or TP- deficient mice and is completely absent in mice lacking both of these receptors less relevant). Deletion of FP has been reported to selectively attenuate pulmonary fibrosis without a change in lung inflammation. Another study of FP-deficient female mice reported normal ovulation and implantation but failure of spontaneous parturition during pregnancy. Elevated biosynthesis of PGF2α has been reported in patients suffering from rheumatoid arthritis, psoriatic arthritis, reactive arthritis, and osteoarthritis. Targeting FP may be an effective therapeutic strategy for many conditions; to date, no specific FP modulators have been approved for therapeutic use.

[0006] In WO 2016 / 037954 A1, substituted N,2-diarylquinoline-4-carboxamide derivatives are described, as are methods for producing the same, and use of the same either alone or in combination in the treatment and / or prevention of diseases, especially for the treatment and / or prevention of fibrotic and inflammatory diseases.

[0007] In WO 2017 / 153234 A1, substituted N-Cyclo-2-aryl-quinoline-4-carboxamide derivatives are described, as are methods for the production thereof, and use thereof either alone or in combination for treating and / or preventing diseases, particularly for the treatment and / or prevention of fibrotic and inflammatory diseases.

[0008] In WO 2016 / 146602 A1, substituted N-bicyclo-2-aryl-quinoline-4-carboxamide derivatives are described, as are methods for the production thereof, and the use thereof either alone or in combination for treating and / or preventing diseases, especially for the treatment and / or prevention of fibrotic and inflammatory diseases.

[0009] There remains a need for small molecule prostaglandin F (FP) receptor modulators that selectively antagonize the FP receptor.SUMMARY

[0010] In one aspect, provided herein is a compound of Formula I:or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: A1is CR, wherein R is hydrogen, halogen, C1-3alkyl, or cyclopropyl; R1is halogen, C1-6alkyl, or C1-6haloalkyl; R2is phenyl; C3-6 cycloalkyl; 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenoxy; or C1-6alkoxy; wherein the phenyl, C3-6 cycloalkyl, and 3- to 8-membered heterocycloalkyl are optionally substituted with one to four R2Aindependently selected from halogen, C1-6alkyl, C1-6alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3- to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen;R3A is C1-6alkyl, C3-6cycloalkyl, or R3B; W is a bond, -NH-, or -O-; andR3B is (a) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or (b) 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or -W-R3B is -NR3CR3D, -NHC(O)-O(C1-6alkyl), -NHC(O)R3D, or -C(O)NR3CR3D; wherein R3C is H or C1-3alkyl, and R3Dis C1-6haloalkyl or C3-4cycloalkyl; or wherein R3Cand R3D, together with the nitrogen atom to which they are attached, form a 3- to 6-membered ring; R4Ais H; R4Bis H, C1-3alkyl, or -OH; and R4B’is H or C1-3alkyl; or R4Aand R4Btogether with the carbon atoms to which they are attached form an oxirane; R5is C1-6alkyl optionally substituted with C3-4cycloalkyl; C1-6haloalkyl; C4-5cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4 cycloalkyl ring; 4- to 5-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 4- to 5-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from -C(O)(benzyl), - C(O)(C1-6alkyl), and -SO2(C1-6alkyl); or phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6 haloalkoxy; and R6 is H or C1-6alkyl; wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).

[0011] In some embodiments, R is hydrogen or C1-3alkyl. In some embodiments, R is C1-3alkyl. In some embodiments, R is methyl.

[0012] In some embodiments, the compound is of Formula Ia:(Formula la) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, R3Ais R3B. In some embodiments, R3Ais phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, R3Ais phenyl optionally substituted with one to four substituents independently selected from halogen and C1-6 alkoxy. In some embodiments, R3AisIn some embodiments, R3Ais5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10- membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, R3Ais a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -OH, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, R3Ais pyrazolyl optionally substituted with one or two substituents independently selected from C1-6 alkyl. In some embodiments, R3Ais pyridinyl, pyrazinyl, pyridazinyl, or 2-pyridonyl, wherein the pyridinyl, pyrazinyl, pyridazinyl, or 2-pyridonyl, is optionally substituted with one or two substituents independently selected from halogen, -OH, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, R3AisIn some embodiments, R3Ais C1-6 alkyl. In some embodiments, R3AIn some embodiments, R3Ais C3-6 cycloalkyl. In some embodiments, R3Ais

[0013] In some embodiments, the compound is of Formula lb:(Formula lb)or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, R3Bis phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, R3Bis phenyl optionally substituted with one or two substituents independentlyAtty. Dkt. No.: 052209-0603 selected from halogen and C1-6haloalkoxy. In some embodiments, R3B isor. In some embodiments, R3B is a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, W is a bond. In some embodiments, W is -O-. In some embodiments, W is -NH-.

[0014] In some embodiments, the compound is of Formula Ic:(Formula Ic) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, R4Ais H and R4Bis H. In some embodiments, R4Ais H and R4Bis –OH. In some embodiments, R4A and R4B together with the carbon atoms to which they are attached form an oxirane. In some embodiments, R3B is phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, R3B is5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10- membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, the 5- to 10-membered heteroaryl is pyrazolyl, indazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy,C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, R3BisAtty. Dkt. No.: 052209-0603In some embodiments, W is a bond. In some embodiments, W is -O-. In some embodiments, W is -NH-. In some embodiments, -W-R3Bis -NR3CR3D, -NHC(O)-O(C1-6 alkyl), -NHC(O)R3D, or - C(O)NR3CR3D; wherein R3C is H or C alkyl, and 3D 1-3 R is C1-6 haloalkyl or C3-4 cycloalkyl; or wherein R3C and R3D, together with the nitrogen atom to which they are attached, form a 3- to 6- membered ring. In some embodiments, -W-R3Bis

[0015] In some embodiments, the compound is of Formula Id:or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, R3B is phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy. In some embodiments, R3B is-9-embodiments, R3Bis 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, R3Bis a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkoxy. In some embodiments, the 5- to 10-membered heteroaryl is pyrazolyl or pyridinyl, wherein the 5- to 10- membered heteroaryl is optionally substituted with one to three substituents independently selected from C1-6 alkyl and C1-6 haloalkoxy. In some embodiments,Atty. Dkt. No.: 052209-0603In some embodiments, W is a bond. In some embodiments, W is -O-. In some embodiments, R4Bis H. In some embodiments, R4Bis methyl.

[0016] In some embodiments, the compound is of Formula Ie:or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, R4B and R4B’ are both H. In some embodiments, R4B is methyl, and R4B’ is H. In some embodiments, R5 is C1-6 haloalkyl or C1-6 alkyl optionally substituted with C3-4 cycloalkyl. In some embodiments,In some embodiments, R5is C4-5 cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4 cycloalkyl ring.Atty. Dkt. No.: 052209-0603 In some embodiments, R5 isI5n some embodiments, R is 4- to 5-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 4- to 5-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from -C(O)(benzyl), -C(O)(C1-6 alkyl), and - SO (C alkyl). I 5 2 1-6 n some embodiments, R is, ,In some embodiments, R5 is phenyl optionally substituted with one or two substituents independently selected from halogen and C haloalkoxy 5 1-6 . In some embodiments, R is5In some embodiments, R is,In someembodiments, R1is halogen. In some embodiments, R1is Br. In some embodiments, R1is C1-6alkyl, o C1-6 haloalkyl. In some embodiments, R1 is ethyl or -CHF2. In some e 2 r mbodiments, R is phenyl, wherein R2is optionally substituted with one to four R2Aindependently selected from -12-halogen, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, R2isIn some embodiments, R2is phenyl. In some embodiments, R2is C3-6 cycloalkyl or 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R2is optionally substituted with one to four R2Aindependently selected from halogen, C1-6 alkyl, C1-6 alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3 - to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen.embodiments, R2is phenoxy or C1-6 alkoxy. In some embodiments, R2isIn some embodiments, R6is H. In some embodiments, R6is C1-6 alkyl.

[0017] In some embodiments, the compound is selected from Table A, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0018] In another aspect, provided herein are salts, hydrates, solvates, analogs, conjugates, isomers, polymorphs, esters, prodrugs, metabolites, complexes, co-crystals, intermediates, modifications and derivatives of the compounds, stereoisomers, and tautomers described herein.

[0019] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein and at least one pharmaceutically acceptable excipient.Atty. Dkt. No.: 052209-0603

[0020] In another aspect, provided herein is a method of modulating prostaglandin F (FP) receptor activity in a subject in need thereof, comprising administering to the subject a compound described herein.

[0021] In another aspect, provided herein is a method of treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof, comprising administering to the subject a compound described herein. In another aspect, provided herein is a method of preventing or reducing risks of pre-term labor in a subject in need thereof, comprising administering to the subject a compound described herein. In another aspect, provided herein is a method of preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof, comprising administering to the subject a compound described herein.

[0022] In another aspect, provided herein is a method of preventing or reducing risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof, comprising administering to the subject a compound described herein. In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound described herein optionally, wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic- obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma,Atty. Dkt. No.: 052209-0603 medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidimytitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders,Atty. Dkt. No.: 052209-0603 osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF). In some embodiments, the method further comprises administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is selected from the group consisting of atosiban, retosiban, barusiban, epelsiban, nolasiban, terbutaline, ritodrine, hexoprenaline, albuterol, fenoterol, nylidrin, orciprenaline, dihydropyridine, nifedipine, nicardipine, magnesium sulfate, progesterone, 17-α- hydroxyprogesterone, and nitroglycerine.

[0023] In another aspect, provided herein is a compound for use in modulating prostaglandin F (FP) receptor activity in a subject in need thereof, for use in treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof, for use in preventing pre-term labor in a subject in need thereof, for use in preventing labor prior to cesarean delivery in a subject in need thereof, for use in preventing one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof, or for use in treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non- classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibroticAtty. Dkt. No.: 052209-0603 skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism,Atty. Dkt. No.: 052209-0603 hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidimytitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

[0024] In another aspect, provided herein is a use of a compound described herein in the preparation of a medicament for modulating prostaglandin F (FP) receptor activity in a subject in need thereof, for treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof, for preventing pre-term labor in a subject in need thereof, for preventing labor prior to cesarean delivery in a subject in need thereof, for preventing one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof, or for treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis,Atty. Dkt. No.: 052209-0603 bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidimytitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias,Atty. Dkt. No.: 052209-0603 liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF). DETAILED DESCRIPTION DEFINITIONS

[0025] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which the present disclosure pertains, unless otherwise defined.

[0026] As used herein, the singular forms "a," "an," and "the" and the like designate both the singular and the plural, unless expressly stated to designate the singular only.

[0027] As used herein, the term "about" means that the stated parameter is not limited to the exact number stated. As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term. As used herein, ranges are to be construed as shorthand for each and every value falling within the range, and each separate value should be understood to be expressly disclosed herein.

[0028] The phrase “consisting essentially of” will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. When “consisting essentially of” is used to refer to compositions with only one active agent disclosed herein, the compositions cannot include any additional active agents that are not otherwise recited. When “consisting essentially of” is used to refer to combinations of active agents disclosed herein, the combinations cannot include any additional active agents that are not otherwise recited. When “consisting essentially of” is used toAtty. Dkt. No.: 052209-0603 refer to a treatment method, the method cannot include administration of any additional therapeutically active agents that are not otherwise recited.

[0029] As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to a patient to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Typically, but not necessarily unless otherwise stated, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present disclosure may comprise acid addition salts. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium, and valerate salts. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this disclosure and these should be considered to form a further aspect of the present technology.

[0030] Where compounds disclosed herein have one or more chiral centers, they may exist as, be provided or formulated as, or be used as, a racemate or as individual enantiomers. It should be noted that all such stereoisomers and mixtures thereof are included in the scope of the present disclosure. Thus, the illustration of a chiral center without a designation of R or S signifies that the scope of the disclosure includes the R isomer, the S isomer, racemic mixtures of the isomers, and mixtures where one isomer is present in greater abundance than another.Atty. Dkt. No.: 052209-0603

[0031] Where processes for the preparation of compounds disclosed herein give rise to mixtures of stereoisomers, such isomers may be separated by conventional techniques such as preparative chiral chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by stereoselective synthesis or by resolution. The compounds may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d- tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary.

[0032] As used herein, “aryl” refers to a carbocyclic (all carbon) ring that is fully aromatized. An “aryl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When an aryl group is a fused ring system, then the ring that is connected to the rest of the molecule is fully aromatized. The other ring(s) in the fused ring system may or may not be fully aromatized. Examples of aryl groups include, without limitation, the radicals of benzene, naphthalene and azulene. Additional non-limiting examples include:

[0033] As used herein, “heteroaryl” refers to a ring that is fully aromatized and contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur in the ring. In some examples, a heteroaryl ring may comprise an oxo group directly appended to a ring carbon, the oxo group forming part of the aromatized system. A “heteroaryl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When a heteroaryl group is a fused ring system, then the ring that is connected to the rest of the molecule is fully aromatized. The other ring(s) in the fused ring system may or may not be fully aromatized. Examples of heteroaryl rings include, without limitation, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, indazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, 2- pyridone, pyridazine, pyrimidine, pyrazine and triazine. As described herein, in some examples,Atty. Dkt. No.: 052209-0603 the heteroaryl group may be substituted. In other words, the heteroaryl group may comprise one or more substituents on the heteroaromatic ring. When a heteroaryl group is substituted, any hydrogen atom(s) may be replaced with the substituent(s) provided that valencies are satisfied. In some cases, the heteroaryl group may be substituted at the heteroatom, e.g., a N-containing heteroaryl group may be an N-substituted heteroaryl group (such as a N-substituted 2-pyridonyl group).

[0034] As used herein, “alkyl” refers to a straight or branched chain fully saturated (no double or triple bonds) hydrocarbon group. An alkyl group of the presently disclosed compounds may comprise from 1 to 15 carbon atoms. An alkyl group herein may have 1 to 4 carbon atoms, 1 to 5 carbon atoms, 1 to 6 carbon atoms, 1 to 7 carbon atoms, 1 to 8 carbon atoms, 1 to 9 carbon atoms, 1 to 10 carbon atoms, 1 to 11 carbon atoms, 1 to 12 carbon atoms, 1 to 13 carbon atoms, 1 to 14 carbon atoms, or 1 to 15 carbon atoms. As used herein, a C1-C6 alkyl represents an alkyl group having 1 to 6 carbon atoms, a C1-C4 alkyl represents an alkyl group having 1 to 4 carbon atoms and a C1-C4alkyl represents an alkyl group having 1 to 3 carbon atoms, etc. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, sec-butyl, t-butyl, amyl, t-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

[0035] As used herein, “cycloalkyl” refers to a completely saturated (no double bonds) hydrocarbon ring. Cycloalkyl groups of the presently disclosed compounds may range from C3 to C5,C3 to C6, C3 to C7, orC3 to C8. As used herein, a C3-C5 cycloalkyl represents a cycloalkyl group containing 3 to 5 carbon atoms and a C3-C6cycloalkyl represents a cycloalkyl group containing 3 to 6 carbon atoms.

[0036] As used herein, “heterocycloalkyl” refers to a ring having in the ring system one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. The ring may also contain one or more double bonds provided that the ring is not fully aromatized. A “heterocycloalkyl” ring as defined herein can be a stable 3- to 18-membered ring (which includes a 3- to 5-membered or 3- to 6-membered ring) that consists of carbon atoms and from one to five ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. A “heterocycloalkyl” ring as defined herein can be a bridged, fused, or spirocyclic ring system.Atty. Dkt. No.: 052209-0603

[0037] As used herein, “alkoxy” refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxy group, -O-. As used herein, a C1-C6 alkoxy represents an alkoxy group containing 1 to 6 carbon atoms and a C1-C3 alkoxy represents an alkoxy group containing 1 to 3 carbon atoms. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy etc.

[0038] As used herein, “haloalkyl” refers to an alkyl group, as defined above, in which one or more of the hydrogen atoms thereon has been replaced with a halogen atom (e.g. F, Cl, Br or I). As used herein, “C1-C6haloalkyl” represents an alkyl group containing 1 to 6 carbon atoms, in which one or more hydrogens thereon has been replaced with a halogen atom.

[0039] As used herein, “haloalkoxy” refers to an alkoxy group, as defined herein, in which one or more of the hydrogen atoms thereon has been replaced with a halogen atom (e.g. F, Cl, Br or I). As used herein, “C1-C3 haloalkoxy” represents a haloalkoxy group containing 1 to 3 carbon atoms.

[0040] As used herein, unless otherwise stated, “independently selected” indicates that each one of a designated group is selected independently from a subsequent list of species.

[0041] It is to be understood that, in any compound of the presently disclosed compounds having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be R or S. In addition, it is to be understood that, in any compound of the presently disclosed compounds having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z.

[0042] It is to be understood that the disclosure of a compound herein inherently includes the disclosure of a tautomer thereof, if applicable. For instance, the disclosure of:(wherein Rxis H) also includes the disclosure of:Atty. Dkt. No.: 052209-0603 and vice versa, even if only one of the two structures is disclosed.

[0043] Throughout the present disclosure, when a compound is illustrated or named, it is to be understood that isotopically enriched analogs of the compound are also contemplated and encompassed by the disclosure. For example, a compound may have a deuterium incorporated instead of a hydrogen, or a carbon-13 instead of carbon with natural isotopic distribution. The isotopic enrichment may be in one location on the compound, i.e., only one hydrogen is replaced by a deuterium, or in more than one location. The present disclosure also encompasses compounds where all the similar atoms are replaced by a less common isotope, for example, a perdeutero compound where all the hydrogen atoms are replaced by a deuterium. The isotopically enriched compounds may be useful, for example, when obtaining NMR spectra or when making use of an isotope effect in managing the kinetics of the reaction the compound is undergoing.

[0044] Throughout the present disclosure, when a compound is illustrated or named, it is to be understood that salts, hydrates, solvates, analogs, conjugates, isomers, polymorphs, esters, prodrugs, metabolites, complexes, co-crystals, intermediates, modifications, and derivatives thereof are contemplated and encompassed by the disclosure.

[0045] The term “pharmaceutical composition” refers to a mixture of one or more compounds disclosed herein with another pharmaceutically acceptable excipient, such as one or more pharmaceutically acceptable diluents or carriers or one or more other pharmaceutically acceptable excipients known in the art. Formulating a compound in a pharmaceutical composition may facilitate administration of the compound to an organism, e.g., the subject to be treated. The specific components of a pharmaceutical composition may depend on and vary with the intended route of administration.

[0046] As used herein, the terms “patient” and “subject” refer to a vertebrate, such as but not limited to a mammal (including a human), bird, fish, or reptile, that has been or will be the object of treatment, observation, or experiment. “Subject” and “patient” may be used interchangeably. Mammals include, but are not limited to, humans, mice, rodents, rats, simians, farm animals, dogs, cats, sport animals, and pets. The methods described herein may be useful in human therapy and / orAtty. Dkt. No.: 052209-0603 veterinary / animal husbandry applications. Without being limiting, the discussion that follows is written with reference to adult human patients.

[0047] As used herein, the terms “therapeutically effective amount” and “effective amount” are used interchangeably and refer to an amount that provides the specific intended pharmacological effect in a patient in need of treatment. It is emphasized that a therapeutically effective amount will not always be effective in treating the conditions described herein in a given patient, even though such amount is deemed to be a therapeutically effective amount by those of skill in the art. Exemplary therapeutically effective amounts are provided herein with reference to adult human patients. The therapeutically effective amount may vary depending upon characteristics of the patient being treated, the condition being treated, and the severity of the condition, for example. COMPOUNDS

[0048] In one aspect, disclosed herein is a compound of Formula I(Formula I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: A1 is CR, wherein R is hydrogen, halogen, C1-3 alkyl, or cyclopropyl; R1 is halogen, C1-6 alkyl, or C1-6 haloalkyl; R2 is phenyl; C3-6 cycloalkyl; 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenoxy; or C1-6alkoxy; wherein the phenyl, C3-6 cycloalkyl, and 3- to 8-membered heterocycloalkyl are optionally substituted with one to four R2A independently selected from halogen, C1-6 alkyl,Atty. Dkt. No.: 052209-0603 C1-6alkoxy, and oxo, or two R2A together with the atom(s) to which they are attached form a 3- to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen;R3Ais C1-6alkyl, C3-6cycloalkyl, or R3B; W is a bond, -NH-, or -O-; and R3Bis (a) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; or (b) 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or -W-R3Bis -NR3CR3D, -NHC(O)-O(C1-6 alkyl), -NHC(O)R3D, or -C(O)NR3CR3D; wherein R3Cis H or C alkyl, and R3D is C haloalkyl or C cycloalkyl; or whe 3C 3D 1-3 1-6 3-4 rein R and R , together with the nitrogen atom to which they are attached, form a 3- to 6-membered ring; R4A is H; R4B is H, C1-3alkyl, or -OH; and R4B’ is H or C1-3alkyl; or R4A and R4B together with the carbon atoms to which they are attached form an oxirane; R5 is C1-6 alkyl optionally substituted with C3-4 cycloalkyl; C1-6 haloalkyl; C4-5 cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6alkyl, C3-4cycloalkyl, and C1-6haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4cycloalkyl ring; 4- to 5-membered heterocycloalkyl containing one or two ring heteroatoms independently selected fromAtty. Dkt. No.: 052209-0603 nitrogen, oxygen, and sulfur, wherein the 4- to 5-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from -C(O)(benzyl), - C(O)(C1-6 alkyl), and -SO2(C1-6 alkyl); or phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6 haloalkoxy; and R6is H or C1-6 alkyl; wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).

[0049] In some embodiments, R is hydrogen or C1-3alkyl. In some embodiments, R is C1-3alkyl. In some embodiments, R is methyl.

[0050] In some embodiments,

[0051] In another aspect, disclosed herein is a compound of Formula I:(Formula I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: A1is CR, wherein R is hydrogen, halogen, C1-3 alkyl, or cyclopropyl; R1is halogen, C1-6 alkyl, or C1-6 haloalkyl; R2is phenyl; C3-6cycloalkyl; 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenoxy; or C1-6 alkoxy; wherein the phenyl, C3-6cycloalkyl, and 3- to 8-membered heterocycloalkyl areAtty. Dkt. No.: 052209-0603 optionally substituted with one to four R2A independently selected from halogen, C1-6alkyl, C1-6 alkoxy, and oxo, or two R2A together with the atom(s) to which they are attached form a 3- to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen;R3A is C3-6cycloalkyl or R3B; W is a bond, -NH-, or -O-; and R3Bis (a) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; or (b) 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or -W-R3B is -NR3CR3D, -NHC(O)-O(C alkyl), -NHC(O)R3D, or - 3C 3D 3C 1-6 C(O)NR R ; wherein R is H or C alkyl, and R3D is C ha 3C 3D 1-3 1-6 loalkyl or C3-4 cycloalkyl; or wherein R and R , together with the nitrogen atom to which they are attached, form a 3- to 6-membered ring; R4Ais H; R4Bis H, C1-3alkyl, or -OH; and R4B’is H or C1-3alkyl; or R4Aand R4Btogether with the carbon atoms to which they are attached form an oxirane; R5is C1-6alkyl optionally substituted with C3-4cycloalkyl; C1-6haloalkyl; C4-5cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6alkyl, C3-4cycloalkyl, and C1-6haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4 cycloalkyl ring; 4- to 5-memberedAtty. Dkt. No.: 052209-0603 heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 4- to 5-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from -C(O)(benzyl), - C(O)(C1-6 alkyl), and -SO2(C1-6 alkyl); or phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6haloalkoxy; and R6 is H or C1-6alkyl; wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).

[0052] In another aspect, disclosed herein is a compound of Formula I:(Formula I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: A1is CR, wherein R is hydrogen, halogen, C1-3alkyl, or cyclopropyl; R1is halogen, C1-6alkyl, or C1-6haloalkyl; R2is phenyl; C3-6cycloalkyl; 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenoxy; or C1-6alkoxy; wherein the phenyl, C3-6 cycloalkyl, and 3- to 8-membered heterocycloalkyl are optionally substituted with one to four R2Aindependently selected from halogen, C1-6 alkyl, C1-6 alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3- to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen;Atty. Dkt. No.: 052209-0603W is a bond, -NH-, or -O-; and R3Bis (a) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or (b) 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6haloalkoxy; or -W-R3Bis -NR3CR3D, -NHC(O)-O(C1-6alkyl), -NHC(O)R3D, or -C(O)NR3CR3D; wherein R3Cis H or C1-3alkyl, and R3D is C1-6haloalkyl or C3-4cycloalkyl; or wherein R3C and R3D, together with the nitrogen atom to which they are attached, form a 3- to 6-membered ring; R4Ais H; R4Bis H, C1-3 alkyl, or -OH; and R4B’is H or C1-3 alkyl; or R4Aand R4Btogether with the carbon atoms to which they are attached form an oxirane; R5 is C1-6 alkyl optionally substituted with C3-4 cycloalkyl; C1-6 haloalkyl; C4-5 cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4cycloalkyl ring; 4- to 5-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 4- to 5-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from -C(O)(benzyl), - C(O)(C1-6 alkyl), and -SO2(C1-6 alkyl); or phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6 haloalkoxy; and R6is H or C1-6 alkyl;Atty. Dkt. No.: 052209-0603 wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).

[0053] In another aspect, disclosed herein is a compound of Formula Ia:(Formula Ia).

[0054] In some embodiments, R3A is R3B. In some embodiments, R3A is C1-6 alkyl. In some embodiments, R3Ais C3-6 cycloalkyl. In some embodiments, R3Ais C3-6 cycloalkyl or R3B.

[0055] In some embodiments, R3Ais phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6haloalkoxy. In some embodiments, R3A is phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy. In some embodiments, R3Ais phenyl optionally substituted with one to four substituents independently selected from halogen and C 3A 1-6 alkoxy. In some embodiments, R is

[0056] In some embodiments, R3A is a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, R3A is a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -OH, C1-6alkyl, and C1-6alkoxy. In some embodiments, R3A is pyrazolyl optionally substituted with one or twoAtty. Dkt. No.: 052209-0603 substituents independently selected from C1-6alkyl. In some embodiments, R3A is pyridinyl, pyrazinyl, pyridazinyl, or 2-pyridonyl, wherein the pyridinyl, pyrazinyl, pyridazinyl, or 2- pyridonyl, is optionally substituted with one or two substituents independently selected from halogen, -OH, C1-6 alkyl, and C1-6 alkoxy. In some embodiments,

[0057] In some embodiments, R3Ais C1-6 alkyl, C3-6 cycloalkyl, or R3B, wherein R3Bis (a) phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6alkoxy; or (b) pyridinyl, pyrazinyl, or pyridazinyl, wherein the pyridinyl, pyrazinyl, or pyridazinyl is optionally substituted with one or two substituents independently selected from halogen, -OH, C1-6alkyl, and C1-6alkoxy. In some embodiments, R3Ais C3-6cycloalkyl or R3B, wherein R3B is (a) phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6 alkoxy; or (b) pyridinyl, pyrazinyl, or pyridazinyl, wherein the pyridinyl, pyrazinyl, or pyridazinyl is optionally substituted with one or two substituents independently selected from halogen, -OH, C 3A 1-6 alkyl, and C1-6 alkoxy. In some embodiments, R is C alkyl. In some embodime 3A3A 1-6 nts, R is . In some embodiments, R is C3-6 cycloalkyl. In some embodiments, R3Ais.Atty. Dkt. No.: 052209-0603

[0060] In another aspect, disclosed herein is a compound of Formula Ib: (Formula Ib).

[0061] In some embodiments, R3Bis phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and Ci- 6 haloalkoxy.

[0062] In some embodiments, R3Bis phenyl optionally substituted with one or two substituents independently selected from halogen and Ci-6 haloalkoxy. In some embodiments, R3Bis

[0063] In some embodiments, R3Bis a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.

[0064] In some embodiments, W is a bond; and R3Bis (a) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or (b) R3Bis a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.

[0065] In some embodiments, W is a -O-; and R3Bis (a) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or (b) R3Bis a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.

[0066] In another aspect, disclosed herein is a compound of Formula Ic:Atty. Dkt. No.: 052209-0603(Formula Ic).

[0067] In some embodiments, R4A is H and R4B is H. In some embodiments, R4A is H and R4B is –OH. In some embodiments, R4A and R4B together with the carbon atoms to which they are attached form an oxirane.

[0068] In some embodiments, R3Bis phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6

[0069] In some embodiments, R3Bis a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl, and C1-6haloalkoxy. In some embodiments, the 5- to 10-membered heteroaryl is pyrazolyl, indazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected fromAtty. Dkt. No.: 052209-0603 halogen, -CN, -NH2, -OH, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy. In some

[0071] In some embodiments, W is a bond. In some embodiments, W is -O-. In some embodiments, W is -NH-.

[0072] In some embodiments, -W-R3B is -NR3CR3D, -NHC(O)-O(C1-6alkyl), -NHC(O)R3D, or -C(O)NR3CR3D; wherein R3Cis H or C1-3alkyl, and R3Dis C1-6haloalkyl or C3-4cycloalkyl; or wherein R3C and R3D, together with the nitrogen atom to which they are attached, form a 3- to 6- membered ring. In some embodiments, -W-R3B,Atty. Dkt. No.: 052209-0603

[0073] In some embodiments, R4A is H; R4B is –OH; W is a bond; and R3B is phenyl optionally substituted with one or two substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.

[0074] In some embodiments, R4Aand R4Btogether with the carbon atoms to which they are attached form an oxirane; W is a bond; and R3Bis phenyl optionally substituted with one or two substituents independently selected from halogen, -CN, -NH2, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy.

[0075] In some embodiments, R4Ais H; R4Bis H; W is -O-; and R3Bis phenyl optionally substituted with one or two substituents independently selected from halogen, -CN, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.

[0076] In some embodiments, R4A is H; R4B is H; W is a bond; and R3B is (a) phenyl optionally substituted with one or two substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or (b) R3Bis a 5- to 10-membered heteroaryl containing one to two ring nitrogens, wherein the heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy. In some embodiments, R4Ais H; R4Bis H; W is a bond; and R3Bis (a) phenyl optionally substituted with one or two substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or (b) pyrazolyl, indazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, wherein the pyrazolyl, indazolyl, pyridinyl, pyrazinyl, or pyrimidinyl are optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.

[0077] In some embodiments, R4A is H; R4B is H; W is a bond; and R3B is phenyl optionally substituted with one or two substituents independently selected from halogen, -CN, -NH2, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy.

[0078] In some embodiments, R4Ais H; R4Bis H; W is a bond; and R3Bis a 5- to 10-membered heteroaryl containing one to two ring nitrogens, wherein the heteroaryl is optionally substitutedAtty. Dkt. No.: 052209-0603 with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, R4A is H; R4B is H; W is a bond; and R3Bis pyrazolyl, indazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, wherein the pyrazolyl, indazolyl, pyridinyl, pyrazinyl, or pyrimidinyl are optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy.

[0079] In another aspect, disclosed herein is a compound of Formula Id:

[0080] In some embodiments, R3Bis phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, andAtty. Dkt. No.: 052209-0603.

[0081] In some embodiments, R3Bis a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, R3Bis a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkoxy. In some embodiments, the 5- to 10-membered heteroaryl is pyrazolyl or pyridinyl, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from C al 3B 1-6 kyl and C1-6 haloalkoxy. In some embodiments, R is ,Atty. Dkt. No.: 052209-0603

[0083] In some embodiments, W is a bond. In some embodiments, W is -O-.

[0084] In some embodiments, R4Bis H. In some embodiments, R4Bis methyl.

[0085] In some embodiments, W is a bond; and R3B is (a) phenyl optionally substituted with one or two substituents independently selected from halogen, -CN, -NH2, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or (b) 5- to 10-membered heteroaryl containing one to two ring nitrogens, wherein the heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, W is a bond; and R3Bis (a) phenyl optionally substituted with one or two substituents independently selected from halogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; or (b) pyrazolyl optionally substituted with one to three substituents independently selected from halogen or C1-6alkyl.

[0086] In another aspect, disclosed herein is a compound of Formula Ie:Atty. Dkt. No.: 052209-0603(Formula Ie).

[0087] In some embodiments, R4B and R4B’ are both H. In some embodiments, R4B is methyl and R4B’ is H.

[0088] In some embodiments, R5 is C1-6 haloalkyl or C1-6 alkyl optionally substituted with C3- ,

[0089] In some embodiments, R5is C4-5cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6alkyl, C3-4cycloalkyl, and C1-6haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4cycloalkyl ring. In some embodiments, R5is, , , ,

[0090] In some embodiments, R5 is 4- to 5-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 4- to 5- membered heterocycloalkyl is optionally substituted with one or two substituents independentlyselected from -C(O)(benzyl), -C(O)(C1-6 alkyl), and -SO2(C1-6 alkyl). In some embodiments, R5is

[0091] In some embodiments, R5is phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6 haloalkoxy. In some embodiments, R5is phenyl optionally substituted with one or two substituents independently selected from halogen. In some embodiments,

[0092] In some embodiments, R5is C1-6 alkyl, C4-5 cycloalkyl, or phenyl optionally substituted with one or two substituents independently selected from halogen.

[0094] Further description of the groups R1, A1, R2and R6is provided below, which may be applicable to Formula (I) or any of the Formulae (la) to (le) as described above and herein.

[0095] In some embodiments, A1is CR, wherein R is selected from chloro, C1-3 alkyl, and cyclopropyl. In some embodiments, R is selected from chloro, methyl, and cyclopropyl. In some embodiments, R is hydrogen or C1-3 alkyl. In some embodiments, R is C1-3 alkyl. In some embodiments, R is methyl.Atty. Dkt. No.: 052209-0603

[0096] In some embodiments, R1 is halogen. In some embodiments, R1 is Br or I. In some embodiments, R1 is Br.

[0097] In some embodiments, R1 is C 1 1-6 alkyl. In some embodiments, R is tert-butyl.

[0098] In some embodiments, R1 is C 1 1-6 haloalkyl. In some embodiments, R is trifluoromethyl.

[0099] In some embodiments, R1is C1-6 alkyl, or C1-6 haloalkyl. In some embodiments, R1is ethyl or -CHF2.

[0100] In some embodiments, R2is phenyl, wherein R2is optionally substituted with one to four R2A independently selected from halogen, C1-6alkyl, and C1-6alkoxy. In some embodiments,. In some embodiments, R2is phenyl.

[0101] In some embodiments, R2is C3-6cycloalkyl or 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R2 is optionally substituted with one to four R2A independently selected from halogen, C1- 6 alkyl, C1-6 alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3- to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen. In some embodiments, R2is,Atty. Dkt. No.: 052209-0603

[0102] In some embodiments, R2 is phenoxy or C1-6alkoxy. In some embodiments, R2 is.

[0103] In some embodiments, R6 is H. In some embodiments, R6 is C1-6 alkyl.

[0104] The presently disclosed compounds were and can be synthesized using the general synthetic procedures set forth in reaction schemes below. The carrying out of each individual illustrated step is within the skill of an ordinary artisan guided by this disclosure, who also knows how to modify the synthetic procedures of the below schemes to synthesize the full scope of the compounds disclosed herein. The synthetic procedure for individual compounds is provided in the Examples section, below.

[0105] In another aspect, disclosed herein is a compound selected from Table A, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. Table A.Atty. Dkt. No.: 052209-0603In the example compounds in the table above, R is Br, I, CF3, or t-Bu. ACTIVITY OF THE COMPOUNDSAtty. Dkt. No.: 052209-0603

[0106] As noted above, the compounds disclosed herein have activity as FP receptor modulators, in particular as FP receptor antagonists. This activity may be assessed by any suitable FP receptor activity assay, such as a FP receptor myo-inositol 1 phsophate (IP1) accumulation assay as illustrated in the examples. The compounds disclosed herein may show IC50 values of less than 1000 nM, less than or equal to 500 nM, less than or equal to 100 nM, or less than or equal to 10 nM.

[0107] The FP receptor myo-inositol 1 phsophate (IP1) accumulation assay uses human embryonic kidney EBNA derived (HEK-EBNA) cell lines stably expressing the FP receptor. Cells are exposed to varying concentrations of test compounds followed by exposure to a submaximal concentration of FP receptor agonist; antagonist inhibition of IP1 accumulation is then assessed. IP1 accumulation is measured through an HTRF (homogeneous time resolved fluorescence)-based competitive IP1 immunoassay.

[0108] EP4 receptor activity may be assessed by any suitable EP4 receptor activity assay, such as an EP4 receptor cyclic adenosine monophosphate (cAMP) accumulation assay. Selectivity for FP versus EP4 may be assessed by comparing the EC50values obtained in the respective assays and calculating a selectivity ratio, i.e., EP4 IC50 / FP IC50.

[0109] In some embodiments, a compound as disclosed herein exhibits at least 5-fold greater selectivity for the FP receptor than for the EP4 receptor. This includes at least 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 22-, 23-, 24-, 25-, 26-, 27-, 28-, 29-, 30-, 31-, 32-, 33-, 34-, 35-, 36-, 37-, 38-, 39-, 40-, 41-, 42-, 43-, 44-, 45-, 46-, 47-, 48-, 49-, or 50-fold, or more, greater selectivity for the prostaglandin F receptor than for the EP4 receptor. A compound as disclosed herein may exhibit about 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 22-, 23-, 24-, 25-, 26-, 27-, 28-, 29-, 30-, 31-, 32-, 33-, 34-, 35-, 36-, 37-, 38-, 39-,Atty. Dkt. No.: 052209-0603 40-, 41-, 42-, 43-, 44-, 45-, 46-, 47-, 48-, 49-, or 50-fold greater selectivity for the prostaglandin F receptor than for the EP4 receptor. SYNTHESIS OF THE COMPOUNDS

[0110] In another aspect there is provided a method of manufacture of any one of the compounds disclosed herein. The presently disclosed compounds were and can be synthesized using the synthetic procedures set forth in Schemes 1-16 in the Examples detailed below. The carrying out of each individual illustrated step is within the skill of an ordinary artisan guided by this disclosure, who also knows how to modify the synthetic procedures of the below schemes to synthesize the full scope of the compounds disclosed herein. Definitions for R1, R2, R3A, R3B, and R5are as provided in the formulas described herein. The synthetic procedure for individual compounds is disclosed in the Examples section below. PHARMACEUTICAL COMPOSITIONS

[0111] In another aspect, disclosed herein are pharmaceutical compositions comprising, consisting essentially of, or consisting of a compound as described herein, and one or more pharmaceutically acceptable excipients.

[0112] In another aspect, disclosed herein are pharmaceutical compositions comprising, consisting essentially of, or consisting of a compound of Formulas I, Ia, Ib, Ic, Id, or Ie, as described herein, and one or more pharmaceutically acceptable excipients.

[0113] The compounds may be formulated for administration by any suitable route of administration, such as for example, oral, topical (including transdermal), rectal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including by intramuscular, subcutaneous, or intravenous injection, as well as inhalation, intrathecal, direct intraperitoneal, or intranasal delivery.

[0114] Pharmaceutical compositions as disclosed herein may comprise, as one or more pharmaceutically acceptable excipients, a pharmaceutically acceptable carrier, diluent, disintegrant, sweetening agent, glidant (such as magnesium stearate), flavoring agent, emulsifyingAtty. Dkt. No.: 052209-0603 agent, suspending agent, stabilizer, isotonic agent, etc. Pharmaceutical compositions as disclosed herein may be formulated into an oral dosage form such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or a topical (including transdermal) or transmucosal dosage form such as liquids, suspensions, emulsions, gels (ointments or the like), or a parenteral dosage form such as liquids, suspensions, emulsions, and freeze-dried powders. Said dosage forms may be formulated in various forms, e.g., a dosage form for single administration or for multiple administrations.

[0115] Exemplary excipients include, without limitation, lactose, polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophors, carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), glidants such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, and the like.

[0116] The amount of any individual excipient in the composition will vary depending on the role of the excipient, the dosage requirements of the active agent, and particular needs of the composition. Generally, however, the excipient will be present in the composition in an amount of from about 1% to about 99% by weight, such as from about 5% to about 98% by weight, including from about 15 to about 95% by weight of the composition. In general, the amount of excipient present in a composition of the disclosure is selected from the following: about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% by weight.

[0117] A pharmaceutical composition as disclosed herein may include a compound disclosed herein as the only active agent, or may be formulated with other active agents.

[0118] Techniques for formulation and administration of the compounds disclosed herein may be found in “Remington: The Science and Practice of Pharmacy,” Academic Press, London, United Kingdom, 23rd edition, 2020.

[0119] Pharmaceutical compositions as disclosed herein may be formulated to provide a therapeutically effective amount of a compound as disclosed herein in a reasonable volume orAtty. Dkt. No.: 052209-0603 mass of the composition, which may be administered by any effective dosing schedule, such as once a day. Although the exact dosage may be determined on a drug-by-drug (compound-by- compound) basis, for most compounds, some generalizations regarding the dosage can be made. For example, the daily dosage regimen for an adult human patient may be between 0.001 mg and 1000 mg, such as between 0.01 mg and 500 mg, for example from 1 to 200 mg of the compound or pharmaceutically acceptable salt thereof, calculated as the free base or free acid. METHODS OF TREATMENT

[0120] In another aspect, disclosed herein are methods of modulating prostaglandin F (FP) receptor activity in a subject, comprising, consisting essentially of, or consisting of administering to a subject in need thereof a compound as disclosed herein or a pharmaceutical composition as disclosed herein.

[0121] In another aspect, disclosed herein are methods of treating pre-term labor in a subject, comprising, consisting essentially of, or consisting of administering to a subject in need thereof a compound as disclosed herein or a pharmaceutical composition as disclosed herein.

[0122] In another aspect, disclosed herein are methods of reducing risks of or preventing pre- term birth in a subject, comprising, consisting essentially of, or consisting of administering to a subject in need thereof a compound as disclosed herein or a pharmaceutical composition as disclosed herein.

[0123] In another aspect, disclosed herein are methods of reducing risks of or preventing pre- term labor in a subject, comprising, consisting essentially of, or consisting of administering to a subject in need thereof a compound as disclosed herein or a pharmaceutical composition as disclosed herein.

[0124] In another aspect, disclosed herein are methods of reducing risks of or preventing labor prior to cesarean delivery in a subject, comprising, consisting essentially of, or consisting of administering to a subject in need thereof a compound as disclosed herein or a pharmaceutical composition as disclosed herein.Atty. Dkt. No.: 052209-0603

[0125] In another aspect, disclosed herein are methods of reducing risks of or preventing dysmenorrhea in a subject, comprising, consisting essentially of, or consisting of administering to a subject in need thereof a compound as disclosed herein or a pharmaceutical composition as disclosed herein. In some embodiments, the dysmenorrhea is primary dysmenorrhea. In some embodiments, the dysmenorrhea is secondary dysmenorrhea.

[0126] In another aspect, disclosed herein are methods of reducing risks of or preventing endometriosis in a subject, comprising, consisting essentially of, or consisting of administering to a subject in need thereof a compound as disclosed herein or a pharmaceutical composition as disclosed herein.

[0127] In another aspect, disclosed herein are methods of reducing risks of or preventing adenomyosis in a subject, comprising, consisting essentially of, or consisting of administering to a subject in need thereof a compound as disclosed herein or a pharmaceutical composition as disclosed herein.

[0128] In another aspect, disclosed herein are methods of reducing risks of or preventing idiopathic pulmonary fibrosis (IPF) in a subject, comprising, consisting essentially of, or consisting of administering to a subject in need thereof a compound as disclosed herein or a pharmaceutical composition as disclosed herein.

[0129] In another aspect is a compound disclosed herein for use as a medicament. In another aspect, disclosed herein are compounds for use in modulating (e.g., antagonizing) prostaglandin F (FP) receptor activity in a subject. In another aspect, disclosed herein are compounds for use in treating pre-term labor in a subject. In another aspect, disclosed herein are compounds for use in reducing risks of or preventing pre-term birth in a subject. In another aspect, disclosed herein are compounds for use in reducing risks of or preventing pre-term labor in a subject. In another aspect, disclosed herein are compounds for use in reducing risks of or preventing labor prior to cesarean delivery in a subject. In another aspect, disclosed herein are compounds for use in reducing risks of or preventing dysmenorrhea in a subject. In another aspect, disclosed herein are compounds for use in reducing risks of or preventing endometriosis in a subject. In another aspect, disclosed hereinAtty. Dkt. No.: 052209-0603 are compounds for use in reducing risks of or preventing adenomyosis in a subject. In another aspect, disclosed herein are compounds for use in reducing risks of or preventing IPF in a subject.

[0130] In another aspect, disclosed herein are uses of the compounds described herein for modulating prostaglandin F (FP) receptor activity in a subject. In another aspect, disclosed herein are uses of the compounds described herein for treating pre-term labor in a subject. In another aspect, disclosed herein are uses of the compounds described herein for reducing risks of pre-term birth in a subject. In another aspect, disclosed herein are uses of the compounds described herein for preventing pre-term labor in a subject. In another aspect, disclosed herein are uses of the compounds described herein for preventing labor prior to cesarean delivery in a subject. In another aspect, disclosed herein are uses of the compounds described herein for preventing dysmenorrhea in a subject. In another aspect, disclosed herein are uses of the compounds described herein for preventing endometriosis in a subject. In another aspect, disclosed herein are uses of the compounds described herein for preventing adenomyosis in a subject. In another aspect, disclosed herein are uses of the compounds described herein for preventing idiopathic pulmonary fibrosis (IPF) in a subject.

[0131] In another aspect, disclosed herein are methods of treating a disease or disorder in a subject in need thereof, comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound as disclosed herein or a pharmaceutical composition as disclosed herein. In another aspect, disclosed herein are compounds for use in treating a disease or disorder in a subject in need thereof. In another aspect, disclosed herein are uses of the compounds described herein for treating a disease or disorder in a subject in need thereof.

[0132] In another aspect, disclosed herein are methods of treating a disease or disorder in a subject in need thereof, comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a compound as disclosed herein or a pharmaceutical composition as disclosed herein, wherein the disease or disorder is associated with abnormal levels (e.g., elevated levels) and / or abnormal expression (e.g., elevated expression) of PGF2α and / or its receptor. In another aspect, disclosed herein are compounds for use in treating a disease or disorderAtty. Dkt. No.: 052209-0603 in a subject in need thereof, wherein the disease or disorder is associated with abnormal levels (e.g., elevated levels) and / or abnormal expression (e.g., elevated expression) of PGF2α and / or its receptor. In another aspect, disclosed herein are uses of the compounds described herein for treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is associated with abnormal levels (e.g., elevated levels) and / or abnormal expression (e.g., elevated expression) of PGF2αand / or its receptor.

[0133] The disease or disorder may be any for which modulation (e.g., antagonization) of FP receptor activity is desired, such as one or more of idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary emphysema (for example pulmonary emphysema induced by cigarette smoke), cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, chronic intestinal inflammations (IBD, Crohn's disease, ulcerative colitis), peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, coughs and colds (chronic inflammatory cough, iatrogenic cough), inflammation of the nasal mucosa (including medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, for example hay fever), inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, and conduction disorders, for example atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrialAtty. Dkt. No.: 052209-0603 fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), boxer cardiomyopathy, aneurysms, shock such as cardiogenic shock, septic shock and anaphylactic shock, thromboembolic disorders and ischemias such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, edema formation such as, for example, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney disorders such as kidney transplant rejection and immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome (which can be characterized diagnostically, for example by abnormally reduced creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes, for example glutamyl synthetase, altered urine osmolarity or urine volume, elevated microalbuminuria, macroalbuminuria, lesions on glomerulae and arterioles, tubular dilatation, hyperphosphatemia and / or need for dialysis), benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), incontinence, for example mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis,Atty. Dkt. No.: 052209-0603 sepsis (SIRS), multiple organ failure (MODS, MOF), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidimytitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, malignant tumors of the lymphoproliferative system, for example Hodgkin's and non-Hodgkin's lymphoma, and disorders of the central nervous system and neurodegenerative disorders (e.g., stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions). In some embodiments, the disease or disorder is one or of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

[0134] In accordance with any of these methods or uses, the compound or composition may be administered by any suitable route of administration as discussed above, and may be administered in a therapeutically effective amount as discussed above. As also discussed above, the administration may be by any effective dosing schedule, such as once a day, 1 to 4 times per day, once a week, 1 to 4 times per week, once a month, 1 to 4 times month, etc. Although the exact dosage may be determined on a drug-by-drug (compound-by-compound) basis, the daily dosage regimen for an adult human patient may be, for example, between 0.001 mg and 1000 mg, such as between 0.01 mg and 500 mg, for example 1 to 200 mg of the compound or pharmaceutically acceptable salt thereof, calculated as the free base or free acid.

[0135] In accordance with any of these methods or uses, the compound or composition may be administered in combination with an additional therapeutic agent. The additional therapeutic agent may be one or more useful for treating the condition or disease or disorder at issue. For example, the additional therapeutic agent may be useful for treating pre-term labor, reducing risks of or preventing pre-term birth, reducing risks of or preventing pre-term labor, reducing risks of or preventing labor prior to cesarean delivery, reducing risks of or preventing dysmenorrhea in a subject, or treating any of the diseases or disorders disclosed above. Non-limiting examples of the additional therapeutic agent include an oxytocin receptor antagonist, (e.g., atosiban, retosiban, barusiban, epelsiban, and nolasiban), a betamimetic (e.g., terbutaline, ritodrine, hexoprenaline, albuterol, fenoterol, nylidrin, or orciprenaline), a calcium channel inhibitor (e.g., dihydropyridine,Atty. Dkt. No.: 052209-0603 nifedipine, or nicardipine), a magnesium salt (e.g., magnesium sulfate), a progestogen (e.g. progestrone or 17-α-hydroxyprogesterone), and a nitric oxide donor (e.g., nitroglycerine).

[0136] The present technology, thus generally described, may be further understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present technology. EXAMPLES

[0137] General Methods

[0138] All reactions were carried out in an oven-dried round-bottomed-flask under an inert nitrogen atmosphere with stirring. Solvents, reagents, and chemicals were purchased from various sources and used as received unless otherwise noted. Nuclear magnetic resonance chemical shifts are reported in δ (ppm) relative units to residual 1H solvent peaks methanol-d4(3.30 ppm), CDCl3(7.26 ppm), and DMSO-d6(2.50 ppm); 1H signals from from exchangeable protons might be missing. Splitting patterns are assigned as s (singlet), d (doublet), t (triplet), multiplet (m), and dd (doublet of doublet).

[0139] Scheme 1. Synthesis of BCO ketoneAtty. Dkt. No.: 052209-0603

[0141] To a mixture of (1-1) (87.13 g, 385.07 mmol, 1 eq) in AcOH (870 mL) was added CrO3(77.01 g, 770.15 mmol, 2 eq) in one portion at 15°C. The mixture was heated to 90 °C and stirred for 18 hours. The mixture was added dropwise into NaHCO3 (sat., 12 L). The mixture was extracted with ethyl acetate (1500 mL*2). The combined organic phases were washed with brine (1000 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate = 8 / 1 to 3 / 1) to give (1-2) (23 g, 95.73 mmol, 24.86% yield). At the same time, 36.4 g of (1-1) was recycled.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.69 - 3.79 (m, 6 H) 2.59 (s, 2 H) 2.26 - 2.37 (m, 2 H) 1.85- 2.14 (m, 6 H).

[0142] Procedure of step 1b

[0143] To a mixture of (1-2) (36.28 g, 151.01 mmol, 1 eq) in THF (170 mL) and MeOH (22 mL) was added LiOH.WATER (6.34 g, 151.01 mmol, 1 eq) as a solution in WATER (22 mL) at 0 °C. The mixture was warmed to 20 °C and stirred for 16 hours. The mixture was concentrated in vacuum, and the residue was diluted with water (320 mL). The mixture was extracted with MTBE (350 mL*2). The aqueous layer was adjusted to pH = 1 with HCl (1 M). The residue was concentrated until a white solid precipitated. The precipitate was collected and dried under high vacuum to afford (1-3) (18 g, 79.57 mmol, 52.69% yield).1H NMR (400 MHz, CHLOROFORM- d) δ ppm 3.76 (s, 3 H) 2.57 - 2.63 (m, 2 H) 2.27 - 2.39 (m, 2 H) 1.99 - 2.14 (m, 4 H) 1.89 - 1.99 (m, 2 H).

[0144] Procedure of step 1c

[0145] To a solution of (1-3) (18 g, 79.57 mmol, 1 eq) in t-BuOH (280 mL) was added pyridine (45.31 g, 572.88 mmol, 7.2 eq) and DMAP (9.72 g, 79.57 mmol, 1 eq). Then Boc2O (86.83 g, 397.83 mmol, 5 eq) was added slowly at 20 °C, and the mixture was stirred at 30 °C for 12 hours. The resulting solution was concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate (350 mL) and water (350 mL). Separated layers and the aqueous phase was extracted with ethyl acetate (350 mL). The combined organic phases were washed with water (160 mL), HCl (1 M, 160 mL*2), NaHCO3 (sat., 160 mL), brine (160 mL), dried with Na2SO4 and concentrated under reduced pressure to afford (1-4) (13.8 g, crude).1H NMR (400 MHz,Atty. Dkt. No.: 052209-0603 CHLOROFORM-d) δ ppm 3.68 - 3.80 (m, 3 H) 2.52 - 2.58 (m, 2 H) 2.20 - 2.38 (m, 2 H) 1.93 - 2.08 (m, 4 H) 1.75 - 1.90 (m, 2 H) 1.44 (s, 9 H).

[0146] Procedure of step 1d

[0147] To a mixture of (1-4) (13.8 g, 48.88 mmol, 1 eq) in THF (130 mL) and MeOH (34 mL) was added NaOH (2.59 g, 64.63 mmol, 1.32 eq) as a solution in WATER (34 mL) at 0 °C. The mixture was warmed to 25°C and stirred for 12 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water (300 mL) and MTBE (400 mL). The mixture was filtered. The organic phase was removed. The aqueous phase was washed with MTBE (400 mL). The aqueous layer was acidified to pH = 1 with aqueous HCl (1 M), and the precipitate was collected by filtration and dried under high vacuum to afford (1-5) (9.16 g, 34.14 mmol, 69.85% yield).1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.59 - 2.65 (m, 2 H) 2.02 - 2.30 (m, 6 H) 1.79 - 1.94 (m, 2 H) 1.42 - 1.50 (m, 9 H).

[0148] Procedure of step 1e

[0149] To a solution of (1-5) (1.92 g, 7.16 mmol, 1 eq) in toluene (150 mL) was added phenylmethanol (2.32 g, 21.47 mmol, 3 eq), TEA (2.17 g, 21.47 mmol, 3 eq) and DPPA (1.97 g, 7.16 mmol, 1 eq) in this order at 15°C. The mixture was then heated to 110 °C and stirred for 19 hours. The reaction mixture was cooled to 25°C and concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (160 mL*2). The combined organic fractions were dried with Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 5 / 1) to give BCO ketone (2.02 g, 5.41 mmol, 75.59% yield).1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28 - 7.43 (m, 4 H) 5.92 - 6.06 (m, 1 H) 5.01 - 5.15 (m, 2 H) 2.83 - 2.99 (m, 2 H) 2.60 - 2.66 (m, 2 H) 2.07 - 2.20 (m, 2 H) 1.81 - 1.93 (m, 2 H) 1.55 - 1.67 (m, 2 H) 1.45 (d, J = 1.76 Hz, 9 H).

[0150] Scheme 2. Synthesis of INT 1Atty. Dkt. No.: 052209-0603

[0151] Procedure of step 2a

[0152] To a mixture of BCO ketone (1 g, 2.68 mmol, 1 eq) in THF (20 mL) was added LiHMDS (1 M, 5.36 mL, 2 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 1 hr. Then, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.24 g, 3.48 mmol, 1.3 eq) in THF (10 mL) was added dropwise to the mixture at -78 °C. Then, the mixture was warmed and stirred at 20 °C for 12 hr. The mixture was poured into NH4Cl (sat., 100 mL). The mixture was extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (20 mL), dried with Na2SO4and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 20) to give INT 1 (400 mg, 791.29 μmol, 29.55% yield).1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.35 - 7.41 (m, 5 H) 6.38 (s, 1 H) 5.11 (s, 2 H) 2.15 - 2.24 (m, 2 H) 2.00 (br d, J = 3.29 Hz, 2 H) 1.71 - 1.78 (m, 2 H) 1.62 - 1.67 (m, 2 H) 1.49 (s, 9 H).

[0153] Scheme 3. Synthesis of INT 2Atty. Dkt. No.: 052209-0603

[0155] To a mixture of BCO Ketone (50 g, 133.89 mmol, 1 eq) and 4A MS (25 g, 8.03 mmol, 16.67 eq) in EtOH (350 mL) was added NH2NH2.WATER (161.76 g, 3.23 mol, 24.13 eq) in one portion at 20 °C. The mixture was heated to 80 °C and stirred for 5 hours. The mixture was filtered and concentrated under vacuum. The residue was extracted between DCM (300 mL*3) and water (200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1) to give (3-1) (45 g, 116.14 mmol, 86.74% yield). [M+H]+= 388.3.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.31 - 7.31 (m, 1H), 7.42 - 7.28 (m, 4H), 6.46 (s, 1H), 5.06 (s, 2H), 4.97 (br s, 2H), 2.86 (dt, J = 4.0, 12.2 Hz, 2H), 2.46 (s, 2H), 2.04 (br d, J = 12.5 Hz, 2H), 1.75 (dt, J = 4.5, 11.3 Hz, 2H), 1.53 - 1.43 (m, 11H)

[0156] Procedure of step 3b

[0157] To a mixture of (3-1) (45 g, 116.14 mmol, 1 eq) in piperidine (300 mL) and THF (250 mL) was added I2 (73.69 g, 290.34 mmol, 2.5 eq) which was dissolved in THF (350 mL) at 0 °C under Ar. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched by the addition of WATER (500 mL). The solution was extracted with ethyl acetate (500 mL*2), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 5 / 1) to give INT 2 (44.5 g, 92.07 mmol, 79.27% yield). [M+H]+= 484.1.1H NMR (400 MHz, ET43896-1202- P1A1,CHLOROFORM-d) δ ppm 7.31 - 7.41 (m, 5 H) 7.04 (s, 1 H) 5.12 (br s, 2 H) 1.81 - 1.98 (m, 6 H) 1.54 - 1.58 (m, 2 H) 1.47 (s, 9 H)

[0158] Scheme 4. Synthesis of INT 3, INT 4Atty. Dkt. No.: 052209-0603

[0159] Procedure of step 4a

[0160] A mixture of (4-1) (when R=Br) (20 g, 88.49 mmol, 1 eq) and 1-phenylpropan-1-one (11.87, 88.49 mmol, 1 eq) in AcOH (240 mL) was stirred at 75°C for 0.5 hr. After that, to this well stirred reaction was added HCl (12 M, 79.99 mL, 10.85 eq). The mixture was stirred at 105°C for 11.5 h. After cooling to room temperature, the mixture was poured into HCl (1M, 2000 mL). The solid was collected by filtration and then washed with the mixture of solvents (petroleum ether / ethyl acetate in a 2:1 ratio, 1.5L) to give INT 3 (23 g, 67.21 mmol, 75.96% yield). [M+H]+= 344.0.1H NMR (400 MHz, DMSO-d6) δ ppm 7.98 - 8.04 (m, 1 H) 7.89 - 7.96 (m, 2 H) 7.58 - 7.64 (m, 2 H) 7.48 - 7.56 (m, 3 H) 2.39 (s, 3 H)

[0161] Procedure of step 4b

[0162] A mixture of INT 3 (R=Br) (3 g, 8.77 mmol, 1 eq) in SOCl2 (49.20 g, 413.55 mmol, 47.17 eq) was stirred at 80 °C for 0.5 hr. Then the reaction mixture was concentrated directly to afford INT 4 (10 g, crude).1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.10 (1 H, d, J = 8.94 Hz) 7.95 - 8.03 (2 H, m) 7.64 (2 H, br d, J = 6.91 Hz) 7.53 - 7.60 (3 H, m) 2.52 (3 H, s).

[0163] Procedure of step 4cAtty. Dkt. No.: 052209-0603

[0164] Compound (4-1) is added to a mixture of 2-cyclopropyl-1-phenylethan-1-one in potassium hydroxide in ethanol, followed by reaction under hydrochloric acid conditions to provide INT 9.

[0165] Procedure of step 4d

[0166] INT 10 is prepared from INT 9 in an analogous manner as described in step 4b.

[0167] Procedure of step 4e

[0168] Compound (4-1) is added to a mixture of 2-chloro-1-phenylethan-1-one in potassium hydroxide in ethanol, followed by reaction under hydrochloric acid conditions to provide INT 11.

[0169] Procedure of step 4f

[0170] INT 12 is prepared from INT 11 in an analogous manner as described in step 4b.

[0171] Scheme 5. Synthesis of INT 5Atty. Dkt. No.: 052209-0603

[0172] Procedure of step 5a

[0173] (5-1) (10 g, 43.85 mmol, 1 eq) in propanoyl propanoate (44.23 g, 339.85 mmol, 7.75 eq) was heated at 170 °C for 9 hours. After the reaction was completed, the reaction was cooled to room temperature. After filtration, the solid was washed with MTBE (500 mL) to give (5-2) (3.6 g, crude).1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (br s, 1 H) 7.63 (dd, J = 8.80, 1.96 Hz, 1 H) 7.52 (d, J = 1.83 Hz, 1 H) 7.27 (d, J = 8.80 Hz, 1 H) 2.05 (s, 3 H).

[0174] Procedure of step 5b

[0175] To a mixture of (5-2) (500 mg, 1.77 mmol, 1 eq) in DMSO (10 mL) was added MeI (301.90 mg, 2.13 mmol, 1.2 eq) and TEA (269.03 mg, 2.66 mmol, 1.5 eq) in one portion at 25°C under N2. The reaction was stirred at 55°C for 12 hours. After the reaction was completed, the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL*3). The organic phase was dried over Na2SO4, filtered and concentrated to give (5-3) (265 mg, 894.92 μmol, 50.49% yield).1H NMR (400 MHz, DMSO-d6) δ ppm 12.20 (s, 1 H) 7.68 (dd, J = 8.75, 2.13 Hz, 1 H) 7.53 (d, J = 2.00 Hz, 1 H) 7.31 (d, J = 8.76 Hz, 1 H) 4.00 (s, 3 H) 2.06 (s, 3 H).

[0176] Procedure of step 5c

[0177] A mixture of (5-3) (265 mg, 894.92 μmol, 1 eq) in POCl3 (9.99 g, 65.18 mmol, 72.83 eq) was stirred at 100 °C for 2 hours. After that, the reaction was concentrated directly to give (5- 4) (250 mg, crude).1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.92 (d, J = 8.93 Hz, 1 H) 7.86 (d, J = 2.08 Hz, 1 H) 7.78 - 7.82 (m, 1 H) 4.11 (s, 3 H) 2.53 (s, 3 H).

[0178] Synthesis of (INT 5)

[0179] To a mixture of morpholine (969.35 mg, 11.13 mmol, 10 eq) in t-BuOH (5 mL) was added (5-4) (350 mg, 1.11 mmol, 1 eq). The mixture was heated to 60 °C and stirred for 12 hours. Then the reaction was heated to 80 °C and stirred for another 60 hours. After the reaction was completed, the reaction mixture was concentrated directly to give a residue which was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 5%-35% B over 10 min) to give INT 5 (320 mg, 911.18 μmol,Atty. Dkt. No.: 052209-0603 81.89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 - 7.86 (m, 1 H) 7.62 (d, J = 1.32 Hz, 2 H) 3.76 (br d, J = 4.17 Hz, 4 H) 3.13 - 3.20 (m, 4 H) 2.30 (s, 3 H).

[0180] Synthesis of (INT 7)

[0181] To a mixture of (5-2) (30 g, 106.35 mmol, 1 eq) in DCM (225 mL) was added SOCl2 (184.47 g, 1.55 mol, 14.58 eq) and DMF (777.35 mg, 10.63 mmol, 0.1 eq). The suspension was degassed under vacuum and purged with N2several times. The mixture was stirred at 50 °C for 1 hr. The mixture was filtered and the filtrate was concentrated to give INT 7 (23 g, crude).1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.90 - 7.96 (m, 2 H) 7.83 - 7.88 (m, 1 H) 2.61 (s, 3 H)

[0182] Scheme 6. Synthesis of INT 6

[0183] Synthesis of (6-1)

[0184] To a mixture of (5-4) (1.4 g, 4.45 mmol, 1 eq) in t-BuOH (15 mL) was added pyrrolidine (1.58 g, 22.25 mmol, 5 eq) in one portion. The mixture was stirred at 60 °C for 12 hr. After the reaction was completed, the reaction mixture was acidified with HCl (1 M) to adjust pH = 4. The residue was collected by filtration to give (6-1) (450 mg, 1.29 mmol, 28.95% yield).1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.53 - 7.64 (m, 3 H) 4.05 (s, 3 H) 3.61 - 3.71 (m, 4 H) 2.39 (s, 3 H) 1.92 - 2.01 (m, 4 H).

[0185] Synthesis of (INT 6)

[0186] To a mixture of (6-1) (450 mg, 1.29 mmol, 1 eq) in MeOH (5 mL), WATER (5 mL) and THF (5 mL) was added LiOH.WATER (162.22 mg, 3.87 mmol, 3 eq) in one portion. The reaction was heated to 80 °C for 12 hr. After the reaction was completed, the reaction was concentrated directly to give INT 6 (400 mg, 1.19 mmol, 82.61% yield). 1H NMR (400 MHz,Atty. Dkt. No.: 052209-0603 METHANOL-d4) δ ppm 7.83 (d, J = 2.00 Hz, 1 H) 7.47 - 7.57 (m, 1 H) 7.47 - 7.57 (m, 1 H) 3.66 (br t, J = 6.57 Hz, 4 H) 2.45 (s, 3 H) 1.92 - 2.01 (m, 4 H).

[0187] Scheme 7. Synthesis of TG1 series

[0189] General procedure of step 7a

[0190] To a mixture of (7-1) / (7-1A) (1 eq) and boronic acid (1.5 eq) in DME and WATER was added K2CO3 (3 eq) and Pd(PPh3)4 (0.05 eq) under N2. Then the mixture was stirred (seeAtty. Dkt. No.: 052209-0603 details in Table 1) under N2. After the reaction was complete, the mixture was filtered and concentrated in vacuum. The crude was purified by column chromatography or used as is for next step to give (7-2).

[0191] Table 1: Detailed conditions: (all reactions conducted under nitrogen gas)Atty. Dkt. No.: 052209-0603-76-Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603cyclopentyl(diphenyl)phosphane;dichloropalladium;iron, K2CO3; E: CuI (1 eq), LiCl (3 eq), Pd(PPh3)4 (0.1 eq); F: CuI, 2-(dimethylamino)acetic acid;hydrochloride, Cs2CO3

[0192] General procedure of step 7b-1

[0193] To a mixture of (7-2) (1 eq) in THF was added Pd(OH)2 (10 wt%, 20% purity). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 Psi) at 20 °C (see details in Table 2). The mixture was filtered and concentrated inAtty. Dkt. No.: 052209-0603 vacuum. The crude product was purified by column chromatography or used as it for next step to give (7-3).

[0194] General procedure of step 7b-2

[0195] Pd(OAc)2 (0.05 eq), Et3SiH (5 eq) and TEA (3 eq) were stirred in DCM for 15 min. The mixture was added dropwise to (7-2) (1 eq) in DCM under N2 and stirred (see details in Table 2). After the reaction was completed, the mixture was concentrated in vacuum and added THF and TFA (adjust pH = 5). The mixture was stirred for 5 min. The reaction mixture was adjust to pH = 7 by NaHCO3(sat.). The combined organic layers was washed with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography or used as is for next step to give (7-3).

[0196] Table 2: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603*under nitrogen gas

[0197] Synthesis of (7c-1)

[0198] To a mixture of (7-3) (1 eq) and INT 7 (1.2 eq) in DCM was added NaHCO3 (6 eq) in one portion at 20 °C for 12 h. The reaction mixture was quenched by addition WATER. The residue was extracted with DCM. The combined organic layers was washed with brine, dried overAtty. Dkt. No.: 052209-0603 Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography or used as is for next step to afford (7c-1). Table 3: Detailed conditions:Atty. Dkt. No.: 052209-0603

[0199] General procedure of step 7c-1

[0200] To a mixture of (7-3) (1 eq) in DCM was added TEA (3 eq) and INT 4 (1.1 eq). Then the mixture was stirred (see details in Table 4). After the reaction was completed, the reaction mixture was quenched by the addition of WATER. The residue was extracted with DCM. The combined organic layers was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatographyor used as is for next step to give (7-4).

[0201] General procedure of step 7c-2

[0202] To a mixture of INT 3 (1.1 eq) and (7-3) (1 eq) in DMF was added DIEA (3 eq). Then the mixture was added HATU (1.5 eq) and stirred at M°C for N hours (see details in Table 4). After the reaction was completed, the reaction mixture was quenched by addition WATER. TheAtty. Dkt. No.: 052209-0603 residue was extracted with ethyl acetate. The combined organic layers was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified bycolumn chromatographyor used as is for next step to give (7-4).

[0203] General procedure of step 7c-3

[0204] To a mixture of (7c-1) (1 eq) and 3,3-difluoroazetidine hydrochloride (5 eq) in DMA was added DIEA (10 eq). The reaction was stirred at M°C for N hours (see details in Table 4). The mixture was added to WATER. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography or used as is for next step to afford (7-4).

[0205] Procedure of step 7c-4

[0206] To a solution of (7c-1) (0.15 g, 225.25 μmol, 1 eq) in MeOH (4.5 mL) was added NaOMe (60.84 mg, 1.13 mmol, 5 eq), then the mixture was stirred at 70 °C for 12 h. The residue was poured into ice-water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (15 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give (7-4) (0.15 g, crude).

[0207] Table 4: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603-101-Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0208] General procedure of step 7d

[0209] A mixture of (7-4) (1 eq) in a mixture of solvents (DCM / TFA in a 4:1 ratio) was stirred (see details in Table 5). After the reaction was completed, the mixture was concentrated and purified by prep-HPLC to give (TG1) (select compounds shown in Table 5).

[0210] Table 5: Detailed conditions: -104-Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0211] Procedure of step 7e

[0212] To a solution of (BCO-Ketone) (5 g, 13.39 mmol, 1 eq) in THF (50 mL) was added LDA (2 M, 16.74 mL, 2.5 eq) at -78 °C. The mixture was stirred at -78 °C for 0.5 hour, then CH3I (3.80 g, 26.78 mmol, 2 eq) was added into the solution and the resulting mixture was stirred at 25°C for 0.5 hr. The solution was quenched by NH4Cl (sat., 100 mL) and extracted with ethyl acetate (60 mL*3). The combined organic phase was washed with brine (100 mL*2), dried over sodium sulfate, filtered and concentrated to give a residue which was purified by prep-HPLC (column: Welch Xtimate C18 250*100mm*10um;mobile phase: [WATER(10mM NH4HCO3)- ACN]; gradient: 45%-80% B over 20.0 min) to give (7S-1) (4.2 g, 10.84 mmol, 80.96% yield).Atty. Dkt. No.: 052209-0603 [M+H]+ = 388.1. 1H NMR (400MHz, CHLOROFORM-d) δ ppm 7.40 - 7.29 (m, 5H), 5.99 (br s, 1H), 5.06 (s, 2H), 2.97 - 2.80 (m, 2H), 2.68 (q, J = 7 Hz, 1H), 2.05 - 1.95 (m, 4H), 1.72 - 1.59 (m, 1H), 1.51 - 1.42 (m, 10H), 1.16 (d, J = 7 Hz, 3H).

[0213] Procedure of step 7f

[0214] To a mixture of (7S-1) (3.7 g, 9.55 mmol, 1 eq) and 4A MS (2 g, 1.00 eq) in EtOH (50 mL) was added NH2NH2.WATER (9.26 g, 184.98 mmol, 13.97 eq) in one portion at 20 °C. The mixture was heated to 80 °C and stirred for 60 hours. The mixture was filtered and concentrated in vacuum and purified by prep-HPLC (column: Agela DuraShell C18250*70mm*10um; mobile phase: [WATER (10mM NH4HCO3)-ACN]; gradient: 50%-80% B over 17.0 min) to give (7S-2) (0.9 g, 2.24 mmol, 23.47% yield). [M+H]+ = 402.3. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.29 - 7.39 (m, 5 H) 6.48 (s, 1 H) 5.05 (s, 4 H) 2.94 (q, J = 6.72 Hz, 1 H) 2.73 - 2.86 (m, 2 H) 2.00 - 2.16 (m, 1 H) 1.83 - 1.97 (m, 2 H) 1.64 - 1.76 (m, 1 H) 1.43 - 1.48 (m, 11 H) 1.18 (d, J = 6.97 Hz, 3 H).

[0215] Procedure of step 7g

[0216] To a solution of (7S-2) (0.9 g, 2.24 mmol, 1 eq) in THF (2.5 mL) and piperidine (3 mL) was added I2(1.42 g, 5.60 mmol, 2.5 eq) in THF (3.5 mL) at 0 °C under N2. The resulting mixture was stirred at 25°C for 0.5 hr. After the reaction was completed, the mixture was poured into WATER (30 mL) and extracted with ethyl acetate (30 mL*3). The organic phase was washed with brine (20 mL*2), dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 9 / 1) to give (7-1A) (646 mg, 1.30 mmol, 57.94% yield). [M+H]+= 498.1.

[0217] Scheme 8. Synthesis of TG2, TG3 seriesAtty. Dkt. No.: 052209-0603-Atty. Dkt. No.: 052209-0603

[0219] Synthesis of 8b-1

[0221] General procedure of step 8a

[0222] To a mixture of (8-1) / (8-1A) (1 eq) and (INT 8a) (1.2 eq) in DME and WATER was added K2CO3 (3 eq) and Pd(PPh3)4 (0.1 eq) in one portion under N2. The mixture was stirred at (see details in Table 6). The residue was poured into water and stirred for 5 min. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, driedAtty. Dkt. No.: 052209-0603 with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified column chromatography or used as is for next step to give (8-2).

[0223] Table 6: Detailed conditions: (all reactions conducted under nitrogen gas)Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603acid;hydrochloride, Cs2CO3

[0224] General procedure of step 8b-1

[0225] To a mixture of (8-2) / (8b-1) / (7-2) (1 eq) in THF was added Pd-catalyst (10 wt%, 20% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2(15 Psi) (see details in Table 7). The mixture was filtered andAtty. Dkt. No.: 052209-0603 concentrated in vacuum. The residue was purified by column chromatography or used as is for next stepto give (8-3).

[0226] General procedure of step 8b-2

[0227] To a solution of (8-2) / (8b-1) / (7-2) (1 eq) in EtOH was added NH2NH2.WATER (6.26 eq). The mixture was stirred at 25°C for 12 hours under air (see details in Table 7). The mixture was concentrated in vacuum. The residue was used to next step without purification to give (8-3).

[0228] Table 7: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603A : Pd(OH)2, H2, THF; B:Pd / C, Pd(OAc)2, H2, MeOH, NH3.WATER; C:Pd / C, H2, THF; D:Pd / C, H2,EtOH; E:Pd / C, H2, MeOH, NH3.WATER, F: NH2NH2.WATER, EtOH; *: under oxygen gas

[0229] General procedure of step 8c-1

[0230] To a mixture of (8-3) (1 eq), DIEA (3 eq) and (INT 3 / INT 5 / INT 6) (1.2 eq) in DMF was added HATU (1.5 eq) in one portion at 20 °C. The mixture was stirred (see details in Table 8). The residue was poured into water and stirred for 5 min. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography or used as is for next stepto give (8-4).

[0231] General procedure of step 8c-2

[0232] To a solution of (8-3) (1 eq) and acyl chloride (1.2 eq) in DCM was added TEA (3 eq) under N2. The mixture was stirred (see details in Table 8). The mixture was filtered andAtty. Dkt. No.: 052209-0603 concentrated in vacuum. The residue was purified by column chromatography or used as is for next stepto give (8-4).

[0233] Table 8: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603-137-Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0234] General procedure of step 8d-1

[0235] To a mixture of (8-4) (1 eq) in a mixture of solvents (DCM / TFA in a 4:1 ratio) was stirred at M°C for N hour. After the reaction was completed, the mixture was concentrated in vacuum. The residue was purified by prep-HPLC to give (TG2). (Select compounds are shown in Table 9.)

[0236] General procedure of step 8d-2

[0237] To a mixture of (8-4) (1 eq) in a mixture of solvents (HCl / WATER in a 1:1 ratio) was added NaNO2 (1.1 eq) for 10 min at 0 °C under N2. The mixture was added CuCl (10 eq). Then the mixture was stirred at M°C for N hour. The mixture was concentrated in vacuum. The crude product was purified by prep-HPLC to give (TG2). (Select compounds are shown in Table 9.)

[0238] Table 9: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603*only this compound was synthesized using this condition.

[0239] General procedure of step 8e

[0240] Selected compounds from TG2 series were separated by prep-SFC to afford the single enantiomers in the TG3 series (absolute stereochemistry not yet assigned) (Table 10).

[0241] Table 10: Detailed conditions: (*indicates an arbitrary stereochemistry assignment was made to distinguish different isomers that were isolated; absolute stereochemistry was not determined and may not match the depicted stereochemistry).Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0242] Procedure of step 8f

[0243] To a mixture of (INT 2) (2 g, 4.14 mmol, 1 eq) in toluene (40 mL) was added 1,1,1,2,2,2-hexamethyldistannane (4.33 g, 13.22 mmol, 3.19 eq). The suspension was degassed under vacuum and purged with N2 three times. Pd(PPh3)4 (478.16 mg, 413.79 μmol, 0.1 eq) was added to the mixture, then the suspension was degassed under vacuum and purged with N2 threeAtty. Dkt. No.: 052209-0603 times. The mixture was stirred at 80 °C for 12 h. The mixture was quenched by addition of water (100 mL). The mixture was extracted with ethyl acetate (100 mL*3). The organic phase was washed with brine (100 mL) and dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 5 / 1) to give (8-1A) (600 mg, 1.15 mmol, 27.87% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.32 - 7.39 (5 H, m) 6.51 (1 H, s) 5.07 (2 H, s) 1.82 - 1.90 (2 H, m) 1.73 - 1.82 (2 H, m) 1.62 - 1.72 (2 H, m) 1.49 - 1.55 (2 H, m) 1.48 (9 H, s) 0.06 - 0.22 (9 H, m).

[0244] General procedure of step 8g

[0245] To a mixture of Et3SiH (10 eq), TEA (1 eq) in DCM was added Pd(OAc)2(1 eq) under N2. The mixture was stirred at 25°C for 15 mins. Then, a solution of (8-2) (1 eq) in DCM was added to the mixture. The mixture was stirred at 25 (°C) for 12 hr. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography or used as is for next stepto give (8b-1).

[0246] Table 11:

[0247] Procedure of step 8h

[0248] A mixture of (8-4AF) (167 mg, 225.46 mol, 1 eq) in DCM (7 mL) and TFA (3.21 g, 28.19 mmol, 125.05 eq) was stirred at 20 °C for 1 hour. The mixture was concentrated in vacuum. The residue was used without purification to give (8d-1) (217 mg, crude, TFA). [M+H]+= 586.1.Atty. Dkt. No.: 052209-0603 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.95 (br s, 2 H) 7.39 - 7.82 (m, 9 H) 7.14 (br s, 1 H) 4.16 - 4.38 (m, 1 H) 2.91 - 3.15 (m, 1 H) 2.32 - 2.59 (m, 3 H) 2.07 - 2.29 (m, 4 H) 1.94 - 2.05 (m, 1 H) 1.75 - 1.93 (m, 2 H) 1.63 (br s, 2 H).

[0249] Scheme 9. Synthesis of TG4 series

[0250] General procedure of step 9a

[0251] To a mixture of (9-1) (1 eq) and boronic acid (3 eq) in toluene and water was added Pd(OAc)2(0.2 eq), PCy3(0.2 eq) and K3PO4(5 eq). The reaction mixture was stirred (see details in Table 12). After the reaction was completed, the mixture was diluted with EtOAc filtered and concentrated in vacuum. The residue was purified by column chromatography or used as is for next stepto give (9-2).Atty. Dkt. No.: 052209-0603

[0252] Table 12: Detailed conditions: (all reactions conducted under nitrogen gas)Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603 A: Pd(OAc)2, PCy3, K3PO4; B: Pd(dppf)Cl2, K2CO3; C: Pd(PPh3)4, K2CO3; D: Pd(dppf)Cl2.CH2Cl2, Cs2CO3

[0253] General procedure of step 9b-1

[0254] To a mixture of (9-2) (1 eq) and Fe (5 eq) in a mixture of solvents (EtOH / WATER in a 2:1 ratio) was added NH4Cl (10 eq). Then the mixture was stirred (see details in Table 13). After the reaction was completed, the mixture was diluted with EtOAc and WATER and filtered. The aqueous layer was extracted with EtOAc. The combined organic layers was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography or used as is for next stepto give (9-3).

[0255] General procedure of step 9b-2

[0256] To a mixture of (9-2) (1 eq) in EtOH was added Pd / C (10 wt%, 10% purity). The suspension was degassed under vacuum and purged with H2 several times.The mixture was stirred (see details in Table 13). The mixture was filtered. The filtrate was concentrated in vacuum. The residue was purified by column chromatography or used as is for next stepto give (9-3).

[0257] Table 13: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0258] General procedure of step 9c-1

[0259] To a mixture of (9-3) (1 eq), INT 4 (1 eq), and CDI (1 eq) in DMF was added t-BuOK (1.5 eq). The reaction was stirred (see details in Table 14). After the reaction was completed, the reaction was quenched by the addition of water. The mixture was extracted with EtOAc. The organic phase was washed with brine and dried with Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography or used as is for next stepto give (9-4).

[0260] General procedure of step 9c-2

[0261] To a mixture of (9-3) (18 mg, 50.08 μmol, 1 eq) and INT 3 (20.56 mg, 60.09 μmol, 1.2 eq) in DMF (1 mL) was added DIEA (19.42 mg, 150.23 μmol, 3 eq) in one portion. Then HATU (28.56 mg, 75.11 μmol, 1.5 eq) was added to the mixture. The mixture was stirred at 70 °C for 12 h. The mixture was added dropwise into water (10 mL). The mixture extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filterd and concentrated in vacuum. The product was purified by prep-TLC (Petroleum ether: Ethyl acetate=1.5:1, Rf = 0.35). To afford (9-4) (20 mg, 29.26 umol, 58.42% yield) (see details in Table 14).Atty. Dkt. No.: 052209-0603

[0262] Table 14: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0263] General procedure of step 9d-1

[0264] To a mixture of (9-4) (1 eq) and LiOH monohydrate (3 eq) in a mixture of solvents (MeOH / THF / WATER in a 1:1:1 ratio) was stirred (see details in Table 15). After the reaction was completed, the mixture was concentrated and purification by prep-HPLC to give TG4 series (selected compounds in Table 15).Atty. Dkt. No.: 052209-0603

[0265] Table 15: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0266] Scheme 10. Synthesis of TG5 series

[0267] General procedure of step 10a

[0268] To a mixture of (10-1) (1 eq) and boronic acid building block (1 eq) in a mixture of solvents (DME / WATER in a 10:1 ratio) was added K2CO3 (3 eq) and the mixture was purged with N2 for 3 times. Then Pd(dppf)Cl2 (0.1 eq) was added and the resulting mixture was purged with N2for 3 times again. The reaction was heated to 100 °C and stirred for N h (see details in Table 16). After the reaction was completed and cooled to room temperature, the mixture was diluted with ethyl acetate. The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography or used as is for next step to give (10-2).

[0269] Table 16: Detailed conditions: (all reactions conducted under nitrogen gas)Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603A: Pd(dppf)Cl2, K2CO3; B: Pd(PPh3)4, K2CO3;

[0270] General procedure of step 10b

[0271] To a mixture of aniline (10-2) (1 eq) and INT 1 / INT 2 / INT 3 (1 eq) in DMF was added t-BuOK (1.5 eq). The reaction was stirred at M°C under N2for 12 h. After the reaction was completed, the reaction was quenched by the addition of water. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate,Atty. Dkt. No.: 052209-0603 filtered and concentrated to give a residue which was purified by column chromatography or used as is for next step to give (10-3). (Other compounds prepared in a similar fashion are shown in Table 17.)

[0272] Table 17: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0273] General procedure of step 10c

[0274] To a solution of (10-3) (1 eq) in a mixture of solvents (MeOH / THF / WATER in a 1:1:1 ratio) was added LiOH.WATER (3 eq). The reaction was stirred at M°C for 12 h. After the reaction was completed, the reaction mixture was concentrated directly to give a residue which was purified by prep-HPLC to give TG5 (select compounds in Table 18).Atty. Dkt. No.: 052209-0603

[0275] Table 18: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0276] Scheme 11. Synthesis of TG6 series

[0278] Procedure of step 11a

[0279] To a solution of (11-1) (1 g, 2.68 mmol, 1 eq) in THF (50 mL) was added Pd(OH)2 (350 mg, 20% purity) under N2. The suspension was degassed under vacuum and purged with H2Atty. Dkt. No.: 052209-0603 several times. The mixture was stirred under H2(15 Psi) at 20 °C for 1.5 hr. After the reaction was completed, the mixture was filtered and concentrated in vacuum to give a residue. WATER (41 mL) was added to the residue, and the resulting mixture was adjusted to pH = 1 with HCl (1.2 M). The aqueous layer was washed with ethyl acetate (60 mL*2), and the aqueous layer was lyophilized to give (11-2) (590 mg, 2.14 mmol, 79.90% yield, HCl). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.72 (s, 2 H) 2.11 - 2.25 (m, 4 H) 1.92 - 2.06 (m, 4 H) 1.46 (s, 9 H).

[0280] Procedure of step 11b

[0281] To a mixture of (11-2) (590 mg, 2.14 mmol, 1 eq, HCl), DIEA (829.53 mg, 6.42 mmol, 3 eq) and (INT 3) (732.09 mg, 2.14 mmol, 1 eq) in DMF (26 mL) was added HATU (1.22 g, 3.21 mmol, 1.5 eq) in one portion at 20 °C. The mixture was heated to 60 °C and stirred for 12 hours. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL*2). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) and prep-TLC (Petroleum ether: Ethyl acetate = 2:1) to afford (11-3) (980 mg, 1.74 mmol, 81.29% yield). [M+H]+= 565.2.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.02 (br d, J = 8.77 Hz, 1 H) 7.92 (s, 1 H) 7.76 (dd, J = 8.99, 1.97 Hz, 1 H) 7.44 - 7.58 (m, 5 H) 7.04 (br s, 1 H) 3.29 - 3.42 (m, 2 H) 2.73 (s, 2 H) 2.39 (s, 3 H) 2.23 - 2.34 (m, 2 H) 1.95 - 2.04 (m, 2 H) 1.88 (br t, J = 11.07 Hz, 2 H) 1.48 (s, 9 H).

[0282] Procedure of step 11c

[0283] A mixture of (11-3) (850 mg, 1.51 mmol, 1 eq) in DCM (20 mL) was added TFA (5 mL) was stirred at 20 °C for 2 hr. After the reaction was completed, the reaction was concentrated in vacuum to afford (11-4) (1 g, crude). [M+H]+ = 509.1.1H NMR (400 MHz, METHANOL-d4) δ ppm 8.74 (s, 1 H) 8.05 (s, 2 H) 7.64 (s, 5 H) 2.99 (s, 1 H) 2.86 (s, 1 H) 2.76 - 2.83 (m, 2 H) 2.49 (s, 3 H) 2.21 - 2.31 (m, 4 H) 2.03 - 2.12 (m, 2 H).

[0284] General procedure of step 11d

[0285] To a mixture of (11-4) (1 eq) and hydroxylamine (HCl salt) (6 eq) in EtOAc was added pyridine (10 eq) in one portion. The mixture was stirred at M°C for N hours. After the reactionAtty. Dkt. No.: 052209-0603 was completed, the mixture was washed with HCl (1 M). The organic phase was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC to give (TG6) (select compounds in Table 19).

[0286] Table 19: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0287] Procedure of step 11e

[0288] To a solution of (TG6-16) (0.18 g, 265.65 μmol, 1 eq) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give (TG6-18) (29.4 mg, 48.40 μmol, 18.22% yield, 95.07% purity). [M+H]+= 579.1.1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 - 8.61 (m, 1 H) 8.29 (d, J = 2.00 Hz, 1 H) 7.93 - 8.00 (m, 1 H) 7.83 -7.91 (m, 1 H) 7.47 - 7.62 (m, 5 H) 5.10 - 5.28 (m, 1 H) 3.92 (br s, 2 H) 3.70 (br dd, J = 9.57, 4.19 Hz, 2 H) 2.71(br s, 2 H) 2.37 (s, 3 H) 1.59 - 2.13 (m, 8 H).

[0289] Procedure of step 11f-1

[0290] To a solution of (TG6-18) (0.25 g, 361.54 μmol, 1 eq, TFA) in THF (2 mL) and WATER (0.7 mL) was added Na2CO3(268.23 mg, 2.53 mmol, 7 eq) and CbzOSu (99.11 mg, 397.69 μmol, 1.1 eq), the mixture was stirred at 25°C under N2 for 2 h. The mixture was poured into ice-water (15 mL). The mixture was extracted with ethyl acetate: THF=1:1 (15 mL*3). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to give a residue which was purified by prep-HPLC to give (TG6-19) (29.98 mg, 40.87 μmol, 11.30% yield, 97% purity). [M+H]+ = 712.9.1H NMR (400 MHz, DMSO-d6) δ ppmAtty. Dkt. No.: 052209-0603 12.83 - 12.22 (m, 1H), 8.66 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.99 - 7.94 (m, 1H), 7.88 (dd, J = 2.1, 8.9 Hz, 1H), 7.60 - 7.47 (m, 5H), 7.38 - 7.27 (m, 5H), 5.20 - 5.11 (m, 1H), 4.99 (s, 2H), 4.23 (br s, 2H), 3.93 (br s, 2H), 2.73 (br s, 2H), 2.38 (s, 3H), 2.06 - 1.73 (m, 6H).

[0291] Procedure of step 11f-2

[0292] To a solution of (TG6-18) (0.3 g, 433.85 μmol, 1 eq, TFA) in DCM was added TEA (219.50 mg, 2.17 mmol, 5 eq) and MsCl (0.14 g, 1.22 mmol, 2.82 eq). The mixture was stirred at 15°C under N2for 1 h. The mixture was poured into ice-water (15 mL). The mixture was extracted with DCM (15 mL*3). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to give a residue which was purified by prep-HPLC to give (TG6-20) (40 mg, 60.29 μmol, 13.90% yield, 98.803% purity). [M+H]+ = 656.9. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.36 (d, J = 2.0 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.89 - 7.81 (m, 1H), 7.60 - 7.44 (m, 5H), 5.30 - 5.20 (m, 1H), 4.20 (dd, J = 6.7, 9.3 Hz, 2H), 4.04 (dd, J = 4.4, 9.3 Hz, 2H), 2.99 - 2.84 (m, 5H), 2.42 (s, 4H), 2.28 - 2.07 (m, 5H), 2.02 - 1.86 (m, 2H).Atty. Dkt. No.: 052209-0603

[0293] Scheme 12. Synthesis of TG7 seriesAtty. Dkt. No.: 052209-0603

[0295] Synthesis of 12-3A

[0297] General procedure of step 12a

[0298] To a mixture of LDA (2 M, 1.1 eq) in THF was added the solution of (12-1) (1 eq) in THF at -75°C under N2. The mixture was stirred at -75°C for 0.5 h. Additional THF was added to the reaction, followed by addition of a solution of methyl prop-2-enoate (2.2 eq) in THF. The mixture was stirred at -75°C for 12 h. After the reaction was completed, the mixture was poured into NH4Cl (sat.). The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC to give (12-2). (see details in Table 20).Atty. Dkt. No.: 052209-0603

[0299] Table 20: Detailed conditions:

[0300] General procedure of step 12b

[0301] To a mixture of (12-2) (1 eq) in DMSO was added NaCl (11 eq) and WATER. The mixture was stirred at 150 °C for 6 hr. After the reaction was completed, the mixture was poured into WATER and extracted with ethyl acetate. The organic phase was washed with brine and dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography or used as is for next step to give (12-3). (see details in Table 21)

[0302] Table 21: Detailed conditions:Atty. Dkt. No.: 052209-0603

[0303] General procedure of step 12c

[0304] To a mixture of (12-3) (1 eq) in MeOH was added NH4OAc (10 eq) at 20 °C under N2. The mixture was stirred at 20 °C for 30 min. Then, NaBH3CN (3 eq) was added to the mixture. The mixture was stirred at 20 °C for 12 hr. After the reaction was completed, the reaction was poured into NaHCO3 (sat.) and ethyl acetate, separated layers and the organic phase was washed with NaHCO3 (sat.). The organic phase was then washed with brine and dried over Na2SO4, filtered and concentrated to give (12-4). (see details in Table 22)

[0305] Table 22: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0306] General procedure of step 12d-1

[0307] To a mixture of methyl (12-4) (1 eq) in DCM was added TEA (3 eq). Then, INT 4 (1.1 eq) was added to the mixture. The mixture was stirred at 20 °C for 2 hr. After the reaction was completed, the reaction was concentrated directly to give a residue which was purified by column chromatography or used as is for next step to give (12-5). (see details in Table 23)

[0308] Procedure of step 12d-2

[0309] To a mixture of (12-4) (630 mg, 1.81 mmol, 1 eq) and INT 3 (620.67 mg, 1.81 mmol, 1 eq) in DMF (10 mL) was added DIEA (703.28 mg, 5.44 mmol, 3 eq) and HATU (1.03 g, 2.72 mmol, 1.5 eq) in one portion at 20 °C under N2. The mixture was stirred at 70 °C for 12 hours. The reaction mixture was quenched by addition of water (10 mL). The mixture was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a residue which was purified by prep-TLC (Petroleum ether : Ethyl acetate = 3:1, Rf=0.37) to give (12-5) (1.17 g, crude). (see details in Table 23)

[0310] Procedure of step 12d-3

[0311] To a mixture of (12-4) (1.55 g, 2.58 mmol, 1 eq) and 3,3-difluoroazetidine hydrochloride (2.01 g, 15.50 mmol, 6 eq, HCl) in DMA (50 mL) was added DIEA (4.01 g, 31.01 mmol, 12 eq). The mixture was stirred at 100 °C for 12 h. The mixture was poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (200 mL*3). The combined organic phase was washed with brine (200 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1) to afford (12-5) (1.25 g, 1.90 mmol, 73.69% yield). (see details in Table 23)Atty. Dkt. No.: 052209-0603

[0312] Table 23: Detailed conditions:Atty. Dkt. No.: 052209-0603

[0313] General procedure of step 12e

[0314] To a mixture of (12-5) (1 eq) in a mixture of solvents (MeOH / THF / WATER in a 1:1:1 ratio) was added LiOH.WATER (3 eq). The mixture was stirred at 20 °C for 2 hr. After the reaction was completed, the reaction was concentrated directly to give residue which was purified by prep- HPLC to give (TG7). (see details in Table 24)Atty. Dkt. No.: 052209-0603

[0315] Table 24: Detailed conditions:Atty. Dkt. No.: 052209-0603

[0316] General procedure of step 12f

[0317] (TG7) was separated by prep-SFC to provide the following isomers (absolute stereochemistry was not assigned).

[0318] Table 25: Detailed conditions: (*indicates an arbitrary stereochemistry assignment was made to distinguish different isomers that were isolated; absolute stereochemistry was not determined and may not match the depicted stereochemistry).Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0319] General procedure of step 12g

[0320] To a mixture of (12S-1) (20 g, 109.2 mmol, 1 eq) in EtOH was added KOH (26.2 g, 655.2 mmol, 6 eq). The mixture was stirred at 100 °C for 12 h. The mixture was added to water (1 L). The aqueous phase was adjust to pH = 1 with HCl (2 M). The aqueous phase was extracted with ethyl acetate (200 mL*5). The combined organic phase was washed with brine (1000 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna c18250mm*100mm*10um; mobile phase: [water (TFA)- ACN]; B%: 15%-45%, 20min) to afford (12S-2) (13 g, 64.31 mmol, 58.89% yield). [M+H]+ = 201.11H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (1 H, br s) 7.30 - 7.38 (2 H, m) 7.15 - 7.23 (2 H, m) 6.93 - 7.14 (1 H, m) 3.61 (2 H, s)

[0321] Genral procedure of step 12h

[0322] To a mixture of (12S-2) (1 eq) and K2CO3(3 eq) in DMF was added iodomethane (2 eq). The mixture was stirred at 20 °C for 3 h. The mixture was added to water. The aqueous phaseAtty. Dkt. No.: 052209-0603 was extracted with ethyl acetate. The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was used directly without purification. (12-1) was obtained. (see details in Table 26)

[0323] Table 26: Detailed conditions:

[0324] Procedure of step 12i

[0325] To a mixture of (12S-3) (10 g, 58.75 mmol, 9.35 mL, 1 eq) in toluene (500 mL) was added NBS (10.46 g, 58.75 mmol, 1 eq) and PTSA (1.01 g, 5.87 mmol, 0.1 eq). The mixture was stirred at 115°C for 12 hours under N2. The mixture was diluted with ethyl acetate (300 mL). The combined organic phase was washed with brine (200 mL) and NaHCO3 (sat., 200 mL), dried over sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (SiO2,Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1) to give (12S-4) (31.8 g, 127.66 mmol, 43.46% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.43 - 4.50 (m, 1 H) 4.18 (q, J = 7.07 Hz, 2 H) 3.02 - 3.22 (m, 2 H) 2.36 - 2.56 (m, 3 H) 2.25 - 2.35 (m, 1 H) 1.85 - 2.00 (m, 1 H) 1.26 - 1.31 (m, 3 H).Atty. Dkt. No.: 052209-0603

[0326] Procedure of step 12j

[0327] To a mixture of 2-(trifluoromethoxy) phenol (2.32 g, 13.00 mmol, 1 eq) in DMF (170 mL) was added KOH (765.79 mg, 13.65 mmol, 1 eq). The mixture was stirred at 25°C for 15 min. (12S-4) (3.4 g, 13.65 mmol, 1 eq) was added to the reaction. The mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by addition of water (150mL). The mixture was extracted with ethyl acetate (150 mL*2), dried over sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 0 / 1 to 2 / 1) ) to give (12-3A) (20 g, 57.75 mmol, 84.63% yield). [M+H]+= 347.0.1H NMR (400 MHz, METHANOL-d4) δ ppm 7.17 - 7.32 (m, 2 H) 6.90 - 7.03 (m, 2 H) 5.07 (dd, J = 12.17, 6.17 Hz, 1 H) 4.13 - 4.23 (m, 2 H) 3.02 - 3.17 (m, 1 H) 2.62 - 2.76 (m, 2 H) 2.44 - 2.53 (m, 1 H) 2.35 (dtd, J = 13.19, 6.33, 2.87 Hz, 1 H) 2.01 (s, 1 H) 1.79 - 1.90 (m, 1 H) 1.25 - 1.29 (m, 3 H)

[0328] Procedure of step 12k

[0329] To a mixture of (12-4C) (1.5 g, 4.73 mmol, 1 eq) and INT 7 (1.51 g, 4.73 mmol, 1 eq) in DCM (40 mL) was added NaHCO3(1 M, 10 eq) in one portion at 20 °C. The mixture was stirred at 20 °C for 12 hr. The reaction mixture was quenched by addition of water (100 mL). The residue was extracted with DCM (30 mL*3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1) to afford (12d-1) (1.6 g, 2.67 mmol, 56.43% yield). [M+H]+= 601.0.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.62 - 7.86 (m, 3 H) 7.28 - 7.55 (m, 4 H) 5.55 (br d, J = 8.76 Hz, 1 H) 4.41 - 4.70 (m, 1 H) 3.69 - 3.75 (m, 3 H) 3.02 - 3.29 (m, 1 H) 2.43 - 2.63 (m, 2 H) 2.18 - 2.42 (m, 3 H) 1.76 - 1.93 (m, 3 H) 1.59 - 1.69 (m, 1 H).Atty. Dkt. No.: 052209-0603

[0330] Scheme 13. Synthesis of TG8

[0331] General procedure of step 13a

[0332] To a mixture of (13-1) (1 eq) in DCM was added NaHCO3 (2 eq) and m-CPBA (85% purity, 1.5 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. After the reaction was completed, the reaction mixture was poured into Na2CO3 (sat.) and stirred for 10 min. Then the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography or used as is for next step to give (13-2). (see details in Table 27)Atty. Dkt. No.: 052209-0603

[0333] Table 27: Detailed conditions:

[0334] General procedure of step 13b

[0335] A mixture of Pd(OAc)2 (0.2 eq), Et3SiH (3 eq) and TEA (3 eq) in DCM was stirred at 20 °C for 15 min. The mixture was added a solution of (13-2) (1 eq) in DCM at 20 °C under N2. The mixture was stirred at 20 °C for 12 hours. After the reaction was completed, the reaction mixture was filtered and the filtrate was dissolved in THF and then acidified to pH = 5 using TFA. After stirring for 10 min, the mixture was poured into NaHCO3(sat.). The resulting mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography or used as is for next stepto give (13-3). (see details in Table 28)Atty. Dkt. No.: 052209-0603

[0336] Table 28: Detailed conditions:

[0337] Procedure of step 13c-1

[0338] To a mixture of (13-3) (110 mg, 348.76 μmol, 1 eq) and INT 3 (119.34 mg, 348.76 μmol, 1 eq) in DMF (3 mL) was added DIEA (135.22 mg, 1.05 mmol, 3 eq) and HATU (198.91 mg, 523.14 mol, 1.5 eq) in one portion. Then the mixture was stirred at 20 °C for 12 h. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with with ethyl acetate (30 mL*2). The combined organic phase was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to give a residue which was purified by prep-TLC (Petroleum ether : Ethyl acetate = 2 : 1, Rf = 0.30) to give (13-4A) (130 mg, 203.26 μmol, 58.28% yield). (see details in Table 29)

[0339] Procedure of step 13c-2

[0340] To a mixture of (13-3) (150 mg, 375.56 μmol, 1 eq) in DCM (3 mL) was added INT 4 (162.53 mg, 450.67 μmol, 1.2 eq) and TEA (114.01 mg, 1.13 mmol, 3 eq). The mixture was stirred at 25°C for 1 hr. The mixture was concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 3:1, Rf=0.35) to afford (13-4B) (50 mg, 69.10 μmol, 18.40% yield). (see details in Table 29)Atty. Dkt. No.: 052209-0603

[0341] Table 29: Detailed conditions:

[0342] General procedure of step 13d-1

[0343] (13-4) (1 eq) in a mixture of solvents (DCM / TFA in a 4:1 ratio) was stirred at 20 °C for 20 min. After the reaction was completed, the reaction mixture was concentrated to give a residue which was purified by prep-HPLC to give (TG8).

[0344] General procedure of step 13d-2

[0345] (TG8) were separated by prep-SFC to afford (TG8). (absolute stereochemistry not yet assigned)

[0346] Table 30: Detailed conditions: (*indicates an arbitrary stereochemistry assignment was made to distinguish different isomers that were isolated; absolute stereochemistry was not determined and may not match the depicted stereochemistry).Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0347] Scheme 14. Synthesis of TG9 seriesAtty. Dkt. No.: 052209-0603

[0350] Synthesis of (14-1B)

[0351] General procedure of step 14a

[0352] To a mixture of INT 2 (1 eq) and (INT 14a) (1.5 eq) in dioxane was added Cs2CO3(2.1 eq), CuI (0.1 eq) and N,N-dimethylglycine hydrochoride (0.3 eq) under N2. The reaction was purged with N2 for 3 times and then heated to M°C for N h (see details in Table 31). After the reaction was completed, the reaction was poured to water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a residue which was purified by prep-TLC / prep-HPLC / column chromatography to give (14-1).Atty. Dkt. No.: 052209-0603

[0353] Table 31: Detailed conditions: (all reactions conducted under nitrogen gas)Atty. Dkt. No.: 052209-0603A: CuI, N,N-dimethylglycine hydrochloride, Cs2CO3, dioxane; B: Pd(dppf)Cl2, K2CO3, DME, WATER; C: bis[(tetrabutylammoniumiodide)copper(I)], Cs2CO3, DMEDA, toluene;Atty. Dkt. No.: 052209-0603 D: bis[(tetrabutylammoniumiodide)copper(I)], 1,10-phenanthroline, Cs2CO3, DMSO; E: CuiBuCx2, Cs2CO3, dioxane

[0354] General procedure of step 14b-1

[0355] To a solution of (14-1) (1 eq) in EtOH and NH3.WATER was added Pd / C (10 wt%, 10% purity) under N2.The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 Psi) at 25°C for N hours (see details in Table 32). The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography or used as is for next step to afford (14-2).

[0356] Procedure of step 14b-2

[0357] To a solution of TEA (8.80 g, 86.95 mmol, 3 eq) and Et3SiH (16.85 g, 144.92 mmol, 5 eq) in DCM (316 mL) was added Pd(OAc)2 (650.71 mg, 2.90 mmol, 0.1 eq). The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 20 °C for 30 min. A solution of (14-1) (15 g, 28.98 mmol, 1 eq) in DCM (158 mL) was added the mixture was stirred at 20 °C under N2for 12 h. The mixture was concentrated in vacuum. The residue was diluted with THF (90 mL). The mixture was adjusted to pH = 5 with TFA. Then the mixture was added dropwise into NaHCO3(sat., 150 ml). The mixture was extracted with ethyl acetate (60 mL*3). The combined organic phase was washed with brine (80 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to afford (14-2) (9 g, 23.47 mmol, 80.99% yield) (see details in Table 32).Atty. Dkt. No.: 052209-0603

[0358] Table 32: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0359] General procedure of step 14c-1

[0360] To a mixture of (14-2) (1 eq) in DCM was added TEA (3 eq) and INT 4 (1.1 eq) at 25°C under N2. The mixture was stirred at M°C for N hour (see details in Table 33). The reaction mixture was quenched by addition WATER. The residue was extracted with DCM. The combined organic layers was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography or used as is for next step to afford (14-3).

[0361] General procedure of step 14c-2

[0362] To a mixture of INT 3 / INT 5 / (20-1E) (1.1 eq) and DIEA (3 eq) in DMF was added HATU (1.5 eq) in one portion at 20 °C under N2. Then, (14-2) (1 eq) was added to the reaction. The mixture was stirred at M°C for N hours (see details in Table 33). Water was added to the mixture. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography or used as is for next step or used as is for next step to afford (14-3).

[0363] General procedure of step 14c-3

[0364] To a mixture of (14c-1) (1 eq) and 3,3-difluoroazetidine hydrochloride (5 eq) in DMA was added DIEA (5 eq) in one portion at 20 °C under N2. The mixture was heated to M°C and stirred for N hours. The reaction mixture was poured into water. The residue was extracted with ethyl acetate. The combined organic layers was washed with brine, dried over Na2SO4, filtered andAtty. Dkt. No.: 052209-0603 concentrated in vacuum. The crude product was purified by column chromatography or used as is for next step / prep-HPLC to afford (14-3) (see details in Table 33).

[0365] Table 33: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0366] General procedure of step 14d

[0367] To a mixture of (14-3) (1 eq) in a mixture of solvents (DCM / TFA in a 4:1 ratio). The mixture was stirred at 25°C for N hr (see details in Table 34). The mixture was concentrated in vacuum. The residue was purified by prep-HPLC to afford (TG9).

[0368] Table 34: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0369] General procedure of step 14e

[0370] Selected compounds from (TG9) were separated by prep-SFC to afford the single enantiomers in the (TG9) (see details in Table 35) (absolute stereochemistry not yet assigned).

[0371] Table 35: Detailed conditions: (*indicates an arbitrary stereochemistry assignment was made to distinguish different isomers that were isolated; absolute stereochemistry was not determined and may not match the depicted stereochemistry).Atty. Dkt. No.: 052209-0603-237-Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0372] General procedure of step 14f

[0373] To a mixture of (14-3) (1 eq) and INT 7 (1.1 eq) in DCM was added NaHCO3(1 M, 2 eq) in one portion at 20 °C. The mixture was stirred at M°C for 12 hours (see details in Table 36). The reaction mixture was added WATER. The residue was extracted with DCM. The combined organic layers was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography or used as is for next step to afford (14c-1).

[0374] Table 36: Detailed conditions:Atty. Dkt. No.: 052209-0603

[0375] Procedure of step 14gAtty. Dkt. No.: 052209-0603

[0376] To a mixture of benzyl alcohol (8.98 g, 83.02 mmol, 4 eq) in DMF (20 mL) was added NaH (1.66 g, 41.51 mmol, 60% purity, 2 eq) at 0 °C under N2. The mixture was stirred at 0 °C for 30 min. Then a solution of (14S-1) (4.1 g, 20.76 mmol, 1 eq) in DMF (5 mL) was added to the reaction. The mixture was stirred at 25°C for 2 hr. The mixture was added dropwise into WATER (50 mL). The mixture was extracted with ethyl acetate (50 mL*2). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to afford (14S-2) (4.5 g, 16.72 mmol, 80.53% yield). [M+H]+= 270.2.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.11 (dd, J = 4.95, 1.41 Hz, 1 H) 7.53 (d, J = 7.82 Hz, 1 H) 7.46 - 7.51 (m, 2 H) 7.36 - 7.43 (m, 2 H) 7.31 - 7.36 (m, 1 H) 6.93 (dd, J = 7.82, 5.01 Hz, 1 H) 5.50 (s, 2 H).

[0377] Procedure of step 14h

[0378] To a mixture of (14S-2) (4.5 g, 16.72 mmol, 1 eq) in EtOH (2 mL) was added Pd / C (250 mg, 10% purity) in one portion under N2. The suspension was degassed with vacuum and purged with H2(15 Psi) several times. The mixture was stirred at 25°C for 3 hr. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 9 / 1 to 0 / 1) to afford (14-1A) (2.5 g, 13.96 mmol, 83.51% yield). [M+H]+= 180.1.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.80 - 13.83 (m, 1 H) 7.48 (br d, J = 7.39 Hz, 1 H) 7.43 (br d, J = 5.72 Hz, 1 H) 6.33 (t, J = 6.91 Hz, 1 H).

[0379] Procedure of step 14j

[0380] To a mixture of (14S-3) (5.48 g, 16.94 mmol, 1 eq) and BPD (5.16 g, 20.33 mmol, 1.2 eq) in dioxane (54.8 mL) was added KOAc (4.99 g, 50.83 mmol, 3 eq) in one portion. The suspension was degassed under vacuum and purged with N2several times. Then Pd(dppf)Cl2(1.38 g, 1.69 mmol, 0.1 eq) was added the mixture. The mixture was stirred at 100 °C for 18 hours. The mixture filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 0 to 97 / 1) to afford (14S-4) (1.46 g, 4.51 mmol, 26.64%Atty. Dkt. No.: 052209-0603 yield). [M+H]+ = 324.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.08 (d, J = 7.75 Hz, 1 H) 7.25 (d, J = 7.63 Hz, 1 H) 1.36 (s, 12 H).

[0381] Procedure of step 14k

[0382] To a mixture of (14S-4) (3.5 g, 10.82 mmol, 1 eq) in THF (35 mL) was added NaOH (16.7 M, 440.85 mg, 17.83 eq) and WATER2 (4.41 g, 38.90 mmol, 30% purity, 3.60 eq) in one portion. The mixture was stirred at 50 °C for 24 hours. The reaction mixture was quenched by Na2SO3(sat., 30 mL). The residue was extracted with ethyl acetate (50 mL*2). The combined organic layers was washed with brine (50 mL*2), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 0 to 92 / 8) to afford (14S-5) (3 g, crude). [M+H]+ = 214.1.1H NMR (400 MHz, DMSO-d6) δ ppm 11.01 (br s, 1 H) 7.49 (d, J = 8.31 Hz, 1 H) 7.39 (d, J = 8.31 Hz, 1 H).

[0383] Procedure of step 14l

[0384] To a solution of (14S-5) (3 g, 14.05 mmol, 1 eq) in EtOH (150 mL) was added Pd / C (1.5 g, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 Psi) at 20 °C for 31 hours. The mixture filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 99 / 1 to 94 / 6) to afford (14-1B) (1 g, 5.58 mmol, 39.74% yield).1H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br s, 1 H) 7.76 (dd, J = 4.65, 1.59 Hz, 1 H) 7.39 - 7.47 (m, 1 H) 7.26 (dd, J = 8.01, 4.71 Hz, 1 H).Atty. Dkt. No.: 052209-0603

[0385] Scheme 15. Synthesis of TG10

[0386] Synthesis of (15-1)

[0387] Similar procedure as step 8b-1 (reagents and solvent A)

[0388] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28 - 7.44 (m, 5 H) 4.42 (dd, J=8.91, 1.25 Hz, 1 H) 3.04 (dd, J=9.03, 1.63 Hz, 1 H) 2.30 - 2.45 (m, 1 H) 2.09 - 2.21 (m, 1 H) 1.97 - 2.07 (m, 1 H) 1.80 - 1.92 (m, 2 H) 1.75 (td, J=11.89, 6.34 Hz, 2 H) 1.53 - 1.62 (m, 1 H) 1.45 (s, 9 H).

[0389] Synthesis of (15-2)

[0390] Similar procedure as step 8c-1

[0391] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.90 (d, J=9.01 Hz, 1 H) 7.69 (dd, J=8.88, 2.00 Hz, 1 H) 7.48 - 7.57 (m, 2 H) 7.40 - 7.48 (m, 6 H) 7.29 - 7.39 (m, 3 H) 4.45 (br d,Atty. Dkt. No.: 052209-0603 J=8.13 Hz, 1 H) 4.08 (br d, J=8.25 Hz, 1 H) 2.81 (s, 3 H) 2.51 - 2.60 (m, 1 H) 2.41 - 2.50 (m, 1 H) 2.32 (d, J=1.88 Hz, 1 H) 2.08 - 2.16 (m, 2 H) 1.88 - 2.01 (m, 3 H) 1.48 (s, 9 H).

[0392] Synthesis of TG10

[0393] Similar procedure as step 8d

[0394] [M+H]+ = 585.1, 587.1.1H NMR (400 MHz, METHANOL-d4) δ ppm 7.66 - 8.07 (m, 3 H) 7.16 - 7.63 (m, 10 H) 4.49 (br d, J=7.50 Hz, 1 H) 4.23 (br d, J=7.88 Hz, 1 H) 2.84 - 3.17 (m, 1 H) 2.53 - 2.69 (m, 1 H) 2.44 (br t, J=11.88 Hz, 1 H) 2.28 - 2.40 (m, 1 H) 1.94 - 2.27 (m, 3 H) 1.63 - 1.93 (m, 3 H) 1.24 - 1.37 (m, 1 H).

[0395] Scheme 16. Synthesis of TG11

[0396] Procedure of step 16a

[0397] To a mixture of (TG2-20) (70 mg, 119.76 µmol, 1 eq) in HCl (1 mL) and WATER (1 mL) was added NaNO2(9.08 mg, 131.55 µmol, 1.10 eq) in WATER (0.3 mL) and stirred for 35 min at 0 °C under N2. The mixture was added to CuCl (59.28 mg, 598.80 µmol, 5 eq) in HCl (1 mL) and WATER (1 mL) at 0 °C. Then the mixture was stirred at 25°C for 50 min.The reaction mixture was adjusted to pH = 3 by NaHCO3 (sat.). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purificated by prep-HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (HCl)-ACN]; B%: 30%-60%, 8min) to give (TG11-01) (40 mg, 66.23 µmol, 55.30% yield). [M+H]+= 605.1.Atty. Dkt. No.: 052209-0603

[0398] Procedure of step 16b

[0399] (TG11-01) was separated by prep-SFC to give TG11 series (absolute stereochemistry was not assigned).

[0400] Table 37: Detailed conditions: (*indicates an arbitrary stereochemistry assignment was made to distinguish different isomers that were isolated; absolute stereochemistry was not determined and may not match the depicted stereochemistry).

[0401] Scheme 17. Synthesis of TG12 seriesAtty. Dkt. No.: 052209-0603

[0403] Synthesis of 17c-2Atty. Dkt. No.: 052209-0603

[0404] General procedure of step 17a

[0405] To a mixture of (17-1) (1 eq) and INT 2 (1.5 eq) in toluene was added K3PO4 (3 eq). The suspension was degassed under vacuum and purged with N2 several times. XPhos (0.2 eq) and Pd2(dba)3 (0.1 eq) were added to the mixture. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 100ºC for 12 h. The mixture was filtered and the filtrate was concentrated in vacuum. The crude product was purified by prep-TLC / prep- HPLC to give (17-2) (see details in Table 38).

[0406] Table 38: Detailed conditions: (all reactions conducted under nitrogen gas)Atty. Dkt. No.: 052209-0603

[0407] General procedure of step 17b

[0408] To a mixture of (17-2) (1 eq) in EtOH was added Pd / C (10 wt%, 10% purity). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2(15 Psi) at 20 °C for 12 h. The mixture was filtered and the filtrate was concentrated in vacuum. The crude product was purified by column chromatography or used as is for next step to afford (17-3). (see details in Table 39)

[0409] Table 39: Detailed conditions:Atty. Dkt. No.: 052209-0603

[0410] General procedure of step 17c

[0411] To a mixture of (17-3) (1 eq) and INT 3 / INT 7 (1.1 eq) in DMF was added TEA (3 eq) and HATU (1.5 eq). The mixture was stirred at M°C for 12 h (see details in Table 40). The mixture was added to WATER. The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried with Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography or used as is for next step to afford (17-4).

[0412] Table 40: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0413] General procedure of step 17d-1

[0414] To a mixture of (17-4) / (17c-1) (1 eq) in DCM was added TFA (3 eq). The mixture was stirred at 25°C for 2 hours. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC to afford (TG12) (Select compounds are shown in Table 41).

[0415] Procedure of step 17d-2

[0416] To a mixture of (17c-2) (45.92 mg, 65.93 μmol, 1 eq) in THF (0.3 mL), MeOH (0.3 mL) and WATER (0.3 mL) was added LiOH.WATER (8.30 mg, 197.79 μmol, 3 eq) in one portion at 20 °C. The mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated in vacuum. The residue was purified by prep-HPLC to afford (TG12-06) (20 mg, 29.30 μmol, 44.44% yield) (Select compounds are shown in Table 41).

[0417] Table 41: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0418] General procedure of step 17e

[0419] Selected compounds from (TG12-01) to (TG12-05) were separated by prep-SFC to afford the single enantiomers in the (TG12) (absolute stereochemistry not yet assigned) (Select compounds are shown in Table 42).

[0420] Table 42: Detailed conditions: (*indicates an arbitrary stereochemistry assignment was made to distinguish different isomers that were isolated; absolute stereochemistry was not determined and may not match the depicted stereochemistry).Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0421] General procedure of step 17f

[0422] To a mixture of (17-4D / E) (1 eq) and 3,3-difluoroazetidine*HCl (6 eq) in solvent was added base (6 eq). The mixture was stirred at M°C for N h (see details in Table 43). The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography or used as is for next step to afford (17c-1).Atty. Dkt. No.: 052209-0603

[0423] Table 43: Detailed conditions:

[0424] Procedure of step 17g

[0425] To a mixture of (TG12-02) (65 mg, 97.23 µmol, 1 eq) and K2CO3 (40.31 mg, 291.70 µmol, 3 eq) in DMF (0.5 mL) was added CH3I (41.40 mg, 291.70 µmol, 3 eq) in one portion at 20 °C under N2. The mixture was stirred at 20 °C for 12 hours. WATER (2 mL) was added to the mixture. The aqueous phase was extracted with ethyl acetate (2 mL*2). The combined organic phase was washed with brine (4 mL*2), dried with anhydrous Na2SO4,filtered and concentrated in vacuum. (17c-2) (50 mg, crude) was used to next step directly without further purification. [M+H]+= 698.1.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.58 (br d, J = 10.51 Hz, 1 H) 8.31 (d, J = 1.83 Hz, 1 H) 8.16 - 8.24 (m, 1 H) 8.03 - 8.10 (m, 1 H) 7.96 - 8.00 (m, 1 H) 7.59 -Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0427] Synthesis of 19d-1

[0428] Procedure of (19-1)

[0429] To a solution of (BCO-Ketone) (0.3 g, 803.34 μmol, 1 eq) in THF (5 mL) was added LDA (2 M, 1.00 mL, 2.5 eq) at -78 °C. The mixture was stirred at -78 °C for 1 h. A solution of alkyl iodide (250.85 mg, 1.77 mmol, 2.2 eq) in THF (0.5 mL) was added into the reaction at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 h, allowed to warm to 20 °C over 0.5 h and stirred for another N h (see Table 51). The reaction mixture was poured into NH4Cl (sat., 10 mL). The mixture was extracted with ethyl acetate (10 mL*3). The organic phase was washed with brine (30 mL), dried over Na2SO4and concentrated in vacuum to give a residue. The residue was purified by column chromatography to give (19).

[0430] Table 51: Detailed conditions:Atty. Dkt. No.: 052209-0603

[0431] General procedure of step 19c

[0432] A mixture of (19-2) / (BCO-Ketone) (1 eq) and Pd / C (10 wt%, 10% purity) in EtOH and ethyl acetate was added into the bottle under Ar. The suspension was degassed under vacuum and purged with H2three times. The mixture was stirred under H2(15 Psi) (see details in Table 52). The suspension was filtered through a pad of Celite. The filter cake was washed with MeOH. The filtrate was concentrated in vacuum to give (19-3).

[0433] Table 52: Detailed conditions:

[0434] Procedure of step 19d-1Atty. Dkt. No.: 052209-0603

[0435] To a solution of (19-3A) (0.66 g, 2.47 mmol, 1 eq) and INT 3 (886.94 mg, 2.59 mmol, 1.05 eq) in DMF (10 mL) was added DIEA (1.12 g, 8.64 mmol, 3.5 eq) and HATU (1.03 g, 2.72 mmol, 1.1 eq). The mixture was stirred at 25°C for 12 h. The reaction mixture was poured into ice-water (80 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (20 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 2 / 1) to give (19-4A) (1.25 g, 2.11 mmol, 85.60% yield). (see details in Table 53)

[0436] Procedure of step 19d-2

[0437] To a solution of (19d-1) (0.5 g, 887.34 μmol, 1 eq) in THF (6 mL) was added LDA (2 M, 1.11 mL, 2.5 eq) at -60 °C. The mixture was stirred at -60 °C for 1 hour. A solution of MeI (377.85 mg, 2.66 mmol, 3 eq) in THF (1 mL) was added into the reaction at -60 °C. The reaction mixture was stirred at -60 °C for 0.5 hour, allowed to warm to 20 °C for 0.5 hour and stirred for 10 hours. The reaction mixture was poured into NH4Cl (sat., 50 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1) to give (19-4B) (0.27 g, 467.53 μmol, 52.69% yield). (see details in Table 53)

[0438] Procedure of step 19d-3

[0439] To a solution of (19-3C) (0.8 g, 2.99 mmol, 1 eq) and INT 4 (1.08 g, 2.99 mmol, 1 eq) in DCM (9 mL) was added NaHCO3 (3.02 g, 35.91 mmol, 12 eq) in WATER (9 mL) at 0 °C. The reaction was stirred at 25°C for 12 hours. The reaction mixture was quenched by addition WATER (10 mL) and extracted with DCM (10 mL*3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 3 / 1) to give (19-4C) (1 g, 1.69 mmol, 56.50% yield). (see details in Table 53)

[0440] Table 53: Detailed conditions:Atty. Dkt. No.: 052209-0603

[0441] General procedure of step 19e

[0442] To a solution of (19-4) (1 eq) in a mixture of solvents (DCM / TFA in a 5:1 ratio) at M°C. The mixture was stirred at (see details in Table 54). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography or used as is for next stepto give (19-5).

[0443] Table 54: Detailed conditions:Atty. Dkt. No.: 052209-0603

[0444] General procedure of step 19f

[0445] To a solution of (19-5) (1 eq) and INT 19f (6 eq, HCl) in THF was added pyridine (12 eq) and Ti(OEt)4 (10 eq). The mixture was stirred at 80 °C for 36 h. The residue was diluted with WATER and filtered through a pad of Celite. The filter cake was washed with a mixture of solvents (ethyl acetate / THF in a 2:1 ratio). The combined filtrate was washed with HCl (1 M), washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give (TG14). (see details in Table 55)

[0446] Table 55: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0447] General procedure of step 19g

[0448] TG14 series was separated by prep-SFC to give TG14 series (in Table 56), absolute stereochemistry was not assigned.

[0449] Table 56: Detailed conditions: (*indicates an arbitrary stereochemistry assignment was made to distinguish different isomers that were isolated; absolute stereochemistry was not determined and may not match the depicted stereochemistry).Atty. Dkt. No.: 052209-0603

[0450] Procedure of step 19h

[0451] To a solution of (19-3B) (3 g, 12.54 mmol, 1 eq) and INT 4 (4.52 g, 12.54 mmol, 1 eq) in DCM (30 mL) was added NaHCO3(11.81 g, 140.53 mmol, 11.21 eq) at 20 °C for 12 hours. The reaction mixture was quenched by addition WATER (70 mL) and extracted with DCM (50 mL). The combined organic layer was washed with brine (60 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 89 / 11) to give (19d-1) (2 g, 3.55 mmol, 28.31% yield). [M+H]+ =565.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.03 (br d, J = 8.70 Hz, 1 H) 7.91 (d, J = 1.67 Hz, 1 H) 7.76 (dd, J = 9.00, 2.09 Hz, 1 H) 7.43 - 7.60 (m, 5 H) 6.99 - 7.08 (m, 1 H) 3.30 - 3.44 (m, 2 H) 2.73 (s, 2 H) 2.39 (s, 3 H) 2.21 - 2.35 (m, 2 H) 1.80 - 2.08 (m, 4 H) 1.48 (s, 9 H).Atty. Dkt. No.: 052209-0603

[0452] Scheme 20. Synthesis of TG15 series

[0455] General procedure of step 20a-1

[0456] To a mixture of (20-1) (1 eq) and DIEA (3 eq) in DMA was added secondary amine (5 eq). The mixture was heated to 100 °C and stirred for 12 h. The mixture was filtered and the filtrateAtty. Dkt. No.: 052209-0603 was concentrated in vacuum. The residue was purified by column chromatography or used as is for next step to give (20-2) (see details in Table 57).

[0457] General procedure of step 20a-2

[0458] To a mixture of (20-1) (1 eq) and (7-3I) (1.2 eq) in DMF was added TEA (3 eq) and HATU (1.5 eq). The mixture was stirred at 60 °C for 12 hr. The mixture was added to WATER. The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried with Na2SO4and concentrated in vacuum. The residue was purified by column chromatography or used as is for next step to afford (20-2) (see details in Table 57).

[0459] Table 57: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0460] General procedure of step 20b

[0461] A solution of (20-2) (1 eq) in a mixture of solvents (DCM / TFA in a 5:1 ratio) was stirred at 25°C for 3 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC to give TG15 series (see details in Table 58).Atty. Dkt. No.: 052209-0603

[0462] Table 58: Detailed conditions:Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0463] General procedure of step 20c

[0464] To a mixture of (20S-1) (1 eq) and secondary amine (6 eq) in NMP was added DIEA (5 eq). The mixture was stirred at 100 °C for 12 hr. The mixture was filtered and the filtrate was concentrated in vacuum. The crude product was purified by prep-HPLC to afford (20-1).Atty. Dkt. No.: 052209-0603

[0465] Table 59: Detailed conditions:

[0466] General procedure of step 20d

[0467] A mixture (5-1) (1 eq) and 1-(3-methoxyphenyl) propan-1-one / 1-(2-methoxyphenyl) propan-1-one (1 eq) in AcOH was stirred at 75°C for 0.5 hr. After that, HCl was added to the mixture. The mixture was stirred at M°C (see details in Table 60) for 11.5 hr. After cooled to 25°C, the reaction mixture was poured into HCl (1 M). The solid was collected by filtration. The filter cake was washed with a mixture of solvents (petroleum ether / ethyl acetate in a 2:1 ratio) and concentrated in vacuum to afford (20-1).Atty. Dkt. No.: 052209-0603

[0468] Table 60: Detailed conditions:

[0469] Scheme 21. Synthesis of TG16-01Atty. Dkt. No.: 052209-0603

[0470] Procedure of step 21a

[0471] To a mixture of (21-1) (2 g, 14.70 mmol, 1 eq) and N-methoxymethanamine (1.58 g, 16.17 mmol, 1.1 eq, HCl) in DMF (50 mL) was added TEA (4.46 g, 44.09 mmol, 3 eq). Then the mixture was added HATU (8.38 g, 22.04 mmol, 1.5 eq). The mixture was stirred at 20 °C for 12 h. The mixture was added to WATER (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phase was washed with brine (200 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 5 / 1) to afford (21-2) (2.1 g, 11.72 mmol, 79.76% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.69 (s, 3 H) 3.24 - 3.33 (m, 1 H) 3.22 (s, 3 H) 2.80 - 2.97 (m, 2 H) 2.66 - 2.79 (m, 2 H).

[0472] Procedure of step 21b

[0473] To a mixture of (21-2) (2.1 g, 11.72 mmol, 1 eq) in THF (40 mL) was added bromo (ethyl) magnesium (3 M, 11.72 mL, 3 eq) at 0 °C under N2. The mixture was stirred at 20 °C for 2 h. The mixture was added to WATER (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL*2). The combined organic phase was washed with brine (100 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was used directly without purification to afford (21-3) (1.2 g, 8.10 mmol, 69.11% yield).1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.99 - 3.16 (m, 1 H) 2.61 - 2.88 (m, 4 H) 2.47 (q, J = 7.25 Hz, 2 H) 1.10 (t, J = 7.25 Hz, 3 H).

[0474] Procedure of step 21c

[0475] To a mixture of (21-3) (100 mg, 674.99 μmol, 1 eq) and (4-1) (152.57 mg, 674.99 μmol, 1 eq) in EtOH (2 mL) was added KOH (37.87 mg, 17.82 mmol, 1 eq). The mixture was stirred at 60 °C for 12 h. The mixture was adjust pH=1 with HCl (1 M). The mixture was filtrated. The filter cake was collected to afford (21-4) (100 mg, crude) which was used directly without purification. [M+H]+= 357.9.Atty. Dkt. No.: 052209-0603

[0476] Procedure of step 21d

[0477] To a mixture of (21-4) (100 mg, 280.77 μmol, 1 eq) and (7-3I) (107.65 mg, 280.77 μmol, 1 eq) in DMF (5 mL) was added DIEA (108.86 mg, 842.31 μmol, 3 eq). Then, the mixture was added HATU (160.14 mg, 421.16 μmol, 1.5 eq). The mixture was stirred at 20 °C for 12 h. The mixture was added to WATER (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL*2). The combined organic phase was washed with brine (100 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 3:1, Rf = 0.45) to afford (21-5) (50 mg, 69.30 μmol, 24.68% yield). [M+H]+= 723.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.87 (d, J = 8.94 Hz, 1 H) 7.68 - 7.72 (m, 1 H) 7.47 - 7.52 (m, 1 H) 7.31 - 7.44 (m, 4 H) 6.46 (s, 1 H) 3.55 - 3.65 (m, 1 H) 3.05 - 3.25 (m, 2 H) 2.85 - 2.96 (m, 2 H) 2.08 - 2.30 (m, 6 H) 1.69 - 1.96 (m, 5 H) 1.51 (s, 9 H).

[0478] Procedure of step 21e

[0479] To a mixture of (21-5) (50 mg, 69.30 μmol, 1 eq) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC to afford (TG16-01) (5 mg, 7.51 μmol, 10.84% yield). [M+H]+ = 667.1.1H NMR (400 MHz, METHANOL-d4) δ ppm 7.88 (d, J = 9.01 Hz, 1 H) 7.72 (dd, J = 8.88, 1.88 Hz, 1 H) 7.51 (br d, J = 7.25 Hz, 3 H) 7.38 (br d, J = 4.25 Hz, 2 H) 6.42 (s, 1 H) 3.68 - 3.76 (m, 1 H) 3.01 - 3.13 (m, 2 H) 2.83 - 3.00 (m, 3 H) 2.09 - 2.30 (m, 4 H) 1.91 (br s, 3 H) 1.74 (br d, J = 2.13 Hz, 3 H).

[0480] Scheme 22. Synthesis of TG17 seriesAtty. Dkt. No.: 052209-0603 [ [Atty. Dkt. No.: 052209-0603

[0483] Procedure of step 22a

[0484] A mixture (BCO-Ketone) (6 g, 16.07 mmol, 1 eq), CH3COONH4 (12.38 g, 160.67 mmol, 10 eq), NaCNBH3 (3.03 g, 48.20 mmol, 3 eq) and FeCl3 (260.61 mg, 1.61 mmol, 0.1 eq) in MeOH (750 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 36 hr under N2 atmosphere. The mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO2, Dichloromethane / Methanol = 20 / 1 to 5 / 1) to afford (22-1) (18 g, 48.07 mmol, 59.83% yield). [M+H]+= 375.1.1H NMR (400 MHz, CHLOROFORM- d) δ ppm 7.29 - 7.40 (m, 5 H) 5.03 - 5.15 (m, 2 H) 4.02 - 4.09 (m, 1 H) 2.40 - 2.50 (m, 1 H) 2.26 - 2.36 (m, 1 H) 2.15 - 2.24 (m, 1 H) 1.98 - 2.04 (m, 1 H) 1.90 (br d, J = 10.88 Hz, 3 H) 1.75 - 1.85 (m, 1 H) 1.55 - 1.70 (m, 2 H) 1.42 (s, 9 H).

[0485] Procedure of step 22b-1

[0486] To a mixture of (22-1) (1 g, 2.67 mmol, 1 eq) in DCM (10 mL) was added TEA (324.26 mg, 3.20 mmol, 1.2 eq). Then, the mixture was added TFAA (324.26 mg, 3.20 mmol, 1.2 eq). The mixture was stirred at 20 °C for 12 h. Then the mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 10 / 1) to afford (22-2A) (0.68 g, 1.45 mmol, 54.12% yield).

[0487] Procedure of step 22b-2

[0488] To a mixture of (22-1) (515 mg, 1.38 mmol, 1 eq) in MeOH (139 mL) was added glutaraldehyde (305.66 mg, 3.05 mmol, 2.22 eq). The mixture was stirred at 25°C for 40 min under N2 atmosphere. Then NaCNBH3 (349.16 mg, 5.56 mmol, 4.04 eq) and CH3COOH (3.30 g, 11.93 mmol, 8.68 eq) was added to the mixture. The mixture was degassed and purged with N2 for 3 times. The mixture was stirred at 25°C for 12 hours under N2 atmosphere. The mixture was concentrated in vacuum. The crude product was purificated by prep-HPLC (column: Waters Xbridge BEH C18250*50mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 70%-95%, 10min) to afford (22-2B) (596 mg, 1.35 mmol, 24.48% yield).Atty. Dkt. No.: 052209-0603

[0489] Table 61: Detailed conditions:

[0490] General procedure of step 22c

[0491] To a mixture of (22-2) (1 eq) in EtOH was added Pd / C (10 wt%, 10% purity). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at (see details 62). The mixture was filtrated and the filtrate was concentrated in vacuum to afford crude (22-3).

[0492] Table 62: Detailed conditions:Atty. Dkt. No.: 052209-0603

[0493] Procedure of step 22d-1

[0494] To a mixture of (22-3A) (0.37 g, 1.10 mmol, 1 eq) and INT 3 (489.35 mg, 1.43 mmol, 1.3 eq) in DMF (5.5 mL) was added DIEA (426.52 mg, 3.30 mmol, 3 eq) and HATU (543.75 mg, 1.43 mmol, 1.3 eq). The mixture was stirred at 25°C for 12 h. The mixture was added WATER (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (30 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 5 / 1) to afford (22-4A) (243 mg, 384.11 μmol, 59.24% yield).

[0495] Procedure of step 22d-2

[0496] To a mixture of (22-3B) (200 mg, 648.39 μmol, 1 eq) and INT 4 (280.59 mg, 778.06 μmol, 1.2 eq) in DCM (7.78 mL) was added NaHCO3(1 M, 7.78 mL, 12 eq). The mixture was stirred at 25°C for 12 h. The reaction mixture was quenched by addition WATER (10 mL). The residue was extracted with DCM (10 mL*3). The combined organic layers were washed with brine (10 mL*2), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate=3:1, Rf=0.33) to afford (22-4B) (243 mg, 384.11 μmol, 59.24% yield).Atty. Dkt. No.: 052209-0603

[0497] Table 63: Detailed conditions:

[0498] General Procedure of step 22e

[0499] To a mixture of (22-4) / (22e-2) / (22e-3) (1 eq) in a mixture of solvents (DCM / TFA in a 5:1 ratio). The mixture was stirred (see details in Table 64). The mixture was concentrated in vacuum. The crude product was purification by prep-HPLC to afford (TG17).Atty. Dkt. No.: 052209-0603

[0500] Table 64: Detailed conditions:Atty. Dkt. No.: 052209-0603

[0501] General Procedure of step 22f

[0502] (TG17) was separated by prep-SFC to give (TG17). (absolute stereochemistry not yet assigned)

[0503] Table 65: Detailed conditions: (*indicates an arbitrary stereochemistry assignment was made to distinguish different isomers that were isolated; absolute stereochemistry was not determined and may not match the depicted stereochemistry).Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0504] Procedure of step 22g

[0505] To a mixture of (22-4A) (0.44 g, 666.14 μmol, 1 eq) in MeOH (6.6 mL), THF (3 mL) and WATER (4.4 mL) was added NaOH (133.22 mg, 3.33 mmol, 5 eq) at 0 °C. The mixture was stirred at 70 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The suspension was filtered and the filter cake was washed with WATER (5 mL*2), dried in vacuum to give product. The crude product was triturated with (Petroleum ether : Ethyl acetate = 1:1, 20 mL) at 25°C for 0.5 h. The suspension was filtered and the filter cake was washed petroleum ether (5 mL*2), dried in vacuum to afford (22e-1) (0.25 g, 442.86 μmol, 66.48% yield). [M+H]+ = 566.2.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.95 - 8.05 (2 H, m) 7.74 (1 H, d, J = 8.94 Hz) 7.45 - 7.56 (5 H, m) 3.25 - 3.52 (1 H, m) 2.73 - 2.83 (1 H, m) 2.43 (3 H, s) 2.30 (1 H, br s) 1.91 - 2.14 (6 H, m) 1.52 - 1.65 (2 H, m) 1.44 (9 H, s).

[0506] Procedure of step 22h-1

[0507] To a mixture of (22e-1) (150 mg, 265.72 μmol, 1 eq) in DCM (5 mL) was added TEA (80.66 mg, 797.15 μmol, 3 eq). Then, the mixture was added cyclobutanecarbonyl chloride (47.26 mg, 398.57 μmol, 1.5 eq). The mixture was stirred at 25°C for 12 h. The mixture was concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 2:1, Rf = 0.40) to afford (22e-2A) (100 mg, 154.65 μmol, 58.20% yield). [M+H]+= 648.2.

[0508] Procedure of step 22h-2

[0509] To a solution of (22e-1) (0.2 g, 354.29 μmol, 1 eq) and bromocyclobutane (239.15 mg, 1.77 mmol, 5 eq) in DMF (4 mL) was added NaI (477.95 mg, 3.19 mmol, 9 eq) and K2CO3 (244.82 mg, 1.77 mmol, 5 eq), then the mixture was stirred at 120 °C under N2 for 3 h. The residue was poured into ice-water (40 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (30 mL*2). The combined organic phase was washed with brine (50 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to give (22e-2B) (0.177 g, 286.13 μmol, 80.76% yield). [M+H]+= 620.3.

[0510] Procedure of step 22h-3Atty. Dkt. No.: 052209-0603

[0511] To a solution of (22e-1) (140 mg, 248.00 μmol, 1 eq), 2-(trifluoromethoxy) acetic acid (35.72 mg, 248.00 μmol, 1 eq) and DIEA (96.16 mg, 744.01 μmol, 3 eq) in DMF (3 mL) was added HATU (141.45 mg, 372.00 μmol, 1.5 eq). The mixture was stirred at 70 °C for 12 hr. The reaction mixture was quenched by addition WATER (20 mL), and then diluted with ethyl acetate (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine (90 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 3:1, Rf=0.40) to give (22e-2C) (80 mg, 115.85 μmol, 46.71% yield). [M+H]+ = 692.3.

[0512] Procedure of step 22h-4

[0513] To a mixture of (22e-1) (150 mg, 265.72 μmol, 1 eq) in DCM (2 mL) was added TEA (161.33 mg, 1.59 mmol, 6 eq). Then, the mixture was added methyl carbonochloridate (75.33 mg, 797.15 μmol, 3 eq) at 0 °C under N2. The mixture was stirred at 25°C for 2 h. The mixture was added to WATER (100 mL). The aqueous phase was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (100 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 2:1, Rf=0.5) to afford (22e-2D) (120 mg, 192.76 μmol, 72.54% yield). [M+H]+= 624.1.

[0514] Procedure of step 22h-5

[0515] To a solution of (22e-1) (0.3 g, 531.43 μmol, 1 eq) and 2,2,2-trifluoroacetaldehyde (641.15 mg, 4.25 mmol, 8 eq) in MeOH (6 mL), the mixture was stirred at 25°C for 30 min, then NaBH3CN (267.17 mg, 4.25 mmol, 8 eq) and CH3COOH (14.67 mg, 53.14 μmol, 0.1 eq) were added, the mixture was stirred at 25°C under N2for 23.5 h. The mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to give (22e-2E) (60 mg, 83.52 μmol, 15.72% yield, 90% purity). [M+H]+= 648.1.

[0516] Procedure of step 22i

[0517] To a solution of (22e-2B) (0.14 g, 226.32 μmol, 1 eq) in MeOH (1.4 mL) was added NaCNBH3(42.67 mg, 678.95 μmol, 3 eq) and formaldehyde (110.20 mg, 1.36 mmol, 37% purity,Atty. Dkt. No.: 052209-0603 6 eq). The mixture was stirred at 25°C for 0.5 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to give (22e-3) (108.3 mg, 171.19 μmol, 75.64% yield). [M+H]+= 634.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.49 - 8.89 (m, 1 H) 7.89 - 7.98 (m, 1 H) 7.80 (br s, 1 H) 7.42 - 7.65 (m, 5 H) 2.29 - 2.86 (m, 10 H) 2.11 - 2.26 (m, 2 H) 1.96 - 2.07 (m, 3 H) 1.79 - 1.96 (m, 5 H) 1.38 - 1.52 (m, 9 H) 0.37 - 0.55 (m, 2 H) 0.04 - 0.16 (m, 2 H).

[0518] Scheme 23. Synthesis of TG18 series

[0519] Procedure of step 23aAtty. Dkt. No.: 052209-0603

[0520] To a solution of INT 2 (0.6 g, 1.24 mmol, 1 eq) in DMF (6 mL) and MeOH (3 mL) was added Et3N (314.03 mg, 3.10 mmol, 2.5 eq) and Pd(dppf)Cl2 (90.83 mg, 124.14 μmol, 0.1 eq). The mixture was stirred at 50 °C for 12 h under CO (15 Psi). The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1) to give (23-1) (0.5 g, 1.20 mmol, 96.94% yield). [M+H]+=416.3.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49 - 7.54 (m, 1 H) 7.30 - 7.41 (m, 5 H) 5.31 (s, 1 H) 5.08 (s, 2 H) 3.75 (s, 3 H) 2.63 (br d, J = 1.43 Hz, 2 H) 1.87 - 2.18 (m, 3 H) 1.50 - 1.55 (m, 3 H) 1.49 (s, 9 H).

[0521] Procedure of step 23b

[0522] To a solution of (23-1) (50 mg, 120.34 μmol, 1 eq) in THF (1 mL), WATER (0.3 mL) and MeOH (0.2 mL) was added LiOH.WATER (7.58 mg, 180.51 μmol, 1.5 eq). The mixture was stirred at 25°C for 3 h. The reaction mixture was diluted with water (10 mL). The mixture was adjust to pH = 2-3 with HCl (1 M) and extracted with DCM (10 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give (23-2) (0.4 g, 896.75 μmol, 82.80% yield, 90% purity).1H NMR (400 MHz, METHANOL-d4) δ ppm 7.27 - 7.44 (m, 6 H) 5.04 (s, 2 H) 2.14 - 2.27 (m, 2 H) 1.94 - 2.06 (m, 2 H) 1.60 - 1.74 (m, 2 H) 1.51 (br s, 2 H) 1.49 (s, 9 H).

[0523] Procedure of step 23c

[0524] To a solution of (23-2) (439.03 mg, 984.24 μmol, 1 eq) and cyclobutanamine (70 mg, 984.24 μmol, 1 eq) in DMF (5 mL) was added DIEA (445.22 mg, 3.44 mmol, 3.5 eq) and HATU (449.09 mg, 1.18 mmol, 1.2 eq). The mixture was stirred at 25°C for 12 h. The reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (20 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1) to give (23-3) (0.4 g, 879.98 μmol, 89.41% yield). [M+H]+=455.3.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.34 - 7.39 (m, 4 H) 7.29 - 7.33 (m, 1 H) 6.89 (s, 1 H) 6.08 (br d, J = 6.79 Hz, 1 H) 5.31 (s, 1 H) 5.06 (s, 2 H) 4.32 - 4.43 (m, 1 H)Atty. Dkt. No.: 052209-0603 2.51 - 2.62 (m, 2 H) 2.29 - 2.40 (m, 2 H) 1.85 - 2.03 (m, 4 H) 1.57 - 1.80 (m, 4 H) 1.50 (br s, 2 H) 1.49 (s, 9 H).

[0525] Procedure of step 23d

[0526] To a solution of (23-3) (0.1 g, 219.99 μmol, 1 eq) in EtOH (2 mL) and ethyl acetate (1 mL) was added Pd / C (30 mg, 10% purity) to the bottle under Ar. NH3.WATER (61.68 mg, 439.99 μmol, 25% purity, 2 eq) was added to the mixture. The suspension was degassed under vacuum and purged with H2three times. The mixture was stirred under H2(15 Psi) at 25°C for 5 h. The suspension was filtered through a pad of Celite. The filter cake was washed with MeOH (10 mL*3). The combined filtrates were concentrated to give (23-4) (0.2 g, 620.27 μmol, 74.20% yield). [M+H]+ =323.2.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.66 (br d, J = 7.27 Hz, 1 H) 4.38 (br d, J = 7.99 Hz, 1 H) 2.23 - 2.39 (m, 7 H) 2.05 (br s, 1 H) 1.79 - 1.96 (m, 6 H) 1.60 - 1.75 (m, 4 H) 1.41 (s, 9 H).

[0527] Procedure of step 23e

[0528] To a solution of (23-4) (65 mg, 201.59 μmol, 1 eq) and INT 3 (75.88 mg, 221.75 μmol, 1.1 eq) in DMF (1 mL) was added DIEA (91.19 mg, 705.55 μmol, 3.5 eq) and HATU (91.98 mg, 241.90 μmol, 1.2 eq). The mixture was stirred at 25°C for 12 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine (20 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1) to give (23-5) (0.3 g, 463.96 μmol, 74.80% yield). [M+H]+=648.2.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 - 8.03 (m, 2 H) 7.76 (dd, J = 9.00, 1.73 Hz, 1 H) 7.44 - 7.54 (m, 5 H) 6.17 (br d, J = 7.27 Hz, 1 H) 5.98 (s, 1 H) 4.40 - 4.54 (m, 1 H) 3.58 (br t, J = 9.24 Hz, 1 H) 2.64 - 2.84 (m, 2 H) 2.38 (s, 4 H) 2.08 - 2.30 (m, 3 H) 1.78 - 2.01 (m, 7 H) 1.69 (td, J = 10.19, 4.53 Hz, 2 H) 1.50 - 1.60 (m, 1 H) 1.44 (s, 9 H).

[0529] Procedure of step 23f To a solution of (23-5) (70 mg, 108.26 μmol, 1 eq) in DCM (0.7 mL) was added TFA (432.03 mg, 3.79 mmol, 35 eq). The mixture was stirred at 25°C for 2 h. The reaction mixture wasAtty. Dkt. No.: 052209-0603 concentrated under reduced pressure and purified by prep-HPLC to give (TG18-01) (0.2 g, 335.31 μmol, 60.00% yield, 99% purity). [M+H]+ =592.2.

[0530] Procedure of step 23g

[0531] (TG18-01) were separated by prep-SFC to afford TG18 series (absolute stereochemistry not yet assigned)

[0532] Table 66: Detailed conditions: (*indicates an arbitrary stereochemistry assignment was made to distinguish different isomers that were isolated; absolute stereochemistry was not determined and may not match the depicted stereochemistry).

[0533] Scheme 24. Synthesis of TG19-01Atty. Dkt. No.: 052209-0603

[0534] Procedure of step 24a

[0535] To a mixture of (24-1) (200 mg, 635.80 μmol, 1 eq) and phenol (59.84 mg, 635.80 μmol, 1 eq) in DMF (4 mL) was added K2CO3(263.62 mg, 1.91 mmol, 3 eq). The mixture was stirred at 100 °C for 12 h. The mixture was filtrated and the filtrate was concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 3:1, Rf = 0.62) to afford (24-2) (500 mg, 1.34 mmol, 42.26% yield). [M+H]+= 374.1.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80 (d, J = 2.00 Hz, 1 H) 7.60 - 7.64 (m, 1 H) 7.55 - 7.59 (m, 1 H) 7.42 - 7.49 (m, 2 H) 7.29 (br s, 1 H) 7.23 (br d, J = 7.63 Hz, 2 H) 4.11 (s, 3 H) 2.50 (s, 3 H).

[0536] Procedure of step 24b

[0537] To a mixture of (24-2) (100 mg, 268.66 μmol, 1 eq) in WATER (2 mL), MeOH (2 mL) and THF (2 mL) was added LiOH.WATER (56.37 mg, 1.34 mmol, 5 eq). The mixture was stirred at 30 °C for 12 h. The mixture was concentrated in vacuum to afford (24-3) (80 mg, crude). [M+H]+= 360.1. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.91 (d, J = 2.00 Hz, 1 H) 7.67 (dd, J = 8.94, 2.06 Hz, 1 H) 7.55 (d, J = 9.01 Hz, 1 H) 7.42 - 7.48 (m, 2 H) 7.24 - 7.30 (m, 1 H) 7.21 (dd, J = 8.57, 0.94 Hz, 2 H) 2.53 (s, 3 H).

[0538] Procedure of step 24c

[0539] To a mixture of (24-3) (80 mg, 223.35 μmol, 1eq) and (7-3I) (94.20 mg, 245.68 μmol, 1.1 eq) in DMF (2 mL) was added DIEA (86.60 mg, 670.04 μmol, 3 eq). Then, the mixture was added HATU (127.39 mg, 335.02 μmol, 1.5 eq). The mixture was stirred at 25°C for 12 h. The mixture was added to WATER (50mL). The aqueous phase was extracted with ethyl acetate (20Atty. Dkt. No.: 052209-0603 mL*3). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 3:1, Rf = 0.35) to afford (24-4) (80 mg, 110.56 μmol, 49.50% yield). [M+H]+= 725.2.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.54 - 7.58 (m, 1 H) 7.47 - 7.53 (m, 2 H) 7.34 - 7.46 (m, 5 H) 7.22 - 7.26 (m, 2 H) 7.17 (d, J = 7.75 Hz, 2 H) 6.47 (s, 1 H) 2.68 - 3.00 (m, 1 H) 2.19 - 2.31 (m, 3 H) 2.10 - 2.19 (m, 4 H) 1.69 - 1.89 (m, 3 H) 1.52 (s, 9 H).

[0540] Procedure of step 24d

[0541] To a mixture of (24-4) (80 mg, 110.56 μmol, 1 eq) in DCM (2.5 mL) was added TFA (6.16 g, 54.02 mmol, 488.63 eq). The mixture was stirred at 25°C for 1 h. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC to afford (TG19-01) (30 mg, 44.95 μmol, 40.65% yield). [M+H]+ = 669.1.1H NMR (400 MHz, METHANOL-d4) δ ppm 7.60 (dd, J = 9.01, 2.13 Hz, 1 H) 7.49 - 7.55 (m, 2 H) 7.43 - 7.49 (m, 2 H) 7.42 (d, J = 0.63 Hz, 1 H) 7.34 - 7.41 (m, 3 H) 7.21 - 7.27 (m, 1 H) 7.14 (d, J = 7.63 Hz, 2 H) 6.43 (s, 1 H) 2.69 - 3.08 (m, 1 H) 2.26 - 2.47 (m, 1 H) 2.14 - 2.25 (m, 2 H) 2.12 - 2.25 (m, 1 H) 2.03 - 2.46 (m, 1 H) 1.86 - 2.03 (m, 1 H) 1.85 - 2.02 (m, 2 H) 1.61 - 1.84 (m, 3 H).

[0542] Scheme 25. Synthesis of TG20 series

[0543] Procedure of step 25a

[0544] Compound (25-1) is prepared from compound (14-2B) and INT 9 or INT 11 in an analogous manner as described in step 14c-2 of Scheme 14.Atty. Dkt. No.: 052209-0603

[0545] Procedure of step 25b

[0546] TG20-01 and TG20-02 are prepared from compound (25-1) in an analogous manner as described in step 14d of Scheme 14.

[0547] Scheme 26. Synthesis of TG21 series

[0548] Procedure of step 26a

[0549] Compound (26-1) is prepared from compound (11-2) and INT 9 or INT 11 in an analogous manner as described in step 19d-1 of Scheme 19.

[0550] Procedure of step 26bAtty. Dkt. No.: 052209-0603

[0551] Compound (26-2) is prepared from compound (26-1) in an analogous manner as described in step 19e of Scheme 19.

[0552] Procedure of step 26c

[0553] TG21-01 and TG21-02 are prepared from compound (26-2) and INT 19f in an analogous manner as described in step 19f of Scheme 19.

[0554] Scheme 27. Synthesis of TG22 series

[0555] Procedure of step 27a

[0556] Compound (27-1) is prepared from reaction of compound (7-3I) with INT 10 or INT 12 as well as triethylamine (TEA) in dichloromethane (DCM).

[0557] Procedure of step 27b

[0558] TG22-01 and TG22-02 are prepared from compound (27-1) in an analogous manner as described in step 20b of Scheme 20.

[0559] Table 67: Purification Methods Column information for Prep-HPLC and SFCAtty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0560] Table 68: Purification ConditionsAtty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603

[0561] Biological Activity Assays

[0562] FP receptor myo-inositol 1 phosphate (IP1) accumulation assay

[0563] Compounds were tested for FP antagonist activity in human embryonic kidney (HEK-EBNA; 293 c18: ATCC, CRL-10852) cell lines stably expressing a cloned human FP receptor. The FP receptor couples to the Gq pathway to induce phospholipase C (PLC) activation and triggers the inositol phosphate (IP) cascade. PLC then cleaves phosphatidylinositol 4,5- bisphosphate (PIP2) into diacylglycerol (DAG) and inositol1,4,5-trisphosphate (IP3), resulting in a transient increase of intracellular calcium. The lifetime of IP3 is very short (less than 30 seconds) before being transformed into inositol bisphosphate (IP2) and then IP1. IP1 is accumulated in the cell and is stable in the presence of LiCl in StimB buffer.

[0564] This method is a competitive immunoassay between native IP1 produced by cells and d2-labeled IP1. The specific signal (energy transfer) is inversely proportional to the concentration of IP1 in the standard or sample. This was measured using the Cisbio IP-One cell- based second messenger accumulation assay kit; competitive immunoassay using d2-labeled IP1 (acceptor) and anti-IP1-Cryptate antibody (donor).

[0565] The following steps were performed on the day of the experiment. Cells in T175 flasks were removed from culture flasks using trypsin buffer and harvested in 1X StimB. Compound solutions for concentration-response analysis of test and reference antagonists were added to HTRF 384-well white low volume assay plates (15nL of 1000x solution), and cells subsequently seeded at a density of 10,000 cells / well in 10 µL; this was incubated for 30 minutes at 37 °C under 5% CO2in a humidified atmosphere. Next, agonist concentration-response curves or agonist compound solution (5 µL of 3x solution) were sequentially added to the appropriate wells of the 384 well assay plate and incubated for 60 minutes at 37 °C under 5% CO2 in aAtty. Dkt. No.: 052209-0603 humidified atmosphere. In a separate HTRF 384 well white low volume assay plate, 15 µL of IP1 standard curve was added to designated wells of the IP1 standard curve plate.

[0566] HTRF reagents were reconstituted with distilled water in accordance with kit instructions. Detection reagents (IP1-d2 and anti-IP1 cryptate) were then added to designated wells of both the assay plate and standard curve plate and incubated for 1 hour in the dark at room temperature. The reference agonist and reference antagonist were run in each assay plate, and one standard curve run per experimental day in a separate assay plate. HTRF signal was measured using a Pherastar plate reader with the default HTRF setting of emissions at 337 nm, 665 nm and 620 nm.

[0567] The ratio of 337 nm / 665 nm and 337 nm / 620 nm time-resolved fluorescence readings (RFU) for each well were calculated and multiplied by 10,000 to obtain whole numbers for data analysis. For the IP standard curve, the ratio*10,000 was plotted on the y-axis versus IP1 concentration on a logarithmic scale on the x-axis. The curve fitting model (Model205), a single- binding site, four parameter concentration response model: (MIN+((MAX- MIN) / (1+((IC50 / x)^Hill)))), was used to perform non-linear regression analysis, generating the concentration response curve for the standards. The expected IP1 standard curve IC50after incubation for 1 hour at room temperature is 100-200 nM. IC50 is the IP1 concentration calculated in regression analysis to displace 50% of the maximal binding of the tracer, and the Hill is the slope of the calculated regression curve at the inflection point. The IP1 standard curve was used to extrapolate the IP1 concentration from the ratio*10,000 data relative to each raw data point for each test compound, if the raw data fall in the linear range of the standard curve. The linear range of the standard curve (typically 10 to 1,000 nM) was calculated based on the widest set of points for which the R2 value is greater than 0.97. For the antagonist reference and test compounds the logarithm of the extrapolated IP1 concentrations of the triplicate test wells were averaged, and the curve-fitting model was used to perform non-linear regression analysis, generating the concentration response curve and the IC50. The KB (equilibrium dissociation constant of the antagonist-receptor complex) is calculated using the Leff-Dougall equation.Atty. Dkt. No.: 052209-0603where [Agonist] is the concentration of reference agonist used in the antagonist testing scheme, Agonist EC50 is the concentration of reference agonist that produces 50% of the maximal possible effect when tested as a concentration-response in the agonist testing scheme, and Hill is the absolute value of the Hill coefficient / slope function for reference agonist when tested as a concentration-response in the agonist testing scheme. Note that the Agonist EC50 and Agonist Hill values are those resulting from the parallel testing (in the same assay plate) of the reference agonist with the test antagonist compounds.

[0568] EP4 receptor cyclic AMP (cAMP) accumulation assay

[0569] Compounds were tested for EP4 antagonist activity in DLD-1 cells (ATCC, CCL- 221) derived from human colon transiently expressing the human EP4 receptor. Cells were exposed to varying concentrations of test compounds followed by exposure to a submaximal concentration of an EP4 selective agonist (TCS2510). Antagonist inhibition of cAMP accumulation is then assessed. cAMP accumulation is measured through an HTRF (homogeneous time resolved fluorescence)-based competitive cAMP immunoassay using the cAMP – Gs Dynamic Kit (Cisbio). This was measured using the Cisbio IP-One cell-based second messenger accumulation assay kit; competitive immunoassay using d2-labeled cAMP and europium cryptate labeled anti-cAMP antibody.

[0570] 1x107DLD-1 cells were placed in a T75 flask with 10ml of growth medium and transfected with EP4 Construct 1 day prior to assay according to table below.Atty. Dkt. No.: 052209-0603

[0571] Tubes were incubated at room temperature for 15 minutes. Contents of Tube 2 were then added to Tube 1 and incubated for another 15 minutes. Combined contents in Tube 1 were added to T75 transfection flasks with DLD-1 cells and incubated overnight at 37 °C under 5% CO2 in a humidified atmosphere. On the day of the assay, cells were detached from the flask with trypsin and harvested for addition to assay plate (10,000 cells / well in cAMP Stimulation Buffer supplemented with 500 μM IBMX). Compound solutions for concentration-response analysis of test and reference antagonists were added to HTRF 384-well white low volume assay plates (10 nL of 1000x solution); 10nL of Agonist 1000X stock solution; and cells subsequently seeded at a density of 10,000 cells / well in 10 µL; this was incubated for 90 minutes at 37 °C under 5% CO2 in a humidified atmosphere.

[0572] Detection reagents (cAMP-d2 and anti-cAMP cryptate) are then added to designated wells of both the assay plate and standard curve plate and incubated for 1 hour in the dark at room temperature. Note that the reference agonist and reference antagonist are run in each assay plate, and one standard curve is run per experimental day in a separate assay plate. HTRF signal is measured using a Pherastar plate reader with the default HTRF setting of emissions at 337 nm, 665 nm and 620 nm. Data analysis and IC50and KBcalculations were performed as described for the FP assay above.

[0573] Data for the FP receptor and EP4 receptor assays are shown in the tables below: the first compares the selectivity of a number of example compounds to comparator compound REF27 and the second compares the selectivity of a number of example compounds to comparator compound REF10. The selectivity ratio for hFP over hEP4 is calculated as hEP4 Kb / hFP Kb. The comparator compounds (REF27 and REF10) are disclosed in J. Med. Chem. 2020, 63, 11639- 11662.Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603Atty. Dkt. No.: 052209-0603selective: where hEP4 Kb values are listed as >3000 or “no fit”, it was not possible to calculate hEP4 Kb / hFP Kb due to lack of hEP4 activity.-328-Atty. Dkt. No.: 052209-0603selective: where hEP4 Kb values are listed as >3000 or “no fit”, it was not possible to calculate hEP4 Kb / hFP Kb due to lack of hEP4 activity.

[0574] Mouse parturition model

[0575] The ability of compounds of the present disclosure to delay parturition is tested in a mouse parturition assay. Primigravid mice are received at gestational day 11 (GD11); mice are acclimatized to the laboratory conditions for at least 3 days before the start of experiments. Animals are housed in groups of 3-5 in polysulfone type Sealsafe plus GM500 cages on a bed of wood chips with free access to food and water. Starting from GD16 (evening) treatment with a compound of the present disclosure is initiated twice daily (morning and evening) for a total of 8 administrations until GD20 (morning). At GD16, just after the first treatment, mice are housed individually with food and water ad libitum. No enrichment is added, and the chow is placed directly into the cage. Mice are continuously monitored using infrared cameras and a digital video recorder to capture the time of parturition of pups. In addition to video recording, cages are visually inspected each morning and the evening during the treatment for the presence of pups or evidence of delivery. The following data are collected: maternal viability; maternal body weight (daily fromAtty. Dkt. No.: 052209-0603 GD16, in grams); time of parturition, defined as the time when the first pup is delivered; percentage of mice delivering on each gestation day; and length of gestation in days. The mice show a positive response to treatment.

[0576] Rat intrauterine pressure (IUP) model

[0577] The methods to test FP antagonists of the present disclosure in vivo for inhibition of PGF2α-induced increase in intrauterine pressure (IUP) in rats are adapted with modifications from Cirillo et al. Am. J. Obstet. Gynecol. (2007), 197(1):54.e1-9,. In brief, non-pregnant Sprague Dawley rats with vendor-placed vessel catheters (carotid artery catheter (CAC), jugular vein catheter (JVC) and femoral vein catheter (FVC)) are used in these studies. On the day of the experiment, rats are placed under terminal anesthesia and a fluid filled catheter is implanted in the uterine horn of each animal for measurement of IUP. PGF2α is administered by intravenous (IV) infusion via JVC for 5 minutes in 5 challenges separated by 30 minutes. A compound of the present disclosure is administered by IV infusion via FVC beginning 5 minutes prior to and during the fourth PGF2α challenge. Thus, compound is infused IV for a total of 10 minutes. The inhibition of PGF2α-induced increase in IUP is determined by comparing the PGF2α-induced change in IUP during the fourth challenge to the third challenge measured in the same animal and expressed as a percentage. Mean arterial pressure (via CAC) and IUP are measured continuously and data is acquired with the Notocord-hem software. The rats show a positive response to treatment.

[0578] Mouse silica-induced pulmonary fibrosis model

[0579] Silica-induced fibrosis mouse model (10 days) is used to assess the in vivo efficacy of a compound of the present disclosure. The method as described in Beck et al., J. Med. Chem.2020, 63, 20, 11639-11662 (Supporting information) is employed. The mouse models show a positive response to treatment.

[0580] Clinical trial in female human subjects: endometriosis-associated pain

[0581] A compound of the present disclosure is administered to female human subjects suffering from endometriosis-associated pain. Subject response to the compound administrationAtty. Dkt. No.: 052209-0603 is evaluated by a pain Visual Analogue Scale (VAS). Subjects show a positive clinical response to treatment.

[0582] Clinical trial in female human subjects: dysmenorrhea

[0583] A compound of the present disclosure is administered to female human subjects suffering from dysmenorrhea. Subject response to the compound administration is evaluated by a pain Visual Analogue Scale (VAS). Subjects show a positive clinical response to treatment.

[0584] Clinical trial in female human subjects: pre-term birth

[0585] A compound of the present disclosure is administered to female human subjects having intact membranes (e.g., without rupture of the amniotic sac) and who are at risk of or in preterm labor. Subjects are evaluated by complete blood count (CBC), bleeding profile, kidney function tests and liver tests, and ultrasound testing. Subjects show a positive clinical response to treatment.

[0586] Clinical trial in human subjects: idiopathic pulmonary fibrosis

[0587] A compound of the present disclosure is administered to human subjects suffering from idiopathic pulmonary fibrosis. Subject response to the compound administration is evaluated by change from baseline in Forced Vital Capacity (FVC) at week 24. Subjects show a positive clinical response to treatment.

[0588] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology disclosed herein in its broader aspects.

Claims

Atty. Dkt. No.: 052209-0603 WHAT IS CLAIMED IS:

1. A compound of Formula I:or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: A1 is CR, wherein R is hydrogen, halogen, C1-3alkyl, or cyclopropyl; R1 is halogen, C1-6alkyl, or C1-6haloalkyl; R2 is phenyl; C3-6 cycloalkyl; 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenoxy; or C1-6alkoxy; wherein the phenyl, C3-6cycloalkyl, and 3- to 8-membered heterocycloalkyl are optionally substituted with one to four R2A independently selected from halogen, C1-6alkyl, C1-6alkoxy, and oxo, or two R2A together with the atom(s) to which they are attached form a 3- to 6- membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen;R3A is C3-6cycloalkyl or R3B; W is a bond, -NH-, or -O-; andAtty. Dkt. No.: 052209-0603 R3B is (a) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or (b) 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6haloalkoxy; or -W-R3B is -NR3CR3D, -NHC(O)-O(C1-6alkyl), -NHC(O)R3D, or -C(O)NR3CR3D; wherein R3C is H or C1-3alkyl, and R3Dis C1-6haloalkyl or C3-4cycloalkyl; or wherein R3Cand R3D, together with the nitrogen atom to which they are attached, form a 3- to 6-membered ring; R4A is H; R4B is H, C1-3 alkyl, or -OH; and R4B’ is H or C1-3 alkyl; or R4A and R4B together with the carbon atoms to which they are attached form an oxirane; R5 is C1-6alkyl optionally substituted with C3-4cycloalkyl; C1-6haloalkyl; C4-5cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4 cycloalkyl ring; 4- to 5-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 4- to 5-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from -C(O)(benzyl), -C(O)(C1-6 alkyl), and -SO2(C1-6 alkyl); or phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6 haloalkoxy; and R6is H or C1-6 alkyl; wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).Atty. Dkt. No.: 052209-0603 2. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1, wherein R is hydrogen or C1-3 alkyl.

3. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 or claim 2, wherein R is C1-3 alkyl.

4. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein R is methyl.

5. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein K is6. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1, having Formula Ia:

7. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 6, wherein R3Ais R3B.

8. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 6 or claim 7, wherein R3Ais phenyl optionally substituted with one to four substituentsAtty. Dkt. No.: 052209-0603 independently selected from halogen, -CN, -NH2, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6 haloalkoxy.

9. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 6-8, wherein R3A is phenyl optionally substituted with one to four substituents independently selected from halogen and C1-6alkoxy.

10. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 6-9, wherein R3Ais11. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 6 or claim 7, wherein R3Ais 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.

12. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 6, 7, or 11, wherein R3Ais a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -OH, C1-6alkyl, and C1-6alkoxy.

13. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 6, 7, 11, or 12, wherein R3A is pyrazolyl optionally substituted with one or two substituents independently selected from C1-6alkyl.

14. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 6, 7, 11, or 12, wherein R3A is pyridinyl, pyrazinyl, pyridazinyl, or 2-Atty. Dkt. No.: 052209-0603 pyridonyl, wherein the pyridinyl, pyrazinyl, pyridazinyl, or 2-pyridonyl, is optionally substituted with one or two substituents independently selected from halogen, -OH, C1-6 alkyl, and C1-6 alkoxy.

15. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of16. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 6, wherein R3Ais C3-6 cycloalkyl.

17. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 16, wherein R3A is18. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of-336-Atty. Dkt. No.: 052209-0603 19. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1, having Formula Ib:(Formula Ib).

20. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 19, wherein R3Bis phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6haloalkoxy.

21. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 19 or claim 20, wherein R3B is phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6 haloalkoxy.

22. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 19-21, wherein R3B is23. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 19, wherein R3B is a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6 haloalkoxy.Atty. Dkt. No.: 052209-0603 24. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 19-23, wherein W is a bond.

25. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 19-23, wherein W is -O-.

26. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 19-23, wherein W is -NH-.

27. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1, having Formula Ic:(Formula Ic).

28. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 27, wherein R4A is H and R4B is H.

29. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 27, wherein R4A is H and R4B is –OH.

30. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 27, wherein R4A and R4B together with the carbon atoms to which they are attached form an oxirane.

31. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 27-30, wherein R3Bis phenyl optionally substituted with one to fourAtty. Dkt. No.: 052209-0603 substituents independently selected from halogen, -CN, -NH2, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.

32. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 31, wherein R3B is, , , , , ,33. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 27-30, wherein R3Bis a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.

34. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 33, wherein the 5- to 10-membered heteroaryl is pyrazolyl, indazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.Atty. Dkt. No.: 052209-0603 35. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 33 or claim 34, wherein R3B is36. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 27-30, wherein R3B is37. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 27-36, wherein W is a bond.

38. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 27-36, wherein W is -O-.Atty. Dkt. No.: 052209-0603 39. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims27-36, wherein W is -NH-.

40. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 27 or claim 28, wherein -W-R3B is -NR3CR3D, -NHC(O)-O(C alkyl), 3D 1-6 -NHC(O)R , or - C(O)NR3CR3D; wherein R3Cis H or C1-3 alkyl, and R3Dis C1-6 haloalkyl or C3-4 cycloalkyl; or wherein R3Cand R3D, together with the nitrogen atom to which they are attached, form a 3- to 6- membered ring.

41. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of.

42. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1, having Formula Id:

43. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42, wherein R3Bis phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.Atty. Dkt. No.: 052209-0603 44. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42 or claim 43, wherein R3B is, , , , ,45. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42, wherein R3Bis 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy.

46. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42 or claim 45, wherein R3Bis a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkoxy.Atty. Dkt. No.: 052209-0603 47. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42, 45, or 46, wherein the 5- to 10-membered heteroaryl is pyrazolyl or pyridinyl, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from C1-6 alkyl and C1-6 haloalkoxy.

48. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42, 45, 46, or 47 wherein R3B is49. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42, wherein R3Bis, , , , ,50. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-49, wherein W is a bond.Atty. Dkt. No.: 052209-0603 51. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-49, wherein W is -O-.

52. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-51, wherein R4Bis H.

53. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-51, wherein R4Bis methyl.

54. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1, having Formula Ie:(Formula Ie).

55. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 54, wherein R4B and R4B’ are both H.

56. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 54, wherein R4Bis methyl, and R4B’is H.

57. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 54-56, wherein R5 is C1-6 haloalkyl or C1-6 alkyl optionally substituted with C3- 4 cycloalkyl.

58. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 57, wherein R5 is-344-Atty. Dkt. No.: 052209-0603 59. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 54-56, wherein R5 is C4-5 cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4cycloalkyl ring.

60. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 59, wherein R5is61. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 54-56, wherein R5 is 4- to 5-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 4- to 5- membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from -C(O)(benzyl), -C(O)(C1-6 alkyl), and -SO2(C1-6 alkyl).

62. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 61, wherein R5 is63. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 54-56, wherein R5 is phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6 haloalkoxy.

64. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 63, wherein R5 is-345-Atty. Dkt. No.: 052209-0603 65. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 54-56, wherein R5 is66. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-65, wherein R1 is halogen.

67. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-65, wherein R1 is Br.

68. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-65, wherein R1is C1-6 alkyl, or C1-6 haloalkyl.

69. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 68, wherein R1is ethyl or -CHF2.

70. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-69, wherein R2 is phenyl, wherein R2 is optionally substituted with one to four R2Aindependently selected from halogen, C1-6alkyl, and C1-6alkoxy.

71. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 70, wherein R2 is-346-Atty. Dkt. No.: 052209-0603 72. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 71, wherein R2 is phenyl.

73. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-69, wherein R2is C3-6 cycloalkyl or 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R2 is optionally substituted with one to four R2A independently selected from halogen, C1-6alkyl, C1-6alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3- to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen.

74. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 73, wherein R2 is75. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-69, wherein R2 is phenoxy or C1-6 alkoxy.

76. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 75, wherein R2 is77. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-76, wherein R6 is H.

78. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-76, wherein R6is C1-6 alkyl.

79. A compound selected from Table A, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. -347-Atty. Dkt. No.: 052209-0603 80. A pharmaceutical composition comprising the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79 and at least one pharmaceutically acceptable excipient.

81. A method of modulating prostaglandin F (FP) receptor activity in a subject in need thereof, comprising administering to the subject the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79.

82. A method of treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof, comprising administering to the subject the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79.

83. A method of preventing or reducing risks of pre-term labor in a subject in need thereof, comprising administering to the subject the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79.

84. A method of preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof, comprising administering to the subject the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79.

85. A method of preventing or reducing risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof, comprising administering to the subject the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79.

86. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79, optionally, wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases ofAtty. Dkt. No.: 052209-0603 unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabeticAtty. Dkt. No.: 052209-0603 nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidimytitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non- Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

87. The method of any one of claims 81-86, further comprising administering an additional therapeutic agent to the subject.

88. The method of claim 87, wherein the additional therapeutic agent is selected from the group consisting of atosiban, retosiban, barusiban, epelsiban, nolasiban, terbutaline, ritodrine, hexoprenaline, albuterol, fenoterol, nylidrin, orciprenaline, dihydropyridine, nifedipine, nicardipine, magnesium sulfate, progesterone, 17-α-hydroxyprogesterone, and nitroglycerine.

89. A compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79, for use as a medicament.

90. A compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79, for use in modulating prostaglandin F (FP) receptor activity in a subject in need thereof.Atty. Dkt. No.: 052209-0603 91. A compound, stereoisomer, a tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79, for use in treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof.

92. A compound, stereoisomer, a tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79, for use in preventing pre-term labor in a subject in need thereof.

93. A compound, stereoisomer, a tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79, for use in preventing labor prior to cesarean delivery in a subject in need thereof.

94. A compound, stereoisomer, a tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79, for use in preventing one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof.

95. A compound, stereoisomer, a tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79, for use in treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung andAtty. Dkt. No.: 052209-0603 related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidimytitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors,Atty. Dkt. No.: 052209-0603 leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

96. Use of a compound, stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof of any one of claims 1-79, in the preparation of a medicament for modulating prostaglandin F (FP) receptor activity in a subject in need thereof.

97. Use of a compound, stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof of any one of claims 1-79, in the preparation of a medicament for treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof.

98. Use of a compound, stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof of any one of claims 1-79, in the preparation of a medicament for preventing pre-term labor in a subject in need thereof.

99. Use of a compound, stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof of any one of claims 1-79, in the preparation of a medicament for preventing labor prior to cesarean delivery in a subject in need thereof.

100. Use of a compound, stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof of any one of claims 1-79, in the preparation of a medicament for preventing one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof.

101. Use of a compound, stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof of any one of claims 1-79, in the preparation of a medicament for treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-Atty. Dkt. No.: 052209-0603 classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease,Atty. Dkt. No.: 052209-0603 nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidimytitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non- Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

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