Small molecule prostaglandin F receptor antagonists

Abstract

Disclosed herein are small molecule prostaglandin F (FP) receptor antagonists, methods of making the same, and methods of treatment using the same.

Description

Cross Reference to Related Applications

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

[0002] The present disclosure is in the field of pharmaceutical compounds and compositions and methods of treatment using them. In particular, the present disclosure is in the field of prostaglandin F (FP) receptor antagonists and uses thereof. BACKGROUND

[0003] Prostaglandins are bioactive metabolites of arachidonic acid, primarily involved in the mediation of inflammation. Arachidonic acid is released from the lipids of cell membranes by the action of phospholipases; arachidonic acid is then metabolized by cyclooxygenases and various isomerases and prostaglandin synthases to form different prostaglandins. The most important and biologically relevant prostaglandins are PGE2, PGI2, PGD2, PGF 2α and TXA2.

[0004] Prostaglandin receptors are members of the G protein-coupled receptor (GPCR) seven-transmembrane superfamily. The prostaglandin hormone receptor subfamily is composed of at least eight members: EP1, EP2, EP3, and EP4 subtypes of the PGE receptor; DP1; FP; IP; and TP. Receptors are usually named after the prostaglandin with the highest efficacy at the receptor; however, receptors can effectively bind more than one prostaglandin. The FP receptor can be considered the least selective of the prostaglandin hormone receptors in terms of binding the primary endogenous prostaglandins; in addition to PGF 2α , both PGD2and PGE2activate FP with EC 50 values in the nanomolar range.

[0005] PGF 2α and FP receptors are associated with a variety of diseases, conditions, and inflammatory disorders. In the reproductive process, PGF 2α is primarily derived from COX-1 in the female reproductive system and plays an important role in ovulation, luteolysis, uterine smooth muscle contraction, and initiation of labor. PGF 2αplays a prominent role in renal function, arterial constriction, myocardial dysfunction, brain injury, and pain. 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 less related receptors). Deletion of FP has been reported to selectively attenuate pulmonary fibrosis without altering pulmonary inflammation. Another study of FP-deficient female mice reported normal ovulation and implantation, but failed to deliver naturally during pregnancy. Increased biosynthesis of PGF 2α has been reported in patients with rheumatoid arthritis, psoriatic arthritis, reactive arthritis, and osteoarthritis. Targeting FP can be an effective therapeutic strategy for many disorders; to date, no specific FP modulator has been approved for therapeutic use.

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

[0007] In WO 2017 / 153234 Al, substituted N-cyclo-2-aryl-quinoline-4-carboxamide derivatives are described, as well as methods of producing these derivatives, and the use of these derivatives, alone or in combination, for the treatment and / or prevention of diseases, especially the treatment and / or prevention of fibrotic diseases and inflammatory diseases.

[0008] In WO 2016 / 146602 Al, substituted N-bicyclo-2-aryl-quinoline-4-carboxamide derivatives are described, as well as methods of producing these derivatives, and the use of these derivatives, alone or in combination, for the treatment and / or prevention of diseases, especially the treatment and / or prevention of fibrotic diseases and inflammatory diseases.

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

[0010] In one aspect, provided herein is a compound of Formula I: (Formula I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: A 1 is CR, wherein R is hydrogen, halogen, C 1-3 alkyl, or cyclopropyl; R 1 is halogen, C 1-6 alkyl, or C 1-6haloalkyl; R 2 is phenyl; C 3-6 cycloalkyl; 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenoxy; or C 1-6 alkoxy; wherein the phenyl, C 3-6 cycloalkyl, and 3- to 8-membered heterocycloalkyl are optionally substituted with one to four R 1-6 substituents independently selected from halogen, C 1-6 alkyl, C 2A alkoxy, and oxo; or two R 2A , together with the atom 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; K is , , , or ; R 3A is C 1-6 alkyl, C 3-6 cycloalkyl, or R 3B ; W is a bond, -NH-, or -O-; and R 3B is (a) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; or -W-R 3B is -NR 3C R 3D , -NHC(O)-O(C 1-6 alkyl), -NHC(O)R 3D , or -C(O)NR 3C R 3D ; wherein R 3C is H or C 1-3 alkyl, and R 3D is C1-6 Halogenated alkyl or C 3-4 cycloalkyl; or wherein R 3C and R 3D Together with the nitrogen atoms to which they are attached, they form 3 to 6-membered rings; R 4A It is H; R 4B It is H, C 1-3 Alkyl or -OH; and R 4B’ Is it H or C? 1-3 Alkyl; or R 4A and R 4B Together with the carbon atoms to which they are attached, they form ethylene oxide; R 5 It is arbitrarily C 3-4 Cycloalkyl-substituted C 1-6 Alkyl; C 1-6 Haloalkyl; optionally independently selected from -OH, halogen, C 1-6 Alkyl, C 3-4 cycloalkyl and C 1-6 The C-axis of the haloalkoxy group is substituted by one or both of its substituents. 4-5 Cycloalkyl groups, or two substituents together with the carbon atoms to which they are attached, form a C12 group. 3-4 Cycloalkyl ring; containing a 4- to 5-membered heterocyclic alkyl group independently selected from one or two cyclic heteroatoms of nitrogen, oxygen, and sulfur, wherein the 4- to 5-membered heterocyclic alkyl group is optionally independently selected from -C(O)(benzyl), -C(O)(C 1-6 alkyl) and -SO2(C 1-6 One or two substituents of the alkyl group are used; or optionally, the alkyl group is independently selected from halogens and C. 1-6 A phenyl group substituted with one or both of the haloalkoxy groups; and R 6 Is it H or C? 1-6 alkyl; The 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced by one or more deuterium atoms.

[0011] In some embodiments, R is hydrogen or C. 1-3 Alkyl group. In some embodiments, R is C 1-3 Alkyl group. In some embodiments, R is methyl.

[0012] In some embodiments, the compound has formula Ia: (Formula Ia) Or its stereoisomers, tautomers, or pharmaceutically acceptable salts. In some embodiments, R 3A It is R 3B In some embodiments, R3A is optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy. In some embodiments, R 3A is optionally substituted with one to four substituents independently selected from halogen and C 1-6 alkoxy. In some embodiments, R 3A is , , , , or . In some embodiments, R 3A 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy. In some embodiments, R 3A 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, C 1-6 alkyl, and C 1-6 alkoxy. In some embodiments, R 3A is pyrazolyl optionally substituted with one or two substituents independently selected from C 1-6 alkyl. In some embodiments, R 3A 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, C 1-6 alkyl, and C 1-6 alkoxy. In some embodiments, R 3A is , , , , , , or . In some embodiments, R 3A is C 1-6 alkyl. In some embodiments, R 3A is . In some embodiments, R 3A is C 3-6cycloalkyl. In some embodiments, R 3A is . In some embodiments, R 3A is , , , , , , , , , , , , , , or .

[0013] In some embodiments, the compound is of Formula Ib: (Formula Ib) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, R 3B is phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy. In some embodiments, R 3B is phenyl optionally substituted with one or two substituents independently selected from halogen and C 1-6 haloalkoxy. In some embodiments, R 3B is , , or . In some embodiments, R 3B is 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 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, R 4A is H and R4B is H. In some embodiments, R 4A is H and R 4B is -OH. In some embodiments, R 4A and R 4B together with the carbon atom to which they are attached form an oxirane. In some embodiments, R 3B is phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy. In some embodiments, R 3B is , , , , , , , , , , , , , , , , , or . In some embodiments, R 3B 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy. In some embodiments, R 3B is , , , , or . In some embodiments, R 3B is , , , , , , , , , , , , , , , , , , , , , or In some embodiments, W is a bond. In some embodiments, W is -O-. In some embodiments, W is -NH-. In some embodiments, -WR 3B Yes -NR 3C R 3D -NHC(O)-O(C) 1-6 Alkyl), -NHC(O)R 3D or -C(O)NR 3C R 3D ;where R 3C Is it H or C? 1-3 Alkyl, and R 3D It is C 1-6 Halogenated alkyl or C 3-4 cycloalkyl; or wherein R 3C and R 3D Together with the nitrogen atoms to which they are attached, they form 3 to 6-membered rings. In some embodiments, -WR 3B yes , , , , or .

[0015] In some embodiments, the compound has the formula Id: (Formula ID) Or its stereoisomers, tautomers, or pharmaceutically acceptable salts. In some embodiments, R 3B It is optionally and independently selected from halogen, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one to four substituents of a haloalkoxy group. In some embodiments, R 3B yes , , , , , , , , , , , , , , , , , , , , , , , , , or In some embodiments, R 3B It is a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the 5- to 10-membered heteroaryl group is optionally and independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are used for substitution. In some embodiments, R 3B It is a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the 5- to 10-membered heteroaryl group is optionally independently selected from halogens, C... 1-6 Alkyl and C 1-6 One to three substituents of the haloalkoxy group are used for substitution. In some embodiments, the 5 to 10-membered heteroaryl group is pyrazolyl or pyridinyl, wherein the 5 to 10-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl and C 1-6 One to three substituents of the haloalkoxy group are used for substitution. In some embodiments, R 3B yes or In some embodiments, R 3B yes , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some embodiments, W is a key. In some embodiments, W is -O-. In some embodiments, R 4B It is H. In some embodiments, R 4B It is a methyl group.

[0016] In some embodiments, the compound has the formula Ie: (Formula Ie) Or its stereoisomers, tautomers, or pharmaceutically acceptable salts. In some embodiments, R 4B and R 4B’ Both are H. In some embodiments, R 4B It is methyl, and R 4B’ It is H. In some embodiments, R 5 It is arbitrarily C 3-4 Cycloalkyl-substituted C 1-6 Halogenated alkyl or C 1-6 Alkyl group. In some embodiments, R 5 yes , , , , , ,or In some embodiments, R 5 It is optionally and independently selected from -OH, halogen, C 1-6 Alkyl, C 3-4 cycloalkyl and C 1-6 The C-axis of the haloalkoxy group is substituted by one or both of its substituents. 4-5 Cycloalkyl groups, or two substituents together with the carbon atoms to which they are attached, form a C12 group. 3-4 Cycloalkyl ring. In some embodiments, R 5 yes , , , , , , , or In some embodiments, R 5 It is a 4- to 5-membered heterocyclic alkyl group containing one or two cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 4- to 5-membered heterocyclic alkyl group is optionally independently selected from -C(O)(benzyl), -C(O)(C 1-6 alkyl) and -SO2(C 1-6 One or two substituents of the alkyl group are substituted. In some embodiments, R 5 yes , ,or In some embodiments, R 5 It is optionally and independently selected from halogens and C 1-6 A phenyl group substituted with one or both of the haloalkoxy groups. In some embodiments, R 5 yes , ,or In some embodiments, R 5 yes , , , , , , , , , , , , , , , , , , , , or In some embodiments, R 1 It is a halogen. In some embodiments, R 1 It is Br. In some embodiments, R 1 It is C 1-6 Alkyl or C 1-6 Haloalkyl. In some embodiments, R 1 It is ethyl or -CHF2. In some embodiments, R 2 It is a phenyl group, where R 2 Optionally selected independently from halogen, C 1-6 Alkyl and C 1-6 One to four Rs of alkoxy 2A Replacement. In some embodiments, R 2 yes , ,or In some embodiments, R 2 It is phenyl. In some embodiments, R 2 It is C 3-6 Cycloalkyl or containing one or two cyclic heteroalkyl groups independently selected from nitrogen, oxygen, and sulfur; wherein R 2 Optionally selected independently from halogen, C 1-6 Alkyl, C 1-6 One to four R groups of alkoxy and oxo groups 2A Replace, or two R 2A Together with one or more atoms to which they are attached, they form a 3- to 6-membered ring optionally comprising a cyclic heteroatom selected from nitrogen, oxygen, and sulfur, wherein the 3- to 6-membered ring is optionally substituted independently by one or two substituents selected from halogens. In some embodiments, R 2 yes , , , , , , , , , , or In some embodiments, R 2 It is phenoxy or C 1-6 Alkoxy. In some embodiments, R 2 yes or In some embodiments, R 6 It is H. In some embodiments, R 6 It is C 1-6 alkyl.

[0017] In some embodiments, the compound is selected from Table A, or its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0018] On the other hand, this document provides salts, hydrates, solvates, analogs, conjugates, isomers, polymorphs, esters, prodrugs, metabolites, complexes, cocrystals, intermediates, modifications and derivatives of the compounds, stereoisomers and tautomers described herein.

[0019] On the other hand, this article provides pharmaceutical compositions comprising the compounds described herein and at least one pharmaceutically acceptable excipient.

[0020] On the other hand, this article provides a method for modulating prostaglandin F (FP) receptor activity in subjects in need, the method comprising administering the compound described herein to the subject.

[0021] In another aspect, this article provides a method for treating preterm labor or reducing the risk of preterm labor in subjects in need, the method comprising administering the compound described herein to the subject. In another aspect, this article provides a method for preventing preterm labor or reducing the risk of preterm labor in subjects in need, the method comprising administering the compound described herein to the subject. In another aspect, this article provides a method for preventing or reducing the risk of preterm labor before cesarean section in subjects in need, the method comprising administering the compound described herein to the subject.

[0022] On the other hand, this article provides a method for preventing or reducing the risk of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in subjects in need, the method comprising administering the compound described herein to the subject. On the other hand, this article provides a method for treating a disease or disorder in subjects in need, the method comprising administering the compound described herein to the subject, wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, nonspecific interstitial pneumonia, lymphointerstitial pneumonia, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonia, desquamative interstitial pneumonia and unclassified idiopathic interstitial pneumonia, granulomatous interstitial lung disease, interstitial lung disease of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary arterial 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), emphysema, cystic fibrosis (CF), inflammatory and fibrotic kidney disorders, 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, refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, drug- or dust-induced asthma, chronic... Bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, drug-related rhinitis, vasomotor rhinitis and seasonal allergic rhinitis, polyposis, hypertension (hypertension), heart failure, coronary artery disease, stable and unstable angina, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, atrial and ventricular rhythm disorders, first- to third-degree atrioventricular block, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, torsades de pointes, atrial and ventricular premature contractions. Premature contractions at the atrioventricular junction, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, Ward-Patwee syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvular heart disease, aortitis, cardiomyopathy, aneurysm, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient ischemic attack, preeclampsia, inflammatory cardiovascular disorders, coronary and peripheral artery spasm, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial ischemia, endothelial dysfunction.Microvascular and macrovascular injury (vasculitis), renal hypoperfusion, hypotension during dialysis, obstructive urinary tract disease, glomerulonephritis, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, primary nephropathy, congenital nephropathy, nephritis, renal impairment caused by renal transplant rejection or immune complexes, nephropathy caused by toxic substances, nephropathy caused by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hypertrophy (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, and filling incontinence. Urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine fibroids, endometriosis, dysmenorrhea, premature contractions, hirsutism, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemia, liposarcoma, gastrointestinal cancer, liver cancer, pancreatic cancer, lung cancer, kidney cancer, ureteral cancer, prostate cancer and reproductive tract cancer, Hodgkin's lymphoma and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depression, 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 includes administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is selected from the group consisting of: atosiban, retosiban, baruciban, epasiban, noraciban, terbutaline, ritodrine, hesonaline, abuterinol, fenoterol, buphenonol, orsinol, dihydropyridine, nifedipine, nicardipine, magnesium sulfate, progesterone, 17-α-hydroxyprogesterone, and nitroglycerin.

[0023] On the other hand, this article provides a compound for modulating prostaglandin F (FP) receptor activity in subjects in need, for treating preterm labor or reducing the risk of preterm labor in subjects in need, for preventing preterm labor in subjects in need, for preventing preterm labor before cesarean section in subjects in need, for preventing dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in subjects in need, or for treating a disease or disorder in subjects in need, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, nonspecific interstitial pneumonia, lymphointerstitial pneumonia, respiratory diseases with interstitial lung disease. Bronchiolitis, cryptogenic organizing pneumonia, desquamative interstitial pneumonia and unclassified idiopathic interstitial pneumonia, granulomatous interstitial lung disease, interstitial lung disease of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary arterial 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), emphysema, cystic fibrosis (CF), inflammatory and fibrotic kidney disorders, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic diseases. Skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractory asthma, bronchial asthma, allergic asthma, endogenous asthma, extrinsic asthma, drug- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, drug-related rhinitis, vasomotor rhinitis and seasonal allergic rhinitis, polyposis, hypertension (hypertension), heart failure, coronary artery disease, stable and unstable angina, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, atrial and ventricular rhythm disorders, first- to third-degree atrioventricular block, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation. Ventricular flutter, ventricular tachycardia, torsades de pointes, premature atrial and ventricular contractions, premature atrioventricular junctional contractions, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, Ward-Patwee syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvular heart disease, aortitis, cardiomyopathy, aneurysm, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient ischemic attack, preeclampsia, inflammatory cardiovascular disorders, coronary and peripheral artery spasm, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial ischemia, endothelial dysfunction.Microvascular and macrovascular injury (vasculitis), renal hypoperfusion, hypotension during dialysis, obstructive urinary tract disease, glomerulonephritis, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, primary nephropathy, congenital nephropathy, nephritis, renal impairment caused by renal transplant rejection or immune complexes, nephropathy caused by toxic substances, nephropathy caused by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hypertrophy (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, and filling incontinence. Urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine fibroids, endometriosis, dysmenorrhea, premature contractions, hirsutism, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemia, liposarcoma, gastrointestinal cancer, liver cancer, pancreatic cancer, lung cancer, kidney cancer, ureteral cancer, prostate cancer and reproductive tract cancer, Hodgkin's lymphoma and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depression, wherein the disease or disorder is optionally one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

[0024] On the other hand, this document provides the use of the compounds described herein in the preparation of a medicament for modulating prostaglandin F (FP) receptor activity in subjects in need, for treating preterm labor or reducing the risk of preterm labor in subjects in need, for preventing preterm labor in subjects in need, for preventing preterm labor before cesarean section in subjects in need, for preventing dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in subjects in need, or for treating a disease or disorder in subjects in need, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, nonspecific interstitial pneumonia, and lymphointerstitial pneumonia. Respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonia, desquamative interstitial pneumonia and unclassified idiopathic interstitial pneumonia, granulomatous interstitial lung disease, interstitial lung disease of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary arterial 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), emphysema, cystic fibrosis (CF), inflammatory and fibrotic kidney disorders, 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, refractory asthma, bronchial asthma, allergic asthma, endogenous asthma, extrinsic asthma, drug- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, drug-related rhinitis, vasomotor rhinitis and seasonal allergic rhinitis, polyposis, hypertension (hypertension), heart failure, coronary artery disease, stable and unstable angina, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, atrial and ventricular rhythm disorders, first- to third-degree atrioventricular block, supraventricular tachycardia, atrial... Fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, torsades de pointes, premature atrial and ventricular contractions, premature atrioventricular junctional contractions, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, Ward-Patwee syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvular heart disease, aortitis, cardiomyopathy, aneurysm, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient ischemic attack, preeclampsia, inflammatory cardiovascular disorders, coronary and peripheral artery spasm, pulmonary edema, cerebral edema, renal edema or edema due to heart failure, peripheral circulatory disturbances, reperfusion injury, arterial and venous thrombosis, microalbuminuria.Myocardial ischemia, endothelial dysfunction, microvascular and macrovascular injury (vasculitis), renal insufficiency, hypotension during dialysis, obstructive urinary tract disease, glomerulonephritis, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, primary nephropathy, congenital nephropathy, nephritis, renal transplant rejection or renal disorders caused by immune complexes, nephropathy caused by toxic substances, nephropathy caused by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hypertrophy (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, etc. Irritable urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine fibroids, endometriosis, dysmenorrhea, premature contractions, hirsutism, sepsis, multiple organ dysfunction syndrome, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemia, liposarcoma, gastrointestinal cancer, liver cancer, pancreatic cancer, lung cancer, kidney cancer, ureteral cancer, prostate cancer and reproductive tract cancer, Hodgkin's lymphoma and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depression, wherein the disease or disorder is optionally one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF). Detailed Implementation definition

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

[0026] As used in this article, the singular forms “a” and “the” can refer to both singular and plural forms, unless explicitly stated otherwise.

[0027] As used herein, the term “about” means that the parameter is not limited to the exact number stated. As used herein, “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. If a term is not readily understood by those skilled in the art, then in the context of its use, “about” will mean at most 10% plus or minus that particular term. As used herein, a range should be interpreted as an abbreviation for each value falling within that range, and each individual value should be understood as explicitly disclosed herein.

[0028] The phrase “consistently composed of…” will be understood to include those elements specifically listed as well as other elements that do not materially affect the essential and novel features of the claimed technology. When “consistently composed of…” is used to refer to a composition having only one active agent disclosed herein, the composition cannot include any other active agents not otherwise listed. When “consistently composed of…” is used to refer to a combination of active agents disclosed herein, these combinations cannot include any other active agents not otherwise listed. When “consistently composed of…” is used to refer to a treatment method, the method cannot include the application of any other therapeutic active agent not otherwise listed.

[0029] As used herein, a "pharmaceutically acceptable salt" means a salt of a compound that will not cause significant irritation to the patient to whom it is administered and will not eliminate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting the compounds disclosed herein with acids or bases. Generally (but not necessarily, unless otherwise stated), the salts of the present invention are pharmaceutically acceptable salts. Salts covered by the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of the present invention. Salts of the compounds disclosed herein may comprise acid addition salts. Representative salts include acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, calcium edetate, dextrorotatory camphor sulfonate, carbonates, chlorides, clavulanates, citrates, dihydrochlorides, edetate, ethanedisulfonate, etolate, ethanesulfonate, fumarate, gluconate, gluconate, glutamate, glycolyllarsanilate, hexylresorcinol, hyaluronic acid, hydrobromide, hydrochloride, hydroxynaphthylcarbamate, iodides, hydroxyethylsulfonate, lactates, and lactose. Aldehydes, laurates, malates, maleates, mandelates, mesylates, methyl bromide, methyl nitrates, methyl sulfates, potassium maleate, mucilages, naphthalene sulfonates, nitrates, N-methylglucosamine, oxalates, pamoate (embonate), palmitate, pantothenate, phosphates / bisphosphonates, polygalacturonic acids, potassium salts, salicylates, sodium salts, stearates, basic acetates, succinates, sulfates, tannates, tartrates, theochloroate, toluenesulfonates, triethyliodide, trimethylammonium, and valerates. Other salts that are not pharmaceutically acceptable may be used to prepare the compounds disclosed herein, and these salts should be considered to form another aspect of the technology.

[0030] When the compounds disclosed herein have one or more chiral centers, they may exist as racemates or as separate enantiomers, provided or formulated as or used as racemates or separate enantiomers. It should be noted that all such stereoisomers and mixtures thereof are included within the scope of this disclosure. Therefore, the statement that no R or S chiral center is specified indicates that the scope of this disclosure includes R isomers, S isomers, racemic mixtures of isomers, and mixtures in which one isomer is present in greater abundance than another isomer.

[0031] In cases where the methods used to prepare the compounds disclosed herein produce mixtures of stereoisomers, such isomers can be separated using conventional techniques such as preparative chromatography. The compounds can be prepared in racemic form, or individual enantiomers can be prepared via stereoselective synthesis or by resolution. The compounds can be resolved to their component enantiomers using standard techniques, for example, by forming salts with optically active acids such as (-)-di-p-toluyl-d-tartaric acid and / or (+)-di-p-toluyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base to form diastereomer pairs. These compounds can also be resolved by forming diastereomeric esters or amides, followed by chromatographic separation and removal of chiral auxiliaries.

[0032] As used herein, “aryl” refers to a fully aromatic carbon (all-carbon) ring. An “aryl” group can consist of two or more fused rings (rings sharing two adjacent carbon atoms). When the aryl group is a fused-ring system, the ring attached to the remainder of the molecule is fully aromatic. One or more other rings in the fused-ring system may or may not be fully aromatic. Examples of aryl groups include, but are not limited to, groups of benzene, naphthalene, and azurite. Further non-limiting examples include: , and .

[0033] As used herein, a “heteroaryl” refers to a ring that is fully aromatic and contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some instances, the heteroaryl ring may contain an oxo group directly attached to a carbon atom of the ring, which forms part of the aromatication system. A “heteroaryl” group may consist of two or more fused rings (rings sharing two adjacent carbon atoms). When the heteroaryl group is a fused ring system, the rings connected to the rest of the molecule are fully aromatic. One or more other rings in the fused ring system may or may not be fully aromatic. Examples of heteroaryl rings include, but are not limited to, furans, thiophenes, phthalazins, pyrroles, oxazoles, thiazoles, imidazoles, pyrazoles, indazoles, isoxazoles, isothiazoles, triazoles, thiadiazoles, pyridines, 2-pyridones, pyridazines, pyrimidines, pyrazines, and triazines. As described herein, in some instances, the heteroaryl group may be substituted. In other words, the heteroaryl group may contain one or more substituents on the heteroaromatic ring. When a heteroaryl group is substituted, any number of hydrogen atoms can be replaced by one or more substituents, provided the valence is satisfied. In some cases, the heteroaryl group can be substituted at the heteroatom; for example, an N-containing heteroaryl group can be an N-substituted heteroaryl group (e.g., an N-substituted 2-pyridone group).

[0034] As used herein, "alkyl" refers to a straight-chain or branched, fully saturated hydrocarbon group (without double or triple bonds). The alkyl groups of the compounds disclosed herein may contain 1 to 15 carbon atoms. Alkyl groups 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, C1-C6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, C1-C4 alkyl refers to an alkyl group having 1 to 4 carbon atoms, and C1-C4 alkyl refers to an alkyl group having 1 to 3 carbon atoms, etc. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl.

[0035] As used herein, “cycloalkyl” refers to a fully saturated (without double bonds) hydrocarbon ring. The cycloalkyl groups in the compounds disclosed herein can be in the range of C3 to C5, C3 to C6, C3 to C7, or C3 to C8. As used herein, C3-C5 cycloalkyl means a cycloalkyl group containing 3 to 5 carbon atoms, and C3-C6 cycloalkyl means a cycloalkyl group containing 3 to 6 carbon atoms.

[0036] As used herein, “heterocyclic alkyl” means a ring having one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur in the ring system. If the ring is not fully aromatic, it may also contain one or more double bonds. A “heterocyclic alkyl” ring as defined herein can be a stable 3- to 18-membered ring (including 3- to 5-membered or 3- to 6-membered rings) consisting of a carbon atom and one to five ring heteroatoms selected from nitrogen, oxygen, and sulfur. A “heterocyclic alkyl” ring as defined herein can be a bridged, fused, or spirocyclic ring system.

[0037] As used herein, “alkoxy” refers to an alkyl group as defined above, attached to the parent molecule via an oxygen group (-O-). As used herein, C1-C6 alkoxy means an alkoxy group containing 1 to 6 carbon atoms, and C1-C3 alkoxy means an alkoxy group containing 1 to 3 carbon atoms. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexoxy.

[0038] As used herein, “haloalkyl” means an alkyl group as defined above, wherein one or more of the hydrogen atoms thereon have been replaced by a halogen atom (e.g., F, Cl, Br, or I). As used herein, “C1-C6 haloalkyl” means an alkyl group containing 1 to 6 carbon atoms, wherein one or more of the hydrogen atoms thereon have been replaced by a halogen atom.

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

[0040] As used herein, unless otherwise stated, “independently selected” means that each of the specified groups is independently selected from the subsequent list of substances.

[0041] It should be understood that in any compound of the present invention having one or more chiral centers, each center may be R or S independently unless explicitly stated in terms of absolute stereochemistry. Furthermore, it should be understood that in any compound of the present invention having one or more double bonds (producing geometric isomers that can be defined as E or Z), each double bond may be E or Z independently.

[0042] It should be understood that, where applicable, the disclosure of compounds herein inherently includes the disclosure of their tautomers. For example, the following disclosures: (where R) x (It is H) This also includes the following disclosures: And vice versa, even if only one of the two structures is disclosed.

[0043] Throughout this disclosure, it should be understood that when describing or naming compounds, this disclosure also considers and covers analogues of compounds with isotopic enrichment. For example, a compound may be doped with deuterium instead of hydrogen, or with carbon-13 instead of carbon having a natural isotopic distribution. Isotopic enrichment can occur at one position on the compound, i.e., only one hydrogen atom is replaced by deuterium, or at more than one position. This disclosure also covers compounds in which all similar atoms are replaced by less common isotopes, such as fully deuterated compounds in which all hydrogen atoms are replaced by deuterium. For example, isotopically enriched compounds can be useful when obtaining NMR spectra or when using isotopic effects to control the kinetics of an ongoing reaction of the compound.

[0044] Throughout this disclosure, when describing or naming compounds, it should be understood that this disclosure considers and covers their salts, hydrates, analogs, conjugates, isomers, polymorphs, esters, prodrugs, metabolites, complexes, cocrystals, intermediates, modifications, and derivatives.

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

[0046] As used herein, the terms “patient” and “subject” refer to a vertebrate that has been or will be used as a subject of treatment, observation, or experimentation, such as, but not limited to, mammals (including humans), birds, fish, or reptiles. “Subject” and “patient” may be used interchangeably. Mammals include, but are not limited to, humans, mice, rodents, rats, apes, farm animals, dogs, cats, racing animals, and pets. The methods described herein can be used in therapeutic and / or veterinary / animal husbandry applications on humans. Without limitation, the following discussion is written with reference to adult patients.

[0047] As used herein, the terms "therapeutic effective amount" and "effective amount" are used interchangeably and refer to the amount that provides a specific, expected pharmacological effect in a patient requiring treatment. It should be emphasized that even if a person skilled in the art considers such an amount to be a therapeutically effective amount, a therapeutically effective amount will not always be effective in treating the condition described herein in a given patient. Exemplary therapeutically effective amounts are provided herein with reference to adult patients. Therapeuticly effective amounts can vary depending on, for example, the characteristics of the patient being treated, the condition being treated, and the severity of the condition. compound

[0048] On the one hand, this article discloses compounds of formula I. (Formula I) Or its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein: A 1 It is CR, where R is hydrogen, halogen, and C. 1-3 Alkyl or cyclopropyl; R 1 It is halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2 It is phenyl; C 3-6 Cycloalkyl; containing a 3- to 8-membered heterocyclic alkyl group independently selected from one or two cyclic heteroatoms of nitrogen, oxygen, and sulfur; phenoxy; or C 1-6 Alkoxy; wherein the phenyl, C 3-6 Cycloalkyl groups and 3- to 8-membered heterocycloalkyl groups are optionally independently selected from halogens, C 1-6 Alkyl, C 1-6 One to four R groups of alkoxy and oxo groups 2A Replace, or two R 2A Together with one or more atoms to which they are attached, they form a 3 to 6 membered ring optionally containing a cyclic heteroatom selected from nitrogen, oxygen and sulfur, wherein the 3 to 6 membered ring is optionally substituted by one or two substituents independently selected from halogens. K is , , , or ; R 3A It is C 1-6 Alkyl, C 3-6 cycloalkyl or R 3B ; W is a bond, -NH- or -O-; and R 3B (a) is optionally and independently selected from halogens, -CN, -NH2, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one to four substituents of a haloalkoxy group; or (b) A 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the heteroaryl group is optionally independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are substituted; or -WR 3B Yes -NR 3C R 3D -NHC(O)-O(C) 1-6 Alkyl), -NHC(O)R 3D or -C(O)NR 3C R 3D ;where R 3C Is it H or C? 1-3 Alkyl, and R 3D It is C 1-6 Halogenated alkyl or C 3-4 cycloalkyl; or wherein R 3C and R 3D Together with the nitrogen atoms to which they are attached, they form 3 to 6-membered rings; R 4A It is H; R 4B It is H, C 1-3 Alkyl or -OH; and R 4B’ Is it H or C? 1-3 Alkyl; or R 4A and R 4B Together with the carbon atoms to which they are attached, they form ethylene oxide; R 5 It is arbitrarily C 3-4 Cycloalkyl-substituted C 1-6 Alkyl; C 1-6 Haloalkyl; optionally independently selected from -OH, halogen, C 1-6 Alkyl, C 3-4 cycloalkyl and C 1-6 The C-axis of the haloalkoxy group is substituted by one or both of its substituents. 4-5 Cycloalkyl groups, or two substituents together with the carbon atoms to which they are attached, form a C12 group. 3-4 Cycloalkyl ring; containing a 4- to 5-membered heterocyclic alkyl group independently selected from one or two cyclic heteroatoms of nitrogen, oxygen, and sulfur, wherein the 4- to 5-membered heterocyclic alkyl group is optionally independently selected from -C(O)(benzyl), -C(O)(C 1-6 alkyl) and -SO2(C 1-6One or two substituents of the alkyl group are used; or optionally, the alkyl group is independently selected from halogens and C. 1-6 A phenyl group substituted with one or both of the haloalkoxy groups; and R 6 Is it H or C? 1-6 alkyl; The 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced by one or more deuterium atoms.

[0049] In some embodiments, R is hydrogen or C. 1-3 Alkyl group. In some embodiments, R is C 1-3 Alkyl group. In some embodiments, R is methyl.

[0050] In some embodiments, K is , , or .

[0051] On the other hand, this paper discloses compounds of formula I: (Formula I) Or its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein: A 1 It is CR, where R is hydrogen, halogen, and C. 1-3 Alkyl or cyclopropyl; R 1 It is halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2 It is phenyl; C 3-6 Cycloalkyl; containing a 3- to 8-membered heterocyclic alkyl group independently selected from one or two cyclic heteroatoms of nitrogen, oxygen, and sulfur; phenoxy; or C 1-6 Alkoxy; wherein the phenyl, C 3-6 Cycloalkyl groups and 3- to 8-membered heterocycloalkyl groups are optionally independently selected from halogens, C 1-6 Alkyl, C 1-6 One to four R groups of alkoxy and oxo groups 2A Replace, or two R 2A Together with one or more atoms to which they are attached, they form a 3 to 6 membered ring optionally containing a cyclic heteroatom selected from nitrogen, oxygen and sulfur, wherein the 3 to 6 membered ring is optionally substituted by one or two substituents independently selected from halogens. K is , , , or ; R 3AIt is C 3-6 cycloalkyl or R 3B ; W is a bond, -NH- or -O-; and R 3B (a) is optionally and independently selected from halogens, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one to four substituents of a haloalkoxy group; or (b) A 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the heteroaryl group is optionally independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are substituted; or -WR 3B Yes -NR 3C R 3D -NHC(O)-O(C) 1-6 Alkyl), -NHC(O)R 3D or -C(O)NR 3C R 3D ;where R 3C Is it H or C? 1-3 Alkyl, and R 3D It is C 1-6 Halogenated alkyl or C 3-4 cycloalkyl; or wherein R 3C and R 3D Together with the nitrogen atoms to which they are attached, they form 3 to 6-membered rings; R 4A It is H; R 4B It is H, C 1-3 Alkyl or -OH; and R 4B’ Is it H or C? 1-3 Alkyl; or R 4A and R 4B Together with the carbon atoms to which they are attached, they form ethylene oxide; R 5 It is arbitrarily C 3-4 Cycloalkyl-substituted C 1-6 Alkyl; C 1-6 Haloalkyl; optionally independently selected from -OH, halogen, C 1-6 Alkyl, C 3-4 cycloalkyl and C 1-6 The C-axis of the haloalkoxy group is substituted by one or both of its substituents. 4-5Cycloalkyl groups, or two substituents together with the carbon atoms to which they are attached, form a C12 group. 3-4 Cycloalkyl ring; containing a 4- to 5-membered heterocyclic alkyl group independently selected from one or two cyclic heteroatoms of nitrogen, oxygen, and sulfur, wherein the 4- to 5-membered heterocyclic alkyl group is optionally independently selected from -C(O)(benzyl), -C(O)(C 1-6 alkyl) and -SO2(C 1-6 One or two substituents of the alkyl group are used; or optionally, the alkyl group is independently selected from halogens and C. 1-6 A phenyl group substituted with one or both of the haloalkoxy groups; and R 6 Is it H or C? 1-6 alkyl; The 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced by one or more deuterium atoms.

[0052] On the other hand, this paper discloses compounds of formula I: (Formula I) Or its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein: A 1 It is CR, where R is hydrogen, halogen, and C. 1-3 Alkyl or cyclopropyl; R 1 It is halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2 It is phenyl; C 3-6 Cycloalkyl; containing a 3- to 8-membered heterocyclic alkyl group independently selected from one or two cyclic heteroatoms of nitrogen, oxygen, and sulfur; phenoxy; or C 1-6 Alkoxy; wherein the phenyl, C 3-6 Cycloalkyl groups and 3- to 8-membered heterocycloalkyl groups are optionally independently selected from halogens, C 1-6 Alkyl, C 1-6 One to four R groups of alkoxy and oxo groups 2A Replace, or two R 2A Together with one or more atoms to which they are attached, they form a 3 to 6 membered ring optionally containing a cyclic heteroatom selected from nitrogen, oxygen and sulfur, wherein the 3 to 6 membered ring is optionally substituted by one or two substituents independently selected from halogens. K is , , or ; W is a bond, -NH- or -O-; and R 3B(a) is optionally and independently selected from halogens, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one to four substituents of a haloalkoxy group; or (b) A 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the heteroaryl group is optionally independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are substituted; or -WR 3B Yes -NR 3C R 3D -NHC(O)-O(C) 1-6 Alkyl), -NHC(O)R 3D or -C(O)NR 3C R 3D ;where R 3C Is it H or C? 1-3 Alkyl, and R 3D It is C 1-6 Halogenated alkyl or C 3-4 cycloalkyl; or wherein R 3C and R 3D Together with the nitrogen atoms to which they are attached, they form 3 to 6-membered rings; R 4A It is H; R 4B It is H, C 1-3 Alkyl or -OH; and R 4B’ Is it H or C? 1-3 Alkyl; or R 4A and R 4B Together with the carbon atoms to which they are attached, they form ethylene oxide; R 5 It is arbitrarily C 3-4 Cycloalkyl-substituted C 1-6 Alkyl; C 1-6 Haloalkyl; optionally independently selected from -OH, halogen, C 1-6 Alkyl, C 3-4 cycloalkyl and C 1-6 The C-axis of the haloalkoxy group is substituted by one or both of its substituents. 4-5 Cycloalkyl groups, or two substituents together with the carbon atoms to which they are attached, form a C12 group. 3-4Cycloalkyl ring; containing a 4- to 5-membered heterocyclic alkyl group independently selected from one or two cyclic heteroatoms of nitrogen, oxygen, and sulfur, wherein the 4- to 5-membered heterocyclic alkyl group is optionally independently selected from -C(O)(benzyl), -C(O)(C 1-6 alkyl) and -SO2(C 1-6 One or two substituents of the alkyl group are used; or optionally, the alkyl group is independently selected from halogens and C. 1-6 A phenyl group substituted with one or both of the haloalkoxy groups; and R 6 Is it H or C? 1-6 alkyl; The 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced by one or more deuterium atoms.

[0053] On the other hand, this paper discloses compounds of formula Ia: (Formula Ia).

[0054] In some embodiments, R 3A It is R 3B In some embodiments, R 3A It is C 1-6 Alkyl group. In some embodiments, R 3A It is C 3-6 Cycloalkyl. In some embodiments, R 3A It is C 3-6 cycloalkyl or R 3B .

[0055] In some embodiments, R 3A It is optionally and independently selected from halogen, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one to four substituents of a haloalkoxy group. In some embodiments, R 3A It is optionally and independently selected from halogen, -CN, -NH2, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one to four substituents of a haloalkoxy group. In some embodiments, R 3A It is optionally and independently selected from halogens and C 1-6 A phenyl group substituted with one to four alkoxy groups. In some embodiments, R 3A yes , , , ,or .

[0056] In some embodiments, R 3A It is a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the 5- to 10-membered heteroaryl group is optionally and independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are used for substitution. In some embodiments, R 3A It is a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the 5- to 10-membered heteroaryl group is optionally independently selected from halogen, -OH, C 1-6 Alkyl and C 1-6 One to three substituents of the alkoxy group are used for substitution. In some embodiments, R 3A It is arbitrarily and independently selected from C 1-6 A pyrazolyl group substituted with one or two alkyl substituents. In some embodiments, R 3A It is a pyridyl, pyrazinyl, pyridazinyl, or 2-pyridoneyl group, wherein the pyridyl, pyrazinyl, pyridazinyl, or 2-pyridoneyl group is optionally and independently selected from halogen, -OH, C 1-6 Alkyl and C 1-6 One or both substituents of the alkoxy group are substituted. In some embodiments, R 3A yes , , , , , , or .

[0057] In some embodiments, R 3A It is C 1-6 Alkyl, C 3-6 cycloalkyl or R 3B , where R 3B (a) is optionally and independently selected from halogens and C. 1-6 (a) A phenyl group substituted with one or two alkoxy groups; or (b) a pyridinyl, pyrazinyl, or pyridazinyl group, wherein the pyridinyl, pyrazinyl, or pyridazinyl group is optionally independently selected from halogen, -OH, C 1-6 Alkyl and C 1-6 One or both substituents of the alkoxy group are substituted. In some embodiments, R 3A It is C 3-6 cycloalkyl or R 3B , where R 3B (a) is optionally and independently selected from halogens and C. 1-6(a) A phenyl group substituted with one or two alkoxy groups; or (b) a pyridinyl, pyrazinyl, or pyridazinyl group, wherein the pyridinyl, pyrazinyl, or pyridazinyl group is optionally independently selected from halogen, -OH, C 1-6 Alkyl and C 1-6 One or both substituents of the alkoxy group are substituted. In some embodiments, R 3A It is C 1-6 Alkyl group. In some embodiments, R 3A yes In some embodiments, R 3A It is C 3-6 Cycloalkyl. In some embodiments, R 3A yes .

[0058] In some embodiments, R 3A yes , , , , , , , , , , , , , ,or .

[0059] In some embodiments, R 3A yes , , , , , , , , , , , , or .

[0060] On the other hand, this paper discloses compounds of formula Ib. (Formula Ib).

[0061] In some embodiments, R 3B It is optionally and independently selected from halogen, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6A phenyl group substituted with one to four substituents of a haloalkoxy group.

[0062] In some embodiments, R 3B It is optionally and independently selected from halogens and C 1-6 A phenyl group substituted with one or both of the haloalkoxy groups. In some embodiments, R 3B yes , ,or .

[0063] In some embodiments, R 3B It is a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the 5- to 10-membered heteroaryl group is optionally and independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are used for substitution.

[0064] In some embodiments, W is a key; and R 3B (a) is optionally and independently selected from halogens, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one to four substituents of a haloalkoxy group; or (b) R 3B It is a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the 5- to 10-membered heteroaryl group is optionally and independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are used for substitution.

[0065] In some embodiments, W is -O-; and R 3B (a) is optionally and independently selected from halogens, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group with one to four substituents of a haloalkoxy group; or (b)R 3B It is a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the 5- to 10-membered heteroaryl group is optionally and independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C1-6 One to three substituents of the haloalkoxy group are used for substitution.

[0066] On the other hand, this paper discloses compounds of formula Ic: (Formula Ic).

[0067] In some embodiments, R 4A It is H and R 4B It is H. In some embodiments, R 4A It is H and R 4B It is -OH. In some embodiments, R 4A and R 4B Together with the carbon atoms to which they are attached, they form ethylene oxide.

[0068] In some embodiments, R 3B It is optionally and independently selected from halogen, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one to four substituents of a haloalkoxy group. In some embodiments, R 3B yes , , , , , , , , , , , , , , , , or .

[0069] In some embodiments, R 3B It is a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the 5- to 10-membered heteroaryl group is optionally and independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 The halogenated alkoxy group is substituted with one to three substituents. In some embodiments, the 5 to 10-membered heteroaryl group is pyrazolyl, indazole, pyridinyl, pyrazinyl, or pyrimidinyl, wherein the 5 to 10-membered heteroaryl group is optionally independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are used for substitution. In some embodiments, R 3B yes , , , or .

[0070] In some embodiments, R 3B yes , , , , , , , , , , , , , , , , , , , , , or .

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

[0072] In some embodiments, -WR 3B Yes -NR 3C R 3D -NHC(O)-O(C) 1-6 Alkyl), -NHC(O)R 3D or -C(O)NR 3C R 3D ;where R 3C Is it H or C? 1-3 Alkyl, and R 3D It is C 1-6 Halogenated alkyl or C 3-4 cycloalkyl; or wherein R 3C and R 3D Together with the nitrogen atoms to which they are attached, they form 3 to 6-membered rings. In some embodiments, -WR 3B yes , , , , or .

[0073] In some embodiments, R 4A It is H; R 4B It is -OH; W is a bond; and R 3B It is optionally and independently selected from halogen, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one or two substituents of a haloalkoxy group.

[0074] In some embodiments, R 4A and R 4B Together with the carbon atoms to which they are attached, they form ethylene oxide; W is a bond; and R 3B It is optionally and independently selected from halogen, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one or two substituents of a haloalkoxy group.

[0075] In some embodiments, R 4A It is H; R 4B It is H; W is -O-; and R is 3B It is optionally and independently selected from halogen, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one or two substituents of a haloalkoxy group.

[0076] In some embodiments, R 4A It is H; R 4B H is H; W is a bond; and R is R. 3B (a) is optionally and independently selected from halogens, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one or both of the haloalkoxy groups; or (b) R 3B It is a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the heteroaryl group is optionally and independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are used for substitution. In some embodiments, R 4A It is H; R4B H is H; W is a bond; and R is R. 3B (a) is optionally and independently selected from halogens, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 (a) A phenyl group substituted with one or two of the haloalkoxy groups; or (b) a pyrazolyl, indazole, pyridinyl, pyrazinyl, or pyrimidinyl group, wherein the pyrazolyl, indazole, pyridinyl, pyrazinyl, or pyrimidinyl group is optionally independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are used for substitution.

[0077] In some embodiments, R 4A It is H; R 4B H is H; W is a bond; and R is R. 3B It is optionally and independently selected from halogen, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one or two substituents of a haloalkoxy group.

[0078] In some embodiments, R 4A It is H; R 4B H is H; W is a bond; and R is R. 3B It is a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the heteroaryl group is optionally and independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are used for substitution. In some embodiments, R 4A It is H; R 4B H is H; W is a bond; and R is R. 3B It is a pyrazolyl, indazole, pyridyl, pyrazinyl, or pyrimidinyl group, wherein the pyrazolyl, indazole, pyridyl, pyrazinyl, or pyrimidinyl group is optionally and independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are used for substitution.

[0079] On the other hand, this paper discloses compounds of formula Id: (Formula Id).

[0080] In some embodiments, R 3B It is optionally and independently selected from halogen, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 A phenyl group substituted with one to four substituents of a haloalkoxy group. In some embodiments, R 3B yes , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0081] In some embodiments, R 3B It is a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the 5- to 10-membered heteroaryl group is optionally and independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are used for substitution. In some embodiments, R 3B It is a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the 5- to 10-membered heteroaryl group is optionally independently selected from halogens, C... 1-6 Alkyl and C 1-6 One to three substituents of the haloalkoxy group are used for substitution. In some embodiments, the 5 to 10-membered heteroaryl group is pyrazolyl or pyridinyl, wherein the 5 to 10-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl and C 1-6 One to three substituents of the haloalkoxy group are used for substitution. In some embodiments, R 3B yes or .

[0082] In some embodiments, R 3B yes , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

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

[0084] In some embodiments, R 4B It is H. In some embodiments, R 4B It is a methyl group.

[0085] In some embodiments, W is a key; and R 3B (a) is optionally and independently selected from halogens, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 (a) A phenyl group substituted with one or two of the haloalkoxy groups; or (b) a 5- to 10-membered heteroaryl group containing one or two cyclic nitrogen atoms, wherein the heteroaryl group is optionally independently selected from halogen, -CN, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One to three substituents of the haloalkoxy group are used. In some embodiments, W is a bond; and R 3B (a) is optionally and independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Halogenated alkyl groups and C 1-6 (a) A phenyl group substituted with one or two of the haloalkoxy groups; or (b) optionally selected independently from halogens or C. 1-6 The pyrazolyl group is substituted with one to three substituents of the alkyl group.

[0086] On the other hand, this paper discloses compounds of formula Ie: (Formula Ie).

[0087] In some embodiments, R 4B and R 4B’ Both are H. In some embodiments, R 4B It is methyl and R 4B’ It's H.

[0088] In some embodiments, R 5 It is arbitrarily C 3-4 Cycloalkyl-substituted C 1-6 Halogenated alkyl or C 1-6 Alkyl group. In some embodiments, R 5 yes , , , , , ,or .

[0089] In some embodiments, R 5 It is optionally and independently selected from -OH, halogen, C 1-6 Alkyl, C 3-4 cycloalkyl and C 1-6 The C-axis of the haloalkoxy group is substituted by one or both of its substituents. 4-5 Cycloalkyl groups, or two substituents together with the carbon atoms to which they are attached, form a C12 group. 3-4 Cycloalkyl ring. In some embodiments, R 5 yes , , , , , , , or .

[0090] In some embodiments, R 5 It is a 4- to 5-membered heterocyclic alkyl group containing one or two cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 4- to 5-membered heterocyclic alkyl group is optionally independently selected from -C(O)(benzyl), -C(O)(C 1-6 alkyl) and -SO2(C1-6 One or two substituents of the alkyl group are substituted. In some embodiments, R 5 yes , ,or .

[0091] In some embodiments, R 5 It is optionally and independently selected from halogens and C 1-6 A phenyl group substituted with one or both of the haloalkoxy groups. In some embodiments, R 5 It is a phenyl group optionally substituted with one or two substituents selected independently from halogens. In some embodiments, R 5 yes , ,or .

[0092] In some embodiments, R 5 C is a C that is optionally substituted by one or two substituents independently selected from halogens. 1-6 Alkyl, C 4-5 Cycloalkyl or phenyl.

[0093] In some embodiments, R 5 yes , , , , , , , , , , , , , , , , , , , , or .

[0094] The following provides information on the group R 1 A 1 R 2 and R 6 Further explanation is needed; these explanations may apply to any of the formulas (I) or (Ia) to (Ie) as described above and in this document.

[0095] In some embodiments, A 1 It is CR, where R is selected from chlorine, C 1-3Alkyl and cyclopropyl. In some embodiments, R is selected from chlorine, methyl, and cyclopropyl. In some embodiments, R is hydrogen or C. 1-3 Alkyl group. In some embodiments, R is C 1-3 Alkyl group. In some embodiments, R is methyl.

[0096] In some embodiments, R 1 It is a halogen. In some embodiments, R 1 It is Br or I. In some embodiments, R 1 It is Br.

[0097] In some embodiments, R 1 It is C 1-6 Alkyl group. In some embodiments, R 1 It is tert-butyl.

[0098] In some embodiments, R 1 It is C 1-6 Haloalkyl. In some embodiments, R 1 It is trifluoromethyl.

[0099] In some embodiments, R 1 It is C 1-6 Alkyl or C 1-6 Haloalkyl. In some embodiments, R 1 It is ethyl or -CHF2.

[0100] In some embodiments, R 2 It is a phenyl group, where R 2 Optionally selected independently from halogen, C 1-6 Alkyl and C 1-6 One to four Rs of alkoxy 2A Replacement. In some embodiments, R 2 yes , ,or In some embodiments, R 2 It is phenyl.

[0101] In some embodiments, R 2 It is C 3-6 Cycloalkyl or containing one or two cyclic heteroalkyl groups independently selected from nitrogen, oxygen, and sulfur; wherein R 2 Optionally selected independently from halogen, C 1-6 Alkyl, C 1-6 One to four R groups of alkoxy and oxo groups 2A Replace, or two R 2ATogether with one or more atoms to which they are attached, they form a 3- to 6-membered ring optionally comprising a cyclic heteroatom selected from nitrogen, oxygen, and sulfur, wherein the 3- to 6-membered ring is optionally substituted independently by one or two substituents selected from halogens. In some embodiments, R 2 yes , , , , , , , , , , or .

[0102] In some embodiments, R 2 It is phenoxy or C 1-6 Alkoxy. In some embodiments, R 2 yes or .

[0103] In some embodiments, R 6 It is H. In some embodiments, R 6 It is C 1-6 alkyl.

[0104] The compounds disclosed in this invention have been and can be synthesized using the general synthetic procedures listed in the reaction schemes below. The implementation of each individual described step is within the skill of a person of ordinary skill as guided by this disclosure, and such person also knows how to modify the synthetic procedures of the schemes below to synthesize the full range of compounds disclosed herein. Synthetic procedures for individual compounds are provided in the Examples section below.

[0105] On the other hand, this article discloses compounds selected from Table A or their stereoisomers, tautomers, or pharmaceutically acceptable salts. Table A. In the exemplary compounds in the table above, R is Br, I, CF3, or t-Bu. The activity of the compound

[0106] As described above, the compounds disclosed herein possess activity as FP receptor modulators (particularly as FP receptor antagonists). This activity can be assessed by any suitable FP receptor activity assay, such as the FP receptor inositol 1-phosphate (IP1) accumulation assay shown in the examples. The compounds disclosed herein exhibit 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. 50 value.

[0107] The FP receptor inositol 1-phosphate (IP1) accumulation assay was performed using a human embryonic kidney EBNA (HEK-EBNA) derived cell line stably expressing the FP receptor. Cells were exposed to different concentrations of the test compound, followed by exposure to the submaximal concentration of the FP receptor agonist; the inhibitory effect of the antagonist on IP1 accumulation was then assessed. IP1 accumulation was measured by a competitive IP1 immunoassay based on HTRF (homogeneous time-resolved fluorescence).

[0108] EP4 receptor activity can be assessed by any suitable EP4 receptor activity assay, such as the EP4 receptor cyclic adenosine monophosphate (cAMP) accumulation assay. The selectivity of FP relative to EP4 can be compared by comparing the EC values ​​obtained from each assay. 50 Value and calculate the selectivity ratio (i.e., EP4 IC). 50 / FP IC 50 (To evaluate)

[0109] In some embodiments, the compounds disclosed herein exhibit at least 5-fold higher 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 times or more higher selectivity for the FP receptor than for the EP4 receptor. The compounds disclosed herein exhibit selectivity for prostaglandin F receptors that is approximately 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 times higher than that for EP4 receptors. Compound Synthesis

[0110] On the other hand, methods for manufacturing any of the compounds disclosed herein are provided. The compounds disclosed herein have been and can be synthesized using the synthetic procedures described in embodiments 1-16 of the examples detailed below. The implementation of each individual described step is within the skill of a person skilled in the art under the guidance of this disclosure, and a person skilled in the art also knows how to modify the synthetic procedures of the embodiments below to synthesize the full range of compounds disclosed herein. 1 R 2 R 3A R 3B and R 5 The definition is provided in the formula described herein. Synthetic procedures for individual compounds are disclosed in the Examples section below. Pharmaceutical Composition

[0111] On the other hand, this document discloses pharmaceutical compositions comprising, substantially consisting of, or consisting of compounds as described herein and one or more pharmaceutically acceptable excipients.

[0112] On the other hand, this document discloses pharmaceutical compositions comprising, substantially consisting of, or consisting of compounds of formula I, Ia, Ib, Ic, Id, or Ie as described herein, and one or more pharmaceutically acceptable excipients.

[0113] The compound can be formulated for administration via any suitable route of administration, such as oral, topical (including transdermal), rectal, vaginal, transmucosal or enteral administration; parenteral delivery, including intramuscular, subcutaneous or intravenous injection; and inhalation, intrathecal, direct intraperitoneal or intranasal delivery.

[0114] The pharmaceutical compositions disclosed herein may contain pharmaceutically acceptable carriers, diluents, disintegrants, sweeteners, gliding agents (such as magnesium stearate), flavoring agents, emulsifiers, suspending agents, stabilizers, isotonic agents, etc., as one or more pharmaceutically acceptable excipients. The pharmaceutical compositions disclosed herein may be formulated into oral dosage forms (such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups); or topical (including transdermal) or mucosal dosage forms (such as liquids, suspensions, emulsions, gels (ointments, etc.)); or parenteral dosage forms (such as liquids, suspensions, emulsions, and lyophilized powders). These dosage forms may be formulated in various formats, such as for single-dose or multiple-dose administration.

[0115] Exemplary excipients include, but are not limited to, lactose, polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophor, carbohydrates, starch (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium stearate or magnesium stearate), flow aids such as talc, disintegrants, diluents, buffers, acids, bases, film coatings, combinations thereof, etc.

[0116] The amount of any single excipient in the composition will vary depending on the function of the excipient, the dosage requirements of the active agent, and the specific needs of the composition. However, typically, excipients will be present in the composition in amounts ranging from about 1% to about 99% by weight of the composition, such as from about 5% to about 98% by weight, including from about 15% to about 95% by weight. Typically, the amount of excipients present in the compositions disclosed herein 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] The pharmaceutical compositions disclosed herein may include the compounds disclosed herein as the sole active agent, or may be formulated together with other active agents.

[0118] The formulation and administration techniques of the compounds disclosed in this article can be found in "Remington: The Science and Practice of Pharmacy", Academic Press, London, UK, 23rd edition, 2020.

[0119] Pharmaceutical compositions as disclosed herein can be formulated to provide a therapeutically effective amount of the compound as disclosed herein in a reasonable volume or mass of composition, which can be administered according to any effective dosing schedule, such as once daily. Although the exact dosage may be determined for each drug (each compound), some generalizations about dosage can be made for most compounds. For example, daily dosing regimens for adult patients may be between 0.001 mg and 1000 mg, such as between 0.01 mg and 500 mg, such as 1 to 200 mg of the compound or its pharmaceutically acceptable salts (calculated as free bases or free acids). Treatment

[0120] On the other hand, this document discloses methods for modulating prostaglandin F (FP) receptor activity in subjects, which include, consist of, or consist of administering to a subject in need a compound or pharmaceutical composition as disclosed herein.

[0121] On the other hand, this document discloses methods for treating subjects in preterm labor, which include, consist of, or consist of administering to the subject in need of a compound or pharmaceutical composition as disclosed herein.

[0122] On the other hand, this article discloses methods for reducing the risk of preterm birth or preventing preterm birth in subjects, which include, consist of, or consist of administering to subjects in need a compound or pharmaceutical composition as disclosed herein.

[0123] On the other hand, this article discloses methods for reducing the risk of preterm labor or preventing preterm labor in subjects, which include, consist of, or consist of administering to subjects in need a compound or pharmaceutical composition as disclosed herein.

[0124] On the other hand, this article discloses methods for reducing or preventing the risk of pre-cesarean delivery in subjects, including, substantially consisting of, or consisting of the following: administering to subjects in need a compound or pharmaceutical composition as disclosed herein.

[0125] On the other hand, this document discloses methods for reducing the risk of or preventing dysmenorrhea in subjects, methods comprising, substantially comprising, or comprising comprising: administering to a subject in need a compound or pharmaceutical composition as disclosed herein. In some embodiments, the dysmenorrhea is primary dysmenorrhea. In some embodiments, the dysmenorrhea is secondary dysmenorrhea.

[0126] On the other hand, this article discloses methods for reducing the risk of or preventing endometriosis in subjects, methods comprising, substantially comprising, or consisting of administering to subjects in need a compound or pharmaceutical composition as disclosed herein.

[0127] On the other hand, this article discloses methods for reducing the risk of or preventing adenomyosis in subjects, which include, consist of, or consist of administering to subjects in need a compound or pharmaceutical composition as disclosed herein.

[0128] On the other hand, this document discloses methods for reducing the risk of or preventing idiopathic pulmonary fibrosis (IPF) in subjects, including, consisting essentially of, or consisting of administering to subjects in need a compound or pharmaceutical composition as disclosed herein.

[0129] In another aspect, this document discloses compounds used as medicines. In another aspect, this document discloses compounds for regulating (e.g., antagonizing) prostaglandin F (FP) receptor activity in subjects. In another aspect, this document discloses compounds for treating preterm labor in subjects. In another aspect, this document discloses compounds for reducing the risk of or preventing preterm labor in subjects. In another aspect, this document discloses compounds for reducing the risk of or preventing preterm labor in subjects. In another aspect, this document discloses compounds for reducing the risk of or preventing preterm labor before cesarean section in subjects. In another aspect, this document discloses compounds for reducing the risk of or preventing dysmenorrhea in subjects. In another aspect, this document discloses compounds for reducing the risk of or preventing endometriosis in subjects. In another aspect, this document discloses compounds for reducing the risk of or preventing adenomyosis in subjects. In another aspect, this document discloses compounds for reducing the risk of or preventing IPF in subjects.

[0130] In another aspect, this document discloses the use of the compounds described herein for modulating prostaglandin F (FP) receptor activity in subjects. In another aspect, this document discloses the use of the compounds described herein for treating preterm labor in subjects. In another aspect, this document discloses the use of the compounds described herein for reducing the risk of preterm birth in subjects. In another aspect, this document discloses the use of the compounds described herein for preventing preterm labor in subjects. In another aspect, this document discloses the use of the compounds described herein for preventing preterm labor before cesarean section in subjects. In another aspect, this document discloses the use of the compounds described herein for preventing dysmenorrhea in subjects. In another aspect, this document discloses the use of the compounds described herein for preventing endometriosis in subjects. In another aspect, this document discloses the use of the compounds described herein for preventing adenomyosis in subjects. In another aspect, this document discloses the use of the compounds described herein for preventing idiopathic pulmonary fibrosis (IPF) in subjects.

[0131] In another aspect, this document discloses methods for treating a disease or disorder in a subject in need, methods comprising, substantially comprising, or comprising comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition as disclosed herein. In another aspect, this document discloses compounds for treating a disease or disorder in a subject in need. In another aspect, this document discloses the use of the compounds described herein for treating a disease or disorder in a subject in need.

[0132] On the other hand, this document discloses methods for treating a disease or disorder in a subject in need, methods comprising, substantially comprising, or comprising comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition as disclosed herein, wherein the disease or disorder is associated with PGF. 2α This is associated with abnormal levels (e.g., elevated levels) and / or abnormal expression (e.g., elevated expression) of its receptors. On the other hand, this document discloses compounds for treating diseases or disorders in subjects in need, wherein the disease or disorder is associated with PGF. 2α This is associated with abnormal levels (e.g., elevated levels) and / or abnormal expression (e.g., elevated expression) of its receptors. On the other hand, this document discloses the use of the compounds described herein for the treatment of a disease or disorder in subjects in need, wherein the disease or disorder is associated with PGF. 2α It is associated with abnormal levels (e.g., elevated levels) and / or abnormal expression (e.g., elevated expression) of its receptors.

[0133] The disease or disorder can be any disease or disorder that requires modulation (e.g., antagonism) of FP receptor activity, such as one or more of the following: idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, nonspecific interstitial pneumonia, lymphointerstitial pneumonia, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonia, desquamative interstitial pneumonia and unclassified idiopathic interstitial pneumonia, granulomatous interstitial lung disease, interstitial lung disease of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary arterial hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), α-1- Antitrypsin deficiency (AATD), emphysema (e.g., smoking-induced emphysema), cystic fibrosis (CF), inflammatory and fibrotic kidney disorders, chronic intestinal inflammation (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, refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, drug- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, cough and cold (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammation (including drug-related rhinitis, vasomotor rhinitis, and seasonal allergic rhinitis),Examples include hay fever, polyps, hypertension, heart failure, coronary artery disease, stable and unstable angina, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, atrial and ventricular rhythm disturbances, and conduction disorders such as first- to third-degree atrioventricular block, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, torsades de pointes, premature atrial and ventricular contractions, premature atrioventricular junctional contractions, sick sinus syndrome, and syncope. Atrioventricular nodal reentrant tachycardia, Ward-Paghett-Huey syndrome, acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, endocarditis, valvularitis, aortitis, cardiomyopathy), boxer cardiomyopathy, aneurysm, shock (such as cardiogenic shock, septic shock, and anaphylactic shock), thromboembolic disorders and ischemia (such as myocardial ischemia), myocardial infarction, stroke, cardiac hypertrophy, transient ischemic attack, preeclampsia, inflammatory cardiovascular disorders, coronary and peripheral artery spasm, edema formation (e.g. Pulmonary edema, cerebral edema, renal edema, or edema caused by heart failure), peripheral circulatory disturbances, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial ischemia, endothelial dysfunction, microvascular and macrovascular injury (vasculitis), renal hypoperfusion, hypotension during dialysis, obstructive urinary tract disease, glomerulonephritis, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, nephrotic disorders such as primary nephropathy and congenital nephropathy, nephritis, immune-mediated kidney disorders such as kidney transplant rejection and immune-mediated kidney disease. Kidney disorders caused by complexes, nephropathy caused by toxic substances, nephropathy caused by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndrome (diagnostologically characterized by, for example, abnormally decreased creatinine and / or water excretion, abnormally elevated concentrations of urea, nitrogen, potassium, and / or creatinine in the blood, altered activity of renal enzymes (such as gamma-glutamyl synthase), altered urine osmolality or urine volume, microalbuminuria, macroalbuminuria, glomerular and arterial vascular lesions, and renal tubular dilation).Hyperphosphatemia and / or the need for dialysis), benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hypertrophy (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), neurogenic overactive bladder (OAB), incontinence (e.g., mixed incontinence, urge incontinence, stress incontinence, or overflow incontinence (MUI, UUI, SUI, OUI)), pelvic pain, erectile dysfunction, female sexual dysfunction, uterine fibroids, endometriosis, dysmenorrhea, premature contractions, hirsutism, sepsis (SIRS), and other conditions. Organ dysfunction syndrome (MODS, MOF), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemia, liposarcoma, gastrointestinal cancer, liver cancer, pancreatic cancer, lung cancer, kidney cancer, ureteral cancer, prostate cancer and reproductive tract cancer, malignant tumors of the lymphoproliferative system (e.g., Hodgkin's lymphoma and non-Hodgkin's lymphoma), and central nervous system disorders and neurodegenerative disorders (e.g., stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depression). In some embodiments, the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

[0134] According to any of these methods or uses, the compound or composition may be administered via any suitable route of administration as discussed above, and may be administered at a therapeutically effective amount as discussed above. As mentioned above, it may be administered according to any effective dosing schedule, such as once daily, 1 to 4 times daily, once weekly, 1 to 4 times weekly, once monthly, 1 to 4 times monthly, etc. Although the exact dose may be determined according to each drug (each compound), the daily dosing regimen for adult patients may be, for example, between 0.001 mg and 1000 mg, such as between 0.01 mg and 500 mg, such as 1 to 200 mg of the compound or its pharmaceutically acceptable salt (calculated as a free base or free acid).

[0135] According to 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 therapeutic agents that can be used to treat the condition, disease, or disorder discussed. For example, the additional therapeutic agent may be used in a subject to treat preterm labor, reduce or prevent the risk of preterm labor, reduce or prevent the risk of preterm labor, reduce or prevent preterm labor before cesarean section, reduce or prevent the risk of dysmenorrhea in a subject, or treat any of the diseases or disorders disclosed above. Other non-limiting examples of therapeutic agents include oxytocin receptor antagonists (e.g., atosiban, retosiban, baruciban, epasiban, and noraziban), beta-analytes (e.g., terbutaline, ritodrine, hesonaline, abumetholone, fenoterol, buphenelzine, or orsinaline), calcium channel inhibitors (e.g., dihydropyridine, nifedipine, or nicardipine), magnesium salts (e.g., magnesium sulfate), progestins (e.g., progesterone or 17-α-hydroxyprogesterone), and nitric oxide donors (e.g., nitroglycerin).

[0136] The technology described in this general way can be further understood by referring to the following examples, which are provided in an illustrative manner and are not intended to limit the technology. Example

[0137] General Method

[0138] All reactions were carried out in oven-dried round-bottom flasks under an inert nitrogen atmosphere with stirring. Solvents, reagents, and chemicals were purchased from various sources and used as received unless otherwise specified. Nuclear magnetic resonance chemical shifts are expressed relative to the residual... 1 The δ (ppm) values ​​of the H solvent peaks for methanol-d4 (3.30 ppm), CDCl3 (7.26 ppm), and DMSO-d6 (2.50 ppm) are reported in units of ppm; values ​​from exchangeable protons are also reported. 1 The H signal may be lost. Split modes are specified as s (single peak), d (double peak), t (triple peak), multiplet (m), and dd (double doublet).

[0139] Scheme 1. Synthesis of BCO ketone

[0140] Step 1a procedure

[0141] At 15°C, CrO3 (77.01 g, 770.15 mmol, 2 equivalents) was added in a single batch to a mixture of (1-1) (87.13 g, 385.07 mmol, 1 equivalent) in AcOH (870 mL). The mixture was heated to 90°C and stirred for 18 hours. The mixture was then added dropwise to NaHCO3 (saturated, 12 L). The mixture was then diluted with ethyl acetate (1500 mL). 2) Extraction. The combined organic phases were washed with brine (1000 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 8 / 1 to 3 / 1) to give (1-2) (23 mg, 95.73 mmol, 24.86% yield). 36.4 g of (1-1) was also recovered. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 3.69 - 3.79 (m, 6H) 2.59 (s, 2H) 2.26 - 2.37 (m, 2H) 1.85- 2.14 (m, 6H).

[0142] Step 1b procedure

[0143] At 0°C, LiOH·water (6.34 g, 151.01 mmol, 1 equivalent) was added as a solution in water (22 mL) to a mixture of (1-2) (36.28 g, 151.01 mmol, 1 equivalent) in THF (170 mL) and MeOH (22 mL). The mixture was warmed to 20°C and stirred for 16 hours. The mixture was concentrated under vacuum, and the residue was diluted with water (320 mL). The mixture was then diluted with MTBE (350 mL). 2) Extraction. 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 give (1-3) (18 g, 79.57 mmol, 52.69% yield). 1 H 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] Step 1c procedure

[0145] Add pyridine (45.31 g, 572.88 mmol, 7.2 equivalents) and DMAP (9.72 g, 79.57 mmol, 1 equivalent) to a solution of (1-3) (18 g, 79.57 mmol, 1 equivalent) in t-BuOH (280 mL). Then slowly add Boc2O (86.83 g, 397.83 mmol, 5 equivalents) at 20°C and stir the mixture at 30°C for 12 hours. Concentrate the resulting solution under reduced pressure to obtain a residue. Dilute the residue with ethyl acetate (350 mL) and water (350 mL). Separate the layers and extract the aqueous phase with ethyl acetate (350 mL). Combine the organic phases with water (160 mL), HCl (1 M, 160 mL) and HCl (1 M, 160 mL) to obtain the organic phases. 2) Wash with NaHCO3 (saturated, 160 mL) and brine (160 mL), dry with Na2SO4, and concentrate under reduced pressure to obtain (1-4) (13.8 g, crude product). 1 H NMR (400 MHz, 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] Step 1d procedure

[0147] At 0°C, NaOH (2.59 g, 64.63 mmol, 1.32 equivalent) was added as a solution in water (34 mL) to a mixture of (1-4) (13.8 g, 48.88 mmol, 1 equivalent) in THF (130 mL) and MeOH (34 mL). 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 give (1-5) (9.16 g, 34.14 mmol, 69.85% yield). 1 H 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] Step 1e procedure

[0149] At 15°C, benzyl alcohol (2.32 g, 21.47 mmol, 3 equivalents), TEA (2.17 g, 21.47 mmol, 3 equivalents), and DPPA (1.97 g, 7.16 mmol, 1 equivalent) were added sequentially to a solution of (1-5) (1.92 g, 7.16 mmol, 3 equivalents) in toluene (150 mL). 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 concentrated with ethyl acetate (160 mL). 2) Extraction. The combined organic fractions were dried over Na2SO4 and concentrated under reduced pressure to obtain the 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). 1 H 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] Option 2. Synthesis of INT 1

[0151] Step 2a procedure

[0152] LiHMDS (1 M, 5.36 mL, 2 equivalents) was added to a mixture of BCO ketone (1 g, 2.68 mmol, 1 equivalent) in THF (20 mL) at -78°C under N2. The mixture was stirred at -78°C for 1 hour. Then, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methylsulfonamide (1.24 g, 3.48 mmol, 1.3 equivalents) in THF (10 mL) was added dropwise to the mixture at -78°C. The mixture was then warmed and stirred at 20°C for 12 hours. The mixture was poured into NH4Cl (saturated, 100 mL). The mixture was then diluted with ethyl acetate (50 mL) 2) Extraction. The organic phase was washed with brine (20 mL), dried over Na2SO4, and concentrated under 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). 1 H NMR (400 MHz, chloroform-d) δppm 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] Option 3. Synthesis of INT 2

[0154] Step 3a procedure

[0155] At 20°C, NH₂NH₂·water (161.76 g, 3.23 mol, 24.13 equivalents) was added in a single batch to a mixture of BCO ketone (50 g, 133.89 mmol, 1 equivalent) and 4A MS (25 g, 8.03 mmol, 16.67 equivalents) in EtOH (350 mL). The mixture was heated to 80°C and stirred for 5 hours. The mixture was filtered and concentrated under vacuum. The residue was then concentrated in DCM (300 mL). 3) Extraction with water (200 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under 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] Step 3b procedure

[0157] At 0°C under Ar conditions, I₂ (73.69 g, 290.34 mmol, 2.5 equivalents) dissolved in THF (350 mL) was added to a mixture of (3-1) (45 g, 116.14 mmol, 1 equivalent) in piperidine (300 mL) and THF (250 mL). The mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched by adding water (500 mL). The solution was then diluted with ethyl acetate (500 mL). 2) Extraction, drying to Na₂SO₄, filtration, and concentration under 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. 1 H 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, 9H)

[0158] Option 4. Combination of INT 3 and INT 4

[0159] Step 4a procedure

[0160] A mixture of (4-1) (R=Br) (20 g, 88.49 mmol, 1 equivalent) and 1-phenylprop-1-one (11.87, 88.49 mmol, 1 equivalent) in AcOH (240 mL) was stirred at 75°C for 0.5 h. Then, HCl (12 M, 79.99 mL, 10.85 equivalent) was added to this well-stirred reaction. The mixture was stirred at 105°C for 11.5 h. After cooling to room temperature, the mixture was poured into HCl (1 M, 2000 mL). The solid was collected by filtration and washed with a mixture of solvents (petroleum ether / ethyl acetate, at a ratio of 2:1, 1.5 L) to give INT 3 (23 g, 67.21 mmol, 75.96% yield). [M+H] + = 344.0. 1 H 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] Step 4b procedure

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

[0163] Step 4c procedure

[0164] Compound (4-1) was added to a mixture of 2-cyclopropyl-1-phenylethyl-1-one in an ethanolic solution of potassium hydroxide, and then reacted under hydrochloric acid conditions to provide INT 9.

[0165] Step 4d of the procedure

[0166] Prepare INT 10 from INT 9 in a similar manner as described in step 4b.

[0167] Step 4e procedure

[0168] Compound (4-1) was added to a mixture of 2-chloro-1-phenylethyl-1-one in an ethanolic solution of potassium hydroxide, and then reacted under hydrochloric acid conditions to provide INT 11.

[0169] Step 4f procedure

[0170] Prepare INT 12 from INT 11 in a similar manner to that described in step 4b.

[0171] Solution 5. Synthesis of INT 5

[0172] Procedure of step 5a

[0173] (5-1) (10 g, 43.85 mmol, 1 equivalent) in propionyl propionate (44.23 g, 339.85 mmol, 7.75 equivalents) was heated at 170°C for 9 hours. After the reaction was complete, 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). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (brs, 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] Step 5b procedure

[0175] MeI (301.90 mg, 2.13 mmol, 1.2 equivalent) and TEA (269.03 mg, 2.66 mmol, 1.5 equivalent) were added in a single dose to a mixture of (5-2) (500 mg, 1.77 mmol, 1 equivalent) in DMSO (10 mL) at 25°C under N2. The reaction was stirred at 55°C for 12 hours. After the reaction was complete, the mixture was poured into water (20 mL) and diluted with ethyl acetate (20 mL). 3) Extraction. The organic phase was dried over Na2SO4, filtered and concentrated to obtain (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] Step 5c procedure

[0177] The mixture of (5-3) (265 mg, 894.92 μmol, 1 equivalent) in POCl3 (9.99 g, 65.18 mmol, 72.83 equivalent) was stirred at 100°C for 2 hours. The reaction was then directly concentrated to give (5-4) (250 mg, crude). 1 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] Add (5-4) (350 mg, 1.11 mmol, 1 equivalent) to a mixture of morpholine (969.35 mg, 11.13 mmol, 10 equivalents) in t-BuOH (5 mL). Heat the mixture to 60°C and stir for 12 hours. Then heat the reaction mixture to 80°C and stir for another 60 hours. After the reaction is complete, concentrate the reaction mixture directly to obtain the residue, which is then subjected to preparative HPLC (column: Waters Xbridge BEH C18 100). 30mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: purified by 10 min with 5%-35% B) to obtain INT 5 (320 mg, 911.18 μmol, 81.89% yield). 1 H 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] SOCl2 (184.47 g, 1.55 mol, 14.58 equivalents) and DMF (777.35 mg, 10.63 mmol, 0.1 equivalents) were added to the mixture of (5-2) (30 g, 106.35 mmol, 1 equivalent) in DCM (225 mL). The suspension was degassed under vacuum and purged several times with N2. The mixture was stirred at 50°C for 1 hour. The mixture was filtered and the filtrate was concentrated to give INT 7 (23 g, crude product). 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 7.90 - 7.96 (m, 2H) 7.83 - 7.88 (m, 1H) 2.61 (s, 3H)

[0182] Solution 6. Synthesis of INT 6

[0183] Synthesis of (6-1)

[0184] Pyrrolidine (1.58 g, 22.25 mmol, 5 equivalents) was added in a single batch to a mixture of (5-4) (1.4 g, 4.45 mmol, 1 equivalent) in t-BuOH (15 mL). The mixture was stirred at 60°C for 12 hours. After the reaction was complete, the reaction mixture was acidified with HCl (1 M) to adjust the pH to 4. The residue was collected by filtration to give (6-1) (450 mg, 1.29 mmol, 28.95% yield). 1 H 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] LiOH·water (162.22 mg, 3.87 mmol, 3 equivalents) was added in a single batch to a mixture of (6-1) (450 mg, 1.29 mmol, 1 equivalent) in MeOH (5 mL), water (5 mL), and THF (5 mL). The reaction was heated to 80°C for 12 hours. After the reaction was complete, the reaction was directly concentrated to give INT 6 (400 mg, 1.19 mmol, 82.61% yield).1 H NMR (400 MHz, 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, 4H).

[0187] Scheme 7. Synthesis of the TG1 series

[0188] Synthesis of 7-1A

[0189] General procedure for step 7a

[0190] Under N2, K2CO3 (3 equivalents) and Pd(PPh3)4 (0.05 equivalents) were added to a mixture of (7-1) / (7-1A) (1 equivalent) and boric acid (1.5 equivalents) in DME and water. The mixture was then stirred under N2 (see Table 1 for details). After the reaction was complete, the mixture was filtered and concentrated under vacuum. The crude product was purified by column chromatography or used as is in the next step to obtain (7-2).

[0191] Table 1: Detailed conditions: (All reactions were carried out under nitrogen atmosphere) A: Pd(PPh3)4, K2CO3; B: Pd(dppf)Cl2, K2CO3; C: Pd(dppf)Cl2.CH2Cl2, Cs2CO3; D: Cyclopentyl(diphenyl)phosphine; Palladium dichloride; Iron, K2CO3; E: CuI (1 equivalent), LiCl (3 equivalents), Pd(PPh3)4 (0.1 equivalents); F: CuI, 2-(dimethylamino)acetic acid; Hydrochloric acid, Cs2CO3

[0192] General procedure for step 7b-1

[0193] Add Pd(OH)₂ (10 wt%, 20% purity) to the mixture of (7-2) (1 equivalent) in THF. Degas the suspension under vacuum and purge several times with H₂. Stir the mixture at 20°C with H₂ (15 Psi) (see Table 2). Filter the mixture and concentrate it under vacuum. Purify the crude product by column chromatography or use it as is in the next step to obtain (7-3).

[0194] General procedure for step 7b-2

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

[0196] Table 2: Detailed conditions: A: Pd(OAc)2, Et3SiH, TEA; B: Pd(OH)2, H2; C: Pd / C, H2; D: PdCl2, Et3SiH, TEA; Under nitrogen

[0197] Synthesis of (7c-1)

[0198] At 20°C, a single addition of NaHCO3 (6 equivalents) to a mixture of (7-3) (1 equivalent) and INT 7 (1.2 equivalents) in DCM was carried out for 12 h. The reaction mixture was quenched by adding water. The residue was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography or used as is in the next step to give (7c-1). Table 3: Detailed conditions:

[0199] General procedure for step 7c-1

[0200] Add TEA (3 equivalents) and INT 4 (1.1 equivalents) to the mixture of (7-3) (1 equivalent) in DCM. Then stir the mixture (see Table 4). After the reaction is complete, quench the reaction mixture by adding water. Extract the residue with DCM. Wash the combined organic layers with brine, dry with Na2SO4, filter, and concentrate under vacuum. Purify the crude product by column chromatography or use it as is in the next step to give (7-4).

[0201] General procedure for step 7c-2

[0202] Add DIEA (3 equivalents) to a mixture of INT 3 (1.1 equivalents) and (7-3) (1 equivalent) in DMF. Then add HATU (1.5 equivalents) to the mixture and stir at M°C for N hours (see Table 4). After the reaction is complete, quench the reaction mixture by adding water. Extract the residue with ethyl acetate. Wash the combined organic layers with brine, dry over Na2SO4, filter, and concentrate under vacuum. Purify the crude product by column chromatography or use it as is in the next step to give (7-4).

[0203] General procedure for step 7c-3

[0204] Add DIEA (10 equivalents) to a mixture of (7c-1) (1 equivalent) and 3,3-difluoroazacyclobutane hydrochloride (5 equivalents) in DMA. Stir the reaction at M°C for N hours (see Table 4). Add the mixture to water. Extract the aqueous phase with ethyl acetate. Wash the combined organic phases with brine, dry with anhydrous Na2SO4, filter, and concentrate under vacuum. Purify the residue by column chromatography or use it as is in the next step to give (7-4).

[0205] Procedure of step 7c-4

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

[0207] Table 4: Detailed Conditions:

[0208] General procedure for step 7d

[0209] The mixture of (7-4) (1 equivalent) in a solvent mixture (DCM / TFA, at a ratio of 4:1) was stirred (see Table 5). After the reaction was complete, the mixture was concentrated and purified by preparative HPLC to obtain (TG1) (selected compounds are shown in Table 5).

[0210] Table 5: Detailed Conditions:

[0211] Step 7e procedure

[0212] LDA (2 M, 16.74 mL, 2.5 equivalents) was added to a solution of (BCO-ketone) (5 g, 13.39 mmol, 1 equivalent) in THF (50 mL) at -78°C. The mixture was stirred at -78°C for 0.5 h, then CH3I (3.80 g, 26.78 mmol, 2 equivalents) was added to the solution, and the resulting mixture was stirred at 25°C for 0.5 h. The solution was quenched with NH4Cl (saturated, 100 mL) and effluent (60 mL) with ethyl acetate. 3) Extraction. The combined organic phases were rinsed with 100 mL of brine. 2) Wash, dry with sodium sulfate, filter and concentrate to obtain the residue, and pass the residue through a preparative HPLC system (column: Welch Ultimate C18 250). 100mm 10 μm, mobile phase: [water (10 mM NH4HCO3)-ACN]; gradient: purified by 45%-80% B for 20.0 min to obtain (7S-1) (4.2 g, 10.84 mmol, 80.96% yield). [M+H] + = 388.1. 1 H 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 in step 7f

[0214] At 20°C, NH₂NH₂·water (9.26 g, 184.98 mmol, 13.97 equivalent) was added in a single batch to a mixture of (7S⁻¹) (3.7 g, 9.55 mmol, 1 equivalent) and 4A MS (2 g, 1.00 equivalent) in EtOH (50 mL). The mixture was heated to 80°C and stirred for 60 hours. The mixture was filtered and concentrated under vacuum and passed by preparative HPLC (column: Agela DuraShell C18 250). 70mm 10 μm, mobile phase: [water (10 mM NH4HCO3)-ACN]; gradient: purified by 50%-80% B for 17.0 min to obtain (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] Step 7g of the procedure

[0216] At 0°C under N2, I2 (1.42 g, 5.60 mmol, 2.5 equivalents) in THF (3.5 mL) was added to a solution of (7S⁻²) (0.9 g, 2.24 mmol, 1 equivalent) in THF (2.5 mL) and piperidine (3 mL). The resulting mixture was stirred at 25°C for 0.5 hours. After the reaction was complete, the mixture was poured into water (30 mL) and diluted with ethyl acetate (30 mL). 3) Extraction. The organic phase is extracted with 20 mL of brine. 2) The sample was washed, dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the 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 and TG3 series

[0218] Synthesis of 8-1A

[0219] Synthesis of 8b-1

[0220] Synthesis of 8d-1

[0221] General procedure for step 8a

[0222] K₂CO₃ (3 equivalents) and Pd(PPh₃)₄ (0.1 equivalents) were added in a single step to a mixture of (8-1) / (8-1A) (1 equivalent) and (INT 8a) (1.2 equivalents) in DME and water under N₂. The mixture was stirred under specific conditions (see Table 6). The residue was poured into water and stirred for 5 min. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography or used as is in the next step to give (8-2).

[0223] Table 6: Detailed conditions: (All reactions were carried out under nitrogen atmosphere) A: Pd(PPh3)4, K2CO3; B: Pd(dppf)Cl2, K2CO3; C: Pd(PPh3)4, Cs2CO3; D: Pd(dppf)Cl2·CH2Cl2, Cs2CO3; E: CuI (1 equivalent), LiCl (3 equivalents), Pd(PPh3)4 (0.1 equivalents); F: CuI, 2-(dimethylamino)acetic acid; hydrochloric acid, Cs2CO3

[0224] General procedure for step 8b-1

[0225] Add the Pd-catalyst (10 wt%, 20% purity) to a mixture of (8-2) / (8b-1) / (7-2) (1 equivalent) in THF under N2. Degas the suspension under vacuum and purge several times with H2. Stir the mixture under H2 (15 Psi) (see Table 7). Filter the mixture and concentrate it under vacuum. Purify the residue by column chromatography or use it as is in the next step to obtain (8-3).

[0226] General procedure for step 8b-2

[0227] Add NH2NH2·water (6.26 equivalents) to a solution of (8-2) / (8b-1) / (7-2) (1 equivalent) in EtOH. Stir the mixture at 25°C for 12 hours under air (see Table 7). Concentrate the mixture under vacuum. Use the residue without purification for the next step to obtain (8-3).

[0228] Table 7: Detailed Conditions: A: 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

[0229] General procedure for step 8c-1

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

[0231] General procedure for step 8c-2

[0232] Add TEA (3 equivalents) to a solution of (8-3) (1 equivalent) and acyl chloride (1.2 equivalents) in DCM under N2. Stir the mixture (see Table 8). Filter the mixture and concentrate it under vacuum. Purify the residue by column chromatography or use it as is in the next step to obtain (8-4).

[0233] Table 8: Detailed Conditions:

[0234] General procedure for step 8d-1

[0235] The mixture of (8-4) (1 equivalent) in a solvent mixture (DCM / TFA, at a ratio of 4:1) was stirred at M°C for N hours. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by preparative HPLC to give (TG2). (The selected compounds are shown in Table 9).

[0236] General procedure for step 8d-2

[0237] At 0°C and under N2, NaNO2 (1.1 equivalents) was added to a mixture of (8-4) (1 equivalent) in a solvent mixture (HCl / water, 1:1 ratio) for 10 min. CuCl (10 equivalents) was then added to the mixture. The mixture was then stirred at M°C for N hours. The mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to give (TG2). (The selected compounds are shown in Table 9).

[0238] Table 9: Detailed Conditions: Only this compound was synthesized using these conditions.

[0239] General procedure for step 8e

[0240] Compounds selected from the TG2 series were isolated by preparative SFC to obtain individual enantiomers (absolute stereochemistry not yet specified) from the TG3 series (Table 10).

[0241] Table 10: Detailed conditions: ( It indicates any stereochemical designation for distinguishing the different isomers; the absolute stereochemistry is not determined and may be inconsistent with the described stereochemistry.

[0242] Step 8f procedure

[0243] Add 1,1,1,2,2,2-hexamethyldistannane (4.33 g, 13.22 mmol, 3.19 equivalents) to a mixture of (INT 2) (2 g, 4.14 mmol, 1 equivalent) in toluene (40 mL). Degas the suspension under vacuum and purge three times with N2. Add Pd(PPh3)4 (478.16 mg, 413.79 μmol, 0.1 equivalents) to the mixture, then degas the suspension under vacuum and purge three times with N2. Stir the mixture at 80°C for 12 h. Quench the mixture by adding water (100 mL). Concentrate the mixture with ethyl acetate (100 mL). 3) Extraction. The organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under 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). 1 H 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] Step 8g of the general program

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

[0246] Table 11:

[0247] Step 8h procedure

[0248] The mixture of (8-4AF) (167 mg, 225.46 mol, 1 equivalent) in DCM (7 mL) and TFA (3.21 g, 28.19 mmol, 125.05 equivalent) was stirred at 20°C for 1 hour. The mixture was concentrated under vacuum. The residue was used without purification to give (8d-1) (217 mg, crude, TFA). [M+H] + = 586.1. 1 H 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 the TG4 series

[0250] General procedure for step 9a

[0251] Add Pd(OAc)₂ (0.2 equivalents), PCy₃ (0.2 equivalents), and K₃PO₄ (5 equivalents) to a mixture of (9-1) (1 equivalent) and boric acid (3 equivalents) in toluene and water. Stir the reaction mixture (see Table 12). After the reaction is complete, dilute the mixture with EtOAc, filter, and concentrate under vacuum. Purify the residue by column chromatography or use it as is in the next step to give (9-2).

[0252] Table 12: Detailed conditions: (All reactions were carried out under nitrogen atmosphere) 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 for step 9b-1

[0254] Add NH4Cl (10 equivalents) to a mixture of (9-2) (1 equivalent) and Fe (5 equivalents) in a solvent mixture (EtOH / water, at a ratio of 2:1). Then stir the mixture (see Table 13). After the reaction is complete, dilute the mixture with EtOAc and water and filter. Extract the aqueous layer with EtOAc. Wash the combined organic layers with brine, dry over Na2SO4, filter, and concentrate under vacuum. Purify the residue by column chromatography or use it as is in the next step to obtain (9-3).

[0255] General procedure for step 9b-2

[0256] Add Pd / C (10 wt%, 10% purity) to the mixture of (9-2) (1 equivalent) in EtOH. Degas the suspension under vacuum and purge with H2 several times. Stir the mixture (see Table 13). Filter the mixture. Concentrate the filtrate under vacuum. Purify the residue by column chromatography or use it as is in the next step to obtain (9-3).

[0257] Table 13: Detailed Conditions:

[0258] General procedure for step 9c-1

[0259] Add t-BuOK (1.5 equivalents) to a mixture of (9-3) (1 equivalent), INT 4 (1 equivalent), and CDI (1 equivalent) in DMF. Stir the reaction (see Table 14). After the reaction is complete, quench the reaction by adding water. Extract the mixture with EtOAc. Wash the organic phase with brine, dry with Na2SO4, filter, and concentrate under vacuum. Purify the residue by column chromatography or use it as is in the next step to give (9-4).

[0260] General procedure for step 9c-2

[0261] DIEA (19.42 mg, 150.23 μmol, 3 equivalents) was added in a single dose to a mixture of (9-3) (18 mg, 50.08 μmol, 1 equivalent) and INT 3 (20.56 mg, 60.09 μmol, 1.2 equivalents) in DMF (1 mL). Then HATU (28.56 mg, 75.11 μmol, 1.5 equivalents) was added to the mixture. The mixture was stirred at 70°C for 12 h. The mixture was added dropwise to water (10 mL). The mixture was then diluted with ethyl acetate (20 mL). 2) Extraction. The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The product was purified by preparative TLC (petroleum ether: ethyl acetate = 1.5: 1, Rf = 0.35) to give (9-4) (20 mg, 29.26 μmol, 58.42% yield) (see Table 14 for details).

[0262] Table 14: Detailed Conditions:

[0263] General procedure for step 9d-1

[0264] The mixture of (9-4) (1 equivalent) and LiOH monohydrate (3 equivalents) in a solvent mixture (MeOH / THF / water, in a 1:1:1 ratio) was stirred (see Table 15). After the reaction was complete, the mixture was concentrated and purified by preparative HPLC to obtain the TG4 series (selected compounds are in Table 15).

[0265] Table 15: Detailed Conditions:

[0266] Scheme 10. Synthesis of the TG5 series

[0267] General procedure for step 10a

[0268] Add K₂CO₃ (3 equivalents) to a mixture of (10⁻¹) (1 equivalent) and boric acid building blocks (1 equivalent) in a solvent mixture (DME / water, at a ratio of 10:1), and purge the mixture three times with N₂. Then add Pd(dppf)Cl₂ (0.1 equivalent), and purge the resulting mixture three more times with N₂. Heat the reaction to 100°C and stir for N h (see Table 16). After the reaction is complete and cooled to room temperature, dilute the mixture with ethyl acetate. Filter the resulting mixture and concentrate the filtrate. Purify the residue by column chromatography or use it as is in the next step to give (10⁻²).

[0269] Table 16: Detailed conditions: (All reactions were carried out under nitrogen atmosphere) A: Pd(dppf)Cl2, K2CO3; B: Pd(PPh3)4, K2CO3;

[0270] General procedure for step 10b

[0271] t-BuOK (1.5 equivalents) was added to a mixture of aniline (10⁻²) (1 equivalent) and INT 1 / INT 2 / INT 3 (1 equivalent) in DMF. The reaction was stirred at M°C under N₂ for 12 h. After the reaction was complete, the reaction was quenched by adding water. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a residue, which was purified by column chromatography or used as is in the next step to give (10⁻³). (Other compounds prepared in a similar manner are shown in Table 17.)

[0272] Table 17: Detailed Conditions:

[0273] General procedure for step 10c

[0274] LiOH·water (3 equivalents) was added to a solution of (10⁻³) (1 equivalent) in a solvent mixture (MeOH / THF / water, in a ratio of 1:1:1). The reaction was stirred at M°C for 12 h. After the reaction was complete, the reaction mixture was directly concentrated to obtain a residue, which was purified by preparative HPLC to obtain TG5 (selected compounds are listed in Table 18).

[0275] Table 18: Detailed Conditions:

[0276] Scheme 11. Synthesis of the TG6 series

[0277] Synthesis of TG6

[0278] Procedure of step 11a

[0279] Under N2, Pd(OH)2 (350 mg, 20% purity) was added to a solution of (11-1) (1 g, 2.68 mmol, 1 equivalent) in THF (50 mL). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 20°C for 1.5 h under H2 (15 Psi). After the reaction was complete, the mixture was filtered and concentrated under vacuum to obtain 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 separated with ethyl acetate (60 mL). 2) Wash and freeze-dry the aqueous layer to obtain (11-2) (590 mg, 2.14 mmol, 79.90% yield, HCl). 1 ¹H NMR (400MHz, 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] At 20°C, HATU (1.22 g, 3.21 mmol, 1.5 equivalence) was added in a single dose to a mixture of (11-2) (590 mg, 2.14 mmol, 1 equivalence, HCl), DIEA (829.53 mg, 6.42 mmol, 3 equivalence), and (INT 3) (732.09 mg, 2.14 mmol, 1 equivalence) in DMF (26 mL). The mixture was heated to 60°C and stirred for 12 hours. After the reaction was complete, the reaction mixture was poured into water (50 mL) and diluted with ethyl acetate (30 mL). 2) Extraction. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) and preparative TLC (petroleum ether: ethyl acetate = 2:1) to give (11-3) (980 mg, 1.74 mmol, 81.29% yield). [M+H] + = 565.2. 1H NMR (400 MHz, chloroform-d) δ ppm 8.02 (brd, 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, 3H) 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] Step 11c procedure

[0283] TFA (5 mL) was added to a mixture of (11-3) (850 mg, 1.51 mmol, 1 equivalent) in DCM (20 mL), and the mixture was stirred at 20°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum to give (11-4) (1 g, crude product). [M+H] + = 509.1. 1 H 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 for step 11d

[0285] Pyridine (10 equivalents) was added in a single reaction to a mixture of (11-4) (1 equivalent) and hydroxylamine (HCl salt) (6 equivalents) in EtOAc. The mixture was stirred at M°C for N hours. After the reaction was complete, the mixture was washed with HCl (1 M). The organic phase was dried over sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by preparative HPLC to give (TG6) (selected compounds are listed in Table 19).

[0286] Table 19: Detailed Conditions:

[0287] Procedure of step 11e

[0288] TFA (0.5 mL) was added to a solution of (TG6-16) (0.18 g, 265.65 μmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to give (TG6-18) (29.4 mg, 48.40 μmol, 18.22% yield, 95.07% purity). [M+H] + = 579.1. 1 H 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 equivalent, TFA) in THF (2 mL) and water (0.7 mL), Na2CO3 (268.23 mg, 2.53 mmol, 7 equivalents) and CbzOSu (99.11 mg, 397.69 μmol, 1.1 equivalents) were added, and the mixture was stirred at 25°C under N2 for 2 h. The mixture was then poured into ice water (15 mL). The mixture was further diluted with ethyl acetate:THF = 1:1 (15 mL). 3) Extraction. The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to obtain a residue. This residue was purified by preparative HPLC to obtain (TG6-19) (29.98 mg, 40.87 μmol, 11.30% yield, 97% purity). [M+H] + = 712.9. 1H NMR (400 MHz, DMSO-d6) δ ppm12.83 - 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] Add TEA (219.50 mg, 2.17 mmol, 5 equivalents) and MsCl (0.14 g, 1.22 mmol, 2.82 equivalents) to a solution of (TG6-18) (0.3 g, 433.85 μmol, 1 equivalent, TFA) in DCM. Stir the mixture at 15°C under N2 for 1 h. Pour the residue into ice water (15 mL). Add the mixture to DCM (15 mL) 3) Extraction. The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to obtain a residue. This residue was purified by preparative HPLC to obtain (TG6-20) (40 mg, 60.29 μmol, 13.90% yield, 98.803% purity). [M+H] + = 656.9. 1 HNMR (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).

[0293] Scheme 12. Synthesis of the TG7 series

[0294] Synthesis of 12-1A

[0295] Synthesis of 12-3A

[0296] Synthesis of 12d-1

[0297] General procedure for step 12a

[0298] At -75°C under N2, a solution of (12-1) (1 equivalent) in THF was added to a mixture of LDA (2 M, 1.1 equivalents) in THF. The mixture was stirred at -75°C for 0.5 h. Additional THF was added to the reaction, followed by a solution of methyl propionate (2.2 equivalents) in THF. The mixture was stirred at -75°C for 12 h. After the reaction was complete, the mixture was poured into saturated NH4Cl. The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a residue. The residue was purified by preparative HPLC to obtain (12-2). (See Table 20 for details.)

[0299] Table 20: Detailed Conditions:

[0300] General procedure for step 12b

[0301] Add NaCl (11 equivalents) and water to the mixture of (12-2) (1 equivalent) in DMSO. Stir the mixture at 150°C for 6 hours. After the reaction is complete, pour the mixture into water and extract with ethyl acetate. Wash the organic phase with brine and dry it over Na2SO4, filter, and concentrate under vacuum to obtain the residue. Purify the residue by column chromatography or use it as is in the next step to obtain (12-3). (See Table 21 for details)

[0302] Table 21: Detailed Conditions:

[0303] General procedure for step 12c

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

[0305] Table 22: Detailed Conditions:

[0306] General procedure for step 12d-1

[0307] Add TEA (3 equivalents) to the mixture of methyl (12-4) (1 equivalent) in DCM. Then, add INT 4 (1.1 equivalents) to the mixture. Stir the mixture at 20°C for 2 hours. After the reaction is complete, concentrate the reaction directly to obtain the residue, which is purified by column chromatography or used as is in the next step to obtain (12-5). (See Table 23 for details)

[0308] Procedure of step 12d-2

[0309] DIEA (703.28 mg, 5.44 mmol, 3 equivalents) and HATU (1.03 g, 2.72 mmol, 1.5 equivalents) were added in a single dose to a mixture of (12-4) (630 mg, 1.81 mmol, 1 equivalent) and INT 3 (620.67 mg, 1.81 mmol, 1 equivalent) in DMF (10 mL) at 20°C under N2. The mixture was stirred at 70°C for 12 hours. The reaction mixture was quenched by adding water (10 mL). The mixture was then quenched with ethyl acetate (10 mL). 2) Extraction. The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to obtain a residue. This residue was purified by preparative TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.37) to give (12-5) (1.17 g, crude product). (See Table 23 for details)

[0310] Procedure of step 12d-3

[0311] Add DIEA (4.01 g, 31.01 mmol, 12 equivalents) to a mixture of (12-4) (1.55 g, 2.58 mmol, 1 equivalent) and 3,3-difluorozazide hydrochloride (2.01 g, 15.50 mmol, 6 equivalents, HCl) in DMA (50 mL). Stir the mixture at 100°C for 12 h. Pour the mixture into water (500 mL). Dilute the aqueous phase with ethyl acetate (200 mL). 3) Extraction. The combined organic phases were washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give (12-5) (1.25 g, 1.90 mmol, 73.69% yield). (See Table 23 for details)

[0312] Table 23: Detailed Conditions:

[0313] General procedure for step 12e

[0314] Add LiOH·water (3 equivalents) to a mixture of (12-5) (1 equivalent) in a solvent mixture (MeOH / THF / water, in a 1:1:1 ratio). Stir the mixture at 20°C for 2 hours. After the reaction is complete, concentrate the reaction directly to obtain the residue, which is then purified by preparative HPLC to obtain (TG7). (See Table 24 for details)

[0315] Table 24: Detailed Conditions:

[0316] General procedure in step 12f

[0317] The following isomers were obtained by preparative SFC separation (TG7) to provide (without specifying absolute stereochemistry).

[0318] Table 25: Detailed Conditions: ( It indicates any stereochemical designation for distinguishing the different isomers; the absolute stereochemistry is not determined and may be inconsistent with the described stereochemistry.

[0319] Step 12g General Program

[0320] Add KOH (26.2 mg, 655.2 mmol, 6 equivalents) to a mixture of (12S⁻¹) (20 g, 109.2 mmol, 1 equivalent) in EtOH. Stir the mixture at 100°C for 12 h. Add the mixture to water (1 L). Adjust the pH of the aqueous phase to 1 with HCl (2 M). Then, dilute the aqueous phase with ethyl acetate (200 mL). 5) Extraction. The combined organic phases were rinsed with 1000 mL of brine. 3) Wash, dry with anhydrous Na2SO4, filter, and concentrate under vacuum. Pass the residue through a preparative HPLC system (column: Phenomenex Luna C18 250mm). 100mm 10 μm; mobile phase: [water (TFA)-ACN]; B%: 15%-45%, 20 min) purification to give (12S⁻²) (13 g, 64.31 mmol, 58.89% yield). [M+H] + = 201.1 1 H 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] General procedure in step 12h

[0322] Iodimethane (2 equivalents) was added to a mixture of (12S⁻²) (1 equivalent) and K₂CO₃ (3 equivalents) in DMF. The mixture was stirred at 20°C for 3 h. The mixture was then added to water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was used directly without purification. (12⁻¹) was obtained. (See Table 26 for details)

[0323] Table 26: Detailed Conditions:

[0324] Step 12i procedure

[0325] NBS (10.46 g, 58.75 mmol, 1 equivalent) and PTSA (1.01 g, 5.87 mmol, 0.1 equivalent) were added to a mixture of (12S-3) (10 g, 58.75 mmol, 9.35 mL, 1 equivalent) in toluene (500 mL). The mixture was stirred at 115°C under N2 for 12 hours. The mixture was diluted with ethyl acetate (300 mL). The combined organic phases were washed with brine (200 mL) and NaHCO3 (saturated, 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). 1 H 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).

[0326] Step 12j procedure

[0327] KOH (765.79 mg, 13.65 mmol, 1 equivalent) was added to a mixture of 2-(trifluoromethoxy)phenol (2.32 g, 13.00 mmol, 1 equivalent) in DMF (170 mL). The mixture was stirred at 25°C for 15 min. (12S-4) (3.4 g, 13.65 mmol, 1 equivalent) was added to the reaction mixture. The mixture was stirred at 25°C for 12 h. The reaction mixture was quenched by adding water (150 mL). The mixture was then quenched with ethyl acetate (150 mL). 2) Extraction, drying with sodium sulfate, filtration, and concentration to obtain 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, 6.17Hz, 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] Step 12k of the procedure

[0329] At 20°C, NaHCO3 (1 M, 10 equivalents) was added in a single addition to a mixture of (12-4C) (1.5 g, 4.73 mmol, 1 equivalent) and INT 7 (1.51 g, 4.73 mmol, 1 equivalent) in DCM (40 mL). The mixture was stirred at 20°C for 12 hours. The reaction mixture was quenched by adding water (100 mL). The residue was then treated with DCM (30 mL). 3) Extraction. The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give (12d⁻¹) (1.6 g, 2.67 mmol, 56.43% yield). [M+H] + = 601.0. 1 H 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).

[0330] Scheme 13. Synthesis of TG8

[0331] General procedure for step 13a

[0332] Add NaHCO3 (2 equivalents) and m-CPBA (85% purity, 1.5 equivalents) to the mixture of (13-1) (1 equivalent) in DCM at 0°C. Stir the mixture at 20°C for 12 h. After the reaction is complete, pour the reaction mixture into saturated Na2CO3 and stir for 10 min. Then extract the mixture with ethyl acetate. Wash the combined organic phases with brine, dry over sodium sulfate, filter, and concentrate to obtain the residue, which is purified by column chromatography or used as is in the next step to obtain (13-2). (See Table 27 for details)

[0333] Table 27: Detailed Conditions:

[0334] General procedure for step 13b

[0335] A mixture of Pd(OAc)₂ (0.2 equivalents), Et₃SiH (3 equivalents), and TEA (3 equivalents) in DCM was stirred at 20°C for 15 min. The mixture was then added to a solution of (13-2) (1 equivalent) in DCM at 20°C under N₂. The mixture was stirred at 20°C for 12 h. After the reaction was complete, 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 saturated NaHCO₃. The resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain a residue, which was purified by column chromatography or used as is in the next step to obtain (13-3). (See Table 28 for details)

[0336] Table 28: Detailed Conditions:

[0337] Procedure of step 13c-1

[0338] DIEA (135.22 mg, 1.05 mmol, 3 equivalents) and HATU (198.91 mg, 523.14 mol, 1.5 equivalents) were added in a single batch to a mixture of (13-3) (110 mg, 348.76 μmol, 1 equivalent) and INT 3 (119.34 mg, 348.76 μmol, 1 equivalent) in DMF (3 mL). The mixture was then stirred at 20°C for 12 h. After the reaction was complete, the reaction mixture was poured into water (50 mL) and diluted with ethyl acetate (30 mL). 2) Extraction. The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated to obtain a residue. This residue was purified by preparative TLC (petroleum ether: ethyl acetate = 2:1, Rf = 0.30) to give (13-4A) (130 mg, 203.26 μmol, 58.28% yield). (See Table 29 for details)

[0339] Procedure of step 13c-2

[0340] Add INT 4 (162.53 mg, 450.67 μmol, 1 equivalent) and TEA (114.01 mg, 1.13 mmol, 3 equivalent) to a mixture of (13-3) (150 mg, 375.56 μmol, 1 equivalent) in DCM (3 mL). Stir the mixture at 25°C for 1 hour. Concentrate the mixture under vacuum. Purify the residue by preparative TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.35) to give (13-4B) (50 mg, 69.10 μmol, 18.40% yield). (See Table 29 for details)

[0341] Table 29: Detailed Conditions:

[0342] General procedure for step 13d-1

[0343] The mixture of (13-4) (1 equivalent) in the solvent mixture (DCM / TFA, at a ratio of 4:1) was stirred at 20°C for 20 min. After the reaction was complete, the reaction mixture was concentrated to obtain a residue, which was purified by preparative HPLC to obtain (TG8).

[0344] General procedure for step 13d-2

[0345] (TG8) was obtained by preparative SFC separation. (Absolute stereochemistry not yet specified)

[0346] Table 30: Detailed conditions: ( It indicates any stereochemical designation for distinguishing the different isomers; the absolute stereochemistry is not determined and may be inconsistent with the described stereochemistry.

[0347] Scheme 14. Synthesis of the TG9 series

[0348] Synthesis of (14c-1)

[0349] Synthesis of (14-1A)

[0350] Synthesis of (14-1B)

[0351] General procedure for step 14a

[0352] Cs₂CO₃ (2.1 equivalents), CuI (0.1 equivalents), and N,N-dimethylglycine hydrochloride (0.3 equivalents) were added to a mixture of INT 2 (1 equivalent) and (INT 14a) (1.5 equivalents) in dioxane under N₂. The reaction was purged with N₂ three times and then heated to M°C for N h (see Table 31 for details). After the reaction was complete, the reaction mixture was poured into 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 preparative TLC / preparative HPLC / column chromatography to give (14-1).

[0353] Table 31: Detailed conditions: (All reactions were carried out under nitrogen atmosphere) A: CuI, N,N-dimethylglycine hydrochloride, Cs2CO3, dioxane; B: Pd(dppf)Cl2, K2CO3, DME, water; C: bis[(tetrabutylammonium iodide)copper(I)], Cs2CO3, DMEDA, toluene; D: Bis[(Tetrabutylammonium iodide)copper(I)], 1,10-phenanthroline, Cs2CO3, DMSO; E: CuiBuCx2, Cs2CO3, dioxane

[0354] General procedure for step 14b-1

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

[0356] Procedure of step 14b-2

[0357] Pd(OAc)₂ (650.71 mg, 2.90 mmol, 0.1 equivalent) was added to a solution of TEA (8.80 g, 86.95 mmol, 3 equivalents) and Et₃SiH (16.85 g, 144.92 mmol, 5 equivalents) in DCM (316 mL). The suspension was degassed under vacuum and purged several times with N₂. The mixture was stirred at 20°C for 30 min. A solution of (14-1) (15 g, 28.98 mmol, 1 equivalent) in DCM (158 mL) was added, and the mixture was stirred at 20°C under N₂ for 12 h. The mixture was concentrated under vacuum. The residue was diluted with THF (90 mL). The mixture was adjusted to pH = 5 with TFA. The mixture was then added dropwise to NaHCO₃ (saturated, 150 mL). The mixture was diluted with ethyl acetate (60 mL). 3) Extraction. The combined organic phases were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give (14-2) (9 g, 23.47 mmol, 80.99% yield) (see Table 32 for details).

[0358] Table 32: Detailed Conditions: Under nitrogen

[0359] General procedure for step 14c-1

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

[0361] General procedure for step 14c-2

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

[0363] General procedure for step 14c-3

[0364] DIEA (5 equivalents) was added in a single step to a mixture of (14c-1) (1 equivalent) and 3,3-difluorozahexacyclic butane hydrochloride (5 equivalents) in DMA 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 were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography or used as is in the next step / preparative HPLC to give (14-3) (see Table 33 for details).

[0365] Table 33: Detailed Conditions:

[0366] General procedure for step 14d

[0367] The mixture of (14-3) (1 equivalent) in a solvent mixture (DCM / TFA, at a ratio of 4:1) was stirred at 25°C for N hours (see Table 34 for details). The mixture was concentrated under vacuum. The residue was purified by preparative HPLC to obtain (TG9).

[0368] Table 34: Detailed Conditions:

[0369] General procedure in step 14e

[0370] The selected compounds from (TG9) were isolated by preparative SFC to obtain individual enantiomers in (TG9) (see Table 35 for details) (absolute stereochemistry not yet specified).

[0371] Table 35: Detailed Conditions: ( It indicates any stereochemical designation for distinguishing the different isomers; the absolute stereochemistry is not determined and may be inconsistent with the described stereochemistry.

[0372] General procedure in step 14f

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

[0374] Table 36: Detailed Conditions:

[0375] Step 14g of the program

[0376] At 0°C under N2, NaH (1.66 g, 41.51 mmol, 60% purity, 2 equivalents) was added to a mixture of benzyl alcohol (8.98 g, 83.02 mmol, 4 equivalents) in DMF (20 mL). The mixture was stirred at 0°C for 30 min. Then, a solution of (14S⁻¹) (4.1 g, 20.76 mmol, 1 equivalent) in DMF (5 mL) was added to the reaction mixture. The mixture was stirred at 25°C for 2 h. The mixture was added dropwise to water (50 mL). The mixture was then diluted with ethyl acetate (50 mL). 2) Extraction. The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give (14S⁻²) (4.5 g, 16.72 mmol, 80.53% yield). [M+H] += 270.2. 1 H 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] Step 14h procedure

[0378] Under N2, Pd / C (250 mg, 10% purity) was added in a single addition to a mixture of (14S⁻²) (4.5 g, 16.72 mmol, 1 equivalent) in EtOH (2 mL). The suspension was degassed under vacuum and purged several times with H₂ (15 Psi). The mixture was stirred at 25°C for 3 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 9 / 1 to 0 / 1) to give (14⁻¹A) (2.5 g, 13.96 mmol, 83.51% yield). [M+H] + = 180.1. 1 H 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] Step 14j procedure

[0380] KOAc (4.99 g, 50.83 mmol, 3 equivalents) was added in a single dose to a mixture of (14S-3) (5.48 g, 16.94 mmol, 1 equivalent) and BPD (5.16 g, 20.33 mmol, 1.2 equivalents) in dioxane (54.8 mL). The suspension was degassed under vacuum and purged several times with N2. Pd(dppf)Cl2 (1.38 g, 1.69 mmol, 0.1 equivalent) was then added to the mixture. The mixture was stirred at 100°C for 18 hours. The mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0 to 97 / 1) to give (14S-4) (1.46 g, 4.51 mmol, 26.64% yield). [M+H] + = 324.1. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.08 (d, J = 7.75Hz, 1 H) 7.25 (d, J = 7.63 Hz, 1 H) 1.36 (s, 12 H).

[0381] Step 14k of the procedure

[0382] To a mixture of (14S-4) (3.5 g, 10.82 mmol, 1 equivalent) in THF (35 mL), add NaOH (16.7 M, 440.85 mg, 17.83 equivalent) and water 2 (4.41 g, 38.90 mmol, 30% purity, 3.60 equivalent) in a single addition. Stir the mixture at 50°C for 24 hours. Quench the reaction mixture with Na2SO3 (saturated, 30 mL). Dissolve the residue in ethyl acetate (50 mL). 2) Extraction. The combined organic layers were rinsed with brine (50 mL). 2) Wash, dry with Na2SO4, filter, and concentrate under vacuum. Purify the residue by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0 to 92 / 8) to give (14S-5) (3 g, crude). [M+H] + = 214.1. 1 H 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] Step 14l procedure

[0384] Under N2, Pd / C (1.5 g, 10% purity) was added to a solution of (14S-5) (3 g, 14.05 mmol, 1 equivalent) in EtOH (150 mL). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 20°C for 31 hours under H2 (15 Psi). The mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 99 / 1 to 94 / 6) to give (14-1B) (1 g, 5.58 mmol, 39.74% yield). 1 H 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).

[0385] Scheme 15. Synthesis of TG10

[0386] Synthesis of (15-1)

[0387] A procedure similar to step 8b-1 (reagents and solvent A)

[0388] 1 H 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] A procedure similar to 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, 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] A procedure similar to step 8d

[0394] [M+H] + = 585.1, 587.1. 1 H 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] At 0°C under N2, NaNO2 (9.08 mg, 131.55 µmol, 1.10 equivalent) in water (0.3 mL) was added to a mixture of (TG2-20) (70 mg, 119.76 µmol, 1 equivalent) in HCl (1 mL) and water (1 mL) and stirred for 35 min. The mixture was then added to CuCl (59.28 mg, 598.80 µmol, 5 equivalent) in HCl (1 mL) and water (1 mL) at 0°C. The mixture was then stirred at 25°C for 50 min. The reaction mixture was adjusted to pH = 3 with NaHCO3 (saturated). The aqueous phase was diluted with ethyl acetate (10 mL) 3) Extraction. The combined organic phases were rinsed with 10 mL of brine. 3) Wash, dry with anhydrous Na2SO4, filter, and concentrate under vacuum. Pass the crude product through a preparative HPLC system (column: Pheromones Luna 80). 30mm 3 μm; mobile phase: [water (HCl)-ACN]; B%: 30%-60%, 8 min) purified to give (TG11-01) (40 mg, 66.23 µmol, 55.30% yield). [M+H] + = 605.1.

[0398] Procedure of step 16b

[0399] The TG11 series (without specifying absolute stereochemistry) was obtained by preparative SFC separation (TG11-01).

[0400] Table 37: Detailed Conditions: ( It indicates any stereochemical designation for distinguishing the different isomers; the absolute stereochemistry is not determined and may be inconsistent with the described stereochemistry.

[0401] Scheme 17. Synthesis of the TG12 series

[0402] Synthesis of 17c-1

[0403] Synthesis of 17c-2

[0404] General procedure for step 17a

[0405] Add K3PO4 (3 equivalents) to a mixture of (17-1) (1 equivalent) and INT 2 (1.5 equivalents) in toluene. Degas the suspension under vacuum and purge several times with N2. Add XPhos (0.2 equivalents) and Pd2(dba)3 (0.1 equivalents) to the mixture. Degas the suspension under vacuum and purge several times with N2. Stir the mixture at 100°C for 12 h. Filter the mixture and concentrate the filtrate under vacuum. Purify the crude product by preparative TLC / preparative HPLC to obtain (17-2) (see Table 38 for details).

[0406] Table 38: Detailed conditions: (All reactions were carried out under nitrogen atmosphere)

[0407] General procedure for step 17b

[0408] Add Pd / C (10 wt%, 10% purity) to the mixture of (17-2) (1 equivalent) in EtOH. Degas the suspension under vacuum and purge several times with H2. Stir the mixture at 20°C for 12 h with H2 (15 Psi). Filter the mixture and concentrate the filtrate under vacuum. Purify the crude product by column chromatography or use it as is in the next step to obtain (17-3). (See Table 39 for details)

[0409] Table 39: Detailed Conditions:

[0410] General procedure in step 17c

[0411] Add TEA (3 equivalents) and HATU (1.5 equivalents) to a mixture of (17-3) (1 equivalent) and INT 3 / INT 7 (1.1 equivalents) in DMF. Stir the mixture at M°C for 12 h (see Table 40). Add the mixture to water. Extract the mixture with ethyl acetate. Wash the organic phase with brine, dry with Na2SO4, and concentrate under vacuum. Purify the residue by column chromatography or use it as is in the next step to give (17-4).

[0412] Table 40: Detailed Conditions:

[0413] General procedure for step 17d-1

[0414] Add TFA (3 equivalents) to the mixture of (17-4) / (17c-1) (1 equivalent) in DCM. Stir the mixture at 25°C for 2 hours. Concentrate the mixture under vacuum. Purify the residue by preparative HPLC to give (TG12) (selected compounds are shown in Table 41).

[0415] Procedure of step 17d-2

[0416] At 20°C, LiOH·water (8.30 mg, 197.79 μmol, 3 equivalents) was added in a single batch to a mixture of (17c-2) (45.92 mg, 65.93 μmol, 1 equivalent) in THF (0.3 mL), MeOH (0.3 mL), and water (0.3 mL). The mixture was stirred at 20°C for 12 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC to give (TG12-06) (20 mg, 29.30 μmol, 44.44% yield) (selected compounds are shown in Table 41).

[0417] Table 41: Detailed Conditions:

[0418] General procedure in step 17e

[0419] The selected compounds from (TG12-01) to (TG12-05) were isolated by preparative SFC to obtain individual enantiomers in (TG12) (absolute stereochemistry not yet specified) (the selected compounds are shown in Table 42).

[0420] Table 42: Detailed conditions: ( It indicates any stereochemical designation for distinguishing the different isomers; the absolute stereochemistry is not determined and may be inconsistent with the described stereochemistry.

[0421] General procedure in step 17f

[0422] To (17-4D / E) (1 equivalent) and 3,3-difluorozazide butane Add 6 equivalents of base to the mixture in solvent with HCl (6 equivalents). Stir the mixture at M°C for N h (see Table 43). Concentrate the reaction mixture under reduced pressure. Purify the residue by column chromatography or use it as is in the next step to give (17c-1).

[0423] Table 43: Detailed Conditions:

[0424] Step 17g of the program

[0425] CH3I (41.40 mg, 291.70 µmol, 3 equivalents) was added in a single addition to a mixture of (TG12-02) (65 mg, 97.23 µmol, 1 equivalent) and K2CO3 (40.31 mg, 291.70 µmol, 3 equivalents) in DMF (0.5 mL) 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 then diluted with ethyl acetate (2 mL). 2) Extraction. The combined organic phases were rinsed with brine (4 mL) 2) Wash, dry with anhydrous Na₂SO₄, filter, and concentrate under vacuum. (17c⁻²) (50 mg, crude) was used directly in the next step without further purification. [M+H] + = 698.1. 1 HNMR (400 MHz, chloroform-d) δ ppm 8.58 (br d, J = 10.51 Hz, 1 H) 8.31 (d, J = 1.83Hz, 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- 7.76 (m, 3 H) 7.14 - 7.21 (m, 3 H) 6.67 (q, J = 8.15 Hz, 1 H) 4.20 (s, 3 H)3.64 (s, 3 H) 2.61 - 2.80 (m, 1 H) 2.44 - 2.59 (m, 2 H) 2.28 (d, J = 1.34 Hz, 3 H) 1.94 - 2.04 (m, 5 H) 1.57 - 1.81 (m, 3 H).

[0426] Scheme 19. Synthesis of the TG14 series

[0427] Synthesis of 19d-1

[0428] (19-1) procedure

[0429] At -78°C, LDA (2 M, 1.00 mL, 2.5 equivalents) was added to a solution of (BCO-ketone) (0.3 g, 803.34 μmol, 1 equivalent) in THF (5 mL). The mixture was stirred at -78°C for 1 h. A solution of alkyl iodine (250.85 mg, 1.77 mmol, 2.2 equivalents) in THF (0.5 mL) was added to the reaction mixture at -78°C. The reaction mixture was stirred at -78°C for 0.5 h, allowing it to be warmed to 20°C and stirred for N h (see Table 51). The reaction mixture was poured into NH4Cl (saturated, 10 mL). The mixture was then diluted with ethyl acetate (10 mL). 3) Extraction. The organic phase was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography to obtain (19).

[0430] Table 51: Detailed Conditions:

[0431] General procedure in step 19c

[0432] Under Ar conditions, a mixture of (19-2) / (BCO-ketone) (1 equivalent) and Pd / C (10 wt%, 10% purity) in EtOH and ethyl acetate was added to a flask. The suspension was degassed under vacuum and purged three times with H2. The mixture was stirred under H2 (15 Psi) (see Table 52 for details). The suspension was filtered through a diatomaceous earth mat. The filter cake was washed with MeOH. The filtrate was concentrated under vacuum to give (19-3).

[0433] Table 52: Detailed Conditions:

[0434] Procedure of step 19d-1

[0435] To a solution of (19-3A) (0.66 g, 2.47 mmol, 1 equivalent) and INT 3 (886.94 mg, 2.59 mmol, 1.05 equivalent) in DMF (10 mL), DIEA (1.12 g, 8.64 mmol, 3.5 equivalent) and HATU (1.03 g, 2.72 mmol, 1.1 equivalent) were added. The mixture was stirred at 25°C for 12 h. The reaction mixture was poured into ice water (80 mL) and mixed with ethyl acetate (30 mL). 3) Extraction. The combined organic layers were rinsed with 20 mL of brine. 2) Wash, dry with Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. Purify the residue 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 Table 53 for details)

[0436] Procedure of step 19d-2

[0437] At -60°C, LDA (2 M, 1.11 mL, 2.5 equivalents) was added to a solution of (19d-1) (0.5 g, 887.34 μmol, 1 equivalent) in THF (6 mL). The mixture was stirred at -60°C for 1 hour. At -60°C, a solution of MeI (377.85 mg, 2.66 mmol, 3 equivalents) in THF (1 mL) was added to the reaction mixture. The reaction mixture was stirred at -60°C for 0.5 hours, allowed to warm to 20°C for 0.5 hours, and stirred for 10 hours. The reaction mixture was poured into NH4Cl (saturated, 50 mL) and mixed with ethyl acetate (20 mL). 3) Extraction. The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the 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 Table 53 for details)

[0438] Procedure of step 19d-3

[0439] At 0°C, NaHCO3 (3.02 g, 35.91 mmol, 12 equivalents) in water (9 mL) was added to a solution of (19-3C) (0.8 g, 2.99 mmol, 1 equivalent) and INT 4 (1.08 g, 2.99 mmol, 1 equivalent) in DCM (9 mL). The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by adding water (10 mL) and then mixed with DCM (10 mL). 3) Extraction. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the 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 Table 53 for details)

[0440] Table 53: Detailed Conditions:

[0441] General procedure for step 19e

[0442] A solution of (19-4) (1 equivalent) in a solvent mixture (DCM / TFA, at a ratio of 5:1) was prepared at M°C. The mixture was stirred under specific conditions (see Table 54). The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography or used as is in the next step to obtain (19-5).

[0443] Table 54: Detailed Conditions:

[0444] General procedure in step 19f

[0445] Pyridine (12 equivalents) and Ti(OEt)4 (10 equivalents) were added to a solution of (19-5) (1 equivalent) and INT 19f (6 equivalents, HCl) in THF. The mixture was stirred at 80°C for 36 h. The residue was diluted with water and filtered through a diatomaceous earth mat. The filter cake was washed with a solvent mixture (ethyl acetate / THF, at a ratio of 2:1). The combined filtrates were washed with HCl (1 M), washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC to obtain (TG14). (See Table 55 for details)

[0446] Table 55: Detailed Conditions:

[0447] General procedure in step 19g

[0448] The TG14 series was isolated by preparative SFC to obtain the TG14 series (in Table 56), without specifying absolute stereochemistry.

[0449] Table 56: Detailed Conditions: ( It indicates any stereochemical designation for distinguishing the different isomers; the absolute stereochemistry is not determined and may be inconsistent with the described stereochemistry.

[0450] Step 19h procedure

[0451] At 20°C, NaHCO3 (11.81 g, 140.53 mmol, 1 equivalence) was added to a solution of (19-3B) (3 g, 12.54 mmol, 1 equivalence) and INT 4 (4.52 g, 12.54 mmol, 1 equivalence) in DCM (30 mL) for 12 hours. The reaction mixture was quenched by adding water (70 mL) and extracted with DCM (50 mL). The combined organic layers were then treated with brine (60 mL). 2) Wash, dry with Na₂SO₄, filter, and concentrate under reduced pressure to obtain the residue. Purify the residue 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. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.03 (br d, J = 8.70Hz, 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).

[0452] Scheme 20. Synthesis of the TG15 series

[0453] Synthesis of 20-1A / B / C

[0454] Synthesis of 20-1D / E

[0455] General procedure for step 20a-1

[0456] Add a secondary amine (5 equivalents) to a mixture of (20-1) (1 equivalent) and DIEA (3 equivalents) in DMA. Heat the mixture to 100°C and stir for 12 h. Filter the mixture and concentrate the filtrate under vacuum. Purify the residue by column chromatography or use it as is in the next step to obtain (20-2) (see Table 57 for details).

[0457] General procedure for step 20a-2

[0458] Add TEA (3 equivalents) and HATU (1.5 equivalents) to a mixture of (20-1) (1 equivalent) and (7-3I) (1.2 equivalents) in DMF. Stir the mixture at 60°C for 12 hours. Add the mixture to water. Extract the mixture with ethyl acetate. Wash the organic phase with brine, dry with Na2SO4, and concentrate under vacuum. Purify the residue by column chromatography or use it as is in the next step to give (20-2) (see Table 57 for details).

[0459] Table 57: Detailed Conditions:

[0460] General procedure for step 20b

[0461] The solution of (20-2) (1 equivalent) in a solvent mixture (DCM / TFA, at a ratio of 5:1) was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC to obtain the TG15 series (see Table 58 for details).

[0462] Table 58: Detailed Conditions:

[0463] General procedure for step 20c

[0464] Add DIEA (5 equivalents) to a mixture of (20S⁻¹) (1 equivalent) and secondary amine (6 equivalents) in NMP. Stir the mixture at 100°C for 12 hours. Filter the mixture and concentrate the filtrate under vacuum. Purify the crude product by preparative HPLC to obtain (20S⁻¹).

[0465] Table 59: Detailed Conditions:

[0466] General procedure for step 20d

[0467] A mixture of (5-1) (1 equivalent) and 1-(3-methoxyphenyl)prop-1-one / 1-(2-methoxyphenyl)prop-1-one (1 equivalent) in AcOH was stirred at 75°C for 0.5 h. Then, HCl was added to the mixture. The mixture was stirred at M°C (see Table 60) for 11.5 h. After cooling 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 solvent mixture (petroleum ether / ethyl acetate, at a ratio of 2:1) and concentrated under vacuum to give (20-1).

[0468] Table 60: Detailed Conditions:

[0469] Scheme 21. Synthesis of TG16-01

[0470] Procedure of step 21a

[0471] TEA (4.46 g, 44.09 mmol, 1 equivalent) was added to a mixture of (21-1) (2 g, 14.70 mmol, 1 equivalent) and N-methoxymethylamine (1.58 g, 16.17 mmol, 1.1 equivalent, HCl) in DMF (50 mL). Then HATU (8.38 g, 22.04 mmol, 1.5 equivalent) was added to the mixture. The mixture was stirred at 20°C for 12 h. The mixture was then added to water (200 mL). The aqueous phase was diluted with ethyl acetate (100 mL). 2) Extraction. The combined organic phases were rinsed with 200 mL of brine. 2) Wash, dry with anhydrous Na2SO4, filter and concentrate under vacuum. Purify the residue by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give (21-2) (2.1 g, 11.72 mmol, 79.76% yield). 1 ¹H NMR (400MHz, chloroform-d) δ ppm 3.69 (s, 3H) 3.24 - 3.33 (m, 1H) 3.22 (s, 3H) 2.80 -2.97 (m, 2H) 2.66 - 2.79 (m, 2H).

[0472] Procedure of step 21b

[0473] At 0°C under N2, add magnesium bromo(ethyl) (3 M, 11.72 mL, 3 equivalents) to a mixture of (21-2) (2.1 g, 11.72 mmol, 1 equivalent) in THF (40 mL). Stir the mixture at 20°C for 2 h. Add the mixture to water (100 mL). Separate the aqueous phase with ethyl acetate (50 mL). 2) Extraction. The combined organic phases were rinsed with 100 mL of brine. 2) Wash, dry with anhydrous Na2SO4, filter and concentrate under vacuum. Use the residue directly without purification to give (21-3) (1.2 g, 8.10 mmol, 69.11% yield). 1 H 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] Step 21c procedure

[0475] KOH (37.87 mg, 17.82 mmol, 1 equivalent) was added to a mixture of (21-3) (100 mg, 674.99 μmol, 1 equivalent) and (4-1) (152.57 mg, 674.99 μmol, 1 equivalent) in EtOH (2 mL). The mixture was stirred at 60°C for 12 h. The mixture was adjusted to pH = 1 with HCl (1 M). The mixture was filtered. The filter cake was collected to obtain (21-4) (100 mg, crude), which was used directly without purification. [M+H] + = 357.9.

[0476] Procedure in step 21d

[0477] DIEA (108.86 mg, 842.31 mmol, 3 equivalents) was added to a mixture of (21-4) (100 mg, 280.77 μmol, 1 equivalent) and (7-3I) (107.65 mg, 280.77 μmol, 1 equivalent) in DMF (5 mL). Then HATU (160.14 mg, 421.16 μmol, 1.5 equivalents) was added to the mixture. The mixture was stirred at 20°C for 12 h. The mixture was then added to water (100 mL). The aqueous phase was diluted with ethyl acetate (50 mL). 2) Extraction. The combined organic phases were rinsed with 100 mL of brine. 2) Wash, dry with anhydrous Na₂SO₄, filter, and concentrate under vacuum. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.45) to give (21-5) (50 mg, 69.30 μmol, 24.68% yield). [M+H] + =723.1. 1 H 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] TFA (1 mL) was added to a mixture of (21-5) (50 mg, 69.30 μmol, 1 equivalent) in DCM (5 mL). The mixture was stirred at 20°C for 2 h. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC to give (TG16-01) (5 mg, 7.51 μmol, 10.84% ​​yield). [M+H] + = 667.1. 1 H 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, 3H).

[0480] Scheme 22. Synthesis of the TG17 series

[0481] Synthesis of 22e-2

[0482] Synthesis of 22e-3

[0483] Procedure of step 22a

[0484] A mixture of (BCO-ketone) (6 g, 16.07 mmol, 1 equivalent), CH3COONH4 (12.38 g, 160.67 mmol, 10 equivalent), NaCNBH3 (3.03 g, 48.20 mmol, 3 equivalent), and FeCl3 (260.61 mg, 1.61 mmol, 0.1 equivalent) in MeOH (750 mL) was degassed and purged three times with N2. The mixture was then stirred at 25°C under N2 atmosphere for 36 hours. The mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 20 / 1 to 5 / 1) to give (22-1) (18 g, 48.07 mmol, 59.83% yield). [M+H] + = 375.1. 1 H 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] TEA (324.26 mg, 3.20 mmol, 1.2 equivalent) was added to a mixture of (22-1) (1 g, 2.67 mmol, 1 equivalent) in DCM (10 mL). Then, TFAA (324.26 mg, 3.20 mmol, 1.2 equivalent) was added to the mixture. The mixture was stirred at 20°C for 12 h. The mixture was then concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give (22-2A) (0.68 g, 1.45 mmol, 54.12% yield).

[0487] Procedure of step 22b-2

[0488] Glutaraldehyde (305.66 mg, 3.05 mmol, 2.22 equivalents) was added to a mixture of (22-1) (515 mg, 1.38 mmol, 1 equivalent) in MeOH (139 mL). The mixture was stirred at 25°C under N2 atmosphere for 40 min. Then, NaCNBH3 (349.16 mg, 5.56 mmol, 4.04 equivalents) and CH3COOH (3.30 g, 11.93 mmol, 8.68 equivalents) were added to the mixture. The mixture was degassed and purged three times with N2. The mixture was stirred at 25°C under N2 atmosphere for 12 h. The mixture was concentrated under vacuum. The crude product was analyzed by preparative HPLC (column: Waters Xbridge BEH C18 250). 50mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 70%-95%, 10 min) purification to obtain (22-2B) (596 mg, 1.35 mmol, 24.48% yield).

[0489] Table 61: Detailed Conditions:

[0490] General procedure for step 22c

[0491] Add Pd / C (10 wt%, 10% purity) to the mixture of (22-2) (1 equivalent) in EtOH. Degas the suspension under vacuum and purge several times with H2. Stir the mixture under specific conditions (see Table 62). Filter the mixture and concentrate the filtrate under vacuum to obtain crude (22-3).

[0492] Table 62: Detailed Conditions:

[0493] Procedure of step 22d-1

[0494] Add DIEA (426.52 mg, 3.30 mmol, 3 equivalents) and HATU (543.75 mg, 1.43 mmol, 1.3 equivalents) to a mixture of (22-3A) (0.37 g, 1.10 mmol, 1 equivalent) and INT 3 (489.35 mg, 1.43 mmol, 1.3 equivalents) in DMF (5.5 mL). Stir the mixture at 25°C for 12 h. Add water (20 mL) to the mixture. Dilute the aqueous phase with ethyl acetate (10 mL) 3) Extraction. The combined organic phases were rinsed with 30 mL of brine. 2) Wash, dry with anhydrous Na2SO4, filter and concentrate under vacuum. Purify the residue by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give (22-4A) (243 mg, 384.11 μmol, 59.24% yield).

[0495] Procedure of step 22d-2

[0496] Add NaHCO3 (1 M, 7.78 mL, 12 equivalents) to a mixture of (22-3B) (200 mg, 648.39 μmol, 1 equivalent) and INT 4 (280.59 mg, 778.06 μmol, 1.2 equivalents) in DCM (7.78 mL). Stir the mixture at 25°C for 12 h. Quench the reaction mixture by adding water (10 mL). Remove the residue with DCM (10 mL). 3) Extraction. The combined organic layers were rinsed with brine (10 mL) 2) The residue was washed, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.33) to give (22-4B) (243 mg, 384.11 μmol, 59.24% yield).

[0497] Table 63: Detailed Conditions:

[0498] General procedure for step 22e

[0499] A mixture of (22-4) / (22e-2) / (22e-3) (1 equivalent) in a solvent mixture (DCM / TFA, at a ratio of 5:1). The mixture was stirred (see Table 64). The mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to obtain (TG17).

[0500] Table 64: Detailed Conditions:

[0501] General procedure in step 22f

[0502] (TG17) was obtained by preparative SFC separation. (Absolute stereochemistry not yet specified)

[0503] Table 65: Detailed Conditions: ( It indicates any stereochemical designation for distinguishing the different isomers; the absolute stereochemistry is not determined and may be inconsistent with the described stereochemistry.

[0504] Step 22g of the program

[0505] At 0°C, NaOH (133.22 mg, 3.33 mmol, 5 equivalents) was added to a mixture of (22-4A) (0.44 g, 666.14 μmol, 1 equivalent) in MeOH (6.6 mL), THF (3 mL), and water (4.4 mL). The mixture was stirred at 70°C for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The suspension was filtered, and the filter cake was diluted with water (5 mL). 2) Wash and dry under vacuum to obtain the product. Grind the crude product with petroleum ether (20 mL, ethyl acetate = 1:1) at 25°C for 0.5 h. Filter the suspension and rinse the filter cake with petroleum ether (5 mL). 2) Wash and dry under vacuum to give (22e⁻¹) (0.25 g, 442.86 μmol, 66.48% yield). [M+H] + = 566.2. 1 H NMR (400 MHz, chloroform-d) δppm 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] TEA (80.66 mg, 797.15 μmol, 3 equivalents) was added to a mixture of (22e-1) (150 mg, 265.72 μmol, 1 equivalent) in DCM (5 mL). Cyclobutylformyl chloride (47.26 mg, 398.57 μmol, 1.5 equivalents) was then added to the mixture. The mixture was stirred at 25°C for 12 h. The mixture was concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 2:1, Rf = 0.40) to give (22e-2A) (100 mg, 154.65 μmol, 58.20% yield). [M+H] + = 648.2.

[0508] Procedure in step 22h-2

[0509] To a solution of (22e-1) (0.2 g, 354.29 μmol, 1 equivalent) and cyclobutane bromide (239.15 mg, 1.77 mmol, 5 equivalent) in DMF (4 mL), NaI (477.95 mg, 3.19 mmol, 9 equivalent) and K2CO3 (244.82 mg, 1.77 mmol, 5 equivalent) were added, and 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 then diluted with ethyl acetate (30 mL). 2) Extraction. The combined organic phases were rinsed with 50 mL of brine. 1) Wash, dry with anhydrous Na₂SO₄, filter, and concentrate under vacuum. Purify the residue 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 22h-3

[0511] HATU (141.45 mg, 372.00 μmol, 1.5 equivalents) was added to a solution of (22e-1) (140 mg, 248.00 μmol, 1 equivalent), 2-(trifluoromethoxy)acetic acid (35.72 mg, 248.00 μmol, 1 equivalent), and DIEA (96.16 mg, 744.01 μmol, 3 equivalents) in DMF (3 mL). The mixture was stirred at 70°C for 12 hours. The reaction mixture was quenched by adding water (20 mL), then diluted with ethyl acetate (20 mL), and further diluted with ethyl acetate (20 mL). 3) Extraction. The combined organic layers were washed with brine (90 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative 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 22h-4

[0513] TEA (161.33 mg, 1.59 mmol, 6 equivalents) was added to a mixture of (22e-1) (150 mg, 265.72 μmol, 1 equivalent) in DCM (2 mL). Then, methyl chloroformate (75.33 mg, 797.15 μmol, 3 equivalents) was added to the mixture at 0°C under N2. The mixture was stirred at 25°C for 2 h. The mixture was then added to water (100 mL). The aqueous phase was separated with ethyl acetate (30 mL). 3) Extraction. The combined organic phases were rinsed with 100 mL of brine. 3) Wash, dry with anhydrous Na₂SO₄, filter, and concentrate under vacuum. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 2:1, Rf = 0.5) to give (22e⁻²D) (120 mg, 192.76 μmol, 72.54% yield). [M+H] + = 624.1.

[0514] Procedure 22h-5

[0515] A solution of (22e-1) (0.3 g, 531.43 μmol, 1 equivalent) and 2,2,2-trifluoroacetaldehyde (641.15 mg, 4.25 mmol, 8 equivalents) in MeOH (6 mL) was stirred at 25°C for 30 min, followed by the addition of NaBH3CN (267.17 mg, 4.25 mmol, 8 equivalents) and CH3COOH (14.67 mg, 53.14 μmol, 0.1 equivalents), and the mixture was stirred at 25°C under N2 for 23.5 h. The mixture was concentrated under 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 in step 22i

[0517] To a solution of (22e-2B) (0.14 g, 226.32 μmol, 1 equivalent) in MeOH (1.4 mL), NaCNBH3 (42.67 mg, 678.95 μmol, 3 equivalents) and formaldehyde (110.20 mg, 1.36 mmol, 37% purity, 6 equivalents) were added. 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. 1 H NMR (400 MHz, methanol-d4) δ ppm 8.49 - 8.89 (m, 1H) 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 the TG18 series

[0519] Procedure of step 23a

[0520] Et3N (314.03 mg, 3.10 mmol, 2.5 equivalents) and Pd(dppf)Cl2 (90.83 mg, 124.14 μmol, 0.1 equivalents) were added to a solution of INT 2 (0.6 g, 1.24 mmol, 1 equivalent) in DMF (6 mL) and MeOH (3 mL). The mixture was stirred at 50°C under CO (15 Psi) for 12 h. The reaction mixture was poured into water (10 mL) and mixed with ethyl acetate (10 mL). 3) Extraction. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the 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. 1 H NMR (400 MHz, chloroform-d) δ ppm7.49 - 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, 3H) 1.50 - 1.55 (m, 3H) 1.49 (s, 9H).

[0521] Procedure in step 23b

[0522] Add LiOH·water (7.58 mg, 180.51 μmol, 1.5 equivalents) to a solution of (23-1) (50 mg, 120.34 μmol, 1 equivalent) in THF (1 mL), water (0.3 mL), and MeOH (0.2 mL). Stir the mixture at 25°C for 3 h. Dilute the reaction mixture with water (10 mL). Adjust the pH of the mixture to 2-3 with HCl (1 M) and with DCM (10 mL). 3) Extraction. 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). 1 H NMR (400 MHz, methanol-d4) δ ppm7.27 - 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] Step 23c procedure

[0524] To a solution of (23-2) (439.03 mg, 984.24 μmol, 1 equivalent) and cyclobutanamine (70 mg, 984.24 μmol, 1 equivalent) in DMF (5 mL), DIEA (445.22 mg, 3.44 mmol, 3.5 equivalent) and HATU (449.09 mg, 1.18 mmol, 1.2 equivalent) were added. The mixture was stirred at 25°C for 12 h. The reaction mixture was poured into water (80 mL) and mixed with ethyl acetate (30 mL). 3) Extraction. The combined organic layers were rinsed with 20 mL of brine. 2) Wash, dry with Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. Purify the residue 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. 1 H NMR (400MHz, 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, 1H) 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] Step 23d of the procedure

[0526] In an Ar-containing flask, Pd / C (30 mg, 10% purity) was added to a solution of (23-3) (0.1 g, 219.99 μmol, 1 equivalent) in EtOH (2 mL) and ethyl acetate (1 mL). NH3·water (61.68 mg, 439.99 μmol, 25% purity, 2 equivalents) was added to the mixture. The suspension was degassed under vacuum and purged three times with H2. The mixture was stirred at 25°C for 5 h under H2 (15 Psi). The suspension was filtered through a diatomaceous earth mat. The filter cake was treated with MeOH (10 mL). 3) Washing. The combined filtrates were concentrated to give (23-4) (0.2 g, 620.27 μmol, 74.20% yield). [M+H] += 323.2. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.66 (br d, J = 7.27 Hz, 1 H) 4.38 (br d, J = 7.99Hz, 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, 4H) 1.41 (s, 9H).

[0527] Procedure in step 23e

[0528] Add DIEA (91.19 mg, 705.55 μmol, 3.5 equivalents) and HATU (91.98 mg, 241.90 μmol, 1.2 equivalents) to a solution of (23-4) (65 mg, 201.59 μmol, 1 equivalent) and INT 3 (75.88 mg, 221.75 μmol, 1.1 equivalents) in DMF (1 mL). Stir the mixture at 25°C for 12 h. Pour the reaction mixture into water (10 mL) and thaw with ethyl acetate (10 mL). 3) Extraction. The combined organic layers were rinsed with 20 mL of brine. 2) Wash, dry with Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. Purify the residue 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. 1 H NMR (400MHz, 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 in step 23f TFA (432.03 mg, 3.79 mmol, 35 equivalents) was added to a solution of (23-5) (70 mg, 108.26 μmol, 1 equivalent) in DCM (0.7 mL). The mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give (TG18-01) (0.2 g, 335.31 μmol, 60.00% yield, 99% purity). [M+H] + = 592.2.

[0530] Step 23g of the program

[0531] The TG18 series (absolute stereochemistry not yet specified) was obtained by preparative SFC separation (TG18-01).

[0532] Table 66: Detailed Conditions: ( It indicates any stereochemical designation for distinguishing the different isomers; the absolute stereochemistry is not determined and may be inconsistent with the described stereochemistry.

[0533] Scheme 24. Synthesis of TG19-01

[0534] Procedure of step 24a

[0535] K₂CO₃ (263.62 mg, 1.91 mmol, 3 equivalents) was added to a mixture of (24-1) (200 mg, 635.80 μmol, 1 equivalent) and phenol (59.84 mg, 635.80 μmol, 1 equivalent) in DMF (4 mL). The mixture was stirred at 100°C for 12 h. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.62) to give (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 (brd, J = 7.63 Hz, 2 H) 4.11 (s, 3 H) 2.50 (s, 3 H).

[0536] Procedure in step 24b

[0537] LiOH·water (56.37 mg, 1.34 mmol, 5 equivalents) was added to a mixture of (24-2) (100 mg, 268.66 μmol, 1 equivalent) in water (2 mL), MeOH (2 mL), and THF (2 mL). The mixture was stirred at 30°C for 12 h. The mixture was concentrated under vacuum to give (24-3) (80 mg, crude). [M+H] + = 360.1. 1 H 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] Step 24c procedure

[0539] DIEA (86.60 mg, 670.04 μmol, 3 equivalents) was added to a mixture of (24-3) (80 mg, 223.35 μmol, 1 equivalent) and (7-3I) (94.20 mg, 245.68 μmol, 1.1 equivalents) in DMF (2 mL). Then HATU (127.39 mg, 335.02 μmol, 1.5 equivalents) was added to the mixture. The mixture was stirred at 25°C for 12 h. The mixture was then added to water (50 mL). The aqueous phase was diluted with ethyl acetate (20 mL). 3) Extraction. The combined organic phases were rinsed with 20 mL of brine. 2) Wash, dry with anhydrous Na₂SO₄, filter, and concentrate under vacuum. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.35) to give (24-4) (80 mg, 110.56 μmol, 49.50% yield). [M+H] + =725.2. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.54 - 7.58 (m, 1 H) 7.47 - 7.53 (m, 2H) 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 in step 24d

[0541] TFA (6.16 g, 54.02 mmol, 488.63 equivalents) was added to a mixture of (24-4) (80 mg, 110.56 μmol, 1 equivalent) in DCM (2.5 mL). The mixture was stirred at 25°C for 1 h. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC to give (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 the TG20 series

[0543] Procedure of step 25a

[0544] Compound (25-1) is prepared from compound (14-2B) and INT 9 or INT 11 in a manner similar to that described in step 14c-2 of scheme 14.

[0545] Procedure in step 25b

[0546] TG20-01 and TG20-02 were prepared from compound (25-1) in a manner similar to that described in step 14d of scheme 14.

[0547] Scheme 26. Synthesis of the TG21 series

[0548] Procedure of step 26a

[0549] Compound (26-1) is prepared from compound (11-2) and INT 9 or INT 11 in a manner similar to that described in step 19d-1 of scheme 19.

[0550] Procedure in step 26b

[0551] Compound (26-2) is prepared from compound (26-1) in a manner similar to that described in step 19e of scheme 19.

[0552] Step 26c procedure

[0553] TG21-01 and TG21-02 were prepared from compound (26-2) and INT 19f in a manner similar to that described in step 19f of scheme 19.

[0554] Scheme 27. Synthesis of the TG22 series

[0555] Procedure of step 27a

[0556] Compound (27-1) is prepared by reacting compound (7-3I) with INT 10 or INT 12 and triethylamine (TEA) in dichloromethane (DCM).

[0557] Procedure of step 27b

[0558] TG22-01 and TG22-02 were prepared from compound (27-1) in a manner similar to that described in step 20b of scheme 20.

[0559] Table 67: Purification Methods Column information for preparative HPLC and SFC

[0560] Table 68: Purification Conditions

[0561] Bioactivity assay

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

[0563] The activity of the compound as an FP antagonist was tested in a human embryonic kidney (HEK-EBNA; 293 c18: ATCC, CRL-10852) cell line stably expressing the human FP receptor clone. The FP receptor couples to the Gq pathway, inducing phospholipase C (PLC) activation and triggering the inositol phosphate (IP) cascade. PLC then cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3), resulting in a transient increase in intracellular calcium. IP3 has a short lifetime (less than 30 seconds) before being converted to inositol diphosphate (IP2) and then to IP1. IP1 accumulates in cells and is stable in the presence of LiCl in StimB buffer.

[0564] This method is a competitive immunoassay between naturally occurring IP1 produced by cells and d2-labeled IP1. A specific signal (energy transfer) is inversely proportional to the concentration of IP1 in the standard or sample. This is measured using the following: a second messenger accumulation assay kit based on Cisbio IP-One cells; a competitive immunoassay using d2-labeled IP1 (receptor) and an anti-IP1-caecil compound antibody (donor).

[0565] The following steps were performed on the day of the experiment. Cells were removed from the culture flasks using trypsin buffer and harvested into 1X StimB. The compound solutions used for concentration-response analysis of the antagonist and reference antagonist were added to an HTRF 384-well white microplate (15 nL of 1000x solution), followed by seeding at a density of 10,000 cells / well in 10 µL; incubated at 37°C in a humidified atmosphere of 5% CO2 for 30 min. Next, the agonist concentration-response curve or agonist compound solution (5 µL of 3x solution) was sequentially added to the appropriate wells of the 384-well microplate and incubated at 37°C in a humidified atmosphere of 5% CO2 for 60 min. In a separate HTRF 384-well white microplate, 15 µL of the IP1 standard curve was added to the designated wells of the IP1 standard curve plate.

[0566] The HTRF reagents were reconstituted with distilled water according to the kit instructions. The detection reagents (IP1-d2 and anti-IP1 cavity compound) were then added to the designated wells of both the assay plate and the standard curve plate, and incubated in the dark at room temperature for 1 hour. Reference agonists and reference antagonists were run on each assay plate, and a standard curve was run on a separate assay plate for each experimental day. HTRF signals were measured using a Pherastar plate reader, with the default HTRF emission settings at 337 nm, 665 nm, and 620 nm.

[0567] The ratios of time-resolved fluorescence readouts (RFUs) per well at 337 nm / 665 nm and 337 nm / 620 nm were calculated and multiplied by 10,000 to obtain integers for data analysis. For the IP standard curve, the ratios... 10,000 is plotted on the y-axis, while the x-axis represents the logarithmic scale of IP1 concentration. The curve fitting model (Model 205) is a single-binding-site, four-parameter concentration-response model: (MIN+((MAX-MIN) / (1+((IC))) 50 Using this model, nonlinear regression analysis was performed to generate concentration response curves for the standards. The expected IP1 standard curve IC1 after 1 hour of incubation at room temperature was then calculated. 50 100-200 nM. IC 50 The IP1 concentration at which the surrogate tracer binds to a maximum of 50% is calculated for regression analysis, and Hill represents the slope of the calculated regression curve at the inflection point. If the raw data fall within the linear range of the standard curve, the ratio of the IP1 standard curve to each raw data point relative to each test compound is used. IP1 concentration is inferred from 10,000 data points. The linear range of the standard curve (typically 10 to 1,000 nM) is based on R. 2 The widest point set with a value greater than 0.97 was used for calculation. For antagonist reference and test compounds, the logarithm of the inferred IP1 concentration from three test wells was taken as the average, and a nonlinear regression analysis was performed using a curve fitting model to generate the concentration response curve and IC1. 50 K is calculated using the Leff-Dougall equation. B (Equilibrium dissociation constant of antagonist-receptor complex). Wherein, [Agonist] is the concentration of the reference agonist used in the antagonist test protocol; agonist EC50 is the concentration of the reference agonist that produces the 50% maximum probable effect when tested as a concentration-response in the agonist test protocol; and Hill is the absolute value of the Hill coefficient / slope function of the reference agonist when tested as a concentration-response in the agonist test protocol. Note that agonist EC... 50 The agonist Hill value is derived from parallel tests (on the same test plate) of the reference agonist and the test antagonist compound.

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

[0569] The EP4 antagonist activity of the compounds was tested in DLD-1 cells (ATCC, CCL-221) derived from the human colon transiently expressing the human EP4 receptor. Cells were exposed to different concentrations of the test compounds, followed by exposure to a submaximal concentration of the EP4-selective agonist (TCS2510). The inhibitory effect of the antagonists on cAMP accumulation was then assessed. cAMP accumulation was measured using a competitive cAMP immunoassay based on HTRF (homogeneous time-resolved fluorescence) using the cAMP-Gs Dynamic Kit (Cisbio). This was performed using the following: a second messenger accumulation assay kit based on the Cisbio IP-One cells; a competitive immunoassay using d2-labeled cAMP and europium cavitation compound-labeled anti-cAMP antibody.

[0570] According to the table below, 1 x 10 7 One DLD-1 cell was placed in a T75 flask containing 10 ml of growth medium and transfected with the EP4 construct one day before the assay.

[0571] The tubes were incubated at room temperature for 15 minutes. The contents of tube 2 were then added to tube 1 and incubated for another 15 minutes. The combined contents of tube 1 were added to a T75 transfection flask containing DLD-1 cells and incubated overnight at 37°C in a humidified atmosphere with 5% CO2. On the day of assay, cells were dissociated from the flasks with trypsin and harvested for addition to assay plates (10,000 cells / well, in cAMP stimulation buffer supplemented with 500 μM IBMX). The compound solutions used for concentration-response analysis of the antagonist and reference antagonist were added to an HTRF 384-well white small-volume assay plate (10 nL of 1000x solution); 10 nL of agonist 1000X stock solution; and then seeded at a density of 10,000 cells / well in 10 µL; and incubated at 37°C in a humidified atmosphere with 5% CO2 for 90 minutes.

[0572] The assay reagents (cAMP-d2 and anti-cAMP cavitation compounds) were then added to the designated wells of both the assay plate and the standard curve plate, and incubated in the dark at room temperature for 1 hour. Note that a reference agonist and a reference antagonist were run on each assay plate, and a standard curve was run on a separate assay plate for each experimental day. HTRF signals were measured using a Pherastar plate reader, with the default HTRF emission settings at 337 nm, 665 nm, and 620 nm. Data analysis and IC were performed as described above for the FP assay. 50 and K B calculate.

[0573] Data from the FP and EP4 receptor assays are shown in the tables below: the first compares the selectivity of a number of exemplary compounds with that of the control compound REF27, and the second compares the selectivity of a number of exemplary compounds with that of the control compound REF10. The selectivity ratio of hFP to hEP4 is calculated as hEP4 K. b / hFP K b Comparative compounds (REF27 and REF10) were disclosed in J. Med. Chem. [Journal of Medicinal Chemistry] 2020, 63, 11639-11662. (REF27) Unfitted: The curve may not fit due to lack of activity. Selectivity: when hEP4 K b When the value is listed as >3000 or "unfitted", hEP4 K cannot be calculated due to the lack of hEP4 activity. b / hFP K b . (REF10) Unfitted: The curve may not fit due to lack of activity. Selectivity: when hEP4 K b When the value is listed as >3000 or "unfitted", hEP4 K cannot be calculated due to the lack of hEP4 activity. b / hFP K b .

[0574] Mouse parturition model

[0575] The ability of the disclosed compounds to delay parturition was tested in a mouse parturition assay. Primiparous mice were received on day 11 of gestation (GD11); mice were acclimatized to laboratory conditions for at least 3 days prior to the start of the experiment. Animals were housed in groups of 3–5 in polysulfone Sealsafe plus GM500 cages on a wood shavings bed with free access to food and water. Treatment with the disclosed compounds was initiated from GD16 (evening), administered twice daily (morning and evening) for a total of 8 times until GD20 (morning). At GD16, immediately after the first treatment, mice were housed individually with free access to food and water. No enrichment was added; food was placed directly into the cages. Mice were continuously monitored using an infrared camera and digital video recording equipment to capture the time of parturition. In addition to video recording, the cages were visually inspected morning and evening during the treatment period for the presence of pups or signs of parturition. The following data were collected: maternal viability; maternal weight (in grams daily from GD16); time of parturition, defined as the time when the first pup was delivered; percentage of mice delivered on each gestation day; and gestation duration in days. Mice showed a positive response to treatment.

[0576] Rat intrauterine pressure (IUP) model

[0577] The method disclosed herein for in vivo testing of the FP antagonist to inhibit PGF2α-induced intrauterine pressure (IUP) elevation in rats is adapted from a modified version of Cirillo et al., Am. J. Obstet. Gynecol. [American Journal of Obstetrics and Gynecology] (2007), 197(1):54.e1-9. In short, these studies used non-pregnant Sprague Dawley rats with vendor-placed vascular catheters (carotid artery catheter (CAC), jugular vein catheter (JVC), and femoral vein catheter (FVC)). On the day of the experiment, rats were placed under terminal anesthesia, and a fluid-filled catheter was inserted into the uterine horn of each animal to measure IUP. PGF2α was administered via intravenous (IV) infusion over 5 minutes, with 5 stimulations at 30-minute intervals. The compound disclosed herein was administered via IV infusion over FVC, starting 5 minutes before the fourth PGF2α stimulation and during the fourth PGF2α stimulation. Thus, the compound was infused IV over a total of 10 minutes. The inhibitory effect on PGF2α-induced IUP increase was determined by comparing the change in IUP induced during the fourth provocation relative to the third provocation, measured in the same animal and expressed as a percentage. Mean arterial pressure (via CAC) and IUP were measured sequentially, and data were acquired using Notocord-hem software. Rats showed a positive response to treatment.

[0578] A silica-induced mouse model of pulmonary fibrosis

[0579] The in vivo efficacy of the disclosed compounds was evaluated using a silica-induced fibrosis mouse model (10 days). The methods described in Beck et al., J. Med. Chem. [Journal of Medicinal Chemistry] 2020, 63, 20, 11639-11662 (Supporting Information) were employed. The mouse model showed a positive response to treatment.

[0580] Clinical trial in female subjects: Endometriosis-related pain

[0581] The disclosed compound was administered to female subjects suffering from endometriosis-related pain. The subjects' responses to the compound were assessed using the Visual Analogue Scale (VAS). The subjects demonstrated a positive clinical response to the treatment.

[0582] Clinical trial on female subjects: dysmenorrhea

[0583] The disclosed compound was administered to female subjects suffering from dysmenorrhea. The subjects' responses to the compound administration were assessed using the Visual Analogue Scale (VAS). The subjects showed a positive clinical response to the treatment.

[0584] Clinical trial with female subjects: Premature birth

[0585] The disclosed compounds were administered to female subjects with intact membranes (e.g., unruptured amniotic sac) and who were at risk of or in the process of preterm labor. Subjects were evaluated by complete blood count (CBC), bleeding profile, renal function tests, liver function tests, and ultrasound. Subjects showed a positive clinical response to treatment.

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

[0587] The disclosed compounds were administered to subjects with idiopathic pulmonary fibrosis. Subjects' response to the compounds was assessed by changes in forced vital capacity (FVC) relative to baseline at week 24. Subjects showed a positive clinical response to treatment.

[0588] While certain embodiments have been described and illustrated, it should be understood that changes and modifications may be made therein by those skilled in the art without departing from the broader aspects of the technology disclosed herein.

Claims

1. A compound of Formula I: (Formula I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: A 1 is CR, wherein R is hydrogen, halogen, C 1-3 alkyl or cyclopropyl; R 1 is halogen, C 1-6 alkyl or C 1-6 haloalkyl; R 2 is phenyl; C 3-6 cycloalkyl; 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenoxy; or C 1-6 alkoxy; wherein the phenyl, C 3-6 cycloalkyl, and 3- to 8-membered heterocycloalkyl are optionally substituted with one to four R 1-6 substituents independently selected from halogen, C 1-6 alkyl, C 2A alkoxy, and oxo, or two R 2A together with the atom or atoms 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; K is , , , or ; R 3A is C 3-6 cycloalkyl or R 3B ; W is a bond, -NH-, or -O-; and R 3B is (a) phenyl optionally substituted with one to four substituents independently selected from the group consisting of halogen, -CN, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; or -W-R 3B is -NR 3C R 3D , -NHC(O)-O(C 1-6 alkyl), -NHC(O)R 3D or -C(O)NR 3C R 3D ; wherein R 3C is H or C 1-3 1-6 alkyl, and R 3D is C 1-6 1-6 haloalkyl or C 3-4 1-6 cycloalkyl; or wherein R 3C and R 3D together with the nitrogen atom to which they are attached form a 3- to 6-membered ring; R 4A is H; R 4B is H, C 1-3 alkyl or -OH; and R 4B’ is H or C 1-3 alkyl; or R 4A and R 4B together with the carbon atom to which they are attached form an oxirane; R 5 is optionally substituted with C 3-4 cycloalkyl; C 1-6 alkyl; C 1-6 haloalkyl; optionally substituted with one or two substituents independently selected from -OH, halogen, C 1-6 alkyl, C 3-4 cycloalkyl, and C 1-6 haloalkoxy; C 4-5 cycloalkyl, or two substituents together with the carbon atom to which they are attached form a C 3-4 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)(C 1-6 alkyl), and -SO2(C 1-6 alkyl); or phenyl optionally substituted with one or two substituents independently selected from halogen and C 1-6 haloalkoxy; and R 6 is H or C 1-6 alkyl; wherein 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced by one or more deuterium atoms.

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

3. The compound of claim 1 or claim 2, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R is C 1-3 alkyl.

4. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt 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 is 、 、 or .

6. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt of claim 1, having Formula la: (Formula Ia).

7. The compound of claim 6, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3A is R 3B .

8. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 6 or claim 7, wherein R 3A is phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

9. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 6-8, wherein R 3A is phenyl optionally substituted with one to four substituents independently selected from halogen and C 1-6 alkoxy.

10. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 6-9, wherein R 3A is , , , or .

11. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 6 or claim 7, wherein R 3A 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

12. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 6, 7, or 11, wherein R 3A 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, C 1-6 alkyl, and C 1-6 alkoxy.

13. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 6, 7, 11, or 12, wherein R 3A is pyrazolyl optionally substituted with one or two substituents independently selected from C 1-6 alkyl.

14. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 6, 7, 11, or 12, wherein R 3A is pyridyl, pyrazinyl, pyridazinyl, or 2-pyridinonyl, wherein the pyridyl, pyrazinyl, pyridazinyl, or 2-pyridinonyl is optionally substituted with one or two substituents independently selected from halogen, -OH, C 1-6 alkyl, and C 1-6 alkoxy.

15. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 11 or claim 12, wherein R 3A is , , , , , , , or .

16. The compound of claim 6, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3A is C 3-6 ycloalkyl.

17. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 16, wherein R 3A is .

18. The compound of claim 6, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3A is , , , , , , , , , , , , or .

19. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt of claim 1, having Formula lb: (Formula Ib).

20. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 19, wherein R 3B is phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

21. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 19 or claim 20, wherein R 3B is phenyl optionally substituted with one or two substituents independently selected from halogen and C 1-6 haloalkoxy.

22. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 19-21, wherein R 3B is , or .

23. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 19, wherein R 3B 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

24. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt of any one of claims 19-23, wherein W is a bond.

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

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

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

28. The compound of claim 27, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A is H and R 4B is H.

29. The compound of claim 27, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A is H and R 4B is -OH.

30. The compound of claim 27, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A and R 4B together with the carbon atom 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 R 3B is phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

32. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 31, wherein R 3B is , , , , , , , , , , , , , , , , , or .

33. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 27-30, wherein R 3B is 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

34. The compound of claim 33, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the 5- to 10-membered heteroaryl is pyrazolyl, indazolyl, pyridyl, 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

35. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 33 or claim 34, wherein R 3B is , , , or .

36. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 27-30, wherein R 3B is , , , , , , , , , , , , , , , , , , , , , or .

37. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt of any one of claims 27-36, wherein W is a bond.

38. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt of any one of claims 27-36, wherein W is -O-.

39. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt of any one of claims 27-36, wherein W is -NH-.

40. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 27 or claim 28, wherein -W-R 3B is -NR 3C R 3D , -NHC(O)-O(C 1-6 alkyl), -NHC(O)R 3D , or -C(O)NR 3C R 3D ; wherein R 3C is H or C 1-3 alkyl, and R 3D is C 1-6 haloalkyl or C 3-4 cycloalkyl; or wherein R 3C and R 3D 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 claim 40, wherein -W-R 3B is , , , , or .

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

43. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42, wherein R 3B is phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

44. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42 or claim 43, wherein R 3B is , , , , , , , , , , , , , , , , , , , , , , , , , or .

45. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42, wherein R 3B is 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

46. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42 or claim 45, wherein R 3B 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, C 1-6 alkyl, and C 1-6 haloalkoxy.

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 C 1-6 alkyl and C 1-6 haloalkoxy.

48. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42, 45, 46, or 47, wherein R 3B is or .

49. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42, wherein R 3B is , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

50. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt of any one of claims 42-49, wherein W is a bond.

51. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt 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 R 4B is H.

53. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-51, wherein R 4B is methyl.

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

55. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 54, wherein R 4B and R 4B’ are both H.

56. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 54, wherein R 4B is methyl, and R 4B’ is H.

57. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 54-56, wherein R 5 is C 3-4 cycloalkyl optionally substituted with C 1-6 haloalkyl or C 1-6 alkyl.

58. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 57, wherein R 5 is , , , , , or .

59. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt as described in any one of claims 54-56, wherein R 5 It is optionally and independently selected from -OH, halogen, C 1-6 Alkyl, C 3-4 cycloalkyl and C 1-6 The C-axis of the haloalkoxy group is substituted by one or both of its substituents. 4-5 Cycloalkyl groups, or two substituents together with the carbon atoms to which they are attached, form a C12 group. 3-4 Cycloalkyl rings.

60. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 59, wherein R 5 is , , , , , , , , or .

61. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 54-56, wherein R 5 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)(C 1-6 alkyl), and -SO2(C 1-6 alkyl).

62. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 61, wherein R 5 is , or .

63. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 54-56, wherein R 5 is phenyl optionally substituted with one or two substituents independently selected from halogen and C 1-6 haloalkoxy.

64. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 63, wherein R 5 is , or .

65. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 54-56, wherein R 5 is , , , , , , , , , , , , , , , , , , , , , .

66. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-65, wherein R 1 is halogen.

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

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

69. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 68, wherein R 1 is ethyl or -CHF2.

70. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, of any one of claims 1-69, wherein R 2 is phenyl, wherein R 2 is optionally substituted with one to four R 1-6 independently selected from halogen, C 1-6 alkyl, and C 2A alkoxy.

71. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 70, wherein R 2 is , or .

72. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 71, wherein R 2 is phenyl.

73. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-69, wherein R 2 is C 3-6 cycloalkyl or 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R 2 is optionally substituted with one to four R 1-6 selected from halogen, C 1-6 alkyl, C 2A alkoxy, and oxo, or two R 2A 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.

74. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 73, wherein R 2 is , , , , , , , , , , or .

75. The compound of any one of claims 1-69, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is phenoxy or C 1-6 alkoxy.

76. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 75, wherein R 2 is or .

77. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-76, wherein R 6 is H.

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

79. A compound selected from Table A, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

80. A pharmaceutical composition comprising a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt 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 a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt of any one of claims 1-79.

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

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

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

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

86. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-79, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, nonspecific interstitial pneumonia, lymphoid interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, cryptogenic organizing pneumonia, desquamative interstitial pneumonia, and unclassifiable idiopathic interstitial pneumonia, granulitic interstitial lung disease, known etiology interstitial lung disease and other unclassifiable interstitial lung disease, 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), emphysema, cystic fibrosis (CF), kidney inflammatory and fibrotic disorders, IBD, Crohn’s disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorder, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, drug- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer’s lung and related disorders, chronic inflammatory cough, iatrogenic cough, drug-related rhinitis, vasomotor rhinitis, and seasonal allergic rhinitis, polyp inflammation, hypertension (hypertensive disease), heart failure, coronary heart disease, stable and unstable angina, renal hypertension, peripheral and cardiovascular disorders, arrhythmia, atrial and ventricular dysrhythmias, first- third-degree atrioventricular block, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, torsades de pointes, atrial and ventricular premature contractions, preexcitation of atrioventricular junction, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvulitis, aortitis, cardiomyopathy, aneurysm, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient ischemic attack, preeclampsia, inflammatory cardiovascular disorders, coronary and peripheral arterial spasm, pulmonary edema, cerebral edema, renal edema, or edema resulting from heart failure, peripheral circulation disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial ischemia, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, dialysis hypotension, obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, primary nephropathy, congenital nephropathy, nephritis,kidney disorders caused by immune complex, kidney diseases caused by toxic substances, kidney diseases caused by contrast agents, diabetic and non-diabetic nephropathies, pyelonephritis, kidney cysts, kidney fibrosis, hypertensive kidney fibrosis, nephrotic syndrome, benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (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 fibroids, endometriosis, dysmenorrhea, premature labor, hirsutism, polycystic ovary syndrome, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemia, liposarcoma, gastrointestinal cancer, liver cancer, pancreatic cancer, lung cancer, kidney cancer, ureter cancer, prostate cancer and reproductive tract cancer, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy and depression, 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 to the subject an additional therapeutic agent.

88. The method of claim 87, wherein the additional therapeutic agent is selected from the group consisting of atosiban, retosiban, barusiban, epelasiban, nolasiban, terbutaline, ritodrine, hexoprenaline, abu torol, fenoterol, butoxamine, orciprenaline, dihydropyridine, nifedipine, nicardipine, magnesium sulfate, progesterone, 17-alpha-hydroxyprogesterone, and nitroglycerin.

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

90. A compound of any one of claims 1-79, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in modulating prostaglandin F (FP) receptor activity in a subject in need thereof.

91. A compound of any one of claims 1-79, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in treating preterm labor or reducing the risk of preterm labor in a subject in need thereof.

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

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

94. The compound, stereoisomer, 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. The compound, stereoisomer, 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, nonspecific interstitial pneumonia, lymphoid interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, cryptogenic organizing pneumonia, desquamative interstitial pneumonia, and unclassifiable idiopathic interstitial pneumonia, granulitic interstitial lung disease, known etiology interstitial lung disease and other interstitial lung disease 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), emphysema, cystic fibrosis (CF), kidney inflammatory and fibrotic disorders, IBD, Crohn’s disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorder, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, drug- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonitis, farmer’s lung and related disorders, chronic inflammatory cough, iatrogenic cough, drug-related rhinitis, vasomotor rhinitis, and seasonal allergic rhinitis, inflammation of polyps, hypertension (hypertensive disease), heart failure, coronary heart disease, stable and unstable angina, renal hypertension, peripheral and cardiovascular disorders, arrhythmia, atrial and ventricular dysrhythmias, first- third degree atrioventricular block, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, torsades de pointes, atrial and ventricular extrasystoles, junctional extrasystoles, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvulitis, aortitis, cardiomyopathy, aneurysm, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient ischemic attack, preeclampsia, inflammatory cardiovascular disorders, coronary and peripheral arterial spasm, pulmonary edema, cerebral edema, renal edema, or edema resulting from heart failure, peripheral circulation disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial ischemia, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, dialysis hypotension, obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, primary nephropathy, congenital nephropathy, nephritis, kidney transplant rejection, or immune complex-induced kidney disorders, nephropathy induced by toxic substances,contrast-induced nephropathy, diabetes and non-diabetic nephropathy, pyelonephritis, kidney cysts, kidney fibrosis, hypertensive renal fibrosis, nephrotic syndrome, benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract symptoms (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 fibroids, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemia, liposarcoma, gastrointestinal cancer, liver cancer, pancreatic cancer, lung cancer, kidney cancer, ureter cancer, prostate cancer and reproductive tract cancer, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depression, 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 pharmaceutically acceptable salt thereof of any one of claims 1-79 in the manufacture of a medicament for modulating prostaglandin F (FP) receptor activity in a subject in need thereof.

97. Use of a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79 in the manufacture of a medicament for treating or reducing the risk of preterm labor in a subject in need thereof.

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

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

100. Use of a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79 in the manufacture 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 of any one of claims 1-79, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture 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, nonspecific interstitial pneumonia, lymphoid interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, cryptogenic organizing pneumonia, desquamative interstitial pneumonia, and unclassifiable idiopathic interstitial pneumonia, granulomatous interstitial lung disease, known etiology interstitial lung disease and other interstitial lung disease of uncertain 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), emphysema, cystic fibrosis (CF), kidney inflammatory and fibrotic disorders, IBD, Crohn’s disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorder, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, drug- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonitis, farmer’s lung and related disorders, chronic inflammatory cough, iatrogenic cough, drug-related rhinitis, vasomotor rhinitis, and seasonal allergic rhinitis, inflammation of polyps, hypertension (hypertensive disease), heart failure, coronary heart disease, stable and unstable angina, renal hypertension, peripheral and cardiovascular disorders, arrhythmia, atrial and ventricular dysrhythmias, first- third degree atrioventricular block, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, torsades de pointes, atrial and ventricular extrasystoles, junctional extrasystoles, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvulitis, aortitis, cardiomyopathy, aneurysm, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient ischemic attack, preeclampsia, inflammatory cardiovascular disorders, coronary and peripheral arterial spasm, pulmonary edema, cerebral edema, renal edema, or edema resulting from heart failure, peripheral circulation disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial ischemia, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, dialysis hypotension, obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, primary renal disease, congenital renal disease, nephritis, renal transplant rejection, or immune complex-induced renal disorders,nephropathy, contrast media-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, kidney cysts, kidney fibrosis, hypertensive renal fibrosis, nephrotic syndrome, benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract symptoms (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 fibroids, endometriosis, dysmenorrhea, premature labor, hirsutism, polycythemia, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemia, liposarcoma, gastrointestinal cancer, liver cancer, pancreatic cancer, lung cancer, kidney cancer, ureter cancer, prostate cancer and reproductive tract cancer, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depression, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

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