Small molecule prostaglandin f receptor antagonists

Abstract

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

Description

[0001] SMALL MOLECULE PROSTAGLANDIN F RECEPTOR ANTAGONISTS

[0002] FIELD

[0003] The present disclosure is in the field of pharmaceutical compounds and compositions and therapeutic methods of their use. In particular, the present disclosure is in the field of prostaglandin F (FP) receptor antagonists and their use.

[0004] BACKGROUND

[0005] Prostaglandins are bioactive metabolites of arachidonic acid, which are principally involved in mediation of inflammation. Arachidonic acid is released from lipids in the cell membrane through the actions of phospholipases; the arachidonic acid is then metabolized by cyclooxygenase and various isomerases and prostaglandin synthases to form the different prostaglandins. The most predominant and biologically relevant prostaglandins are PGE2, PGL, PGD2, PGF2a and TXA2.

[0006] Prostaglandin receptors are members of the seven transmembrane superfamily of G-protein coupled receptors (GPCR). The prostanoid receptor subfamily is comprised of at least eight members: EPl, EP2, EP3, and EP4 subtypes of the PGE receptor; DPI; FP; IP; and TP. The receptors are generally named for the prostaglandin that has the highest potency at the receptor; however, the receptors may effectively bind more than one prostaglandin. The FP receptor may be considered the least selective of the prostanoid receptors in binding the principal endogenous prostaglandins; in addition to PGF2a, both PGD2and PGE2activate the FP with EC50 values in the nanomolar range.

[0007] PGF2a and the FP receptor are associated with various diseases, conditions, and inflammatory disorders. During reproduction, PGF2a, derived mainly from COX-1 in the female reproductive system, plays an important role in ovulation, luteolysis, contraction of uterine smooth muscle and initiation of parturition. PGF2ahas also been shown to play a significant role in renal function, contraction of arteries, myocardial dysfunction, brain injury and pain. The tachycardia induced in wild-type mice by injection of LPS is greatly attenuated in FP-deficient mice (or TP-deficient mice) and is completely absent in mice lacking both of these receptors. Deletion of FP has been reported to selectively attenuate pulmonary fibrosis without a change in lung inflammation. Another study of FP-deficient female mice reported normal ovulation and implantation but failure of spontaneous parturition during pregnancy. Elevated biosynthesis of PGF2ahas been reported in patients suffering from rheumatoid arthritis, psoriatic arthritis, reactive arthritis, and osteoarthritis. Targeting FP may be an effective therapeutic strategy for many conditions; to date, no specific FP modulators have been approved for therapeutic use.

[0008] There remains a need for small molecule prostaglandin F (FP) receptor modulators that selectively antagonize the FP receptor.

[0009] Once a suitable small molecule prostaglandin F (FP) receptor modulator has been identified there can be further challenges associated with the manufacture and formulation of such compounds. By way of example, the presence of solvates, poor stability, and / or poor solubility can cause issues during later drug development. Thus, there remains a need for small molecule prostaglandin F (FP) receptor modulators that additionally exhibit beneficial physical properties, e.g. to assist in the manufacture, formulation and / or ease of administration of such modulators.

[0010] The present invention addresses one or more of these needs.

[0011] SUMMARY

[0012] The present invention is based on the inventors having found that particular salts of particular prostaglandin F (FP) receptor antagonists exhibit unexpectedly advantageous physical properties for drug formulation, including a low propensity to form solvates, a high degree of crystallinity, a high solubility (e.g. in biologically relevant solvents) and / or a high stability. Tromethamine or lysine salts, in particular, of specific prostaglandin F (FP) receptor antagonists have demonstrated unexpectedly advantageous physical properties. By way of example only, the tromethamine and lysine salts as described herein may be particularly useful as they unexpectedly exhibit a low propensity to form solvates and provide good levels of solubility (e.g. in simulated biological solvents).

[0013] Accordingly, in one aspect, provided herein is a tromethamine or lysine salt of a compound of Formula la: (Formula la) or a stereoisomer, or tautomer thereof, wherein:

[0014] R1is halogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0015] R2is phenyl; C3-6 cycloalkyl; 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenoxy; or C1-6 alkoxy; wherein the phenyl, C3-6 cycloalkyl, and 3- to 8-membered heterocycloalkyl are optionally substituted with one to four R2Aindependently selected from halogen, C1-6 alkyl, C1-6 alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3 - to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen;

[0016] R4Bis H, C1-3 alkyl, or -OH; and R4Bis H or C1-3 alkyl;

[0017] R5is C1-6 alkyl optionally substituted with C3-4 cycloalkyl; C1-6 haloalkyl; C4-5 cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, Ci- 6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4 cycloalkyl ring; 4- to 5 -membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 4- to 5 -membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from -C(O)(benzyl), -C(O)(Ci-6 alkyl), and -SO2(Ci-6 alkyl); or phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6 haloalkoxy; and

[0018] R6is H or Ci -6 alkyl; wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).

[0019] In some embodiments, R4Band R4Bare both H. In some embodiments, R4Bis methyl, and R4Bis H. In some embodiments, R5is C1-6 haloalkyl or C1-6 alkyl optionally substituted with C3-4 cycloalkyl. In some embodiments, R5is . In some embodiments, R5is C4-5 cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, Ci-6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4 cycloalkyl ring. In some embodiments, R5is some embodiments, R5is 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)(Ci-6 alkyl), and -SO2(Ci-6 alkyl). In some embodiments, R5is substituted with one or two substituents independently selected from halogen and C1-6 haloalkoxy.

[0020] In some embodiments, R5is In some embodiments, R5

[0021]

[0022] . In some embodiments, R1is halogen. In some embodiments, R1is Br. In some embodiments, R1is Ci-6 alkyl, or Ci-6 haloalkyl. In some embodiments, R1is ethyl or -CHF2. In some embodiments, R2is phenyl, wherein R2is optionally substituted with one to four R2Aindependently selected from halogen, Ci-6 alkyl, and Ci-6 alkoxy. In some embodiments, R2is In some embodiments, R2is phenyl. In some embodiments, R2is C3-6 cycloalkyl or 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R2is optionally substituted with one to four R2Aindependently selected from halogen, Ci-6 alkyl, Ci-6 alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3 - to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen. embodiments, R2is phenoxy or Ci-6 alkoxy. In some embodiments, R2is

[0023] In some embodiments, R6is H. In some embodiments, R6is Ci-6 alkyl.

[0024] In some embodiments, the compound is selected from Table A, or a stereoisomer, or tautomer thereof. In another aspect, provided herein are hydrates, solvates, analogs, conjugates, isomers, polymorphs, esters, prodrugs, metabolites, complexes, co-crystals, intermediates, modifications and derivatives of the compounds, stereoisomers, and tautomers described herein.

[0025] Viewed from another aspect, the invention provides a crystalline form of a tromethamine salt of a compound of structure:

[0026] In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20 ± 0.2 of:

[0027] 8.4 and 14.0; and optionally a further peak at 19.7; as measured by X-ray powder diffraction using a Cu K a source.

[0028] In some embodiments, the crystalline form is obtainable by crystallising in any one or a mixture of ethanol, acetonitrile, dimethylacetamide and methyl isobutyl ketone.

[0029] Viewed from another aspect, the invention provides a crystalline form of a tromethamine salt of a compound of structure:

[0030]

[0031] In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20 ± 0.2 of:

[0032] 9.0 and 20.2; and optionally a further peak at 14.9; as measured by X-ray powder diffraction using a Cu K a source.

[0033] In some embodiments, the crystalline form is obtainable by crystallising in any one or a mixture of tetrahydrofuran, dimethyl formamide, dimethylacetamide and 1,4-dioxane.

[0034] Viewed from another aspect, the invention provides a crystalline form of a lysine salt of a compound of structure:

[0035] In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20 ± 0.2 of:

[0036] 4.2 and 4.8; and optionally a further peak at 18.8; as measured by X-ray powder diffraction using a Cu K a source.

[0037] In some embodiments, the crystalline form is obtainable by crystallising in ethanol.

[0038] Viewed from another aspect, there is provided a method of crystallising a tromethamine salt of a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of ethanol, acetonitrile, dimethylacetamide and methyl isobutyl ketone, allowing the salt to re-precipitate and isolating the resultant precipitate. In some embodiments, the method may comprise allowing the salt to crystallise and isolating the resultant crystalline form.

[0039] Viewed from a further aspect, there is provided a method of crystallising a tromethamine salt of a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of tetrahydrofuran, dimethyl formamide, dimethylacetamide and 1,4-di oxane, allowing the salt to re-precipitate and isolating the resultant precipitate.

[0040] In another aspect, the invention provides a method of crystallising a lysine salt of a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with ethanol, allowing the salt to re-precipitate and isolating the resultant precipitate.

[0041] In another aspect, provided herein is a pharmaceutical composition comprising a salt described herein and at least one pharmaceutically acceptable excipient.

[0042] In a further aspect, provided herein is a salt or a pharmaceutical composition disclosed herein for use in therapy.

[0043] In another aspect, provided herein is a salt or a pharmaceutical composition disclosed herein for use in:

[0044] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0045] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0046] (iii) preventing or reducing the risks of pre-term labor in a subject in need thereof;

[0047] (iv) preventing or reducing the risks of labor prior to cesarean delivery in a subject in need thereof; (v) treating, preventing or reducing the risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof; or

[0048] (vi) treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha- 1 -antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididimytis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

[0049] In a further aspect, provided herein is a method of:

[0050] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0051] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0052] (iii) preventing or reducing risks of pre-term labor in a subject in need thereof;

[0053] (iv) preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof; (v) treating, preventing or reducing risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof; or

[0054] (vi) treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha- 1 -antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididimytis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF); wherein the method comprises administering to the subject a salt or pharmaceutical composition disclosed herein.

[0055] In a further aspect, there is provided the use of a salt or a pharmaceutical composition disclosed herein in the preparation of a medicament for use in:

[0056] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0057] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof; (iii) preventing or reducing risks of pre-term labor in a subject in need thereof;

[0058] (iv) preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof;

[0059] (v) treating, preventing or reducing risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof; or

[0060] (vi) treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha- 1 -antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididimytis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

[0061] In some embodiments, the composition for use, the method, or the use further comprises administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is selected from the group consisting of atosiban, retosiban, barusiban, epelsiban, nolasiban, terbutaline, ritodrine, hexoprenaline, albuterol, fenoterol, nylidrin, orciprenaline, dihydropyridine, nifedipine, nicardipine, magnesium sulfate, progesterone, 17-a- hydroxyprogesterone, and nitroglycerine.

[0062] DETAILED DESCRIPTION

[0063] DEFINITIONS

[0064] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which the present disclosure pertains, unless otherwise defined.

[0065] As used herein, the singular forms "a," "an," and "the" and the like designate both the singular and the plural, unless expressly stated to designate the singular only.

[0066] As used herein, the term "about" means that the stated parameter is not limited to the exact number stated. As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term. As used herein, ranges are to be construed as shorthand for each and every value falling within the range, and each separate value should be understood to be expressly disclosed herein.

[0067] The phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. When “consisting essentially of’ is used to refer to compositions with only one active agent disclosed herein, the compositions cannot include any additional active agents that are not otherwise recited. When “consisting essentially of’ is used to refer to combinations of active agents disclosed herein, the combinations cannot include any additional active agents that are not otherwise recited. When “consisting essentially of’ is used to refer to a treatment method, the method cannot include administration of any additional therapeutically active agents that are not otherwise recited. Salts can be obtained by reaction of a compound disclosed herein with an acid or base. Salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of this disclosure.

[0068] Crystalline forms of the salts and compounds disclosed herein may be obtained or obtainable by crystallising the salt or compound in any suitable solvent or solvent mixture. Suitable solvents may include any suitable organic solvent or inorganic (e.g. aqueous) solvent. An “organic solvent” refers to a chemical compound containing carbon that may be used to dissolve other substances and / or compounds. Examples of organic solvents may include hydrocarbons (both aliphatic and aromatic), heterocycles (both aliphatic and aromatic), halogenated hydrocarbons, ethers, carboxylic acids, esters, amines, amides, alcohols and the like. Representative examples of suitable solvents include, but are not limited to, acetic acid, acetone, acetonitrile, Ci-6 hydrocarbons (including aliphatic compounds such as heptane and pentane, and also aromatic compounds toluene and xylene the like), Ci-6 alcohols (such as methanol, ethanol, isopropylalcohol (IP A) and the like), chlorinated Ci-6 hydrocarbons (e.g. dichloromethane, chloroform or dichloroethane), dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, ethyl acetate (EtOAc), isopropyl acetate (iPrOAc), methyl tert-butyl ether (MTBE), N-methyl-2-pyrrolidinone (NMP), heteroaromatic compounds (such as pyridine), tetrahydrofuran (THF), or an alkylated (e.g. Ci-6 alkylated) tetrahydrofuran, such as 2-methyltetrahydrofuran (2-MeTHF), and combinations thereof. By way of further example only, suitable solvents may be selected from acetone, acetonitrile, butanol (e.g. 1 -butanol and 2-butanol), 2-butanone, dichloromethane, N,N- dimethylformamide, 1 ,4-dioxane, ethanol, ethyl acetate, ethyl formate, methanol, methyl acetate, methyl ethyl ketone, 2-methyl-l -propanol, methyl tert-butyl ether, 1 -propanol, 2-propanol, tetrahydrofuran, and toluene, or combinations thereof. Where a solvent has been identified as finding particular utility in the crystallization of any particular salt or compound as defined herein, an alternative solvent belonging to the same solvent cluster or solvent type may also be used to obtain that crystalline form. Solvents may belong to the solvent clusters as defined in Xu D, Redman-Furey N. Statistical cluster analysis of pharmaceutical solvents. Int J Pharm. 2007 Jul 18;339(l-2):175-88, the entire contents of which are herein incorporated by reference. Where compounds disclosed herein have one or more chiral centers, they may exist as, be provided or formulated as, or be used as, a racemate or as individual enantiomers. It should be noted that all such stereoisomers and mixtures thereof are included in the scope of the present disclosure. Thus, the illustration of a chiral center without a designation of R or S signifies that the scope of the disclosure includes the R isomer, the S isomer, racemic mixtures of the isomers, and mixtures where one isomer is present in greater abundance than another.

[0069] Where processes for the preparation of compounds disclosed herein give rise to mixtures of stereoisomers, such isomers may be separated by conventional techniques such as preparative chiral chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by stereoselective synthesis or by resolution. The compounds may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d- tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary.

[0070] As used herein, “aryl” refers to a carbocyclic (all carbon) ring that is fully aromatized. An “aryl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When an aryl group is a fused ring system, then the ring that is connected to the rest of the molecule is fully aromatized. The other ring(s) in the fused ring system may or may not be fully aromatized. Examples of aryl groups include, without limitation, the radicals of benzene, naphthalene and azulene. Additional non-limiting examples include:

[0071] As used herein, “heteroaryl” refers to a ring that is fully aromatized and contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur in the ring. In some examples, a heteroaryl ring may comprise an oxo group directly appended to a ring carbon, the oxo group forming part of the aromatized system. A “heteroaryl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When a heteroaryl group is a fused ring system, then the ring that is connected to the rest of the molecule is fully aromatized. The other ring(s) in the fused ring system may or may not be fully aromatized. Examples of heteroaryl rings include, without limitation, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, indazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, 2-pyridone, pyridazine, pyrimidine, pyrazine and triazine. As described herein, in some examples, the heteroaryl group may be substituted. In other words, the heteroaryl group may comprise one or more substituents on the heteroaromatic ring. When a heteroaryl group is substituted, any hydrogen atom(s) may be replaced with the substituent(s) provided that valencies are satisfied. In some cases, the heteroaryl group may be substituted at the heteroatom, e.g., a N-containing heteroaryl group may be an N-substituted heteroaryl group (such as a N-substituted 2-pyridonyl group).

[0072] As used herein, “alkyl” refers to a straight or branched chain fully saturated (no double or triple bonds) hydrocarbon group. An alkyl group of the presently disclosed compounds may comprise from 1 to 15 carbon atoms. An alkyl group herein may have 1 to 4 carbon atoms, 1 to 5 carbon atoms, 1 to 6 carbon atoms, 1 to 7 carbon atoms, 1 to 8 carbon atoms, 1 to 9 carbon atoms, 1 to 10 carbon atoms, 1 to 11 carbon atoms, 1 to 12 carbon atoms, 1 to 13 carbon atoms, 1 to 14 carbon atoms, or 1 to 15 carbon atoms. As used herein, a Ci-Ce alkyl represents an alkyl group having 1 to 6 carbon atoms, a C1-C4 alkyl represents an alkyl group having 1 to 4 carbon atoms and a C1-C4 alkyl represents an alkyl group having 1 to 3 carbon atoms, etc. Examples of alkyl groups include, without limitation, methyl, ethyl, / ?-propyl, isopropyl, / ?-butyl, i -butyl, .scc-butyl, / -butyl, amyl, t- amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

[0073] As used herein, “cycloalkyl” refers to a completely saturated (no double bonds) hydrocarbon ring. Cycloalkyl groups of the presently disclosed compounds may range from C3 to C5, C3 to Ce, C3 to C7, or C3 to Cs. As used herein, a C3-C5 cycloalkyl represents a cycloalkyl group containing 3 to 5 carbon atoms and a C3-C6 cycloalkyl represents a cycloalkyl group containing 3 to 6 carbon atoms.

[0074] As used herein, “heterocycloalkyl” refers to a ring having in the ring system one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. The ring may also contain one or more double bonds provided that the ring is not fully aromatized. A “heterocycloalkyl” ring as defined herein can be a stable 3- to 18-membered ring (which includes a 3- to 5-membered or 3- to 6-membered ring) that consists of carbon atoms and from one to five ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. A “heterocycloalkyl” ring as defined herein can be a bridged, fused, or spirocyclic ring system.

[0075] As used herein, “alkoxy” refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxy group, -O-. As used herein, a Ci-Ce alkoxy represents an alkoxy group containing 1 to 6 carbon atoms and a C1-C3 alkoxy represents an alkoxy group containing 1 to 3 carbon atoms. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy etc.

[0076] As used herein, “haloalkyl” refers to an alkyl group, as defined above, in which one or more of the hydrogen atoms thereon has been replaced with a halogen atom (e.g. F, Cl, Br or I). As used herein, “Ci-Ce haloalkyl” represents an alkyl group containing 1 to 6 carbon atoms, in which one or more hydrogens thereon has been replaced with a halogen atom.

[0077] As used herein, “haloalkoxy” refers to an alkoxy group, as defined herein, in which one or more of the hydrogen atoms thereon has been replaced with a halogen atom (e.g. F, Cl, Br or I). As used herein, “C1-C3 haloalkoxy” represents a haloalkoxy group containing 1 to 3 carbon atoms.

[0078] As used herein, unless otherwise stated, “independently selected” indicates that each one of a designated group is selected independently from a subsequent list of species.

[0079] It is to be understood that, in any compound of the presently disclosed compounds having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be R or S. In addition, it is to be understood that, in any compound of the presently disclosed compounds having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z.

[0080] It is to be understood that the disclosure of a compound herein inherently includes the disclosure of a tautomer thereof, if applicable. For instance, the disclosure of: (wherein Rxis H) also includes the disclosure of: and vice versa, even if only one of the two structures is disclosed.

[0081] Throughout the present disclosure, when a compound is illustrated or named, it is to be understood that isotopically enriched analogs of the compound are also contemplated and encompassed by the disclosure. For example, a compound may have a deuterium incorporated instead of a hydrogen, or a carbon-13 instead of carbon with natural isotopic distribution. The isotopic enrichment may be in one location on the compound, i.e., only one hydrogen is replaced by a deuterium, or in more than one location. The present disclosure also encompasses compounds where all the similar atoms are replaced by a less common isotope, for example, a perdeutero compound where all the hydrogen atoms are replaced by a deuterium. The isotopically enriched compounds may be useful, for example, when obtaining NMR spectra or when making use of an isotope effect in managing the kinetics of the reaction the compound is undergoing.

[0082] Throughout the present disclosure, when a compound is illustrated or named, it is to be understood that hydrates, solvates, analogs, conjugates, isomers, polymorphs, esters, prodrugs, metabolites, complexes, co-crystals, intermediates, modifications, and derivatives thereof are contemplated and encompassed by the disclosure.

[0083] The term “pharmaceutical composition” refers to a mixture of one or more compounds or salts disclosed herein with another pharmaceutically acceptable excipient, such as one or more pharmaceutically acceptable diluents or carriers or one or more other pharmaceutically acceptable excipients known in the art. Formulating a compound or salt in a pharmaceutical composition may facilitate administration of the compound or salt to an organism, e.g., the subject to be treated. The specific components of a pharmaceutical composition may depend on and vary with the intended route of administration.

[0084] As used herein, the terms “patient” and “subject” refer to a vertebrate, such as but not limited to a mammal (including a human), bird, fish, or reptile, that has been or will be the object of treatment, observation, or experiment. “Subject” and “patient” may be used interchangeably. Mammals include, but are not limited to, humans, mice, rodents, rats, simians, farm animals, dogs, cats, sport animals, and pets. The methods described herein may be useful in human therapy and / or veterinary / animal husbandry applications. Without being limiting, the discussion that follows is written with reference to adult human patients.

[0085] As used herein, the terms “therapeutically effective amount” and “effective amount” are used interchangeably and refer to an amount that provides the specific intended pharmacological effect in a patient in need of treatment. It is emphasized that a therapeutically effective amount will not always be effective in treating the conditions described herein in a given patient, even though such amount is deemed to be a therapeutically effective amount by those of skill in the art. Exemplary therapeutically effective amounts are provided herein with reference to adult human patients. The therapeutically effective amount may vary depending upon characteristics of the patient being treated, the condition being treated, and the severity of the condition, for example.

[0086] COMPOUNDS

[0087] In one aspect, disclosed herein is a tromethamine or lysine salt of a compound of Formula la: (Formula la) or a stereoisomer, or tautomer thereof, wherein:

[0088] R1is halogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0089] R2is phenyl; C3-6 cycloalkyl; 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenoxy; or C1-6 alkoxy; wherein the phenyl, C3-6 cycloalkyl, and 3- to 8-membered heterocycloalkyl are optionally substituted with one to four R2Aindependently selected from halogen, Ci-6 alkyl, Ci-6 alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3 - to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen;

[0090] R4Bis H, Ci-3 alkyl, or -OH; and R4Bis H or C1-3 alkyl;

[0091] R5is C1-6 alkyl optionally substituted with C3-4 cycloalkyl; C1-6 haloalkyl; C4-5 cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, Ci- 6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4 cycloalkyl ring; 4- to 5 -membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 4- to 5 -membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from -C(O)(benzyl), -C(0)(Ci-6 alkyl), and -SO2(Ci-6 alkyl); or phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6 haloalkoxy; and

[0092] R6is H or Ci -6 alkyl; wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).

[0093] In some embodiments, R4Bis H. In some embodiments, R4Band R4Bare both H. In some embodiments, R4Bis methyl and R4Bis H.

[0094] In some embodiments, R5is C1-6 haloalkyl or C1-6 alkyl optionally substituted with C3-4 cycloalkyl.

[0095] In some embodiments, R5is C4-5 cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4 cycloalkyl ring.

[0096] In some embodiments, R5is 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)(Ci-6 alkyl), and -SO2(Ci-6 alkyl). In some embodiments, R5is

[0097] In some embodiments, R5is phenyl optionally substituted with one or two substituents independently selected from halogen and Ci-6 haloalkoxy. In some embodiments, R5is phenyl optionally substituted with one or two substituents independently selected from halogen. In some embodiments,

[0098] In some embodiments, R5is Ci-6 alkyl, C4-5 cycloalkyl, or phenyl optionally substituted with one or two substituents independently selected from halogen.

[0099] ,

[0100] In some embodiments, R1is halogen. In some embodiments, R1is Br or I. In some embodiments, R1is Br.

[0101] In some embodiments, R1is Ci-6 alkyl. In some embodiments, R1is tert-butyl.

[0102] In some embodiments, R1is Ci-6 haloalkyl. In some embodiments, R1is trifluoromethyl.

[0103] In some embodiments, R1is Ci-6 alkyl, or Ci-6 haloalkyl. In some embodiments, R1is ethyl or -

[0104] CHF2. In some embodiments, R2is phenyl, wherein R2is optionally substituted with one to four R2Aindependently selected from halogen, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, R2is

[0105] In some embodiments, R2is C3-6 cycloalkyl or 3- to 8 -membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R2is optionally substituted with one to four R2Aindependently selected from halogen, C1-6 alkyl, C1-6 alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3- to 6- membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen. In some embodiments, R2is

[0106]

[0107] In some embodiments, R2is phenoxy or Ci-6 alkoxy. In some embodiments, R2is In some embodiments, R6is H. In some embodiments, R6is Ci-6 alkyl.

[0108] The presently disclosed compounds were and can be synthesized using the general synthetic procedures set forth in reaction schemes below. The carrying out of each individual illustrated step is within the skill of an ordinary artisan guided by this disclosure, who also knows how to modify the synthetic procedures of the below schemes to synthesize the full scope of the compounds disclosed herein. The synthetic procedure for individual compounds is provided in the Examples section, below.

[0109] In another aspect, disclosed herein is a tromethamine or lysine salt of a compound selected from Table A, or a stereoisomer, or tautomer thereof.

[0110] Table A.

[0111]

[0112] In some embodiments, the tromethamine or lysine salt is of a compound selected from: ,or is a stereoisomer, or tautomer thereof.

[0113] In more specific embodiments, the tromethamine or lysine salt is of a compound selected from: In the second structure, the chiral carbon atom bonded to the methyl group depicted as a block bond has R (Rectus) stereochemistry.

[0114] In some embodiments, the salt is a tromethamine salt, such as a tromethamine salt of a compound of structure:

[0115]

[0116] In other embodiments, the salt is a lysine salt, such as a lysine salt of a compound of structure:

[0117] CRYSTALLINE FORMS Any one or more of the salts described herein may be in a crystalline form, i.e. they comprise or consist of a regular arrangement of molecules that repeats in three dimensions with long range periodicity, in the solid state. A unit cell is the smallest repeating unit of the crystalline solid form that contains all structural and symmetry elements. .

[0118] The present inventors have unexpectedly identified that the tromethamine and lysine salts of the compounds described herein may find particular application in providing crystalline forms with favourable properties, including one or more of a decreased propensity to form solvates, a high degree of crystallinity, good stability and / or good solubility in biological solvents.

[0119] Crystalline tromethamine salts Typically, the salt of the invention is a crystalline form of a tromethamine salt of a compound of structure:

[0120] A number of crystalline forms of such salts have been identified. By way of example, a first and second crystalline form are described in detail below and may be referred to herein as “Hit 1” and “Hit 2” respectively.

[0121] First crystalline form of tromethamine salt

[0122] In some embodiments, the crystalline tromethamine salt has an X-ray powder diffraction pattern comprising two or more, such as five or more or 10 or more, peaks at a 20 ± 0.2 selected from any of 2.8, 5.6, 8.4, 8.7, 10.0, 11.2, 14.0, 18.2, 18.5, 18.9, 19.7, 21.3, 22.5, 24.0, 25.4, 28.3, 31.1, and 34.0, as measured by X-ray powder diffraction using a Cu K a source.

[0123] In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 8.4 and 14.0. These peaks may have relative intensities of about 100% and 38%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 8.4, 14.0 and 19.7. These peaks may have relative intensities of about 100%, 38% and 47%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or all, of a 20 ± 0.2 of 5.6 and 22.5, optionally with relative intensities of about 24% and 46%, repectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, such as at three, five or ten or more, or all, of a 20 ± 0.2 of: 2.8, 8.7, 10.0, 11.2, 18.2, 18.5, 18.9, 21.3, 24.0, 25.4, 28.3, 31.1, and 34.0, or combinations thereof. In more specific embodiments, the X-ray powder diffraction pattern comprises peaks at 2.8, 5.6, 8.4, 8.7, 10.0, 11.2, 14.0, 18.2, 18.5, 18.9, 19.7, 21.3, 22.5, 24.0, 25.4, 28.3, 31.1, and 34.0, optionally with the relative intensities shown in Table 29.

[0124] In some embodiments, the tromethamine salt has an onset melting point of about 215 to 230 °C, such as about 222 °C. The salt may alternatively or in addition have a peak melting point of about 226 °C. The onset melting point may be determined by differential scanning calorimetry (DSC) as described herein

[0125] In some embodiments, the tromethamine salt comprises a volatile component of less than about 5% mass, such as less than about 4.5% mass. In particular embodiments, the volatile component is less than 3% mass, such as less than 1% mass. The % mass of volatile component may be determined by thermal gravimetric analysis (TGA) as described herein.

[0126] In some embodiments, the tromethamine salt has a solubility in FaSSIF v2 at a pH of 6.5 after 1 hour of at least about 100 pg / mL, or at least about 150 pg / mL, optionally a minimum of about 150 to about 250 pg / mL.

[0127] In particular embodiments, the tromethamine salt has a solubility in SIF at a pH of 6.8-6.9 after 1 hour of at least about 20 pg / mL, or at least about 25 pg / mL, optionally a minimum of about 25 to 35 150 pg / mL.

[0128] In some embodiments, the tromethamine salt has a solubility in Simulated Gastric Fluid (SGF) at a pH of 1.2-1.3 after 1 hour of at least about 20 pg / mL, at least about 25 pg / mL, or at least about 30 pg / mL, optionally a minimum of about 30 to about 40 pg / mL.

[0129] In some embodiments, the tromethamine salt has a morphology comprising thin shavings of rodlike shape gathered together in parallel stacks.

[0130] In some embodiments, the tromethamine salt has a water uptake from 0 to 80%RH of up to about 10%, such as about 0.5 to about 10%, or such as about 0.5 to about 6% or about 0.5 to about 1.5%. In some embodiments, the tromethamine salt has a water uptake from 0 to 80%RH of up to about 1%. In particular embodiments, the tromethamine salt has a water uptake from 0 to 80%RH of about 0.9%. The water uptake may be determined by Gravimetric Vapour Sorption (GVS) as detailed below and herein.

[0131] In some embodiments, the tromethamine salt has an FT-IR spectrum comprising two or more, such as five or more or 10 or more, peaks at a wavenumber of 601.8, 636.5, 657.7, 700.2, 761.9, 775.4,

[0132] 825.5, 868.0, 896.9, 958.6, 966.3, 995.3, 1014.6, 1055.1, 1076.3, 1139.9, 1238.3, 1249.9, 1286.5, 1303.9, 1344.4, 1381.0, 1411.9, 1477.5, 1516.1, 1541.1, 1647.2, 2937.6, 3221.1, and 3313.7. In some embodiments, the FT-IR spectrum comprises peaks at a wavenumber of 700.2 and 1076.3. In some embodiments, the FT-IR spectrum comprises peaks at a wavenumber of 700.2, 1076.3, and 1541.1. In some embodiments, the FT-IR spectrum comprises further peaks at one or all, of a wavenumber of 1411.9 and 1055.1. In some embodiments, the FT-IR spectrum comprises further peaks at one or more, such as at three, five or ten or more, or all, of a wavenumber of 601.8, 636.5,

[0133] 657.7, 761.9, 775.4, 825.5, 868.0, 896.9, 958.6, 966.3, 995.3, 1014.6, 1139.9, 1238.3, 1249.9,

[0134] 1286.5, 1303.9, 1344.4, 1381.0, 1477.5, 1516.1, 1647.2, 2937.6, 3221.1, and 3313.7, or combinations thereof. In more specific embodiments, the FT-IR spectrum comprises peaks at

[0135] 601.8, 636.5, 657.7, 700.2, 761.9, 775.4, 825.5, 868.0, 896.9, 958.6, 966.3, 995.3, 1014.6, 1055.1, 1076.3, 1139.9, 1238.3, 1249.9, 1286.5, 1303.9, 1344.4, 1381.0, 1411.9, 1477.5, 1516.1, 1541.1, 1647.2, 2937.6, 3221.1, and 3313.7, optionally with the intensities shown in Table 32.

[0136] In some embodiments, the invention provides a crystalline form of a tromethamine salt of a compound of structure: wherein the crystalline form is obtainable by crystallising in any one or a mixture of ethanol, acetonitrile, dimethylacetamide and methyl isobutyl ketone. In some embodiments, the crystalline form is obtainable by crystallising in ethanol.

[0137] Advantageously the present inventors have identified that the crystalline tromethamine salts of such embodiments may be prepared in substantially anhydrous form, show low hygroscopity, and may show a good solubility in simulated intestinal fluid (such as FaSSIF-V2). Thus, this particular crystalline form has many favourable properties to facilitate later drug development.

[0138] Second crystalline form of tromethamine salt

[0139] In some embodiments, the crystalline tromethamine salt has an X-ray powder diffraction pattern comprising two or more, such as five or more or 10 or more, peaks at a 20 ± 0.2 selected from any of 6.4, 6.7, 8.4, 8.8, 9.0, 10.1, 12.6, 13.1, 13.4, 14.9, 15.6, 15.9, 16.2, 16.9, 17.2, 18.0, 18.8, 19.1, 19.9, 20.2, 20.7, 21.4, 22.4, 22.9, 23.2, 24.1, 25.0, 25.4, 25.6, 26.2, 26.8, 27.2, 27.8, 28.1, 28.4, 29.5, 30.7, 31.3, 32.0, 32.7, and 33.5, as measured by X-ray powder diffraction using a Cu K a source.

[0140] In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 9.0 and 20.2. These peaks may have relative intensities of about 75% and 100%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 9.0, 14.9 and 20.2. These peaks may have relative intensities of about 75%, 16% and 100%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or all, of a 20 ± 0.2 of 19.9 and 21.4, optionally with relative intensities of about 25% and 22%, repectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, such as at three, five or ten or more, or all, of a 20 ± 0.2 of: 6.4, 6.7, 8.4, 8.8, 10.1, 12.6, 13.1, 13.4, 15.6, 15.9, 16.2, 16.9, 17.2, 18.0, 18.8, 19.1, 20.7, 22.4, 22.9, 23.2, 24.1, 25.0, 25.4, 25.6, 26.2, 26.8, 27.2, 27.8, 28.1, 28.4, 29.5, 30.7, 31.3, 32.0, 32.7, and 33.5, or combinations thereof. In more specific embodiments, the X-ray powder diffraction pattern comprises peaks at 6.4, 6.7, 8.4, 8.8, 9.0, 10.1, 12.6, 13.1, 13.4, 14.9, 15.6, 15.9, 16.2, 16.9, 17.2, 18.0, 18.8, 19.1, 19.9, 20.2, 20.7, 21.4, 22.4, 22.9, 23.2, 24.1, 25.0, 25.4, 25.6, 26.2, 26.8, 27.2, 27.8, 28.1, 28.4, 29.5, 30.7, 31.3, 32.0, 32.7, and 33.5, optionally with the relative intensities shown in Table 30. In some embodiments, the tromethamine salt has an onset melting point of about 205 to about 220 °C, such as about 213 °C. The salt may alternatively or in addition have a peak melting point of about 218 °C. The onset melting point may be determined by differential scanning calorimetry (DSC) as described herein.

[0141] In some embodiments, the tromethamine salt has a solubility in FaSSIF v2 at a pH of 6.5 after 1 hour of at least about 50 pg / mL, or at least about 100 pg / mL, optionally about 100 to about 150 pg / mL.

[0142] In particular embodiments, the tromethamine salt has a solubility in SIF at a pH of 6.8-6.9 after 1 hour of at least about 40 pg / mL, or at least about 50 pg / mL, optionally about 70 to about 80 pg / mL.

[0143] In some embodiments, the tromethamine salt has a solubility in SGF at a pH of 1.2-1.3 after 1 hour of at least about 20 pg / mL, or at least about 30 pg / mL, optionally about 30 to about 40 pg / mL.

[0144] In some embodiments, the tromethamine salt has a rock-like morphology.

[0145] In some embodiments, the tromethamine salt has a water uptake from 0 to 80%RH of up to about 6%, such as about 3 to about 6%, such as about 5 to about 6%, e.g. 5.2%. The water uptake may be determined by Gravimetric Vapour Sorption (GVS) as detailed below and herein.

[0146] In some embodiments, the tromethamine salt has an FT-IR spectrum comprising two or more, such as five or more or 10 or more, peaks at a wavenumber of 613.4, 626.9, 657.7, 686.7, 707.9, 748.4, 769.6, 837.1, 866.0, 881.5, 922.0, 939.3, 966.3, 983.7, 1012.6, 1035.8, 1057.0, 1084.0, 1236.4,

[0147] 1288.5, 1313.5, 1346.3, 1388.8, 1419.6, 1454.3, 1477.5, 1510.3, 1556.6, 1643.4, 1658.8, 2868.2,

[0148] 2939.5, 2976.2, and 3344.6. In some embodiments, the FT-IR spectrum comprises peaks at a wavenumber of 1084.0 and 1510.3. In some embodiments, the FT-IR spectrum comprises peaks at a wavenumber of 769.6, 1084.0 and 1510.3. In some embodiments, the FT-IR spectrum comprises further peaks at one or all, of a wavenumber of 1388.8 and 837.1. In some embodiments, the FT-IR spectrum comprises further peaks at one or more, such as at three, five or ten or more, or all, of a wavenumber of 613.4, 626.9, 657.7, 686.7, 707.9, 748.4, 866.0, 881.5, 922.0, 939.3, 966.3, 983.7, 1012.6, 1035.8, 1057.0, 1236.4, 1288.5, 1313.5, 1346.3, 1419.6, 1454.3, 1477.5, 1556.6, 1643.4, 1658.8, 2868.2, 2939.5, 2976.2, and 3344.6, or combinations thereof. In more specific embodiments, the FT-IR spectrum comprises peaks at 613.4, 626.9, 657.7, 686.7, 707.9, 748.4, 769.6, 837.1, 866.0, 881.5, 922.0, 939.3, 966.3, 983.7, 1012.6, 1035.8, 1057.0, 1084.0, 1236.4, 1288.5, 1313.5, 1346.3, 1388.8, 1419.6, 1454.3, 1477.5, 1510.3, 1556.6, 1643.4, 1658.8, 2868.2, 2939.5, 2976.2, and 3344.6, optionally with the intensities shown in Table 33.

[0149] In some embodiments, the invention provides a crystalline form of a tromethamine salt of a compound of structure: wherein the crystalline form is obtainable by crystallising in any one or a mixture of tetrahydro furan, dimethyl formamide, dimethylacetamide and 1,4-di oxane.

[0150] Without being bound by theory, the present inventors have identified that the crystalline tromethamine salts of such embodiments may comprise a desolvated channel hydrate structure, in which the desovlation has not resulted in the collapse of the channel structure. Advantageously and unexpectedly, the crystalline form of this embodiment may show good crystallinity and / or stability, and may show a good solubility in simulated intestinal fluid (such as FaSSIF-V2). Thus, this particular crystalline form surprisingly has many favourable properties to facilitate later drug development.

[0151] Crystalline lysine salts

[0152] Sometimes, the salt of the invention is a crystalline form of a lysine salt of a compound of structure:

[0153] In some embodiments, the crystalline lysine salt has an X-ray powder diffraction pattern comprising two or more, such as five or more or 10 or more, peaks at a 20 ± 0.2 selected from any of 4.2, 4.8, 7.6, 16.5, 16.8, 17.9, 18.8, 19.4, 20.3, and 21.9, as measured by X-ray powder diffraction using a Cu K a source.

[0154] In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 4.2 and 4.8. These peaks may have relative intensities of about 83% and 100%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 4.2, 4.8 and 18.8. These peaks may have relative intensities of about 83%, 100% and 15%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or all, of a 20 ± 0.2 of 17.9 and 19.4, optionally with relative intensities of about 10% and 11%, repectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, such as at three or more, or all, of a 20 ± 0.2 selected from: 7.6, 16.5, 16.8, 20.3, and 21.9, or combinations thereof. In more specific embodiments, the X-ray powder diffraction pattern comprises peaks at 4.2, 4.8, 7.6, 16.5, 16.8, 17.9, 18.8, 19.4, 20.3, and 21.9, optionally with the relative intensities shown in Table 20.

[0155] In some embodiments, the lysine salt comprises a volatile component of less than about 3% mass, such as less than about 2.8% mass. The % mass of volatile component may be determined by thermal gravimetric analysis (TGA) as described herein.

[0156] In some embodiments, the lysine salt has a first onset melting point of about 185 to about 200 °C, such as about 192 °C. In some embodiments, the lysine salt has a second onset melting event at about 240 to about 250 °C, such as about 245 °C. The onset melting point and / or second onset melting event may be determined by differential scanning calorimetry (DSC) as described herein.

[0157] In some embodiments, the lysine salt has a solubility in FaSSIF v2 at a pH of 6.5 after 1 hour of at least about 100 pg / mL, or at least about 150 pg / mL or 160 pg / mL, optionally a minimum of about 150 and about 200 pg / mL.

[0158] In particular embodiments, the lysine salt has a solubility in SIF at a pH of 6.8-6.9 after 1 hour of at least about 25 pg / mL, or at least about 30 pg / mL, optionally a minimum of about 25 to about 35 pg / mL.

[0159] In some embodiments, the lysine salt has a solubility in Simulated Gastric Fluid (SGF) at a pH of 1.2-1.3 after 1 hour of at least about 25 pg / mL, or at least about 30 pg / mL, optionally a minimum of about 30 to about 40 pg / mL.

[0160] In another aspect, the invention provides a crystalline form of a lysine salt of a compound of structure: wherein the crystalline form is obtainable by crystallising in ethanol.

[0161] Other crystalline salt forms

[0162] As described herein, the inventors have found that particular salts of particular prostaglandin F (FP) receptor antagonists exhibit unexpectedly advantageous physical properties for drug formulation, including a high degree of crystallinity, a high solubility in biological solvents and / or a high stability. Whilst specific crystalline tromethamine and lysine salts have been described in detail above, the present disclosure further encompasses crystalline tromethamine, lysine, tosylate, meglumine and potassium salts of a compound of Formula la, which may demonstrate unexpectedly advantageous physical properties.

[0163] In a further aspect of the invention, therefore, the salt is a crystalline salt selected from a tromethamine, lysine, tosylate, meglumine and potassium salt of a compound of Formula la. For the avoidance of doubt, the embodiments described in relation to Formula la of the first aspect may apply mutatis mutandis to this further aspect. For example, R5may be may be

[0164] H, R2may may be H.

[0165] In particular embodiments, the crystalline tromethamine, lysine, tosylate, meglumine or potassium salt comprises a compound selected from: ,or is a stereoisomer, or tautomer thereof.

[0166] In even more particular embodiments, the crystalline tromethamine, lysine, tosylate, meglumine or potassium salt comprises a volatile component of less than about 5% mass, such as less than about 4.5% mass. The % mass of volatile component may be determined by thermal gravimetric analysis (TGA) as described herein.

[0167] In some embodiments, the crystalline tromethamine, lysine, tosylate, meglumine or potassium salt has a solubility in FaSSIF v2 at a pH of 6.5 after 1 hour of at least about 15 pg / mL, at least about 30 pg / mL, or at least about 50 pg / mL, optionally a minimum of about 15 to about 250 pg / mL. In some embodiments, the crystalline tromethamine, lysine, tosylate, meglumine or potassium salt has a solubility in SIF at a pH of 6.8 after 1 hour of at least about 5 pg / mL or at least about 10 pg / mL, optionally a minimum of about 5 to about 40 pg / mL.

[0168] In some embodiments, the crystalline tromethamine, lysine, tosylate, meglumine or potassium salt has a solubility in SGF at a pH of 1.2 of at least about 1 pg / mL, at least about 20 pg / mL, or at least about 30 pg / mL, optionally a minimum of about 1 to about 50 pg / mL.

[0169] In particular embodiments, the crystalline salt is a tosylate salt of a compound of structure: wherein the crystalline form has an X-ray powder diffraction pattern comprising two or more, such as five or more or 10 or more, peaks at a 20 ± 0.2 selected from any of 5.1, 6.6, 8.6, 9.9, 10.0,

[0170] 10.1, 10.9, 12.0, 13.2, 13.8, 14.9, 16.3, 17.6, 17.9, 18.3, 19.1, 19.5, 19.6, 19.9, 20.1, 20.3, 20.5,

[0171] 21.2, 22.6, 22.9, 23.9, 24.6, and 28.7, as measured by X-ray powder diffraction using a Cu K a source.

[0172] In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 6.6 and 19.6. These peaks may have relative intensities of about 100% and 63%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 6.6, 17.6 and 19.6. These peaks may have relative intensities of about 100%, 38% and 63%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or all, of a 20 ± 0.2 of 8.6 and 9.9, optionally with relative intensities of about 26% and 32%, repectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, such as at three or more, five or more, ten or more, or all, of a 20 ± 0.2 selected from: 5.1, 10.0, 10.1, 10.9, 12.0, 13.2, 13.8, 14.9, 16.3, 17.9, 18.3, 19.1, 19.5, 19.9, 20.1, 20.3, 20.5, 21.2, 22.6, 22.9, 23.9, 24.6, and 28.7, or combinations thereof. In more specific embodiments, the X-ray powder diffraction pattern comprises peaks at 5.1, 6.6, 8.6, 9.9, 10.0, 10.1, 10.9, 12.0, 13.2, 13.8, 14.9, 16.3, 17.6, 17.9, 18.3, 19.1, 19.5, 19.6, 19.9, 20.1, 20.3, 20.5, 21.2, 22.6, 22.9, 23.9, 24.6, and 28.7, optionally with the relative intensities shown in Table 22.

[0173] The crystalline toylate salt may comprise a volatile component of less than about 4% mass, such as about or less than 3.9% mass. The % mass of volatile component may be determined by thermal gravimetric analysis (TGA) as described herein.

[0174] In some embodiments, the crystalline tosylate salt has a solubility in FaSSIF v2 at a pH of 6.5 after 1 hour of at least about 40 pg / mL, or at least about 45 pg / mL, optionally a minimum of about 40 to about 70 pg / mL.

[0175] In some embodiments, the crystalline tosylate salt has a solubility in SIF at a pH of 6.8 after 1 hour of at least about 40 pg / mL, or at least about 45 pg / mL, optionally a minimum of about 40 to about 70 pg / mL.

[0176] In some embodiments, the crystalline tosylate salt has a solubility in SGF at a pH of 1.2 of at least about 25 pg / mL or at least about 30 pg / mL, optionally a minimum of about 30 to about 40 pg / mL.

[0177] In particular embodiments, the crystalline salt is a meglumine salt of a compound of structure: wherein the crystalline form has an X-ray powder diffraction pattern comprising two or more, such as five or more or 10 or more, peaks at a 20 ± 0.2 selected from any of 4.6, 4.8, 8.0, 8.1, 9.1, 9.6, 10.3, 12.7, 13.4, 13.6, 14.4, 15.0, 15.9, 16.1, 17.0, 17.2, 18.8, 19.3, 19.9, 20.6, 21.3, 24.0, 24.7, 25.2, 25.9, and 29.4 as measured by X-ray powder diffraction using a Cu K a source.

[0178] In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 8.0 and 17.0. These peaks may have relative intensities of about 100% and 52%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 8.0, 13.6 and 17.0. These peaks may have relative intensities of about 100%, 52% and 52%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or all, of a 20 ± 0.2 of 9.1 and 18.8, optionally with relative intensities of about 45% and 57%, repectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, such as at three or more, five or more, ten or more, or all, of a 20 ± 0.2 selected from: 4.6, 4.8, 8.1, 9.6, 10.3, 12.7, 13.4, 14.4, 15.0, 15.9, 16.1, 17.2, 19.3, 19.9, 20.6, 21.3, 24.0, 24.7, 25.2, 25.9, and 29.4, or combinations thereof. In more specific embodiments, the X- ray powder diffraction pattern comprises peaks at 4.6, 4.8, 8.0, 8.1, 9.1, 9.6, 10.3, 12.7, 13.4, 13.6,

[0179] 14.4, 15.0, 15.9, 16.1, 17.0, 17.2, 18.8, 19.3, 19.9, 20.6, 21.3, 24.0, 24.7, 25.2, 25.9, and 29.4, optionally with the relative intensities shown in Table 21.

[0180] In some embodiments, the crystalline meglumine salt has an onset melting point of about 200 to 215 °C, such as about 207 °C. The salt may alternatively or in addition have a peak melting point of about 212 °C. The onset melting point may be determined by differential scanning calorimetry (DSC) as described herein.

[0181] The crystalline meglumine salt may comprise a volatile component of less than about 4% mass, such as about or less than about 3.4% mass. The % mass of volatile component may be determined by thermal gravimetric analysis (TGA) as described herein.

[0182] In some embodiments, the crystalline meglumine salt has a solubility in FaSSIF v2 at a pH of 6.5 after 1 hour of at least about 20 pg / mL, optionally a minimum of about 20 to about 30 pg / mL.

[0183] In some embodiments, the crystalline meglumine salt has a solubility in SIF at a pH of 6.8 after 1 hour of at least about 5 pg / mL, or at least about 8 pg / mL, optionally a minimum of about 5 to about 10 pg / mL. In some embodiments, the crystalline meglumine salt has a solubility in SGF at a pH of 1.2 of at least about 0.5 pg / mL, or at least about 0.9 pg / mL, optionally a minimum of about 0.5 to about 1.5 pg / mL.

[0184] In particular embodiments, the crystalline salt is a potassium salt of a compound of structure: wherein the crystalline form has an X-ray powder diffraction pattern comprising two or more, such as five or more or 10 or more, peaks at a 20 ± 0.2 selected from any of 5.2, 5.7, 8.8, 9.6, 13.5,

[0185] 14.4, 14.8, 15.7, 18.5, 19.4, 20.4, 21.0, 22.3, 22.8, 23.9, 24.6, 26.0, 29.0, 29.9, and 34.3 as measured by X-ray powder diffraction using a Cu K a source.

[0186] In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 5.2 and 5.7. These peaks may have relative intensities of about 80% and 100%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 5.2, 5.7 and 15.7. These peaks may have relative intensities of about 80%, 100% and 34%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or all, of a 20 ± 0.2 of 9.6 and 18.5, optionally with relative intensities of about 16% and 27%, repectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, such as at three or more, five or more, ten or more, or all, of a 20 ± 0.2 selected from: 8.8,

[0187] 13.5, 14.4, 14.8, 19.4, 20.4, 21.0, 22.3, 22.8, 23.9, 24.6, 26.0, 29.0, 29.9, and 34.3, or combinations thereof. In more specific embodiments, the X-ray powder diffraction pattern comprises peaks at 5.2, 5.7, 8.8, 9.6, 13.5, 14.4, 14.8, 15.7, 18.5, 19.4, 20.4, 21.0, 22.3, 22.8, 23.9, 24.6, 26.0, 29.0, 29.9, and 34.3, optionally with the relative intensities shown in Table 24. The crystalline potassium salt may comprise a volatile component of less than about 4.5% mass, such as about or less than about 4.2% mass. The % mass of volatile component may be determined by thermal gravimetric analysis (TGA) as described herein.

[0188] In another aspect, the invention provides a crystalline form of a tromethamine, lysine, tosylate, meglumine and potassium salt of a compound of structure: wherein the crystalline form is obtainable by crystallising in any one or a mixture of ethanol, acetonitrile, tetrahydrofuran, dimethylacetamide and methyl isobutyl ketone, such as ethanol.

[0189] CHARACTERISATION OF SALTS AND CRYSTALLINE FORMS THEREOF

[0190] As described above, the salt of the invention may be characterisable by one or more parameters. For example, the salt may have a specific: onset melting point, solubility in a solvent, percentage of volatile components, percentage water uptake, morphology and / or infra-red spectrum. Where the salt is crystalline, it may also have a particular X-ray powder diffraction diffractogram. The determination and / or measurement of these parameters are described further below.

[0191] The onset melting point may be measured by differential scanning calorimetry (DSC), where the difference in the amount of heat required to increase the temperature of a sample and reference is measured as a function of temperature. When a solid sample begins to melt to a liquid, more heat is required to increase the temperature of the sample at the same rate as the reference, owing to the absorption of heat by the sample as it undergoes the endothermic melting process. The melting of a solid is depicted as a peak with positive heat flow in the DSC thermogram. The onset temperature, as measured by DSC, is the intersection of the tangent and base line to the left side of the melting peak.

[0192] For the avoidance of doubt, all onset melting points referred to herein were obtained by DSC. A Netzsch DSC 204F1 is suitable for carrying out DSC on samples of the salt of the invention. A non-hermetic, aluminium sample pan may be used to house the sample. A pre-made pinhole lid may be used to encase the sample during DSC analysis. To assess the onset melting point, the temperature should be varied from below to above the melting point of the sample. A temperature range of 0 °C to 300 °C may be used, at a ramp rate of, for example, 5 K / min. A modulation period (time to measure heat flow between the sensor and the sample) of 20 s and a modulation amplitude of ± 0.25 °C may be used. The onset melting point may be obtained using the methods defined in the experimental section below.

[0193] The salt may have a specific solubility in a biological solvent, such as in Simulated Gastric Fluid (SGF), Simulated Intestinal Fluid (SIF) or Fasted State Simulated Intestinal Fluid V2 (FaSSIF v2). The solubility of the salt after an hour within the biological solvent provides a more realistic indication of solubility on administration to a patient.

[0194] FaSSIF v2 is a well known biological solvent that can be prepared by dissolving 112 mg (0.96 mmol) of maleic acid, 200 mg (3.4 mmol) of sodium chloride and 1.74 mb of 1.0 M (3.48 mmol) NaOH solution in 50.0 mL of water and analysing the pH (which was confirmed to be 6.5). 88.6 mg (3mM) of sodium taurocholate and 8.4 mg (0.2 mM) of L-a-lecithin are then added and dissolved into the solution, which is immediately used for solubility analysis.

[0195] SIF is also well known and can be prepared by first making a 1 M NaOH solution by dissolving 3.2 g of NaOH in 80.0 mL water. 339 mg (2.5 mmol) of KH2PO4 and 1.1 mL of the 1 M NaOH solution are then diluted to 50.0 mL with water, to provide a buffer solution with a buffer strength of 50 mM, [K+] = 50 mM and [Na+] = 22 mM and with a pH of 6.8.

[0196] SGF is another well known biological solvent that may be prepared by dissolving 100 mg of NaCl in 50.0 mL of water (34 mM) and adding concentrated HC1 dropwise until a pH of 1.2 is obtained. F or the avoidance of doubt, the solubility values referred to herein were determined at temperatures of 23 °C. Solubility may be determined by HPLC / UV detecting at, for example, 215 nm. Mobile phases of 0.1% formic acid in water and 0.1% formic acid in acetonitrile may be used, at a ratio of e.g. 1 :4. The sample matrix may comprise acetonitrile and water at a ratio of, for example, 2: 1. HPLC may be carried out at a column temperature of 40 °C and / or at a flow rate of 1.25 mL / min for 6 minutes. The column used for HPLC may be 250 x 4.6 mm. A 50 pL injection volume may be used. The solubility values referred to herein may be obtained using the methods defined in the experimental section below.

[0197] The crystalline salt of the invention may be characterisable by a particular morphology. The morphology may be viewed by scanning electron miscroscopy (SEM). For example, the salt may be contacted with an adhesive carbon tape and coated, e.g. with platinum and / or palladium optionally at 40 mA, to produce a conducting surface. Images may be collected by secondary electron imaging using voltage of, for example, 6 kV. The morphology of the salt may be viewed using the SEM methods defined in the experimental section below.

[0198] The crystalline salt of the invention may be characterisable by a particular percentage of volatile component. This may be determined by Thermal Gravimetric Analysis (TGA). For example, the salt may be heated, e.g. from about 25 °C to about 250 or 300 °C, in an inert atmosphere, e.g. of dry nitrogen gas, optionally at a flow rate of 40 ml / min, and the mass of the salt may be measured as the temperature increases. The temperature may be increased at a rate of about 10 K / min. The percentage volatile component of the salt may be determined using the TGA methods defined in the experimental section below.

[0199] The salt of the invention may be characterisable by a particular water uptake or water loss at a particular relative humidity (% p / po), where p = partial pressure of water vapour and po = saturation pressure of water vapour at the same temperature. This is indicative of how hygroscopic the salt is. Salts of higher hygroscopicity (with a relatively large water uptake) can be more difficult to store and transport than those of lower hygroscopicity. The water uptake and loss may be determined by Gravimetric Vapour Sorption (GVS). For example, the salt may be exposed to cycles of increasing and decreasing relative humidities, e.g. from about 20 to about 80 or 90%RH, with water uptake and loss indicated by an increase or decrease in the mass of the sample. GVS may be measured at about 25 °C, optionally with a water vapour flow rate of about 200 mL / min. The water uptake or loss of the salt may be determined using the GVS methods defined in the experimental section below.

[0200] The salt of the invention may be characterisable by particular peaks being present in the Infra-red (IR) spectrum of the salt. An IR spectrum may be obtained using Fourier Transform IR (FT-IR). It may be obtained using attenuated total reflection (ATR) sampling so that the salt may be analysed without the need for further sample preparation steps. The salt may be scanned in the range of 3600 to 600 cm'1. The IR spectrum may be obtained using the FT-IR methods defined in the experimental section below.

[0201] Where the salt is crystalline, it may have a particular crystalline form characterisable by a particular X-ray powder diffraction pattern. For the avoidance of doubt, all X-ray powder diffraction peaks referred to herein were obtained using a Cu K a source, with an ouput wavelength of about 1.54 A (e.g. 1.540598 A) and a tolerance set to ± 0.18 °20 from theoretical values. Suitable operation conditions for a Cu anode include a potential of 45 kV and a current of 40 mA. An example of a suitable detection range is 20 in the range of to 2 to 35 °. This may be scanned at a speed of 0.03 or 0.01° / s, with a step size of, for example, 0.013°.

[0202] A Ka-1 Johansson monochromator may be used to select the output X-ray wavelength and / or a programmable divergency slit may be used to direct the x-rays onto the sample, with anti-scatter shields used to reduce noise. The diffracted rays may be detected using a Pixcel detector. Slow spinning sample holders may be used to rotate the samples during analysis. Samples may be rotated at 7.5 rpm. XRPD diffractogram peak positions may be determined using the software Highscore Plus, version 4.9 (Malvern Panalytical B. V). The X-ray powder diffraction pattern may be obtained using the methods defined in the experimental section below.

[0203] For the avoidance of doubt, an X-ray powder diffraction pattern comprises a peak at a specific 20 value when the relative intensity in respect of the largest peak (which has a relative intensity of 100%) is at least 0.5 or 1%. ACTIVITY OF THE COMPOUNDS

[0204] As noted above, the compounds disclosed herein have activity as FP receptor modulators, in particular as FP receptor antagonists. This activity may be assessed by any suitable FP receptor activity assay, such as a FP receptor myo-inositol 1 phsophate (IP1) accumulation assay as illustrated in the examples. The compounds disclosed herein may show IC50 values of less than 1000 nM, less than or equal to 500 nM, less than or equal to 100 nM, or less than or equal to 10 nM.

[0205] The FP receptor myo-inositol 1 phosphate (IP1) accumulation assay uses human embryonic kidney EBNA derived (HEK-EBNA) cell lines stably expressing the FP receptor. Cells are exposed to varying concentrations of test compounds followed by exposure to a submaximal concentration of FP receptor agonist; antagonist inhibition of IP1 accumulation is then assessed. IP1 accumulation is measured through an HTRF (homogeneous time resolved fluorescence)-based competitive IP1 immunoassay.

[0206] EP4 receptor activity may be assessed by any suitable EP4 receptor activity assay, such as an EP4 receptor cyclic adenosine monophosphate (cAMP) accumulation assay. Selectivity for FP versus EP4 may be assessed by comparing the EC50 values obtained in the respective assays and calculating a selectivity ratio, i.e., EP4 IC50 / FP IC50.

[0207] In some embodiments, a compound as disclosed herein exhibits at least 5 -fold greater selectivity for the FP receptor than for the EP4 receptor. This includes at least 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 22-, 23-, 24-, 25-, 26-, 27-, 28-, 29-, 30-, 31-, 32-, 33-, 34-, 35-, 36-, 37-, 38-, 39-, 40-, 41 -, 42-, 43-, 44-, 45-, 46-, 47-, 48-, 49-, or 50-fold, or more, greater selectivity for the prostaglandin F receptor than for the EP4 receptor. A compound as disclosed herein may exhibit about 5-, 6-, 7-, 8-, 9-, 10-, 11 -, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 22-, 23-, 24-, 25-, 26-, 27-, 28-, 29-, 30-, 31-, 32-, 33-, 34-, 35-, 36-, 37-, 38-, 39-, 40-, 41 42-, 43-, 44-, 45-, 46-, 47-, 48-, 49-, or 50-fold greater selectivity for the prostaglandin F receptor than for the EP4 receptor.

[0208] SYNTHESIS OF THE COMPOUNDS, SALTS AND CRYSTALLINE FORMS THEREOF

[0209] In another aspect there is provided a method of manufacture of any one of the salt forms of the compounds disclosed herein. The presently disclosed compounds were and can be synthesized using the synthetic procedures set forth in the Schemes in the Examples detailed below. The carrying out of each individual illustrated step is within the skill of an ordinary artisan guided by this disclosure, who also knows how to modify the synthetic procedures of the below schemes to synthesize the full scope of the compounds disclosed herein. Definitions for R1, R2, R4B, R4B, R5and R6are as provided in the formulas described herein. The synthetic procedure for individual compounds is disclosed in the Examples section below.

[0210] In another aspect, the invention provides a method of crystallising a tromethamine or lysine salt of a compound of formula la, wherein the method comprises contacting (e.g. dissolving or suspending) the salt with a solvent, optionally wherein the solvent is one or a mixture of ethanol, acetonitrile, tetrahydrofuran, dimethylacetamide, dimethyl formamide, 1,4-di oxane and methyl isobutyl ketone, allowing the salt to re-precipitate and isolating the resultant precipitate.

[0211] In some embodiments, the method may comprise crystallising a tromethamine or lysine salt of a compound having one of the following structures:

[0212]

[0213] In some embodiments, the invention provides a method of crystallising a tromethamine salt of a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of ethanol, acetonitrile, dimethylacetamide and methyl isobutyl ketone, allowing the salt to re-precipitate and isolating the resultant precipitate. By way of example, the method may comprise contacting the salt with ethanol. In some embodiments, the invention provides a method of crystallising a tromethamine salt of a compound of structure:

[0214] wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of tetrahydrofuran, dimethyl formamide, dimethylacetamide and 1,4-di oxane, allowing the salt to re-precipitate and isolating the resultant precipitate. In some embodiments, the invention provides a method of crystallising a lysine salt of a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with ethanol, allowing the salt to re-precipitate and isolating the resultant precipitate. In another aspect, the invention provides a method of crystallising a tromethamine, lysine, tosylate, meglumine and potassium salt of a compound of structure:

[0215] wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of ethanol, acetonitrile, dimethylacetamide, dimethyl formamide, 1,4-dioxane and methyl isobutyl ketone, allowing the salt to re-precipitate and isolating the resultant precipitate. In some embodiments, the method comprises contacting the salt with ethanol.

[0216] In any of the methods described above, the step of allowing the salt to re-precipitate may comprise allowing the salt to crystallise. Additionally or alternatively, the step of isolating the resultant precipitate may comprise isolating the resultant crystalline form.

[0217] PHARMACEUTICAL COMPOSITIONS In another aspect, disclosed herein are pharmaceutical compositions comprising, consisting essentially of, or consisting of a salt as described herein, and one or more pharmaceutically acceptable excipients.

[0218] In another aspect, disclosed herein are pharmaceutical compositions comprising, consisting essentially of, or consisting of a tromethamine or lysine salt selected from structures:

[0219] tautomer thereof, and one or more pharmaceutically acceptable excipients.

[0220] The compounds may be formulated for administration by any suitable route of administration, such as for example, oral, topical (including transdermal), rectal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including by intramuscular, subcutaneous, or intravenous injection, as well as inhalation, intrathecal, direct intraperitoneal, or intranasal delivery.

[0221] Pharmaceutical compositions as disclosed herein may comprise, as one or more pharmaceutically acceptable excipients, a pharmaceutically acceptable carrier, diluent, disintegrant, sweetening agent, glidant (such as magnesium stearate), flavoring agent, emulsifying agent, suspending agent, stabilizer, isotonic agent, etc. Pharmaceutical compositions as disclosed herein may be formulated into an oral dosage form such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or a topical (including transdermal) or transmucosal dosage form such as liquids, suspensions, emulsions, gels (ointments or the like), or a parenteral dosage form such as liquids, suspensions, emulsions, and freeze-dried powders. Said dosage forms may be formulated in various forms, e.g., a dosage form for single administration or for multiple administrations.

[0222] Exemplary excipients include, without limitation, lactose, polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophors, carbohydrates, starches (e.g., com starch), inorganic salts, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), glidants such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, and the like.

[0223] The amount of any individual excipient in the composition will vary depending on the role of the excipient, the dosage requirements of the active agent, and particular needs of the composition. Generally, however, the excipient will be present in the composition in an amount of from about 1% to about 99% by weight, such as from about 5% to about 98% by weight, including from about 15 to about 95% by weight of the composition. In general, the amount of excipient present in a composition of the disclosure is selected from the following: about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% by weight.

[0224] A pharmaceutical composition as disclosed herein may include a salt disclosed herein as the only active agent, or may be formulated with other active agents.

[0225] Techniques for formulation and administration of the compounds disclosed herein may be found in “Remington: The Science and Practice of Pharmacy,” Academic Press, London, United Kingdom, 23rd edition, 2020.

[0226] Pharmaceutical compositions as disclosed herein may be formulated to provide a therapeutically effective amount of a salt as disclosed herein in a reasonable volume or mass of the composition, which may be administered by any effective dosing schedule, such as once a day. Although the exact dosage may be determined on a drug-by-drug (compound-by-compound) basis, for most salts, some generalizations regarding the dosage can be made. For example, the daily dosage regimen for an adult human patient may be about 0.001 mg to about 1000 mg, such as about 0.01 mg to about 500 mg, for example about 1 to about 200 mg of the compound or pharmaceutically acceptable salt thereof, calculated as the free base or free acid.

[0227] METHODS OF TREATMENT

[0228] In a further aspect, there is provided a salt or a pharmaceutical composition disclosed herein, for use in therapy, e.g. for use in:

[0229] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0230] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0231] (iii) preventing or reducing risks of pre-term labor in a subject in need thereof;

[0232] (iv) preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof; (v) treating, preventing or reducing risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof; or

[0233] (vi) treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha- 1 -antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex- induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididimytis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and nonHodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

[0234] In another aspect, there is provided a method of:

[0235] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof; (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0236] (iii) preventing or reducing risks of pre-term labor in a subject in need thereof;

[0237] (iv) preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof;

[0238] (v) treating, preventing or reducing risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof; or

[0239] (vi) treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha- 1 -antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex- induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididimytis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and nonHodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF); wherein the method comprises administering to the subject a salt or pharmaceutical composition disclosed herein.

[0240] In a further aspect, there is provided use of a salt or pharmaceutical composition disclosed herein in the preparation of a medicament, e.g. for use in:

[0241] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0242] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0243] (iii) preventing or reducing risks of pre-term labor in a subject in need thereof;

[0244] (iv) preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof;

[0245] (v) treating, preventing or reducing risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof; or

[0246] (vi) treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha- 1 -antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, T orsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididimytis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions. In some embodiments, the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

[0247] In another aspect, disclosed herein are methods of treating a disease or disorder in a subject in need thereof, comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of a salt or pharmaceutical composition disclosed herein, wherein the disease or disorder is associated with abnormal levels (e.g., elevated levels) and / or abnormal expression (e.g., elevated expression) of PGF2a. In another aspect, there is provided a salt or pharmaceutical composition disclosed herein for use in treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is associated with abnormal levels (e.g., elevated levels) and / or abnormal expression (e.g., elevated expression) of PGF2a. In another aspect, there is provided the use of a salt or pharmaceutical composition disclosed herein for treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is associated with abnormal levels (e.g., elevated levels) and / or abnormal expression (e.g., elevated expression) of PGF2a.

[0248] In accordance with any of these methods or medical uses, the salt or pharmaceutical composition may be administered by any suitable route of administration as discussed above, and may be administered in a therapeutically effective amount as discussed above. As also discussed above, the administration may be by any effective dosing schedule, such as once a day, 1 to 4 times per day, once a week, 1 to 4 times per week, once a month, 1 to 4 times month, etc. Although the exact dosage may be determined on a drug-by-drug (compound-by-compound) basis, the daily dosage regimen for an adult human patient may be, for example, about 0.001 mg to about 1000 mg, such as about 0.01 mg to about 500 mg, for example about 1 to about 200 mg of the salt or pharmaceutically acceptable composition, calculated as the free base or free acid.

[0249] In accordance with any of these methods or medical uses, the salt or pharmaceutical composition may be administered in combination with an additional therapeutic agent. The additional therapeutic agent may be one or more useful for treating the condition or disease or disorder at issue. For example, the additional therapeutic agent may be useful for treating pre-term labor, reducing risks of or preventing pre-term birth, reducing risks of or preventing pre-term labor, reducing risks of or preventing labor prior to cesarean delivery, reducing risks of or preventing dysmenorrhea in a subject, or treating any of the diseases or disorders disclosed above. Nonlimiting examples of the additional therapeutic agent include an oxytocin receptor antagonist, (e.g. , atosiban, retosiban, barusiban, epelsiban, and nolasiban), a betamimetic (e.g., terbutaline, ritodrine, hexoprenaline, albuterol, fenoterol, nylidrin, or orciprenaline), a calcium channel inhibitor e.g., dihydropyridine, nifedipine, or nicardipine), a magnesium salt (e.g., magnesium sulfate), a progestogen (e.g. progestrone or 17-a-hydroxyprog esterone), and a nitric oxide donor (e.g., nitroglycerine).

[0250] The present technology, thus generally described, may be further understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present technology.

[0251] LIST OF FIGURES:

[0252] The present invention will now further be described, by way of example only, with reference to the following figures:

[0253] Fig. 1. a. XRPD diffractogram of tromethamine TG6-02 Hit 1 (obtained from ethanol), b. XRPD diffractogram of tromethamine TG6-02 Hit 2 (obtained from THF).

[0254] Fig. 2. a. XRPD diffractogram of lysine TG6-02 Hit 1 (obtained from ethanol), b. DSC thermogram for lysine TG6-02 Hit 1.

[0255] Fig. 3. a. XRPD diffractogram of meglumine TG6-02 Hit 1 (obtained from ethanol), b. XRPD diffractogram of meglumine TG6-02 Hit 2 (obtained from THF). c. DSC thermogram for meglumine TG6-02 Hit 1.

[0256] Fig. 4. a. XRPD diffractogram of tosylate TG6-02 Hit 1 (obtained from ethanol), b. XRPD diffractogram of tosylate TG6-02 Hit 2 (obtained from THF). c. DSC thermogram for tosylate TG6-02 Hit l.Fig. 5. a. XRPD diffractogram of potassium TG6-02 Hit 1 (obtained from ethanol), b. XRPD diffractogram of potassium TG6-02 Hit 2 (obtained from THF).Fig. 6. a. Detailed XRPD diffractogram of tromethamine TG6-02 Hit 1. b. Detailed XRPD diffractogram of tromethamine TG6-02 Hit 2.

[0257] Fig. 7. DSC thermogram for tromethamine TG6-02 Hit 1.

[0258] Fig. 8. DSC thermogram for tromethamine TG6-02 Hit 2.

[0259] Fig. 9. a. Gravimetric vapor sorption data for tromethamine TG6-02 Hit 1 ; change in mass (curve 1), target relative humidity (curve 2). b. GVS isotherm plot for tromethamine TG6-02 Hit 1; Sorption cycle 1, diamonds; desorption cycle 1, squares; sorption cycle 2, triangles; desorption cycle 2, circles.

[0260] Fig. 10. a. Gravimetric vapor sorption data for tromethamine TG6-02 Hit 2; change in mass (curve 1), target relative humidity (curve 2). b. GVS isotherm plot for tromethamine TG6-02 Hit 2; Sorption cycle 1, diamonds; desorption cycle 1, squares; sorption cycle 2, triangles; desorption cycle 2, circles.

[0261] Fig. 11. FT-IR spectrum of tromethamine TG6-02 Hit 1.

[0262] Fig. 12. FT-IR spectrum of tromethamine TG6-02 Hit 2.

[0263] Fig. 13. a. to d. SEM micrograph of tromethamine TG6-02 Hit 1 at increasing magnification.

[0264] Fig. 14. a. to d. SEM micrograph of tromethamine TG6-02 Hit 2 at increasing magnification.

[0265] EXAMPLES

[0266] General Methods All reactions were carried out in an oven-dried round-bottomed-flask under an inert nitrogen atmosphere with stirring. Solvents, reagents, and chemicals were purchased from various sources and used as received unless otherwise noted. Nuclear magnetic resonance chemical shifts are reported in 8 (ppm) relative units to residual 'H solvent peaks methanol-^ (3.30 ppm), CDCh (7.26 ppm), and DMSO-rfo (2.50 ppm); 'H signals from from exchangeable protons might be missing. Splitting patterns are assigned as s (singlet), d (doublet), t (triplet), multiplet (m), and dd (doublet of doublet).

[0267] Synthesis of BCO ketone

[0268] Procedure of step la

[0269] To a mixture of (1-1) (87.13 g, 385.07 mmol, 1 eq) in AcOH (870 mL) was added CrCh (77.01 g, 770.15 mmol, 2 eq) in one portion at 15°C. The mixture was heated to 90 °C and stirred for 18 hours. The mixture was added dropwise into NaHCCT (sat., 12 L). The mixture was extracted with ethyl acetate (1500 mL*2). The combined organic phases were washed with brine (1000 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate = 8 / 1 to 3 / 1) to give (1-2) (23 g, 95.73 mmol, 24.86% yield). At the same time, 36.4 g of (1-1) was recycled.JH NMR (400 MHz, chloroform-d) 8 ppm 3.69 - 3.79 (m, 6 H) 2.59 (s, 2 H) 2.26 - 2.37 (m, 2 H) 1.85- 2.14 (m, 6 H).

[0270] Procedure of step lb To a mixture of (1-2) (36.28 g, 151.01 mmol, 1 eq) in THF (170 mL) and MeOH (22 mL) was added LiOH. water (6.34 g, 151.01 mmol, 1 eq) as a solution in water (22 mL) at 0 °C. The mixture was warmed to 20 °C and stirred for 16 hours. The mixture was concentrated in vacuum, and the residue was diluted with water (320 mL). The mixture was extracted with MTBE (350 mL*2). The aqueous layer was adjusted to pH = 1 with HC1 (1 M). The residue was concentrated until a white solid precipitated. The precipitate was collected and dried under high vacuum to afford (1-3) (18 g, 79.57 mmol, 52.69% yield). ' H NMR (400 MHz, chloroform-d) 8 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).

[0271] Procedure of step 1c

[0272] To a solution of (1-3) (18 g, 79.57 mmol, 1 eq) int-BuOH (280 mL) was added pyridine (45.31 g, 572.88 mmol, 7.2 eq) and DMAP (9.72 g, 79.57 mmol, 1 eq). Then Boc2O (86.83 g, 397.83 mmol, 5 eq) was added slowly at 20 °C, and the mixture was stirred at 30 °C for 12 hours. The resulting solution was concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate (350 mL) and water (350 mL). Separated layers and the aqueous phase was extracted with ethyl acetate (350 mL). The combined organic phases were washed with water (160 mL), HC1 (1 M, 160 mL*2), NaHCCh (sat., 160 mL), brine (160 mL), dried with Na2SC>4 and concentrated under reduced pressure to afford (1-4) (13.8 g, crude). 'H NMR (400 MHz, chloroform-d) 8 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).

[0273] Procedure of step Id

[0274] To a mixture of (1-4) (13.8 g, 48.88 mmol, 1 eq) in THF (130 mL) and MeOH (34 mL) was added NaOH (2.59 g, 64.63 mmol, 1.32 eq) as a solution in water (34 mL) at 0 °C. The mixture was warmed to 25 °C and stirred for 12 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water (300 mL) and MTBE (400 mL). The mixture was filtered. The organic phase was removed. The aqueous phase was washed with MTBE (400 mL). The aqueous layer was acidified to pH = 1 with aqueous HC1 (1 M), and the precipitate was collected by filtration and dried under high vacuum to afford (1-5) (9.16 g, 34.14 mmol, 69.85% yield). 'H NMR (400 MHz, chloroform-d) 8 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).

[0275] Procedure of step le

[0276] To a solution of (1-5) (1.92 g, 7.16 mmol, 1 eq) in toluene (150 mL) was added phenylmethanol (2.32 g, 21.47 mmol, 3 eq), TEA (2.17 g, 21.47 mmol, 3 eq) and DPPA (1.97 g, 7.16 mmol, 1 eq) in this order at 15 °C. The mixture was then heated to 110 °C and stirred for 19 hours. The reaction mixture was cooled to 25°C and concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (160 mL*2). The combined organic fractions were dried with Na2SC>4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 10 / 1 to 5 / 1) to give BCO ketone (2.02 g, 5.41 mmol, 75.59% yield). 'H NMR (400 MHz, chloroform-d) 8 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).

[0277] Synthesis of INT 1

[0278] BCO Ketone INT 1

[0279] Procedure of step 2a

[0280] To a mixture of BCO ketone (1 g, 2.68 mmol, 1 eq) in THF (20 mL) was added LiHMDS (1 M, 5.36 mL, 2 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 1 hr. Then, 1 , 1 , 1 -trifluoro- N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.24 g, 3.48 mmol, 1.3 eq) in THF (10 mL) was added dropwise to the mixture at -78 °C. Then, the mixture was warmed and stirred at 20 °C for 12 hr. The mixture was poured into NH4CI (sat., 100 mL). The mixture was extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (20 mL), dried with Na2SC>4 and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 20) to give INT 1 (400 mg, 791.29 pmol, 29.55% yield).XH NMR (400 MHz, chloroform-d) 8 ppm 7.35 - 7.41 (m, 5 H) 6.38 (s, 1 H) 5.11 (s, 2 H) 2.15 - 2.24 (m, 2 H) 2.00 (br d, J = 3.29 Hz, 2 H) 1.71 - 1.78 (m, 2 H) 1.62 - 1.67 (m, 2 H) 1.49 (s, 9 H).

[0281] Synthesis of INT 2

[0282] Procedure of step 3a

[0283] To a mixture of BCO Ketone (50 g, 133.89 mmol, 1 eq) and 4A MS (25 g, 8.03 mmol, 16.67 eq) in EtOH (350 mL) was added NH2NH2. water (161.76 g, 3.23 mol, 24.13 eq) in one portion at 20 °C. The mixture was heated to 80 °C and stirred for 5 hours. The mixture was filtered and concentrated under vacuum. The residue was extracted between DCM (300 mL*3) and water (200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1) to give (3-1) (45 g, 116.14 mmol, 86.74% yield). [M+H]+= 388.3. 'H NMR (400 MHz, chloroform-d) 8 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)

[0284] Procedure of step 3b

[0285] To a mixture of (3-1) (45 g, 116.14 mmol, 1 eq) in piperidine (300 mL) and THF (250 mL) was added I2 (73.69 g, 290.34 mmol, 2.5 eq) which was dissolved in THF (350 mL) at 0 °C under Ar. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched by the addition of water (500 mL). The solution was extracted with ethyl acetate (500 mL*2), dried over Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCh, 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. 'H NMR (400 MHz, chloroform-d) 8 ppm 7.31 - 7.41 (m, 5 H) 7.04 (s, 1 H) 5.12 (br s, 2 H) 1.81 - 1.98 (m, 6 H) 1.54 - 1.58 (m, 2 H) 1.47 (s, 9 H)

[0286] Synthesis of INT 3, INT 4

[0287] R1= Br, I, CF3, t-Bu

[0288] Procedure of step 4a

[0289] A mixture of (4-1) (when R1=Br) (20 g, 88.49 mmol, 1 eq) and 1 -phenylpropan-1 -one (11.87, 88.49 mmol, 1 eq) in AcOH (240 mb) was stirred at 75 °C for 0.5 hr. After that, to this well stirred reaction was added HCI (12 M, 79.99 mL, 10.85 eq). The mixture was stirred at 105°C for 11.5 h. After cooling to room temperature, the mixture was poured into HCI (IM, 2000 mL). The solid was collected by filtration and then washed with the mixture of solvents (petroleum ether / ethyl acetate in a 2: 1 ratio, 1.5L) to give INT 3 (23 g, 67.21 mmol, 75.96% yield). [M+H]+= 344.0. 'H NMR (400 MHz, DMSO-d6) 8 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)

[0290] Procedure of step 4b

[0291] A mixture of INT 3 (R1=Br) (3 g, 8.77 mmol, 1 eq) in SOCh (49.20 g, 413.55 mmol, 47.17 eq) was stirred at 80 °C for 0.5 hr. Then the reaction mixture was concentrated directly to afford INT 4 (10 g, crude). ' H NMR (400 MHz, chloroform-d) 8 ppm 9.10 (1 H, d, J = 8.94 Hz) 7.95 - 8.03 (2 H, m) 7.64 (2 H, br d, J = 6.91 Hz) 7.53 - 7.60 (3 H, m) 2.52 (3 H, s).

[0292] Synthesis of INT 5

[0293] 5-2 INT 7

[0294] Procedure of step 5a

[0295] (5-1) (10 g, 43.85 mmol, 1 eq) in propanoyl propanoate (44.23 g, 339.85 mmol, 7.75 eq) was heated at 170 °C for 9 hours. After the reaction was completed, the reaction was cooled to room temperature. After filtration, the solid was washed with MTBE (500 mL) to give (5-2) (3.6 g, crude). ' H NMR (400 MHz, DMSO-d6) 8 ppm 12.00 (br s, 1 H) 7.63 (dd, J = 8.80, 1.96 Hz, 1 H) 7.52 (d, J = 1.83 Hz, 1 H) 7.27 (d, J = 8.80 Hz, 1 H) 2.05 (s, 3 H).

[0296] Procedure of step 5b To a mixture of (5-2) (500 mg, 1.77 mmol, 1 eq) in DMSO (10 mL) was added Mel (301.90 mg, 2.13 mmol, 1.2 eq) and TEA (269.03 mg, 2.66 mmol, 1.5 eq) in one portion at25°C under N2. The reaction was stirred at 55°C for 12 hours. After the reaction was completed, the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL*3). The organic phase was dried over Na2SC>4, filtered and concentrated to give (5-3) (265 mg, 894.92 pmol, 50.49% yield). 'H NMR (400 MHz, DMSO-d6) 8 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).

[0297] Procedure of step 5c

[0298] A mixture of (5-3) (265 mg, 894.92 pmol, 1 eq) in POCh (9.99 g, 65.18 mmol, 72.83 eq) was stirred at 100 °C for 2 hours. After that, the reaction was concentrated directly to give (5-4) (250 mg, crude). 'H NMR (400 MHz, chloroform-d) 8 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).

[0299] Synthesis of (INT 5)

[0300] To a mixture of morpholine (969.35 mg, 11.13 mmol, 10 eq) in t-BuOH (5 mL) was added (5-4) (350 mg, 1.11 mmol, 1 eq). The mixture was heated to 60 °C and stirred for 12 hours. Then the reaction was heated to 80 °C and stirred for another 60 hours. After the reaction was completed, the reaction mixture was concentrated directly to give a residue which was purified by prep-HPLC (column: Waters Xbridge BEH Cl 8 100*30mm*10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 5%-35% B over 10 min) to give INT 5 (320 mg, 911.18 pmol, 81.89% yield). 'H NMR (400 MHz, DMSO-de) 8 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).

[0301] Synthesis of (INT 7)

[0302] To a mixture of (5-2) (30 g, 106.35 mmol, 1 eq) in DCM (225 mL) was added SOCI2 (184.47 g, 1.55 mol, 14.58 eq) and DMF (777.35 mg, 10.63 mmol, 0.1 eq). The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 50 °C for 1 hr. The mixture was filtered and the filtrate was concentrated to give INT 7 (23 g, crude). 'H NMR (400 MHz, chloroform- ) 8 ppm 7.90 - 7.96 (m, 2 H) 7.83 - 7.88 (m, 1 H) 2.61 (s, 3 H)

[0303] Synthesis of INT 6

[0304]

[0305] Synthesis of (6-1)

[0306] To a mixture of (5-4) (1.4 g, 4.45 mmol, 1 eq) in t-BuOH (15 mL) was added pyrrolidine (1.58 g, 22.25 mmol, 5 eq) in one portion. The mixture was stirred at 60 °C for 12 hr. After the reaction was completed, the reaction mixture was acidified with HC1 (1 M) to adjust pH = 4. The residue was collected by filtration to give (6-1) (450 mg, 1.29 mmol, 28.95% yield).1H NMR (400 MHz, chloroform-d) 8 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). Synthesis of (INT 6)

[0307] To a mixture of (6-1) (450 mg, 1.29 mmol, 1 eq) in MeOH (5 mL), water (5 mL) and THF (5 mL) was added LiOH. water (162.22 mg, 3.87 mmol, 3 eq) in one portion. The reaction was heated to 80 °C for 12 hr. After the reaction was completed, the reaction was concentrated directly to give INT 6 (400 mg, 1.19 mmol, 82.61% yield). 'H NMR (400 MHz, methanol-4) 8 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)

[0308] 1.92 - 2.01 (m, 4 H).

[0309] Synthesis of TG6 series

[0310]

[0311] Procedure of step Ila

[0312] To a solution of (11-1) (1 g, 2.68 mmol, 1 eq) in THF (50 mL) was added Pd(OH)2 (350 mg, 20% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 Psi) at 20 °C for 1.5 hr. After the reaction was completed, the mixture was filtered and concentrated in vacuum to give a residue. Water (41 mL) was added to the residue, and the resulting mixture was adjusted to pH = 1 with HC1 (1.2 M). The aqueous layer was washed with ethyl acetate (60 mL*2), and the aqueous layer was lyophilized to give (11- 2) (590 mg, 2.14 mmol, 79.90% yield, HC1). 'H NMR (400 MHz, methanol-d4) 8 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).

[0313] Procedure of step 11b

[0314] To a mixture of (11-2) (590 mg, 2.14 mmol, 1 eq, HC1), DIEA (829.53 mg, 6.42 mmol, 3 eq) and (INT 3) (732.09 mg, 2.14 mmol, 1 eq) in DMF (26 mL) was added HATU (1.22 g, 3.21 mmol, 1.5 eq) in one portion at 20 °C. The mixture was heated to 60 °C and stirred for 12 hours. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL*2). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) and prep-TLC (Petroleum ether: Ethyl acetate = 2:1) to afford (11-3) (980 mg, 1.74 mmol, 81.29% yield). [M+H]+= 565.2. 'H NMR (400 MHz, chloroform-d) 8 ppm 8.02 (br d, J = 8.77 Hz, 1 H) 7.92 (s, 1 H) 7.76 (dd, J = 8.99, 1.97 Hz, 1 H) 7.44 - 7.58 (m, 5 H) 7.04 (br s, 1 H) 3.29 - 3.42 (m, 2 H) 2.73 (s, 2 H) 2.39 (s, 3 H) 2.23 - 2.34 (m, 2 H) 1.95 - 2.04 (m, 2 H) 1.88 (br t, J = 11.07 Hz, 2 H) 1.48 (s, 9 H).

[0315] Procedure of step 11c

[0316] A mixture of (11-3) (850 mg, 1.51 mmol, 1 eq) in DCM (20 mL) was added TFA (5 mL) was stirred at 20 °C for 2 hr. After the reaction was completed, the reaction was concentrated in vacuum to afford (11-4) (1 g, crude). [M+H]+= 509.1. 'H NMR (400 MHz, methanol-d-i) 8 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).

[0317] General procedure of step lid

[0318] To a mixture of (11-4) (1 eq) and hydroxylamine (HC1 salt) (6 eq) in EtOAc was added pyridine (10 eq) in one portion. The mixture was stirred at M°C for N hours. After the reaction was completed, the mixture was washed with HC1 (1 M). The organic phase was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC to give (TG6) (select compounds in Table 1).

[0319] Table 1: Detailed conditions:

[0320] Procedure of step lie

[0321] To a solution of (TG6-16) (0.18 g, 265.65 pmol, 1 eq) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give (TG6-18) (29.4 mg, 48.40 pmol, 18.22% yield, 95.07% purity). [M+H]+= 579.1. 'H NMR (400 MHz, DMSO-d6) 8 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). Procedure of step llf-1

[0322] To a solution of (TG6-18) (0.25 g, 361.54 pmol, 1 eq, TFA) in THF (2 mL) and water (0.7 mL) was added ISfeCCh (268.23 mg, 2.53 mmol, 7 eq) and CbzOSu (99.11 mg, 397.69 pmol, 1.1 eq), the mixture was stirred at 25°C under N2 for 2 h. The mixture was poured into ice-water (15 mL). The mixture was extracted with ethyl acetate: THF=1: 1 (15 mL*3). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to give a residue which was purified by prep-HPLC to give (TG6-19) (29.98 mg, 40.87 pmol, 11.30% yield, 97% purity). [M+H]+= 712.9. 'H NMR (400 MHz, DMSO-d6) 8 ppm 12.83 - 12.22 (m, 1H), 8.66 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.99 - 7.94 (m, 1H), 7.88 (dd, J = 2.1, 8.9 Hz, 1H), 7.60 - 7.47 (m, 5H), 7.38 - 7.27 (m, 5H), 5.20 - 5.11 (m, 1H), 4.99 (s, 2H), 4.23 (br s, 2H), 3.93 (br s, 2H), 2.73 (br s, 2H), 2.38 (s, 3H), 2.06 - 1.73 (m, 6H).

[0323] Procedure of step llf-2

[0324] To a solution of (TG6-18) (0.3 g, 433.85 pmol, 1 eq, TFA) in DCM was added TEA (219.50 mg, 2.17 mmol, 5 eq) and MsCl (0.14 g, 1.22 mmol, 2.82 eq). The mixture was stirred at 15°C under IS for 1 h. The mixture was poured into ice-water (15 mL). The mixture was extracted with DCM (15 mL*3). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to give a residue which was purified by prep-HPLC to give (TG6- 20) (40 mg, 60.29 pmol, 13.90% yield, 98.803% purity). [M+H]+= 656.9. 'H NMR (400 MHz, methanol-d4) 8 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).

[0325] Synthesis of TG14 series

[0326]

[0327] 19-3B 19d-1

[0328] Procedure of (19-1) To a solution of (BCO-Ketone) (0.3 g, 803.34 pmol, 1 eq) in THF (5 mL) was added LDA (2 M, 1.00 mL, 2.5 eq) at -78 °C. The mixture was stirred at -78 °C for 1 h. A solution of alkyl iodide (250.85 mg, 1.77 mmol, 2.2 eq) in THF (0.5 mL) was added into the reaction at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 h, allowed to warm to 20 °C over 0.5 h and stirred for another N h (see Table 2). The reaction mixture was poured into NH4CI (sat., 10 mL). The mixture was extracted with ethyl acetate (10 mL*3). The organic phase was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuum to give a residue. The residue was purified by column chromatography to give (19).

[0329] Table 2: Detailed conditions:

[0330] General procedure of step 19c

[0331] A mixture of (19-2) / (BCO-Ketone) (1 eq) and Pd / C (10 wt%, 10% purity) in EtOH and ethyl acetate was added into the bottle under Ar. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 Psi) (see details in Table 3). The suspension was filtered through a pad of Celite. The filter cake was washed with MeOH. The filtrate was concentrated in vacuum to give (19-3).

[0332] Table 3: Detailed conditions:

[0333] Procedure of step 19d-l

[0334] To a solution of (19-3A) (0.66 g, 2.47 mmol, 1 eq) and INT 3 (886.94 mg, 2.59 mmol, 1.05 eq) in DMF (10 mL) was added DIEA (1.12 g, 8.64 mmol, 3.5 eq) and HATU (1.03 g, 2.72 mmol, 1.1 eq). The mixture was stirred at 25°C for 12 h. The reaction mixture was poured into ice-water (80 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (20 mL*2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 1 / 0 to 2 / 1) to give (19-4A) (1.25 g, 2.11 mmol, 85.60% yield), (see details in Table 4) Procedure of step 19d-2

[0335] To a solution of (19d-l) (0.5 g, 887.34 pmol, 1 eq) in THF (6 mL) was added LDA (2 M, 1.11 mL, 2.5 eq) at -60 °C. The mixture was stirred at -60 °C for 1 hour. A solution of Mel (377.85 mg, 2.66 mmol, 3 eq) in THF (1 mL) was added into the reaction at -60 °C. The reaction mixture was stirred at -60 °C for 0.5 hour, allowed to warm to 20 °C for 0.5 hour and stirred for 10 hours. The reaction mixture was poured into NH4CI (sat., 50 mL) and extracted with ethyl acetate (20 mL*3).

[0336] The combined organic layers were washed with brine (15 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1) to give (19-4B) (0.27 g, 467.53 pmol, 52.69% yield), (see details in Table 4)

[0337] Procedure of step 19d-3

[0338] To a solution of (19-3C) (0.8 g, 2.99 mmol, 1 eq) and INT 4 (1.08 g, 2.99 mmol, 1 eq) in DCM (9 mL) was added NaHCCb (3.02 g, 35.91 mmol, 12 eq) in water (9 mL) at 0 °C. The reaction was stirred at 25°C for 12 hours. The reaction mixture was quenched by addition water (10 mL) and extracted with DCM (10 mL*3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 1 / 0 to 3 / 1) to give (19- 4C) (1 g, 1.69 mmol, 56.50% yield), (see details in Table 4)

[0339] Table 4: Detailed conditions:

[0340] General procedure of step 19e To a solution of (19-4) (1 eq) in a mixture of solvents (DCM / TFA in a 5:1 ratio) at M°C. The mixture was stirred at (see details in Table 5). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography or used as is for next stepto give (19-5). Table 5: Detailed conditions:

[0341] General procedure of step 19f

[0342] To a solution of (19-5) (1 eq) and INT 19f (6 eq, HC1) in THF was added pyridine (12 eq) and Ti(OEt)4 (10 eq). The mixture was stirred at 80 °C for 36 h. The residue was diluted with water and filtered through a pad of Celite. The filter cake was washed with a mixture of solvents (ethyl acetate / THF in a 2: 1 ratio). The combined filtrate was washed with HC1 (1 M), washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give (TG14). (see details in Table 6)

[0343] Table 6: Detailed conditions:

[0344]

[0345] General procedure of step 19g

[0346] TG14 series was separated by prep-SFC to give TG14 series (in Table 7), absolute stereochemistry was not assigned. Table 7: Detailed conditions: (indicates an arbitrary stereochemistry assignment was made to distinguish different isomers that were isolated; absolute stereochemistry was not determined and may not match the depicted stereochemistry).

[0347] Procedure of step 19h

[0348] To a solution of (19-3B) (3 g, 12.54 mmol, 1 eq) and INT 4 (4.52 g, 12.54 mmol, 1 eq) in DCM (30 mL) was added NaHCCb (11.81 g, 140.53 mmol, 11.21 eq) at 20 °C for 12 hours. The reaction mixture was quenched by addition water (70 mL) and extracted with DCM (50 mL). The combined organic layer was washed with brine (60 mL*2), dried over IS^SCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 / 0 to 89 / 11) to give (19d-l) (2 g, 3.55 mmol, 28.31% yield). [M+H]+=565.1. 'H NMR (400 MHz, chloroform-d) 8 ppm 8.03 (br d, J = 8.70 Hz, 1 H) 7.91 (d, J = 1.67 Hz, 1 H) 7.76 (dd, J = 9.00, 2.09 Hz, 1 H) 7.43 - 7.60 (m, 5 H) 6.99 - 7.08 (m, 1

[0349] 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). Table 8: Purification Methods

[0350] Column information for Prep-HPLC and SFC Table 9: Purification Conditions

[0351]

[0352] Biological Activity Assays

[0353] FP receptor myo-inositol 1 phosphate (IP1) accumulation assay

[0354] Compounds were tested for FP antagonist activity in human embryonic kidney (HEK-EBNA; 293 cl 8: ATCC, CRL-10852) cell lines stably expressing a cloned human FP receptor. The FP receptor couples to the Gq pathway to induce phospholipase C (PLC) activation and triggers the inositol phosphate (IP) cascade. PLC then cleaves phosphatidylinositol 4, 5 -bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4, 5 -trisphosphate (IP3), resulting in a transient increase of intracellular calcium. The lifetime of IP3 is very short (less than 30 seconds) before being transformed into inositol bisphosphate (IP2) and then IP1. IP1 is accumulated in the cell and is stable in the presence of LiCl in StimB buffer.

[0355] This method is a competitive immunoassay between native IP1 produced by cells and d2-labeled IP1. The specific signal (energy transfer) is inversely proportional to the concentration of IP1 in the standard or sample. This was measured using the Cisbio IP-One cell-based second messenger accumulation assay kit; competitive immunoassay using d2-labeled IP1 (acceptor) and anti-IPl-

[0356] Cryptate antibody (donor). The following steps were performed on the day of the experiment. Cells in T175 flasks were removed from culture flasks using trypsin buffer and harvested in IX StimB. Compound solutions for concentration -response analysis of test and reference antagonists were added to HTRF 384- well white low volume assay plates (15nL of lOOOx solution), and cells subsequently seeded at a density of 10,000 cells / well in 10 pL; this was incubated for 30 minutes at 37 °C under 5% CO2 in a humidified atmosphere. Next, agonist concentration-response curves or agonist compound solution (5 pL of 3x solution) were sequentially added to the appropriate wells of the 384 well assay plate and incubated for 60 minutes at 37 °C under 5% CO2 in a humidified atmosphere. In a separate HTRF 384 well white low volume assay plate, 15 pL of IP1 standard curve was added to designated wells of the IP1 standard curve plate.

[0357] HTRF reagents were reconstituted with distilled water in accordance with kit instructions. Detection reagents (IPl-d2 and anti -IP 1 cryptate) were then added to designated wells of both the assay plate and standard curve plate and incubated for 1 hour in the dark at room temperature. The reference agonist and reference antagonist were run in each assay plate, and one standard curve run per experimental day in a separate assay plate. HTRF signal was measured using a Pherastar plate reader with the default HTRF setting of emissions at 337 nm, 665 nm and 620 nm.

[0358] The ratio of 337 nm / 665 nm and 337 nm / 620 nm time-resolved fluorescence readings (RFU) for each well were calculated and multiplied by 10,000 to obtain whole numbers for data analysis. For the IP standard curve, the ratio* 10,000 was plotted on the y-axis versus IP1 concentration on a logarithmic scale on the x-axis. The curve fitting model (Model205), a single-binding site, four parameter concentration response model: (MIN+((MAX-MIN) / (l+((IC5o / x)AHill)))), was used to perform non-linear regression analysis, generating the concentration response curve for the standards. The expected IP1 standard curve IC50 after incubation for 1 hour at room temperature is 100-200 nM. IC50 is the IP1 concentration calculated in regression analysis to displace 50% of the maximal binding of the tracer, and the Hill is the slope of the calculated regression curve at the inflection point. The IP1 standard curve was used to extrapolate the IP1 concentration from the ratio* 10,000 data relative to each raw data point for each test compound, if the raw data fall in the linear range of the standard curve. The linear range of the standard curve (typically 10 to 1 ,000 nM) was calculated based on the widest set of points for which the R2value is greater than 0.97. For the antagonist reference and test compounds the logarithm of the extrapolated IP1 concentrations of the triplicate test wells were averaged, and the curve-fitting model was used to perform nonlinear regression analysis, generating the concentration response curve and the IC50. The KB (equilibrium dissociation constant of the antagonist-receptor complex) is calculated using the Leff- Dougall equation.

[0359] KB = IC50

[0360] (2 + ([Agonist] / Agonist EC50 )Hill)1 / Hi" - 1 where [Agonist] is the concentration of reference agonist used in the antagonist testing scheme, Agonist EC50 is the concentration of reference agonist that produces 50% of the maximal possible effect when tested as a concentration-response in the agonist testing scheme, and Hill is the absolute value of the Hill coefficient / slope function for reference agonist when tested as a concentration-response in the agonist testing scheme. Note that the Agonist EC50 and Agonist Hill values are those resulting from the parallel testing (in the same assay plate) of the reference agonist with the test antagonist compounds.

[0361] EP4 receptor cyclic AMP (cAMP) accumulation assay

[0362] Compounds were tested for EP4 antagonist activity in DLD-1 cells (ATCC, CCL-221) derived from human colon transiently expressing the human EP4 receptor. Cells were exposed to varying concentrations of test compounds followed by exposure to a submaximal concentration of an EP4 selective agonist (TCS2510). Antagonist inhibition of cAMP accumulation is then assessed. cAMP accumulation is measured through an HTRF (homogeneous time resolved fluorescence)-based competitive cAMP immunoassay using the cAMP - Gs Dynamic Kit (Cisbio). This was measured using the Cisbio IP-One cell-based second messenger accumulation assay kit; competitive immunoassay using d2-labeled cAMP and europium cryptate labeled anti-cAMP antibody.

[0363] 1x107DLD-1 cells were placed in a T75 flask with 10ml of growth medium and transfected with EP4 Construct 1 day prior to assay according to table below.

[0364] Tubes were incubated at room temperature for 15 minutes. Contents of Tube 2 were then added to Tube 1 and incubated for another 15 minutes. Combined contents in Tube 1 were added to T75 transfection flasks with DLD-1 cells and incubated overnight at 37 °C under 5% CO2 in a humidified atmosphere. On the day of the assay, cells were detached from the flask with trypsin and harvested for addition to assay plate (10,000 cells / well in cAMP Stimulation Buffer supplemented with 500 pM IBMX). Compound solutions for concentration-response analysis of test and reference antagonists were added to HTRF 384-well white low volume assay plates (10 nL of lOOOx solution); lOnL of Agonist 1000X stock solution; and cells subsequently seeded at a density of 10,000 cells / well in 10 pL; this was incubated for 90 minutes at 37 °C under 5% CO2 in a humidified atmosphere.

[0365] Detection reagents (cAMP-d2 and anti-cAMP cryptate) are then added to designated wells of both the assay plate and standard curve plate and incubated for 1 hour in the dark at room temperature. Note that the reference agonist and reference antagonist are run in each assay plate, and one standard curve is run per experimental day in a separate assay plate. HTRF signal is measured using a Pherastar plate reader with the default HTRF setting of emissions at 337 nm, 665 nm and 620 nm. Data analysis and IC50 and KB calculations were performed as described for the FP assay above.

[0366] Data for the FP receptor and EP4 receptor assays are shown in the table below. In this, the selectivity of a number of example compounds is compared to that of comparator compound REF27. The selectivity ratio for hFP over hEP4 is calculated as hEP4 Kb / hFP Kb. The comparator compound (REF27) is disclosed in J. Med. Chem. 2020, 63, 11639-11662.

[0367]

[0368] (REF27)

[0369] Mouse parturition model

[0370] The ability of a salt or pharmaceutical composition of the present disclosure to delay parturition is tested in a mouse parturition assay. Primigravid mice are received at gestational day 11 (GDI 1); mice are acclimatized to the laboratory conditions for at least 3 days before the start of experiments. Animals are housed in groups of 3-5 in polysulfone type Sealsafe plus GM500 cages on a bed of wood chips with free access to food and water. Starting from GDI 6 (evening) treatment with a a salt or pharmaceutical composition of the present disclosure is initiated twice daily (morning and evening) for a total of 8 administrations until GD20 (morning). At GDI 6, just after the first treatment, mice are housed individually with food and water ad libitum. No enrichment is added, and the chow is placed directly into the cage. Mice are continuously monitored using infrared cameras and a digital video recorder to capture the time of parturition of pups. In addition to video recording, cages are visually inspected each morning and the evening during the treatment for the presence of pups or evidence of delivery. The following data are collected: maternal viability; maternal body weight (daily from GDI 6, in grams); time of parturition, defined as the time when the first pup is delivered; percentage of mice delivering on each gestation day; and length of gestation in days. The mice show a positive response to treatment.

[0371] Rat intrauterine pressure (IUP) model

[0372] The methods to test FP antagonists of the present disclosure in vivo for inhibition of PGF2a- induced increase in intrauterine pressure (IUP) in rats are adapted with modifications from Cirillo etal. Am. J. Obstet. Gynecol. (2007), 197(l):54.el-9,. In brief, non-pregnant Sprague Dawley rats with vendor-placed vessel catheters (carotid artery catheter (CAC), jugular vein catheter (JVC) and femoral vein catheter (FVC)) are used in these studies. On the day of the experiment, rats are placed under terminal anesthesia and a fluid filled catheter is implanted in the uterine horn of each animal for measurement of IUP. PGF2a is administered by intravenous (IV) infusion via JVC for 5 minutes in 5 challenges separated by 30 minutes. A a salt or pharmaceutical composition of the present disclosure is administered by IV infusion via FVC beginning 5 minutes prior to and during the fourth PGF2achallenge. Thus, the salt or pharmaceutical composition is infused IV for a total of 10 minutes. The inhibition of PGF2a-induced increase in IUP is determined by comparing the PGF2a-induced change in IUP during the fourth challenge to the third challenge measured in the same animal and expressed as a percentage. Mean arterial pressure (via CAC) and IUP are measured continuously and data is acquired with the Notocord-hem software. The rats show a positive response to treatment.

[0373] Mouse silica-induced pulmonary fibrosis model

[0374] Silica-induced fibrosis mouse model (10 days) is used to assess the in vivo efficacy of a salt or pharmaceutical composition of the present disclosure. The method as described in Beck et al, J. Med. Chem. 2020, 63, 20, 11639-11662 (Supporting information) is employed. The mouse models show a positive response to treatment.

[0375] Clinical trial in female human subjects: endometriosis-associated pain

[0376] A a salt or pharmaceutical composition of the present disclosure is administered to female human subjects suffering from endometriosis-associated pain. Subject response to the salt or pharmaceutical composition administration is evaluated by a pain Visual Analogue Scale (VAS). Subjects show a positive clinical response to treatment.

[0377] Clinical trial in female human subjects: dysmenorrhea

[0378] A salt or pharmaceutical composition of the present disclosure is administered to female human subjects suffering from dysmenorrhea. Subject response to the salt or pharmaceutical composition administration is evaluated by a pain Visual Analogue Scale (VAS). Subjects show a positive clinical response to treatment.

[0379] Clinical trial in female human subjects: pre-term birth

[0380] A salt or pharmaceutical composition of the present disclosure is administered to female human subjects having intact membranes (e.g., without rupture of the amniotic sac) and who are at risk of or in preterm labor. Subjects are evaluated by complete blood picture (CBC), bleeding profile, kidney function tests and liver tests, and ultrasound testing. Subjects show a positive clinical response to treatment.

[0381] Clinical trial in human subjects: idiopathic pulmonary fibrosis

[0382] A salt or pharmaceutical composition of the present disclosure is administered to human subjects suffering from idiopathic pulmonary fibrosis. Subject response to the salt or pharmaceutical composition administration is evaluated by change from baseline in Forced Vital Capacity (FVC) at week 24. Subjects show a positive clinical response to treatment.

[0383] Salt screen of TG6-02 and crystalline form screen of tromethamine salt Experimental

[0384] Material

[0385] Solvents

[0386] Solvents used in the crystallisation and salt screens are listed in Table 10, below. All solvents (except water) were dried using molecular sieves before use. Table 10. Properties of solvents used in the screen a: According to Statistical cluster analysis of pharmaceutical solvents, D. Xu, N.Redman-Furey, International Journal of Pharmaceutics 339 (2007), 175-188.

[0387] Acid counterions

[0388] The compounds used as acid counterions in the salt screen are listed in Table 11, below. Table 11. Acidic compounds used as counterions in the salt screen

[0389] Basic counterions

[0390] The compounds used as basic counterions in the salt screen are listed in Table 12, below.

[0391] Table 12: Basic compounds used as counterions in the salt screen

[0392] Material for biorelevant solubility determinations

[0393] The materials used for the biorelevant solubility determinations are listed in Table 13 below.

[0394] Table 13. Materials used for biorelevant solubility determinations Instrumentation

[0395] X-ray powder diffraction (XRPD)

[0396] Instrument: PanAlytical X’Pert Pro

[0397] The instrument was regularly quality controlled with respect to peak positions using NIST standard 1976b. The tolerance was set to ±0.18 °20 from theoretical values.

[0398] Measurement parameters are set out in Table 14, below.

[0399] Table 14. Measurement parameters for XRPD measurements

[0400] Sample preparation: Powder samples (approximately 5 to 10 mg) were applied with a spatula and smeared out on the zero-background holder. Suspension samples (approximately 5 to 10 mg) were added dropwise to the zero background wafers of silicon and the solvent was allowed to evaporate, after which analysis was started immediately.

[0401] XRPD diffractogram peak positions were determined using the software Highscore Plus, version 4.9 (Malvern Panalytical B.V).

[0402] A typical accepted error of the XRPD methods is ± 0.2 °2theta. The error is a sum of the detector position (zero point) error and sample height error. The zero-point error is constant over the 2theta- range. It is checked regularly with an external standard and has always been less than 0.05 °2theta at Magle Chemoswed. The sample height error is variable over the 2theta-range and is largest at low angles. It varies from sample to sample, and it may be determined for an individual sample by adding an internal standard, but this was not applied when obtaining any of the data below. However, for low amounts of fine powder, as have been used in this case, the height error is likely to be small, e.g. < 0.05 °2theta. Thus, the true precision is likely to be better than the variation of ± 0.2 °2theta suggested.

[0403] The relative intensities should only be taken as approximative, since particle shape, size and orientation may have a significant impact on the intensity of individual peaks.

[0404] Thermal Gravimetric Analysis (TGA)

[0405] Instrument: PerkinElmer TGA8000

[0406] The instrument was quality checked regularly with respect to recorded weight (using a platina standard weight) and temperature (using alumel and nickel standards). The accuracy is >0.02% and precision is about 0.01%.

[0407] Method: About 2-5 mg of sample was gently placed into open Pt-pans and analysed by weight in a flow of dry nitrogen gas (40 ml / min), to ensure an inert atmosphere, from 25 °C up to a final temperature of 250 or 300 °C, using a continuous heating rate of 10 K / min and without any initial hold time. For selected samples, additional TGA experiments were carried out with the purpose to provide a modified sample without volatile component. This was performed by heating the original samples to 180 °C at 10 K / min. These samples were subsequently analysed by XRPD.

[0408] Differential scanning calorimetry (DSC)

[0409] Instrument: Netzsch DSC 204F1

[0410] The instrument was quality checked regularly with respect to temperature and sensitivity (enthalpy) using indium metal. The instrument was thoroughly serviced annually with respect to temperature and sensitivity using adamantane, indium, tin, bismuth and caesium chloride.

[0411] Method: About 1-2 mg of sample was gently placed into an Al non-hermetic pan, and weighed. A lid with a pre-made pinhole was adapted and crimped onto the pan. Each sample was analysed using a modulated temperature profile with an average heating rate of 5 K / min, modulation period of 20 s and an amplitude of ± 0.5 or 0.25 K. Minimum temperature (start) was 0 °C and maximum temperature was 250, 300 or 350 °C depending on decomposition observed on TGA analysis.

[0412] The melting point onset for a substance may be impacted by many factors, both instrument- and sample-related, such as temperature ramp speed, sample cup type, pin hole geometry, sample purity, bulk density, crystallinity, particle size and particle shape. For a very reproducible sample run on the same instrument, precision is within ±1 °C, but because of the factors described above, melting point depressions of up to 10 °C are possible.

[0413] FTIR spectroscopy

[0414] Instrument: Shimadzu IRAffinity-1 FTIR instrument with Pike Miracle ATR accessory

[0415] System suitability test: The instrument was regularly quality checked with respect to the position of peak positions using a polystyrene film (International Crystal Laboratories, lot 0009-8448- 5212). The accuracy is about ±1 cm .

[0416] Sample preparation: About 2-5 mg of sample was applied to the ATR crystal. Measurement parameters are set out in Table 15, below.

[0417] Table 15. Measurement parameters for FTIR measurements

[0418] Scanning Electron Microscopy (SEM) Instrument: Zeiss EVO LS 10.

[0419] Sample preparation: The samples self-adhered onto adhesive carbon tape on a SEM sample holder stub. The samples were then coated to produce a conducting surface.

[0420] Measurement parameters are set out in Table 16, below.

[0421] Table 16. Measurement parameters for SEM measurements

[0422] Gravimetric vapor sorption (GES) Instrument: SMS DVS Advantage

[0423] System suitability test: The instrument was regularly quality checked with respect to weight, temperature and relative humidity using standard weights, a pre-checked thermometer and saturated LiCl and NaCl solutions, repsectively. Sample preparation: About 1 -5 mg of sample was gently charged into a sample pan.

[0424] Measurement parameters are set out in Table 17, below.

[0425] Table 17. Measurement parameters for GVS measurements Instrument: Mettler-Toledo FP20 pH meter equipped with a LE422 micro electrode

[0426] System suitability test: The pH probe was calibrated daily using standard buffers at pH 1.68, 4.00 and 7.00.

[0427] Method: The pH probe was inserted into vials containing equilibrated solutions after sampling for concentration determination.

[0428] HPLC / UV

[0429] Instrument: Agilent 1100 HPLC

[0430] Method: An isocratic method was applied according to the parameters given in the Table 18, below. The retention time for the compound was ca. 3.95 minutes. Calibration curves based on samples of TG6-02 of known concentration were obtained.

[0431] The calibration curve, with the intercept forced through zero, gave slope factors of 27.9 or 27.0.

[0432] Table 18. Measurement parameters for HPLC / UV measurements

[0433] Procedures

[0434] Solvent screen

[0435] Samples of about 4 mg of TG6-02 were weighed into HPLC vials.

[0436] Subsequent aliquots of 20 and 100 pL of various different solvents were added until complete dissolution of the solid material was visually confirmed. If solid material remained after addition of 1.5 mL of solvent, the vial was left for 24 hours, before concluding the result.

[0437] Salt screen experiments

[0438] Salt screen experiments were performed in slurries, composed of about 15 mg TG6-02, in 0.2 mL of THF or 0.3 mL of ethanol. These solvents were selected based on the results of the initial solubility screen. Eight different counter ions (two acids and six bases), see Tables 11 and 12, above, were selected. The added amount of counter ion was adjusted to an approximative ratio of Ljust over 1 of TG6-02:counter ion. Additionally, samples of TG6-02 without any counterion were run in both solvents, for reference. The experiments were carried out in 1.5 ml HPLC-vials which were sealed with screw caps and stirred at ambient conditions. Slurries were analysed after four days.

[0439] Formation of tromethamine salt ofTG6-02 (Hit 1)

[0440] A first batch was produced by suspending 441 mg (0.76 mmol) of TG6-02 and 99 mg (0.82 mmol) of tromethamine in 10 mL ethanol at room temperature overnight. The solid was isolated by vacuum filtration. A second batch was produced by suspending 279 mg (0.48 mmol) of TG6-02 and 63 mg (0.52 mmol) of tromethamine in 4 mb of ethanol at room temperature overnight. The solid was isolated by vacuum filtration.

[0441] Visual solubility of tromethamine salt ofTG6-02 (Hit 1)

[0442] The solubility of the tromethamine salt of TG6-02, formed in ethanol, was visually assessed in various organic solvents, at room temperature. Samples of about 2 mg of the tromethamine salt of TG6-02 (Hit 1) were weighed into HPLC vials. Subsequent aliquots of 50 pL of different solvents were added until complete dissolution of the solid material was visually confirmed. If solid material remained after addition of 1.0 mL of solvent, the vial was left overnight, before concluding the result. If solid was still present, the assessed solubility was assumed to be less than 2 mg / mL.

[0443] Slurry experiments of tromethamine salt ofTG6-02

[0444] Samples of 20 mg of tromethamine salts of TG6-02 were used in slurry experiments (13 samples in total). The suspensions were magnetically stirred at room temperature for four days or at 40 °C for two days.

[0445] Solubility determination - biorelevant media

[0446] Preparation of solubility media for tests with TG6-02 and different salts thereof:

[0447] 1. “Blank SGF”: 201 mg of NaCl was dissolved in 100.0 mL of water (34 mM) in a volumetric flask. Concentrated HC1 was added dropwise until pH 1.2 was obtained.

[0448] 2. SIF (USP): A 1.0 M NaOH solution was prepared by dissolving 4.0 g of NaOH in 100.0 mL water. 681 mg (5.0 mmol) of KH2PO4 and 2.2 mL of the 1 MNaOH solution was diluted to 100.0 mL with water in a volumetric flask, to provide a buffer solution with a buffer strength of 50 mM, [K+] = 50 mM and [Na+] = 22 mM. The pH had to be adjusted to 6.8 with a few drops of 1.0 M NaOH solution. 3. FASSIF v2: 223 mg (1.9 mmol) of maleic acid, 401 mg (6.9 mmol) of sodium chloride and 3.48 mL of 1.0 M (3.48 mmol) NaOH solution (from SIF preparation) were dissolved in 100.0 mL of water. The pH was adjusted to 6.5 using a drop of 5 M HC1.

[0449] At the day of each solubility determination experiment, 70.7 mg (3 mM) of sodium taurocholate and 6.6 mg (0.2 mM) of L-a-lecithin were dissolved in 40 mL of the prepared maleic acid buffer, and the media was immediately used.

[0450] Solubility equilibration: Samples of the nominated isolated salts were weighed into separate vials, 1 -2 mg in 6 vials per salt and 3 mL of the three different solubility media was added to two each of the vials, respectively. The resulting suspensions were magnetically stirred at ambient temperature, ca. 23 °C. After 60 ± 5 minutes, 1.0 mL of each suspension was transferred to an Eppendorf tube and the equilibration quenched by centrifugation for 15 minutes. After 48 ± 1 hour, the remaining volumes of the samples were transferred to new Eppendorf tubes and centrifuged for 15 minutes to separate the solid. Directly after centrifugation, 500 pL of the clear solutions were transferred to vials and diluted with 1000 pL of acetonitrile, to obtain analytical samples with an acetonitrile to water ratio of 2 to 1 and a dilution factor of three. For the 48 hours samples, the final pH and end solid form (by XRPD, pooled material from both duplicates) were also determined. The samples were stored in freezer at -20 °C between solubility determination and HPLC analysis. The samples were analysed with HPLC / UV using a 50 pL injection volume.

[0451] Results and discussion

[0452] XRPD characterization of TG6-02

[0453] Two batches of this material were characterized by XRPD. The diffractograms signals were identical, showing that each batch had the same structure, and, in view of the sharp shape of the signals, the structure was crystalline.

[0454] Solubility of TG6-02 in organic solvents A solubility screen using TG6-02 was carried out with ten solvents, each having different solvating properties (see first ten solvents of Table 10, above).

[0455] The estimated solubilities, based on visual observation, of TG6-02 are given in Table 19. Based on these solubility data obtained, it can be concluded that TG6-02 has limited solubility in many typical solvents. THF and ethanol were nominated as solvents to use for the salt screen.

[0456] Table 19. Solubility, by visual inspection, of TG6-02 at room temperature (RT).

[0457] * Not dissolved after 24 hours

[0458] Salt screen of TG6-02

[0459] These were carried out in THF and ethanol. Reference samples of TG6-02 without a counterion were also carried out to assess if any new forms, such as new crystalline forms, were associated with the counterion used. The salts were analysed by XRPD and, if a new diffractogram was observed, the material was assessed by TGA to assess the percentage volatile component. The results are shown in Table 20.

[0460] Table 20. Overall summary of the results from the salt screen experiments, where the numbers in parenthesis indicate the salt form observed in that experiment (ie. Hit (1) and Hit (2) have different diffractograms). 3Weight loss in TGA, 25-160 °CbWeight loss in TGA 25-120 °C only, due to subsequent degradation “Poor Hit” = peaks in diffractogram are not very well-resolved.

[0461] The tromethamine Hit 1 (formed in ethanol) was identified as having no detectable levels of a volatile component. Many of the salt forms obtained from THF contained large amount of volatile component, indicative of solvate formation. In general, no agreement in diffractogram between the ethanol and THF slurries was observed for any of the counterions.

[0462] Based on these results, the meglumine, sodium, tromethamine, L-lysine and tosylate salts formed in ethanol were selected for further characterization, including DSC and solubility determination in biorelevant media. DSC of meglumine, sodium, tromethamine. L-lysine and tosylate salts of TG6-02 formed in ethanol

[0463] The results of DSC analyses are summarised in Table 21 .

[0464] Table 21. Summary of DSC analyses of different salts of TG6-02 isolated from ethanol

[0465] Solubility of meglumine, sodium, tromethamine. L-lysine and tosylate salts of TG6-02 formed in ethanol, in biorelevant media

[0466] Solubility in different biorelevant media (SGF, SIF and FASSIF v2), was determined for each salt in duplicate (i.e. analysis was repeated) using shake-flask methodology and quantified with HPLC. Solubility in SGF and SIF was also determined for the amorphous compound without a counterion. Solid form and solution pH at the end of the experiments were also determined. Data for the different tested salts are presented per biorelevant media in Tables 22 - Table 24

[0467] Table 22. Solubility of different salts and amorphous compound of TG6-02 in SIF (pH 6.8, end pH = 6.6- 6.9) aCalculation of solubility is based on a calibration curve with Area = 27.879 * [TG6-02] (nominal injection 10 pL), an injection volume of 50 pL and a dilution factor of 3 for the analysed samples.

[0468] Table 23. Solubility of different salts and amorphous compound of TG6-02 in SGF (pH 1.2, end pH = 1.3- 1-4) aCalculation of solubility is based on a calibration curve with Area = 27.879 * [TG6-02] (nominal injection 10 p L), an injection volume of 50 pL and a dilution factor of 3 for the analysed samples.

[0469] Table 24. Solubility of different salts of TG6-02 in FaSSIF v2 (pH 6.5, end pH = 6.4-6.6) aCalculation of solubility is based on a calibration curve with Area = 27.879 * [TG6-02] (nominal injection 10 p L), an injection volume of 50 pL and a dilution factor of 3 for the analysed samples.

[0470] Three general effects can be deduced from the data: a) There is a significant (but transient) effect on the solubility from the salt formation. The SIF solubilities after one hour for the different salts are larger than those of TG6-02 without a counterion by a factor of 5-30, depending on the salt. b) The solubilities of the salts reduced between the 1 and 48 hours, which is consistent with the parent compound slowly precipitating, as determined by XRPD. c) The measured solubilities of the TG6-02 salts were generally higher in FaSSIF v2 than in SIF and SGF, particularly for salts comprising weak basic counterions. Solubility ranking of all the different salt forms of TG6-02 (ordered according to solubility in FaSSIF v2 were: Tromethamine > L-lysine > Tosylate > Na+ >Meglumine - ranging from 206 to 23 pg / mL in average solubility after one hour.

[0471] The solids isolated after 48 hours were analysed by XRPD (duplicates pooled). Most of the obtained diffractograms were very similar owing to precipitation of TG6-02 without a counterion. The transformation of the salts back to the parent compound (TG6-02 without a counterion) means that low solubility values may correspond to faster transformation of the salt back to the parent compound.

[0472] In summary, the dissolution rate of TG6-02 can be increased by salt formation, and that the salts most soluble in biorelevant solvents are tromethamine, L-lysine and tosylate, with tromethamine and L-lysine being the most soluble in FaSSIF v2 (the solvent best mirroring the conditions in the intestine). Tromethamine salt of TG6-02

[0473] XRPD diffractograms of the solid materials isolated from an ethanol or THF slurry of TG6-02 together with tromethamine are shown in Fig. la and lb. The solids obtained from ethanol and THF have diffractograms that differ from each other and from reference diffractograms of TG6- 02 without a counterion, confirming that salt formation has occurred. The diffractograms comprise a large number of sharp peaks, consistent with a crystalline nature of the tromethamine salt forms.

[0474] TGA curves for these materials were similar, with just a small initial weight loss of 2.2% for the THF sample and 0.7 % for the ethanol sample, up to 120 °C. Significant degradation occurred from 150 °C. The DSC curve for this sample indicated a large endothermic event with an onset melting point of 219 °C.

[0475] L-lysine salt of TG6-02

[0476] The XRPD diffractogram of the solid material isolated from an ethanol slurry of TG6-02 together with L-lysine is shown in Fig. 2a. A crystalline form did not form in THF. A new diffractogram signal pattern comprising sharp peaks was detected from the sample formed in ethanol, suggesting that a crystalline salt had formed. The diffractogram comprises peaks at positions listed in Table 25.

[0477] Table 25. Peak positions and relative intensities of the peaks in XRPD diffractogram corresponding to lysine TG6-02

[0478] 1Using Cu Ka\ radiation, wavelength 1.5406 A

[0479] The recorded weight loss by TGA from the solid material isolated from ethanol was 2.8% up to 160 °C. Significant degradation starts from 180 °C.

[0480] The DSC curve for this sample is shown in Fig. 2b, which includes two significant endotheric events, with onset temperatures of 192 °C and 245 °C.

[0481] Meglumine salt of TG6-02

[0482] XRPD diffractograms of the solid materials isolated from an ethanol or THF slurry of TG6-02 together with meglumine are shown in Fig. 3a and 3b, respectively.

[0483] The solids obtained from ethanol and THF have diffractograms that differ from each other and from reference diffractograms of TG6-02 without a counterion, confirming that salt formation has occurred. The diffractogram of the sample obtained from ethanol contains many peaks that are well-resolved and with high intensity, suggesting high crystallinity of the solid. The diffractogram comprises peaks at positions listed in Table 26.

[0484] Table 26. Peak positions and relative intensities of the peaks in XRPD diffractogram corresponding to meglumine TG6-02 Hit 1

[0485] 1Using Cu Ka\ radiation, wavelength 1.5406 A

[0486] The diffractogram of the sample obtained from THF is of poorer quality, which may be a consequence of the smaller amount of sample analysed.

[0487] TGA curves for the two solid samples showed significant weight losses, likely due to the evaporation of volatile components, such as solvent or water. The sample formed in THF has a continuous weight loss and 9.2 % weight is lost up to 160°C. In contrast, the sample formed in ethanol has a distinct weight loss step of 3.4%, after which a stable weight is established until degradation starts at 200 °C. Part of the solid isolated from ethanol was heated by TGA to 180 °C, ie. above the temperature of the weight loss, but below the melting point. XRPD was used to analyse the final sample and a new diffractogram of high crystallinity was obtained (Hit 3).

[0488] The sample isolated from ethanol, (Hit 1), was analysed by DSC. The DSC curve for this sample is displayed in Fig. 3c. The total heat curve includes several weak endotherms, likely related to the evaporation of volatile components, and a clear melting point onset at 207 °C, which is attributed to melting of the Hit 3 crystalline form, in view of this crystalline form forming on heating Hit 1 to 180 °C.

[0489] Tosylate salt of TG6-02

[0490] XRPD diffractograms of the solid materials isolated from an ethanol or THF slurry of TG6-02 together with toluenesulfonic acid are shown in Fig. 4a and 4b.

[0491] The solids obtained from ethanol and THF have diffractograms that differ from each other and from reference diffractograms of TG6-02 without a counterion, confirming that salt formation has occurred. Both diffractograms contain well-resolved peaks, indicating high crystallinity of the solids obtained. The diffractogram of the sample obtained from ethanol (Hit 1) comprises peaks at positions listed in Table 27. Table 27. Peak positions and relative intensities of the peaks in XRPD diffractogram corresponding to tosylate TG6-02 Hit 1

[0492] 1Using Cu Ka\ radiation, wavelength 1.5406 A

[0493] The TGA curve for the sample obtained from THF (Hit 2) shows a large weight loss of 10.9 %, while that for the sample obtained from ethanol (Hit 1) shows a smaller weight loss of 3.9 % up to 160 °C, with a significant step at around 80 °C. The DSC curve for the sample obtained from ethanol is shown in Fig. 4c and does not contain a clear endotherm. A sharp break in the curve was observed at 200 °C, which may indicate decomposition and is in agreement with the increased weight loss in the TGA curves above 200 °C.

[0494] Sodium salt of TG6-02 XRPD diffractograms of the solid materials isolated from an ethanol or THF slurry of TG6-02 together with sodium hydroxide were obtained. The solids obtained from ethanol and THF have diffractograms that differ from each other and from reference diffractograms of TG6-02 without a counterion, confirming that salt formation has occurred. Both diffractograms contain poorly- resolved peaks, indicating poor crystallinity of the solids obtained. The diffractogram of the sample obtained from ethanol (Hit 1) comprises peaks at positions listed in Table 28. Table 28. Peak positions and relative intensities of the peaks in XRPD diffractogram corresponding to sodium TG6-02 Hit 1

[0495] 1Using Cu Ka\ radiation, wavelength 1.5406 A

[0496] The TGA curves for both samples indicate significant weight losses. The TGA curve for the sample obtained from ethanol (Hit 1) contains two distinct steps: the first at 25-75 °C with a weight reduction of 2.0 % and the second at 75 to 180 °C with a weight reduction of approximately 3 %. Degradation of the sample began at 320 °C. The sample formed in THF exhibits a continuous weight loss and 7.5 % weight is lost up to 160°C.

[0497] The DSC curve for the sample obtained from ethanol was obtained and did not contain a clear endotherm. Several weak endotherms were observed, seemingly related to evaporation of volatile components. These results suggest that Hit 1 has a channel structure.

[0498] Potassium salt of TG6-02

[0499] XRPD diffractograms of the solid materials isolated from an ethanol or THF slurry of TG6-02 together with potassium hydroxide are shown in Fig. 5a and 5b. The solids obtained from ethanol and THF have diffractograms that differ from each other and from reference diffractograms of TG6-02 without a counterion, confirming that salt formation has occurred. The diffractogram of the solid obtained from ethanol contains well-resolved peaks, indicating high crystallinity. That of the solid obtained from THF contains poorly-resolved peaks, indicating poor crystallinity of this solid. The diffractogram of the sample obtained from ethanol (Hit 1) comprises peaks at positions listed in Table 29.

[0500] Table 29. Peak positions and relative intensities of the peaks in XRPD diffractogram corresponding to potassium TG6-02 Hit 1

[0501] 1Using Cu Ka\ radiation, wavelength 1.5406 A

[0502] The TGA curves for both samples indicate significant weight losses. The TGA curve for the sample obtained from ethanol (Hit 1 ) contains two distinct steps, with an accumulated weight loss of 4.2%. Degradation of the sample began at around 300 °C. The sample formed in THF exhibits a continuous weight loss and 14.7 % weight is lost up to 160°C.

[0503] Hydrogen chloride salt of TG6-02

[0504] XRPD diffractograms of the solid materials isolated from an ethanol or THF slurry of TG6-02 together with hydrochloric acid were obtained. The solids obtained from ethanol and THF have diffractograms that differ from each other and from reference diffractograms of TG6-02 without a counterion, confirming that salt formation had occurred. Both diffractograms contain well- resolved peaks, indicating high crystallinity. The diffractogram of the sample obtained from ethanol (Hit 1) comprises peaks at positions listed in Table 30.

[0505] Table 30. Peak positions and relative intensities of the peaks in XRPD diffractogram corresponding to hydrogen chloride TG6-02 Hit 1

[0506] 1Using Cu Ka\ radiation, wavelength 1.5406 A

[0507] The TGA curves for both samples indicate very significant weight losses, each of more than 10%.

[0508] L- Arginine salt of TG6-02

[0509] XRPD diffractograms of the solid materials isolated from an ethanol or THF slurry of TG6-02 together with L-arginine were compared.

[0510] The solid obtained from THF has an identical diffractogram to that of the reference diffractogram (TG6-02 without a conterion and in THF), suggesting no salt formation. The solid obtained from ethanol has a diffractogram that differs from the reference diffractogram, confirming that salt formation has occurred. However, the peaks in the diffractogram are very poorly resolved, suggesting that this is an amorphous solid.

[0511] Crystalline form screen of tromethamine salt of TG6-02 For this, a larger amount of tromethamine salt of TG6-02 was synthesised. The process followed the route previously used in the salt screen described above, in which the parent compound is suspended in ethanol with a stochiometric amount of tromethamine. Successful salt formation was confirmed after 24 hours. The solid material was isolated by vacuum filtration and further dried in vacuo at room temperature for two hours. XRPD analysis confirmed formation of tromethamine salt TG6-02 Hit 1.

[0512] Solubility assessment of tromethamine TG6-02 Hit 1

[0513] Solubilities in organic solvents were assessed by visual observation at room temperature. The data are shown in Table 31. The solubility is low, except in dimethylformamide (DMF), dimethylacetamide (DMA), formamide and methanol.

[0514] For suspension experiments at room temperature, the solvents with moderate solubility (DMF, formamide, methanol, ethanol) together with the common solvents acetonitrile and THF were nominated. Additionally, to include solvents with diverse properties (from other solvent clusters) while obtaining reasonable solubility, mixtures of 1 ,4-dioxane and methyl isobutyl ketone (MiBK) with DMA were also used.

[0515] Table 31. Solubility, by visual inspection, of tromethamine TG6-02 Hit 1 at room temperature (RT).

[0516] Crystalline form screen

[0517] Suspensions of tromethamine salt TG6-02 Hit 1 in each of methanol, ethanol, THF, DMF, formamide, acetonitrile, MiBK / DMA (9:1) and 1,4-dioxane / DMA (9: 1) at room temperature and in each of methanol, ethanol, 1 ,4-dioxane and acetonitrile at 40 °C were analysed by XRPD. Any solid indicating the formation of a new type of diffractogram was submitted to thermogravimetric analysis (TGA) to assess if it consisted of an anhydrous form or a solvated / hydrated form. The outcome of the analyses is summarized in Tables 32 and 33 for room temperature and 40 °C suspensions, respectively. Table 32. Outcome from suspensions of tromethamine TG6-02 Hit 1 at room temperature (4 days).

[0518] 3The THF sample diffractogram contains an additional peak at 6.3 °20.bThe MiBK:DMA sample diffractogram contains four additional peaks at 7.8, 15.6, 23.4 and 31.2 °20, seemingly related to a low-dimensional phase.

[0519] N.D. Not determined Table 33. Outcome from suspensions of tromethamine TG6-02 Hit 1 at 40 °C (2 days).

[0520] N.D Not determined

[0521] At room temperature, original Hit 1 was retained in ethanol, acetonitrile, MiBK / DMA 9:12 and THF, while it had transformed to Hit 2 in DMF and 1 ,4-dioxane. TGA analysis of all non-Hit 1 samples was carried out. The two different Hit 2 materials displayed different TGA profiles, with the solid from DMF displaying a typical solvate profile with a weight loss of 4.5 % while the sample from 1,4-dioxane / DMA did not display any obvious weight loss step indicative of it being a solvate, and only lost 1.2 % up to 120 °C.

[0522] Suspension in methanol and formamide led to two new Hits: Hit 3 and Hit 4, respectively. Both of these appear to be solvates according to TGA data, with Hit 3 losing 3.8% of weight and Hit 4 losing 8.9% of weight. There are several peaks in the diffractogram of Hit 4 that match with peaks of TG6-02 without counterion, suggesting that partial dissociation of tromethamine has occurred. To check the effect of heating the methanol and DMF solvates above the temperature of weight loss, aliquots of these samples were heated to 80 °C for about 15 minutes and their diffractograms analysed again. The methanol solvate changed from Hit 3 to Hit 5, with a significantly different diffractogram. The diffractogram of the resultant DMF solvate was substantially unchanged, with just some shifts in peak positions observed at higher angles, which is a common effect from heating a channel-containing structure.

[0523] After suspension at 40 °C, Hit 1 was retained in ethanol and acetonitrile and Hit 2 was retained in 1,4-di oxane. In methanol, Hit 5 (previously observed from heating Hit 3 at 80 °C in methanol) was obtained. TGA analysis of Hit 5 revealed a weight loss up to 120 °C of 2.8%, indicating that this crystalline form contains a volatile component, and suggesting that Hit 5 might be a channel hydrate.

[0524] Based on TGA analysis, it is likely that Hits 2 to 5 are solvated or desolvated crystalline forms. Hit 1 was revealed to be the most stable form at all temperatures. To further support this, binary mixtures comprising either about 5 mg of each of Hit 1 and Hit 2 or about 5 mg of each of Hit 1 and Hit 5, were suspended in either ethanol or acetonitrile. The suspensions were analysed by XRPD after 24 hours. In each case, Hit 1 had formed or was retained.

[0525] Detailed XRPD characterisation of tromethamine TG6-02 Hit 1 and Hit 2

[0526] Hit 1 and Hit 2 were analysed using XRPD with longer run times. The more detailed diffractograms are shown in Fig. 6a and Fig. 6b. Peak positions are as listed in Table 34 and Table 35.

[0527] Table 34. Peak positions and relative intensities of XRPD diffractogram corresponding to tromethamine TG6-02 Hit 1

[0528] 1Using Cu Karadiation, wavelength 1.5406 A

[0529] Table 35. Peak positions and relative intensities of XRPD diffractogram corresponding to tromethamine TG6-02 Hit 2

[0530] 1Using Cu Ka\ radiation, wavelength 1.5406 A

[0531] Thermal properties (DSC) of tromethamine TG6-02 Hit 1 and Hit 2

[0532] Each hit was analysed by differential scanning calorimetry (DSC), up to 300 °C (see Fig. 7 and 8).

[0533] The thermogram of Hit 1 comprises a large endotherm with an onset melting point of 222 °C. The minor endotherm at 135 °C is likely caused by evaporation of free counterion. The thermogram of Hit 2 comprises a double endotherm, the first with an onset melting point of 213 °C. The second peak may be related to melting of Hit 1, recrystallised after the melting of Hit 2. A broad and low intensity endotherm is also present in the temperature range 50 - 100 °C, suggestive of evaporation of solvents. Humidity interaction (GVS) of tromethamine TG6-02 Hit 1 and Hit 2

[0534] The humidity interaction and isotherms of Hit 1 are presented in Fig. 9a and Fig. 9b, respectively, and the humidity interaction and isotherms of Hit 2 are presented in Fig. 10a and Fig. 10b. The sorption values for both forms are tabulated in Table 36.

[0535] Table 36. Sorption values (change of mass at the end of each target RH-cycle) of tromethamine TG6-02 Hit l and Hit 2

[0536] RH = Relative Humidity (% p / po), where p = partial pressure of water vapour and po = saturation pressure of water vapour at the same temperature.

[0537] Hit 1 is slightly hygroscopic with a water uptake from 0 to 80% RH of 0.9% (w / w). The two cycles overlap and a slight hysteresis is observed above 40% RH suggesting a small amount of water is locked into the structure.

[0538] Hit 2 exhibits a dramatic weight loss when reducing the RH from 10% to 0%. This is in line with this crystalline form being a desolvated solvate. The cycles are overlapping and completely reversible suggesting the material contains water and no other solvent molecules at the start of the analysis. The water uptake is 5.2% (w / w) from 0 to 80% RH, but only 0.4% from 10 to 80% RH.

[0539] Thus, once the channels of Hit 2 have become occupied with water molecules (at 10 % RH), Hit 2 becomes less hygroscopic than Hit 1.

[0540] The solid forms after the GVS experiments were confirmed by XRPD analysis to be unchanged.

[0541] FT-IR of tromethamine TG6-02 Hit 1 and Hit 2 The FT-IR spectrum of tromethamine TG6-02 Hit 1 is shown in Fig. 11. Peak positions are as listed in Table 37.

[0542] Table 37. Peak positions and intensities of FT -IR spectrum corresponding to tromethamine TG6-02 Hit 1

[0543] The FT-IR spectrum of tromethamine TG6-02 Hit 2 is shown in Fig. 12. Peak positions are as listed in Table 38.

[0544] Table 38. Peak positions and intensities of FT -IR spectrum corresponding to tromethamine TG6-02 Hit 2

[0545] SEM of tromethamine TG6-02 Hit 1 and Hit 2

[0546] SEM images of tromethamine TG6-02 Hit 1 are shown in Fig. 13a to Fig. 13d in increasing order of magnification. Primary particles are very small with a high degree of agglomeration. The particles have a morphology comprising thin shavings of rod-like shape gathered together in parallel stacks.

[0547] SEM images of tromethamine TG6-02 Hit 2 are shown in Fig. 14a to Fig. 14d in increasing order of magnification. The primary particles are also very small but slightly less agglomerated than Hit 1, and have a rock-like morphology. Solubility of tromethamine TG6-02 Hit 1 and Hit 2 in biorelevant media

[0548] Solubility in different biorelevant media (SGF, SIF and FASSIF v2), was determined for each salt in duplicate (i.e. analysis was repeated) using shake-flask methodology and quantified with HPLC. Solid form and solution pH at the end of the experiments were also determined.

[0549] The solubilities of the Hits reduced between the 1 and 48 hours, which is consistent with the parent compound (TG6-02 without counterion) slowly precipitating, as determined by XRPD. Despite this precipitation, the solubility of both Hits of the tromethamine salt was substantially higher than for the parent compound. The solubility of Hit 1 was higher than that of Hit 2, substantially higher when in FaSSIF v2. The measured solubilities of the tromethamine TG6-02 Hits were substantially higher in FaSSIF v2 than in SIF and SGF, particularly for Hit 1.

[0550] Hit 2 has only a slightly lower solubility than Hit 1 in SGF and SIF, but the solubility of Hit 2 is lower than Hit 1 in FaSSIF v2.

[0551] The solids isolated after 48 hours were analysed by XRPD (duplicates pooled). The obtained diffractograms were very similar owing to precipitation of TG6-02 without a counterion. The transformation of the salts back to the parent compound (TG6-02 without a counterion) means that low solubility values may correspond to faster transformation of the salt back to the parent compound.

[0552] In summary, the dissolution rate of TG6-02 can be increased by tromethamine salt formation, and formation of Hit 1 or Hit 2, with Hit 1 being the most soluble.

[0553] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology disclosed herein in its broader aspects. In addition the disclosures of all patent and scientific literature cited herein are expressly incorporated herein in their entirety by reference.

[0554] CLAUSES

[0555] By way of further example, the invention will now be described by way of example only, with reference to the following clauses.

[0556] Clause 1. A tromethamine or lysine salt of a compound of Formula la:

[0557] (Formula la) or a stereoisomer, or tautomer thereof, wherein:

[0558] R1is halogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0559] R2is phenyl; C3-6 cycloalkyl; 3- to 8 -membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenoxy; or C1-6 alkoxy; wherein the phenyl, C3-6 cycloalkyl, and 3- to 8-membered heterocycloalkyl are optionally substituted with one to four R2Aindependently selected from halogen, C1-6 alkyl, C1-6 alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3- to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen;

[0560] R4Bis H, C1-3 alkyl, or -OH;

[0561] R4Bis H or C1-3 alkyl;

[0562] R5is C1-6 alkyl optionally substituted with C3-4 cycloalkyl; C1-6 haloalkyl; C4-5 cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4 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)(Ci-6 alkyl), and -SO2(Ci-6 alkyl); or phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6 haloalkoxy; and R6is H or Ci-6 alkyl; wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).

[0563] Clause 2. The salt of clause 1, wherein R4Band R4Bare both H, or wherein R4Bis methyl, and R4B’ IS H.

[0564] Clause 3. The salt of clause 1 or clause 2, wherein R5is:

[0565] (i) C1-6 haloalkyl or C1-6 alkyl optionally substituted with C3-4 cycloalkyl, optionally wherein R5is selected from:

[0566] (ii) C4-5 cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4 cycloalkyl ring, optionally wherein R5is selected from:

[0567] (iii) 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)(Ci-6 alkyl), and -SO2(Ci-6 alkyl), optionally wherein R5is selected from:

[0568] (iv) phenyl optionally substituted with one or two substituents independently selected from halogen and Ci-6 haloalkoxy, optionally wherein R5is selected from:

[0569] Clause 4. The salt of any one of clauses 1-3, wherein R5is

[0570] Clause 5. The salt of any one of clauses 1-4, wherein R4Bis H.

[0571] Clause 6. The salt of any one of clauses 1-5, wherein R1is:

[0572] (i) halogen, optionally wherein R1is Br; or

[0573] (ii) Ci-6 alkyl, or Ci-6 haloalkyl, optionally wherein R1is ethyl or -CHF2.

[0574] Clause 7. The salt of any one of claims clauses 1-6, wherein R2is:

[0575] (i) phenyl optionally substituted with one to four R2Aindependently selected from halogen, C1-6 alkyl, and C1-6 alkoxy, optionally wherein R2is selected from:

[0576] (ii) C3-6 cycloalkyl or 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R2is optionally substituted with one to four R2Aindependently selected from halogen, C1-6 alkyl, C1-6 alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3- to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen, optionally wherein R2is selected from:

[0577] (iii) phenoxy or Ci-6 alkoxy, optionally wherein R2is methoxy.

[0578] Clause 8. The salt of any of any one of clauses 1-7, wherein R2is

[0579] Clause 9. The salt of any one of clauses 1-8, wherein R6is H. Clause 10. The salt of clause 1 , wherein the compound is selected from any one of the following:

[0580]

[0581] 5

[0582] Clause 11. The salt of clause 1 , wherein the compound is selected from:

[0583]

[0584] Clause 12. The salt of clause 11, wherein the compound is selected from: Clause 13. The salt of any one of clauses 1-12, which is a tromethamine salt.

[0585] Clause 14. The salt of clause 1, which is a tromethamine salt of a compound of structure:

[0586] Clause 15. The salt of any one of clauses 1-12, which is a lysine salt. Clause 16. The salt of clause 1, which is a lysine salt of a compound of structure:

[0587] Clause 17. The salt of any one of clauses 1-16, which is in a crystalline form. Clause 18. The salt of clause 1 , wherein the salt is a crystalline form of a tromethamine salt of a compound of structure: wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20 ±0.2 of: 8.4 and 14.0; and optionally a further peak at 19.7; as measured by X-ray powder diffraction using a Cu K a source. Clause 19. The salt of clause 18, wherein the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of:

[0588] 5.6 and 22.5.

[0589] Clause 20. The salt of clause 18 or 19, wherein the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of:

[0590] 2.8, 8.7, 10.0, 11.2, 18.2, 18.5, 18.9, 21.3, 24.0, 25.4, 28.3, 31.1, and 34.0, or combinations thereof.

[0591] Clause 21. The salt of any one of clauses 18-20, which comprises an onset melting point of about 215 to 230 °C.

[0592] Clause 22. The salt of any one of clauses 18-21, which has a solubility in Fasted State Simulated Intestinal Fluid V2 (FaSSIF v2) at a pH of 6.5 after 1 hour of at least about 100 pg / mL, at least about 150 pg / mL, optionally a minimum of about 150 to about 250 pg / mL.

[0593] Clause 23. The salt of any one of clauses 18-22, which is anhydrous and / or has a water uptake from 0 to 80%RH of up to about 1%.

[0594] Clause 24. A crystalline form of a tromethamine salt of a compound of structure: wherein the crystalline form is obtainable by crystallising in any one or a mixture of ethanol, acetonitrile, dimethylacetamide and methyl isobutyl ketone.

[0595] Clause 25. The salt of clause 1, wherein the salt is in a crystalline form of a tromethamine salt of a compound of structure: wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20 ±

[0596] 0.2 of:

[0597] 9.0 and 20.2; and optionally a further peak at 14.9; as measured by X-ray powder diffraction using a Cu K a source.

[0598] Clause 26. The salt of clause 25, wherein the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of:

[0599] 19.9 and 21.4.

[0600] Clause 27. The salt of clause 25 or 26, wherein the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of:

[0601] 6.4, 6.7, 8.4, 8.8, 10.1, 12.6, 13.1, 13.4, 15.6, 15.9, 16.2, 16.9, 17.2, 18.0, 18.8, 19.1, 20.7, 22.4, 22.9, 23.2, 24.1, 25.0, 25.4, 25.6, 26.2, 26.8, 27.2, 27.8, 28.1, 28.4, 29.5, 30.7, 31.3, 32.0, 32.7, and 33.5, or combinations thereof.

[0602] Clause 28. The salt of any one of clauses 25-27, which is further characterized by an onset melting point of about 205 to about 220 °C. Clause 29. The salt of any one of clauses 25-28, which is further characterized by a solubility in Fasted State Simulated Intestinal Fluid V2 (FaSSIF v2) at a pH of 6.5 after 1 hour of at at least about 50 pg / mL, or at least about 100 pg / mL, optionally about 100 to about 150 pg / mL. Clause 30. A crystalline form of a tromethamine salt of a compound of structure: wherein the crystalline form is obtainable by crystallising in any one or a mixture of tetrahydrofuran, dimethyl formamide, dimethylacetamide and 1,4-dioxane. Clause 31. The salt of clause 1 , wherein the salt is a crystalline form of a lysine salt of a compound of structure: wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20 ±

[0603] 0.2 of:

[0604] 4.2 and 4.8; and optionally a further peak at 18.8; as measured by X-ray powder diffraction using a Cu K a source.

[0605] Clause 32. The salt of clause 31, wherein the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of: 7.6, 16.5, 16.8, 17.9, 19.4, 20.3, and 21.9.

[0606] Clause 33. A crystalline form of a lysine salt of a compound of structure: wherein the crystalline form is obtainable by crystallising in ethanol.

[0607] Clause 34. A method of crystallising a tromethamine salt of a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of ethanol, acetonitrile, dimethylacetamide and methyl isobutyl ketone, allowing the salt to re-precipitate and isolating the resultant precipitate. Clause 35. A method of crystallising a tromethamine salt of a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of tetrahydrofuran, dimethyl formamide, dimethylacetamide and 1,4-dioxane, allowing the salt to re-precipitate and isolating the resultant precipitate.

[0608] Clause 36. A method of crystallising a lysine salt of a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with ethanol, allowing the salt to re-precipitate and isolating the resultant precipitate.

[0609] Clause 37. A pharmaceutical composition comprising the salt of any one of clauses 1-33 and at least one pharmaceutically acceptable excipient. Clause 38. A salt of any one of clauses 1-33 or a pharmaceutical composition of clause 37, for use in therapy.

[0610] Clause 39. A salt of any one of clauses 1-33 or a pharmaceutical composition of clause 37, for use in:

[0611] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0612] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0613] (iii) preventing or reducing the risks of pre-term labor in a subject in need thereof;

[0614] (iv) preventing or reducing the risks of labor prior to cesarean delivery in a subject in need thereof;

[0615] (v) treating, preventing or reducing the risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof; or

[0616] (vi) treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1 - antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust- induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkins on-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididimytis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

[0617] Clause 40. A method of:

[0618] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0619] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0620] (iii) preventing or reducing the risks of pre-term labor in a subject in need thereof;

[0621] (iv) preventing or reducing the risks of labor prior to cesarean delivery in a subject in need thereof;

[0622] (v) treating, preventing or reducing the risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof; or

[0623] (vi) treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1 - antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust- induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkins on-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididimytis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF); wherein the method comprises administering to the subject the salt of any one of clauses 1-33 or a pharmaceutical composition of clause 37.

[0624] Clause 41. Use of a salt of any one of clauses 1-33 or a pharmaceutical composition of clause 37, in the preparation of a medicament for use in:

[0625] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0626] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0627] (iii) preventing or reducing the risks of pre-term labor in a subject in need thereof;

[0628] (iv) preventing or reducing the risks of labor prior to cesarean delivery in a subject in need thereof;

[0629] (v) treating, preventing or reducing the risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof; or

[0630] (vi) treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1 - antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust- induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkins on-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididimytis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

Claims

WHAT IS CLAIMED IS:

1. A tromethamine or lysine salt of a compound of Formula la:(Formula la) or a stereoisomer, or tautomer thereof, wherein:R1is halogen, Ci-6 alkyl, or Ci-6 haloalkyl;R2is phenyl; C3-6 cycloalkyl; 3- to 8 -membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenoxy; or C1-6 alkoxy; wherein the phenyl, C3-6 cycloalkyl, and 3- to 8-membered heterocycloalkyl are optionally substituted with one to four R2Aindependently selected from halogen, C1-6 alkyl, C1-6 alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3- to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted with one or two substituents independently selected from halogen;R4Bis H, C1-3 alkyl, or -OH;R4Bis H or C1-3 alkyl;R5is C1-6 alkyl optionally substituted with C3-4 cycloalkyl; C1-6 haloalkyl; C4-5 cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4 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 optionallysubstituted with one or two substituents independently selected from -C(O)(benzyl), - C(O)(Ci-6 alkyl), and -SO2(Ci-6 alkyl); or phenyl optionally substituted with one or two substituents independently selected from halogen and Ci-6 haloalkoxy; andR6is H or Ci-6 alkyl, optionally H; wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).

2. The salt of claim 1, wherein R4Band R4Bare both H, or wherein R4Bis methyl, and R4Bis H, optionally wherein R4Bis H.

3. The salt of claim 1 or claim 2, wherein R5is:(i) Ci-6 haloalkyl or Ci-6 alkyl optionally substituted with C3-4 cycloalkyl, optionally wherein R5is selected from:(ii) C4-5 cycloalkyl optionally substituted with one or two substituents independently selected from -OH, halogen, C1-6 alkyl, C3-4 cycloalkyl, and C1-6 haloalkoxy, or two substituents together with the carbon atom to which they are attached form a C3-4 cycloalkyl ring, optionally wherein R5is selected from:(iii) 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)(Ci-6 alkyl), and -SO2(Ci-6 alkyl), optionally wherein R5is selected from:(iv) phenyl optionally substituted with one or two substituents independently selected from halogen and C1-6 haloalkoxy, optionally wherein R5is selected from:

4. The salt of any one of claims 1-3, wherein R1is:(i) halogen, optionally wherein R1is Br; or(ii) C1-6 alkyl, or C1-6 haloalkyl, optionally wherein R1is ethyl or -CHF2.

5. The salt of any one of claims 1 -4, wherein R2is:(i) phenyl optionally substituted with one to four R2Aindependently selected from halogen, C1-6 alkyl, and C1-6 alkoxy, optionally wherein R2is selected from:(ii) C3-6 cycloalkyl or 3- to 8-membered heterocycloalkyl containing one or two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R2is optionally substituted with one to four R2Aindependently selected from halogen, C1-6 alkyl, C1-6 alkoxy, and oxo, or two R2Atogether with the atom(s) to which they are attached form a 3- to 6-membered ring optionally containing a ring heteroatom selected from nitrogen, oxygen, and sulfur, and wherein the 3- to 6-membered ring is optionally substituted withone or two substituents independently selected from halogen, optionally wherein R2is selected from:(iii) phenoxy or Ci-6 alkoxy, optionally wherein R2is methoxy.

6. The salt of claim 1, wherein the compound is selected from any one of the following:selected from:,or is a stereoisomer, or tautomer thereof, optionally wherein the compound is of structure:

7. The salt of claim 1, wherein the salt is a crystalline form of a tromethamine salt of a compound of structure:wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20±0.2 of:8.4 and 14.0; and optionally further peaks at: one or more, or all of a 20 ± 0.2 of 19.7, 5.6 and 22.5, or combinations thereof; or at one or more, or all of a 20 ± 0.2 of 2.8, 8.7, 10.0, 11.2, 18.2, 18.5, 18.9, 21.3, 24.0, 25.4, 28.3, 31.1, and 34.0, or combinations thereof; as measured by X-ray powder diffraction using a Cu K a source.

8. The salt of claim 7, which:(i) comprises an onset melting point of about 215 to 230 °C;(ii) has a solubility in Fasted State Simulated Intestinal Fluid V2 (FaSSIF v2) at a pH of 6.5 after 1 hour of at least about 100 pg / mL, at least about 150 pg / mL, optionally a minimum of about 150 to about 250 pg / mL; and / or(iii) is anhydrous and / or has a water uptake from 0 to 80%RH of up to about 1%.

9. The salt of claim 1, wherein the salt is in a crystalline form of a tromethamine salt of a compound of structure:wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20 ± 0.2 of:9.0 and 20.2; and optionally further peaks at: one or more, or all, of a 20 ± 0.2 of 14.9, 19.9 and 21.4, or combinations thereof; or one or more, or all, of a 20 ± 0.2 of 6.4, 6.7, 8.4, 8.8, 10.1, 12.6, 13.1, 13.4, 15.6, 15.9, 16.2, 16.9, 17.2, 18.0, 18.8, 19.1, 20.7, 22.4, 22.9, 23.2, 24.1, 25.0, 25.4, 25.6, 26.2, 26.8, 27.2, 27.8, 28.1, 28.4, 29.5, 30.7, 31.3, 32.0, 32.7, and 33.5, or combinations thereof, as measured by X-ray powder diffraction using a Cu K a source.

10. The salt of claim 9, which is further characterized by:(i) an onset melting point of about 205 to about 220 °C; and / or(ii) a solubility in Fasted State Simulated Intestinal Fluid V2 (FaSSIF v2) at a pH of 6.5 after 1 hour of at at least about 50 pg / mL, or at least about 100 pg / mL, optionally about 100 to about 150 pg / mL.

11. The salt of claim 1, wherein the salt is a crystalline form of a lysine salt of a compound of structure:wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20 ±0.2 of:4.2 and 4.8; and optionally: a further peak at a 20 ± 0.2 of 18.8; or further peaks at one or more, or all, of a 20 ± 0.2 of:7.6, 16.5, 16.8, 17.9, 19.4, 20.3, and 21.9 as measured by X-ray powder diffraction using a Cu K a source.

12. A crystalline form of: a tromethamine salt of a compound of structure:wherein the crystalline form is obtainable by crystallising in:(i) any one or a mixture of ethanol, acetonitrile, dimethylacetamide and methyl isobutyl ketone; or(ii) any one or a mixture of tetrahydrofuran, dimethyl formamide, dimethylacetamide and 1,4-di oxane; or a lysine salt of a compound of structure:wherein the crystalline form is obtainable by crystallising in ethanol.

13. A method of crystallising: a tromethamine salt of a compound of structure:wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of:(i) ethanol, acetonitrile, dimethylacetamide and methyl isobutyl ketone; or(ii) tetrahydrofuran, dimethyl formamide, dimethylacetamide and 1,4-dioxane, allowing the salt to re-precipitate and isolating the resultant precipitate, or a lysine salt of a compound of structure:wherein the method comprises contacting (e.g. dissolving or suspending) the salt with ethanol, allowing the salt to re-precipitate and isolating the resultant precipitate.

14. A pharmaceutical composition comprising the salt of any one of claims 1-12 and at least one pharmaceutically acceptable excipient.

15. A salt of any one of claims 1-12 or a pharmaceutical composition of claim 14, for use in therapy; optionally for use in:(i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;(ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;(iii) preventing or reducing the risks of pre-term labor in a subject in need thereof;(iv) preventing or reducing the risks of labor prior to cesarean delivery in a subject in need thereof;(v) treating, preventing or reducing the risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof; or(vi) treating a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is selected from idiopathic pulmonary fibrosis (IPF), adenomyosis, acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and non-classifiable idiopathic interstitial pneumonias, granulomatous interstitial lung diseases, interstitial lung diseases of known etiology and other interstitial lung diseases of unknown etiology, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic-obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha- 1- antitrypsin deficiency (AATD), pulmonary emphysema, cystic fibrosis (CF), inflammatory and fibrotic disorders of the kidney, IBD, Crohn's disease, ulcerative colitis, peritonitis, peritoneal fibrosis, rheumatoid disorders, multiple sclerosis, inflammatory and fibrotic skin disorders, sickle cell anemia, inflammatory and fibrotic eye disorders, refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust- induced asthma, chronic bronchitis, infectious bronchitis, eosinophilic bronchitis, bronchiectasis, pneumonia, farmer's lung and related disorders, chronic inflammatory cough, iatrogenic cough, medicament-related rhinitis, vasomotoric rhinitis and seasonalallergic rhinitis, inflammation of polyps, high blood pressure (hypertension), heart failure, coronary heart disorders, stable and unstable angina pectoris, renal hypertension, peripheral and cardiovascular disorders, arrhythmias, rhythm disorders of the atria and ventricles, atrioventricular blocks of degrees I-III, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV nodal reentrant tachycardia, Wolff-Parkins on-White syndrome, acute coronary syndrome (ACS), pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, primary kidney disease, congenital kidney disease, nephritis, kidney transplant rejection or immunocomplex-induced kidney disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, nephrotic syndrome, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, overflow urinary incontinence, pelvic pain, erectile dysfunction, female sexual dysfunction, uterine myoma, endometriosis, dysmenorrhea, premature contractions, hirsutism, hypertrichosis, sepsis, multiple organ failure, pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididimytis, oophoritis, salpingitis, vulvovaginitis, rheumatoid disorders, osteoarthritis, skin cancer,brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, the pancreas, the lung, the kidney, the ureter, the prostate and the genital tract, Hodgkin's and non-Hodgkin's lymphoma, stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, and depressions, optionally wherein the disease or disorder is one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF).

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