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 crystalline salts or forms 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. Tosylate salts, in particular, of specific prostaglandin F (FP) receptor antagonists have demonstrated unexpectedly advantageous physical properties. By way of example only, the tosylate 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] In one aspect, provided herein is a tosylate salt of a compound of Formula le, optionally in crystalline form: (Formula le) 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] W is a bond, -NH-, or -O-; and

[0017] R3Bis (a) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or

[0018] (b) 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or

[0019] -W-R3BIS -NR3CR3D, -NHC(O)-O(CI-6alkyl), -NHC(O)R3D, or -C(O)NR3CR3D; wherein R3Cis H or C1-3 alkyl, and R3Dis C1-6 haloalkyl or C3-4 cycloalkyl; or wherein R3Cand R3D, together with the nitrogen atom to which they are attached, form a 3- to 6-membered ring; R4Bis H, Ci-3 alkyl, or -OH; and

[0020] 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). In some embodiments, R3Bis phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and

[0021] Ci-6 haloalkoxy. In some embodiments, some embodiments, R3Bis 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy. In some embodiments, R3Bis a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, Ci-6 alkyl, and Ci- 6 haloalkoxy. In some embodiments, the 5- to 10-membered heteroaryl is pyrazolyl or pyridinyl, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from Ci-6 alkyl and Ci-6 haloalkoxy. In some embodiments, R3Bis R2is . In some embodiments, W is a bond. In some embodiments, W is -O-. In some embodiments, R4Bis H. In some embodiments, R4Bis methyl.

[0022] 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.

[0023] In another aspect, provided herein is a crystalline form of a tosylate salt of a compound of structure: In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20 ± 0.2 of:

[0024] 17.0 and 22.1 ; and optionally a further peak at 14.1 ; as measured by X-ray powder diffraction using a Cu K a source.

[0025] In some embodiments, the crystalline form is obtainable by crystallising in any one or a mixture of ethyl acetate, ethanol and methyl ethyl ketone.

[0026] Viewed from another aspect, there is provided a method of crystallising a tosylate salt of a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of ethyl acetate, ethanol and methyl ethyl 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.

[0027] In another aspect, provided herein is a pharmaceutical composition comprising a salt described herein and at least one pharmaceutically acceptable excipient.

[0028] In another aspect, provided herein is a salt or pharmaceutical composition described herein for use in therapy.

[0029] In another aspect, provided herein is a salt or pharmaceutical composition described herein for use in:

[0030] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0031] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0032] (iii) preventing or reducing the risks of pre-term labor in a subject in need thereof;

[0033] (iv) preventing or reducing the risks of labor prior to cesarean delivery in a subject in need thereof;

[0034] (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

[0035] (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, epididymitis, 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).

[0036] In a further aspect, provided herein is a method of:

[0037] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0038] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0039] (iii) preventing or reducing risks of pre-term labor in a subject in need thereof;

[0040] (iv) preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof;

[0041] (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

[0042] (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, epididymitis, 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 a pharmaceutical composition described herein.

[0043] In another aspect, provided herein is the use of a salt or a pharmaceutical composition described herein, in the preparation of a medicament 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 risks of pre-term labor in a subject in need thereof;

[0047] (iv) preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof;

[0048] (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 (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, epididymitis, 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 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. DETAILED DESCRIPTION

[0050] DEFINITIONS

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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-di oxane, 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.

[0057] 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. 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.

[0058] 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:

[0059] 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).

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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. 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.

[0069] 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.

[0070] The term “pharmaceutical composition” refers to a mixture of one or more compounds disclosed herein with another pharmaceutically acceptable excipient, such as one or more pharmaceutically acceptable diluents or carriers or one or more other pharmaceutically acceptable excipients known in the art. Formulating a compound in a pharmaceutical composition may facilitate administration of the compound to an organism, e.g., the subject to be treated. The specific components of a pharmaceutical composition may depend on and vary with the intended route of administration.

[0071] 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. 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.

[0072] COMPOUNDS

[0073] In one aspect, disclosed herein is a tosylate salt of a compound of Formula le, optionally in crystalline form: (Formula le) or a stereoisomer, or tautomer thereof, wherein:

[0074] R1is halogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0075] 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;

[0076] W is a bond, -NH-, or -O-; and

[0077] R3Bis (a) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or

[0078] (b) 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or

[0079] -W-R3BIS -NR3CR3D, -NHC(O)-O(CI-6alkyl), -NHC(O)R3D, or -C(O)NR3CR3D; wherein R3Cis H or C1-3 alkyl, and R3Dis C1-6 haloalkyl or C3-4 cycloalkyl; or wherein R3Cand R3D, together with the nitrogen atom to which they are attached, form a 3- to 6-membered ring;

[0080] R4Bis H, C1-3 alkyl, or -OH; and

[0081] 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).

[0082] In some embodiments, R4Bis H.

[0083] In some embodiments, R1is halogen. In some embodiments, R1is Br or I. In some embodiments, R1is Br.

[0084] In some embodiments, R1is C1-6 alkyl. In some embodiments, R1is tert-butyl.

[0085] In some embodiments, R1is C1-6 haloalkyl. In some embodiments, R1is trifluoromethyl.

[0086] In some embodiments, R1is C1-6 alkyl, or C1-6 haloalkyl. In some embodiments, R1is ethyl or - CHF2.

[0087] 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,

[0088] In some embodiments, R2is phenyl.

[0089] 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

[0090] In some embodiments, R2is phenoxy or C1-6 alkoxy. In some embodiments, R2is

[0091] In particular embodiments, R2is

[0092] In particular embodiments, W is a bond.

[0093] In some embodiments, R6is H. In some embodiments, R6is Ci-6 alkyl. In some embodiments, R3Bis phenyl, optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.

[0094] In some embodiments, R3Bis selected from:

[0095] In some embodiments, R3Bis a 5 - to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkoxy.

[0096] In some embodiments, R3Bis selected from: In particular embodiments, R is selected from

[0097] 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.

[0098] In another aspect, disclosed herein is a tosylate salt of a compound selected from Table A, or a stereoisomer, or tautomer thereof, optionally wherein the tosylate salt is in crystalline form.

[0099] Table A. In some embodiments, the crystalline tosylate salt is of a compound selected from: or is a stereoisomer, or tautomer thereof.

[0100] In more specific embodiments, the crystalline tosylate salt is of a compound selected from:

[0101] In some embodiments, the crystalline tosylate salt is of a compound of structure:

[0102]

[0103] CRYSTALLINE FORMS

[0104] 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.

[0105] The present inventors have unexpectedly identified that the tosylate 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.

[0106] Crystalline tosylate salts

[0107] Typically, the salt of the invention is a crystalline form of a tosylate salt of a compound of structure:

[0108]

[0109] By way of example, a first crystalline form of a tosylate salt is described in detail below and may be referred to herein as “Tosylate TGI -08 Hit 1”.

[0110] Crystalline form o f tosylate salt

[0111] In some embodiments, the crystalline tosylate 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 6.5, 8.6, 10.7, 11.2, 11.5, 11.8, 13.5, 14.1, 14.2, 15.3, 16.7, 16.9, 17.0, 18.9, 19.5, 20.1, 20.5, 21.2, 21.3, 22.1, 22.4, 23.1, 23.5, 23.8, 24.6, 25.1, 26.1, 26.4, 27.0, 28.0, 28.1, 28.4, 28.6, 29.6, 31.0, 31.3, 31.6, 32.4, and 32.8, as measured by X-ray powder diffraction using a Cu K a source.

[0112] In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 17.0; and 22.1. These peaks may have relative intensities of about 100% and 59%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 14.1; 17.0; and 22.1. These peaks may have relative intensities of about 37%, 100% and 59%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of 6.5 and 19.5, optionally with relative intensities of about 18% and 37%, respectively. 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: 8.6, 10.7, 11.2, 11.5, 11.8, 13.5, 14.2, 15.3, 16.7, 16.9, 18.9, 20.1, 20.5, 21.2, 21.3, 22.4, 23.1, 23.5, 23.8, 24.6, 25.1, 26.1, 26.4, 27.0, 28.0, 28.1, 28.4, 28.6, 29.6, 31.0, 31.3, 31.6, 32.4, and 32.8, or combinations thereof. In more specific embodiments, the X-ray powder diffraction pattern comprises peaks at 6.5, 8.6, 10.7, 11.2, 11.5, 11.8, 13.5, 14.1, 14.2, 15.3, 16.7, 16.9, 17.0, 18.9, 19.5, 20.1, 20.5, 21.2, 21.3, 22.1, 22.4, 23.1, 23.5, 23.8, 24.6, 25.1, 26.1, 26.4, 27.0, 28.0, 28.1, 28.4, 28.6, 29.6, 31.0, 31.3, 31.6, 32.4, and 32.8, optionally with the relative intensities shown in Table 21.

[0113] In some embodiments, the tosylate salt has an onset melting point of about 315 to 325 °C, such as about 318 °C. The salt may alternatively or in addition have a peak melting point of about 322 °C. The onset melting point may be determined by differential scanning calorimetry (DSC) as described herein.

[0114] In some embodiments, the tosylate salt comprises a volatile component of less than about 1% mass, such as less than about 0.5% mass. In particular embodiments, the volatile component is about or less than 0.3% mass. The % mass of volatile component may be determined by thermal gravimetric analysis (TGA) as described herein.

[0115] In some embodiments, the tosylate salt has a solubility in Simulated Intestinal Fluid (SIF) at a pH of 6.8 after 1 hour of at least about 5 pg / mL, at least about 10 pg / mL at least about 15 pg / mL, at least about 20 pg / mL, at least about 25 pg / mL, at least about 30 pg / mL, at least about 35 pg / mL, at least about 40 pg / mL, at least about 45 pg / mL, or at least about 50 pg / mL, optionally from about 1 to about 500 pg / mL, from about 5 to 250 pg / mL, or from 10 to 100 pg / mL. In some embodiments, the tosylate salt has a solubility in Simulated Intestinal Fluid (SIF) at a pH of 6.8 after 1 hour of at least about 25 pg / mL, at least about 30 pg / mL, optionally between about 40 and about 70 pg / mL.

[0116] In some embodiments, the tosylate salt has a solubility in Simulated Gastric Fluid (SGF) at a pH of 1.2 after 1 hour of at least about 5 pg / mL, at least about 10 pg / mL at least about 15 pg / mL, at least about 20 pg / mL, or at least about 25 pg / mL, optionally from about 1 to about 500 pg / mL, from about 5 to 250 pg / mL, or from 10 to 100 pg / mL. In some embodiments, the tosylate salt has a solubility in Simulated Gastric Fluid (SGF) at a pH of 1.2 after 1 hour of at least about 15 pg / mL, optionally about 20 to about 35 pg / mL.

[0117] In some embodiments, the tosylate salt has a water uptake from 0 to 80%RH of up to about 0.8%, such as about 0.4 to about 0.8%, or such as about 0.4 to about 0.7%. In particular embodiments, the tosylate salt has a water uptake from 0 to 80%RH of up to about 0.5%. In particular embodiments, the tosylate salt has a water uptake from 0 to 80%RH of about 0.4 to about 0.65%. The water uptake may be determined by Gravimetric Vapour Sorption (GVS) as detailed below and herein. In some embodiments, the invention provides a crystalline form of a tosylate salt of a compound of structure: wherein the crystalline form is obtainable by crystallising in any one or a mixture of ethyl acetate, ethanol and methyl ethyl ketone. Alternatively, or in additionally, the crystalline form may be obtainable by crystallising in any one or a mixture of ethyl acetate, ethanol, methyl ethyl ketone, methyl acetate, 2-butanone, tetrahydrofuran, ethyl formate, acetone, ethyl acetate, 1 -propanol, 2- propanol, 2-methyl-l -propanol, 2-butanol, 1 -butanol and butanol.

[0118] In some embodiments, the crystalline form is obtainable by crystallising in ethanol.

[0119] Advantageously the present inventors have identified that the crystalline tosylate 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 SIF). Thus, this particular crystalline form has many favourable properties to facilitate later drug development.

[0120] Crystalline form of compound (without a counterion) In an alternative aspect, the compound of the invention is a crystalline form of a compound of structure:

[0121] This compound may be absent a counterion, i.e. may not be in the form of a salt. By way of example, a first crystalline form is described in detail below and may be referred to herein as “Crystalline TGI -08 Hit 1”. By way of further example, a second crystalline form is described in detail below and may be referred to herein as “Crystalline TGI -08 Hit 2”.

[0122] A first crystalline form of compound (without a counterion) “Crystalline TG1-08 Hit 1 ”

[0123] In some embodiments, the crystalline compound 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 7.6, 10.7, 13.0, 13.4, 14.9, 15.0, 15.1, 15.5, 18.0, 18.7, 18.9, 19.8, 19.9, 20.0, 20.1, 20.4, 21.0,

[0124] 21.4, 21.8, 22.1, 22.4, 22.5, 22.7, 23.1, 23.4, 24.9, 25.3, 25.7, 26.0, 26.1, 26.2, 26.9, 27.3, 27.7,

[0125] 28.4, and 30.5, as measured by X-ray powder diffraction using a Cu K a source.

[0126] In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 7.6; and 10.7. These peaks may have relative intensities of about 47% and 100%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 7.6; 10.7; and 28.4. These peaks may have relative intensities of about 47%, 100%, and 45% respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of 13.0; and 15.1, optionally with relative intensities of about 37% and 29%, respectively. 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: 13.4, 14.9, 15.0, 15.5, 18.0, 18.7, 18.9, 19.8, 19.9, 20.0, 20.1, 20.4, 21.0, 21.4, 21.8, 22.1, 22.4, 22.5, 22.7, 23.1, 23.4, 24.9, 25.3, 25.7, 26.0, 26.1, 26.2, 26.9, 27.3, 27.7, and 30.5, or combinations thereof. In more specific embodiments, the X-ray powder diffraction pattern comprises peaks at 7.6, 10.7, 13.0, 13.4, 14.9, 15.0, 15.1, 15.5, 18.0, 18.7, 18.9, 19.8, 19.9, 20.0, 20.1, 20.4, 21.0, 21.4, 21.8, 22.1, 22.4, 22.5, 22.7, 23.1, 23.4, 24.9, 25.3, 25.7, 26.0, 26.1, 26.2, 26.9, 27.3, 27.7, 28.4, and 30.5, optionally with the relative intensities shown in Table 16.

[0127] In some embodiments, the crystalline compound has an onset melting point of about 230 to about 240 °C, such as about 235 °C. The compound may alternatively or in addition have a peak melting point of about 238°C. The onset melting point may be determined by differential scanning calorimetry (DSC) as described herein.

[0128] In some embodiments, the crystalline compound comprises a volatile component of less than about 2% mass, such as about or less than 1.5% mass. The % mass of volatile component may be determined by thermal gravimetric analysis (TGA) as described herein.

[0129] In some embodiments, the crystalline compound has a solubility in Simulated Intestinal Fluid (SIF) at a pH of 6.8 after 1 hour of at least about 1 pg / mL, at least about 2 pg / mL, at least about 3 pg / mL, at least about 4 pg / mL, or at least about 5 pg / mL, optionally from about 1 to about 100 pg / mL, or from about 5 to about 75 pg / mL . In some embodiments, the crystalline compound has a solubility in Simulated Intestinal Fluid (SIF) at a pH of 6.8 after 1 hour of at least about 3 pg / mL, or at least about 5 pg / mL, optionally about 3 to about 12 pg / mL, or about 5 to about 10 pg / mL.

[0130] In some embodiments, the crystalline compound has a solubility in Simulated Gastric Fluid (SGF) at a pH of 1.2 after 1 hour of at least about 1 pg / mL, at least about 2 pg / mL, at least about 3 pg / mL, at least about 4 pg / mL, or at least about 5 pg / mL, optionally from about 1 to about 100 pg / mL, or from about 5 to about 75 pg / mL. In some embodiments, the crystalline compound has a solubility in Simulated Gastric Fluid (SGF) of at least about 3 pg / mL, or at least about 5 pg / mL, optionally about 3 to about 12 pg / mL, or about 5 to about 10 pg / mL.

[0131] In some embodiments, the crystalline compound has a water uptake from 0 to 80%RH of up to about 0.5%, such as about 0.2 to about 0.5%, such as about 0.2 to about 0.4%. In particular embodiments, the tosylate salt has a water uptake from 0 to 80%RH of about 0.2 to about 0.35%. The water uptake may be determined by Gravimetric Vapour Sorption (GVS) as detailed below and herein.

[0132] In some embodiments, the invention provides a crystalline form of a compound of structure: wherein the crystalline form is obtainable by crystallising in any one or a mixture of acetonitrile, ethyl acetate and methanol. Alternatively, or in additionally, the crystalline form may be obtainable by crystallising in any one or a mixture of acetonitrile, ethyl acetate, methanol, methyl ethyl ketone and acetone. Advantageously the present inventors have identified that the crystalline compound of such embodiments may be prepared in substantially anhydrous form and show low hygroscopity. Thus, this particular crystalline form has many favourable properties to facilitate later drug development.

[0133] A second crystalline form of compound (without a counterion) “Crystalline TG1-08 Hit 2 ” In some embodiments, the crystalline compound 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 5.9, 6.9, 11.7, 12.5, 12.9, 13.4, 13.6, 13.8, 14.3, 14.5, 15.3, 15.8, 15.9, 16.4, 17.2, 17.6, 19.6, 20.0, 20.8, 21.5, 22.1, 23.5, 23.9, 24.5, 25.3, 25.9, 26.2, 26.7, 27.0, 27.2, 27.8, 28.0, and 29.7, as measured by X-ray powder diffraction using a Cu K a source. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 5.9 and 17.6. These peaks may have relative intensities of about 87% and 100%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 5.9, 17.6 and

[0134] 20.8. These peaks may have relative intensities of about 87%, 100%, and 81% respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of 6.9 and 23.9, optionally with relative intensities of about 37% and 66%, respectively. 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: 11.7, 12.5, 12.9, 13.4, 13.6, 13.8, 14.3, 14.5, 15.3, 15.8, 15.9, 16.4, 17.2, 19.6, 20.0, 21.5, 22.1, 23.5, 24.5, 25.3, 25.9, 26.2, 26.7, 27.0, 27.2, 27.8, 28.0, and 29.7, or combinations thereof. In more specific embodiments, the X-ray powder diffraction pattern comprises peaks at 5.9, 6.9, 11.7, 12.5, 12.9, 13.4, 13.6, 13.8, 14.3, 14.5, 15.3, 15.8, 15.9, 16.4, 17.2, 17.6, 19.6, 20.0, 20.8, 21.5, 22.1, 23.5,

[0135] 23.9, 24.5, 25.3, 25.9, 26.2, 26.7, 27.0, 27.2, 27.8, 28.0, and 29.7, optionally with the relative intensities shown in Table 17.

[0136] In some embodiments, the crystalline compound has an onset melting point of about 255 to about 265 °C, such as about 260 °C. The onset melting point may be determined by differential scanning calorimetry (DSC) as described herein.

[0137] In some embodiments, the crystalline compound has a solubility in Simulated Intestinal Fluid (SIF) at a pH of 6.8 after 1 hour of at least about 1 pg / mL, at least about 2 pg / mL, at least about 3 pg / mL, at least about 4 pg / mL, at least about 5 pg / mL, at least about 10 pg / mL, or at least about 15 pg / mL, optionally from about 1 to about 100 pg / mL, or from about 5 to about 75 pg / mL . In some embodiments, the crystalline compound has a solubility in Simulated Intestinal Fluid (SIF) at a pH of 6.8 after 1 hour of at least about 3 pg / mL, at least about 5 pg / mL, or at least about 10 pg / mL optionally between about 3 and about 25 pg / mL.

[0138] In some embodiments, the crystalline compound has a solubility in Simulated Gastric Fluid (SGF) at a pH of 1.2 after 1 hour of at least about 1 pg / mL, at least about 2 pg / mL, at least about 3 pg / mL, at least about 4 pg / mL, at least about 5 pg / mL, at least about 10 pg / mL, optionally from about 1 to about 100 pg / mL, or about 5 to about 75 pg / mL. In some embodiments, the crystalline compound has a solubility in Simulated Gastric Fluid (SGF) at a pH of 1.2 after 1 hour of at least about 5 pg / mL, at least about 7.5 pg / mL, or at least about 10 pg / mL, optionally about 5 to about 20 pg / mL. Other crystalline salt forms

[0139] 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 tosylate salts have been described in detail above, the present disclosure further encompasses crystalline meglumine, mesylate, and sodium salts of a compound of Formula le, which may demonstrate unexpectedly advantageous physical properties.

[0140] In a further aspect of the invention, therefore, the salt is a crystalline salt selected from a tosylate, meglumine, mesylate, and sodium salt of a compound of Formula le. For the avoidance of doubt, the embodiments described in relation to Formula le of the first aspect may apply mutatis mutandis to this further aspect. For example, R2may be abond, R3Bmay be selected from may be Br and / or R6may be H.

[0141] In particular embodiments, the crystalline tosylate, meglumine, mesylate, or sodium salt comprises a compound of structure:

[0142] , or is a stereoisomer, or tautomer thereof.

[0143] In even more particular embodiments, the crystalline tosylate, meglumine, mesylate, or sodium salt comprises a volatile component of less than about 4% mass, such as less than about 3.5% mass. In some embodiments, the crystalline tosylate, meglumine, mesylate, or sodium salt has a solubility in SIF at a pH of 6.8 after 1 hour of at least about 1 pg / mL, at least about 2 pg / mL, at least about 3 pg / mL, at least about 4 pg / mL, at least about 5 pg / mL, at least about 10 pg / mL, at least about 15 pg / mL, at least about 20 pg / mL, or at least about 25 pg / mL, optionally about 1 to about 100 pg / mL, or about 5 to about 75 pg / mL. In some embodiments, the crystalline tosylate, meglumine, mesylate, or sodium salt has a solubility in SGF at a pH of 1.2 of at least about 1 pg / mL, at least about 2 pg / mL, at least about 3 pg / mL, at least about 4 pg / mL, at least about 5 pg / mL, at least about 10 pg / mL, at least about 15 pg / mL, at least about 20 pg / mL, or at least about 25 pg / mL, optionally about 1 to about 100 pg / mL, or about 5 to about 75 pg / mL. In particular embodiments, the crystalline salt is a meglumine salt of a compound of structure:

[0144]

[0145] By way of example, a crystalline form of a meglumine salt is described in detail below and may be referred to herein as “Meglumine TGI -08 Hit 1”.

[0146] In some embodiments, the crystalline meglumine 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 10.9, 14.5, 16.3, 18.0, 18.9, 20.3, 21.8, 23.3, 23.9, 25.5, 27.3, 28.5, and 29.0, as measured by X-ray powder diffraction using a Cu K a source.

[0147] In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 10.9; and 21.8. These peaks may have relative intensities of about 100% and 58%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 10.9; 21.8; and 25.5. These peaks may have relative intensities of about 100%, 58% and 37%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of 16.3 and 23.9, optionally with relative intensities of about 16% and 25%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, such as at three, or five or more, or all, of a 20 ± 0.2 of: 14.5, 18.0, 18.9, 20.3, 23.3, 27.3, 28.5, and 29.0, or combinations thereof. In more specific embodiments, the X-ray powder diffraction pattern comprises peaks at 10.9, 14.5, 16.3, 18.0, 18.9, 20.3, 21.8, 23.3, 23.9, 25.5, 27.3, 28.5, and 29.0, optionally with the relative intensities shown in Table 25.

[0148] In some embodiments, the meglumine salt has an onset melting point of about 128 to about 138 °C, such as about 133 °C. The salt may alternatively or in addition have a peak melting point of about 136 °C. In some embodiments, the meglumine salt comprises a volatile component of less than about 1.5% mass, such as less than about 1% mass. In particular embodiments, the volatile component is about or less than 0.9% mass.

[0149] In some embodiments, the invention provides a crystalline form of a meglumine salt of a compound of structure: wherein the crystalline form is obtainable by crystallising in methyl ethyl ketone.

[0150] In particular embodiments, the crystalline salt is a mesylate salt of a compound of structure: By way of example, a crystalline form of a mesylate salt is described in detail below and may be referred to herein as “Mesylate TGI -08 Hit 3”.

[0151] In some embodiments, the crystalline mesylate 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 4.6, 6.4, 9.1, 10.2, 12.9, 13.6, 13.7, 14.4, 14.7, 17.0, 18.2, 18.3, 18.7, 19.3, 19.9, 20.4, 22.2, 22.8, 23.4, 24.5, 25.0, 25.8, and 27.5, as measured by X-ray powder diffraction using a Cu K a source.

[0152] In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 6.4; and 9.1. These peaks may have relative intensities of about 15% and 100%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 6.4; 9.1 ; and

[0153] 12.9. These peaks may have relative intensities of about 15%, 100% and 13%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of 14.4 and 18.3, optionally with relative intensities of about 11% and 9%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, such as at three, or five or more or 10 or more, peaks at a 20 ± 0.2 selected from any of 4.6, 10.2, 13.6, 13.7, 14.7, 17.0, 18.2, 18.7, 19.3, 19.9, 20.4, 22.2, 22.8, 23.4, 24.5, 25.0, 25.8, and 27.5, or combinations thereof. In more specific embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 4.6, 6.4, 9.1, 10.2, 12.9, 13.6, 13.7, 14.4, 14.7, 17.0, 18.2, 18.3, 18.7, 19.3, 19.9, 20.4, 22.2, 22.8, 23.4, 24.5, 25.0, 25.8, and 27.5, optionally with the relative intensities shown in Table 23.

[0154] In some embodiments, the mesylate salt has an onset melting point of about 280 to about 290 °C, such as about 285 °C. The salt may alternatively or in addition have a peak melting point of about 288 °C.

[0155] In some embodiments, the mesylate salt comprises a volatile component of less than about 3% mass, such as less than about 2.5% mass. In particular embodiments, the volatile component is about or less than 2.4% mass.

[0156] In some embodiments, the invention provides a crystalline form of a mesylate salt of a compound of structure:

[0157] wherein the crystalline form is obtainable by crystallising in methyl ethyl ketone.

[0158] In particular embodiments, the crystalline salt is a sodium salt of a compound of structure: By way of example, a crystalline form of a sodium salt is described in detail below and may be referred to herein as “Sodium TGI -08 Hit 1”.

[0159] In some embodiments, the crystalline sodium 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 7.0, 8.4, 11.0, 11.3, 14.0, 15.8, 16.8, 19.1, 21.0, 22.6, 25.3, and 27.3, as measured by X-ray powder diffraction using a Cu K a source.

[0160] In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 7.0; and 16.8. These peaks may have relative intensities of about 100% and 31%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of 7.0; 8.4; and 16.8. These peaks may have relative intensities of about 100%, 10% and 31%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of 21.0 and 22.6, optionally with relative intensities of about 10% and 11%, respectively. In some embodiments, the X-ray powder diffraction pattern comprises further peaks at one or more, such as at three, or five or more, peaks at a 20 ± 0.2 selected from any of 7.0, 8.4, 11.0, 11.3, 14.0, 15.8, 16.8, 19.1, 21.0, 22.6, 25.3, and 27.3, or combinations thereof. In more specific embodiments, the X-ray powder diffraction pattern comprises peaks at a 20 ± 0.2 of, optionally with the relative intensities shown in Table 24.

[0161] In some embodiments, the sodium salt has an onset melting point of about 263 to about 273 °C, such as about 268 °C. The salt may alternatively or in addition have a peak melting point of about 271 °C.

[0162] In some embodiments, the sodium salt comprises a volatile component of less than about 4% mass, such as less than about 3.5% mass. In particular embodiments, the volatile component is about or less than 3.2% mass.

[0163] In some embodiments, the invention provides a crystalline form of a sodium salt of a compound of structure: wherein the crystalline form is obtainable by crystallising in ethanol. Alternatively or additionally, the crystalline form may be obtainable by crystallising in one or a mixture of ethanol and 2- propanol.

[0164] CHARACTERISATION OF SALTS AND CRYSTALLINE FORMS THEREOF As described above, the salt, crystalline salt or form of the invention may be characterisable by one or more parameters. For example, the salt or form may have a specific: onset melting point, solubility in a solvent, percentage of volatile components, percentage water uptake, and / or X-ray powder diffraction diffractogram. The determination and / or measurement of these parameters are described further below.

[0165] 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.

[0166] 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 or 350 °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 ± 0.5 °C may be used. The onset melting point may be obtained using the methods defined in the experimental section below.

[0167] The salt or crystalline form may have a specific solubility in a biological solvent, such as in Simulated Gastric Fluid (SGF), or Simulated Intestinal Fluid (SIF). The solubility of the salt or crystalline form after an hour within the biological solvent provides a more realistic indication of solubility on administration to a patient.

[0168] SIF is also well known and can be prepared by first making a 1 M NaOH solution, e.g. by dissolving 4 g of NaOH in 100 mL water and then diluting 340 mg (2.5 mmol) of KH2PO4 and 1.1 mL of the 1 M NaOH solution 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.

[0169] 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.

[0170] For the avoidance of doubt, the solubility values referred to herein were determined at temperatures of 23 °C ± 3°C. Solubility may be determined by UV-vis spectroscopy detecting at, for example, 234 nm (for SIF solubilities) or 240 nm (for SGF solubilities). The sample matrix may comprise methanol and water at a ratio of, for example, 9:1. The solubility values referred to herein may be obtained using the methods defined in the experimental section below.

[0171] The crystalline salt or form 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 350 °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 or crystalline form may be determined using the TGA methods defined in the experimental section below.

[0172] The salt or crystalline form 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 material is. Salts or crystalline forms 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 or crystalline form 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. The crystalline salt or form may have a particular structure 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°.

[0173] 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.

[0174] 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%.

[0175] ACTIVITY OF THE COMPOUNDS

[0176] 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 phosphate (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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] SYNTHESIS OF THE COMPOUNDS, SALTS AND CRYSTALLINE FORMS THEREOF

[0181] In another aspect there is provided a method of manufacture of any one of the salts, crystalline compounds or crystalline forms disclosed herein. The presently disclosed compounds were and can be synthesized using the synthetic procedures set forth 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, R3B, R4B, W and R6are as provided in the formulas described herein. The synthetic procedure for individual compounds is disclosed in the Examples section below.

[0182] In another aspect, the invention provides a method of crystallising a tosylate salt of a compound of formula le, 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 ethyl acetate, ethanol and methyl ethyl ketone, allowing the salt to re-precipitate and isolating the resultant precipitate. Alternatively, or in additionally, the solvent may be any one or a mixture of ethyl acetate, ethanol, methyl ethyl ketone, methyl acetate, 2-butanone, tetrahydrofuran, ethyl formate, acetone, ethyl acetate, 1 -propanol, 2-propanol, 2-methyl-l -propanol, 2-butanol, 1 -butanol and butanol.

[0183] In some embodiments, the method may comprise crystallising a tosylate salt of a compound having one of the following structures: a stereoisomer, or tautomer thereof. In some embodiments, the invention provides a method of crystallising a tosylate salt of a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of ethyl acetate, ethanol and methyl ethyl ketone, allowing the salt to re-precipitate and isolating the resultant precipitate. Alternatively, or in additionally, the contacting may with any one or a mixture of ethyl acetate, ethanol, methyl ethyl ketone, methyl acetate, 2-butanone, tetrahydrofuran, ethyl formate, acetone, ethyl acetate, 1 -propanol, 2-propanol, 2-methyl-l- propanol, 2-butanol, 1 -butanol and butanol. By way of example, the method may comprise contacting the salt with ethanol. In some embodiments, the invention provides a method of crystallising a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of acetonitrile, ethyl acetate and methanol, allowing the salt to re-precipitate and isolating the resultant precipitate. Alternatively, or additionally, the contacting may be with one or a mixture of acetonitrile, ethyl acetate, methanol, methyl ethyl ketone and acetone.

[0184] In another aspect, the invention provides a method of crystallising a tosylate, meglumine or mesylate salt of a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with ethyl methyl ketone, allowing the salt to re-precipitate and isolating the resultant precipitate. In another aspect, the invention provides a method of crystallising a tosylate or sodium 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. Alternatively or additionally, the contacting may be with one or a mixture of ethanol and 2-propanol.

[0185] In any of the methods described above, the step of allowing the material (salt or compound) to reprecipitate may comprise allowing the salt or compound to crystallise. Additionally or alternatively, the step of isolating the resultant precipitate may comprise isolating the resultant crystalline form.

[0186] PHARMACEUTICAL COMPOSITIONS

[0187] In another aspect, disclosed herein are pharmaceutical compositions comprising, consisting essentially of, or consisting of a salt, crystalline salt or crystalline form as described herein, and one or more pharmaceutically acceptable excipients. For the avoidance of doubt, the embodiments described in relation to Formula le of the first aspect may apply mutatis mutandis to this further aspect. For example, R2may be , W may be a bond, R3Bmay be selected from may be Br and / or R6may be H.

[0188] For example, the pharmaceutical composition may comprise, consist essentially of, or consist of a tosylate salt selected from structures: a stereoisomer, or tautomer thereof, and one or more pharmaceutically acceptable excipients.

[0189] The salt, crystalline salt or form 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.

[0190] 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.

[0191] Exemplary excipients include, without limitation, lactose, polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophors, carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), glidants such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, and the like.

[0192] 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.

[0193] A pharmaceutical composition as disclosed herein may include a salt, crystalline salt, or crystalline form disclosed herein as the only active agent, or may be formulated with other active agents.

[0194] 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.

[0195] Pharmaceutical compositions as disclosed herein may be formulated to provide a therapeutically effective amount of a crystalline salt or form 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 (salt / compound-by- salt / compound) basis, for most salts or compounds, some generalizations regarding the dosage can be made. For example, the daily dosage regimen for an adult human patient may be between 0.001 mg and 1000 mg, such as between 0.01 mg and 500 mg, for example from 1 to 200 mg of the salt or compound or pharmaceutically acceptable salt thereof, calculated as the free base or free acid. METHODS OF TREATMENT

[0196] In a further aspect, there is provided a salt, crystalline salt, crystalline form, or a pharmaceutical composition disclosed herein, for use in therapy, e.g. for use in:

[0197] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0198] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0199] (iii) preventing or reducing risks of pre-term labor in a subject in need thereof;

[0200] (iv) preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof;

[0201] (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

[0202] (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, epididymitis, 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).

[0203] In another aspect, there is provided a method of:

[0204] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0205] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0206] (iii) preventing or reducing risks of pre-term labor in a subject in need thereof;

[0207] (iv) preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof;

[0208] (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

[0209] (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, epididymitis, 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 crystalline salt, form, or pharmaceutical composition disclosed herein.

[0210] In a further aspect, there is provided use of a salt, crystalline salt, crystalline form, or pharmaceutical composition disclosed herein in the preparation of a medicament, e.g. for use in:

[0211] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0212] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0213] (iii) preventing or reducing risks of pre-term labor in a subject in need thereof;

[0214] (iv) treating, preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof;

[0215] (v) preventing or reducing risks of one or more of dysmenorrhea, endometriosis, adenomyosis, and idiopathic pulmonary fibrosis (IPF) in a subject in need thereof; or

[0216] (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, epididymitis, 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).

[0217] In accordance with any of these methods or uses, the salt, crystalline salt, crystalline form, or composition may be administered by any suitable route of administration as discussed above, and may be administered in a therapeutically effective amount as discussed above. As also discussed above, the administration may be by any effective dosing schedule, such as once a day, 1 to 4 times per day, once a week, 1 to 4 times per week, once a month, 1 to 4 times month, etc. Although the exact dosage may be determined on a drug-by-drug (salt / compound-by-salt / compound) basis, the daily dosage regimen for an adult human patient may be, for example, between 0.001 mg and 1000 mg, such as between 0.01 mg and 500 mg, for example 1 to 200 mg of the crystalline salt, compound or pharmaceutically acceptable salt thereof, calculated as the free base or free acid.

[0218] 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, crystalline salt, crystalline form, compound or 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, crystalline salt, crystalline form, compound or 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, crystalline salt, crystalline form, compound or 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.

[0219] In accordance with any of these methods or uses, the salt, crystalline salt, crystalline form, compound or composition may be administered in combination with an additional therapeutic agent. The additional therapeutic agent may be one or more useful for treating the condition or disease or disorder at issue. For example, the additional therapeutic agent may be useful for treating pre-term labor, reducing risks of or preventing pre-term birth, reducing risks of or preventing preterm labor, reducing risks of or preventing labor prior to cesarean delivery, reducing risks of or preventing dysmenorrhea in a subject, or treating any of the diseases or disorders disclosed above. Non-limiting examples of the additional therapeutic agent include an oxytocin receptor antagonist, (e.g., atosiban, retosiban, barusiban, epelsiban, and nolasiban), a betamimetic (e.g., terbutaline, ritodrine, hexoprenaline, albuterol, fenoterol, nylidrin, or orciprenaline), a calcium channel inhibitor (e.g., dihydropyridine, 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).

[0220] 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. LIST OF FIGURES:

[0221] The present invention will now further be described, by way of example only, with reference to the following figures:

[0222] Fig. 1. XRPD diffractogram of crystalline TGI -08 Hit 1. Fig. 2. a. DSC thermogram of crystalline TGI -08 Hit 1, single cycle 0 - 300 °C. b. DSC thermogram of crystalline TGI -08 Hit 1, cycled experiment; 1) heating cycle 1, 0 - 250 °C, 2) cooling cycle 1, 250 - 0 °C, 3) heating cycle 2, 0 - 300 °C. Curves have been shifted in y- direction for clarity.

[0223] Fig. 3 XRPD diffractogram of crystalline TGI -08 Hit 2. Fig. 4. a. Gravimetric vapor sorption data for crystalline TGI -08 Hit 1 ; change in mass (curve 1), target relative humidity (curve 2). b. GVS isotherm plot for crystalline TGI -08 Hit 1; Sorption cycle 1, diamonds; desorption cycle 1, squares; sorption cycle 2, triangles; desorption cycle 2, circles.

[0224] Fig. 5. a. XRPD diffractogram of tosylate TGI -08 Hit 1. b. DSC thermogram for tosylate TG1- 08 Hit 1. c. Gravimetric vapor sorption data for tosylate TGI -08 Hit 1 ; change in mass (curve 1), target relative humidity (curve 2). d. GVS isotherm plot for tosylate TGI -08 Hit 1; Sorption

[0225] cycle 1, diamonds; desorption cycle 1, squares; sorption cycle 2, triangles; desorption cycle 2, circles.

[0226] Fig. 6. a. XRPD diffractogram of mesylate TGI -08 Hit 3. b. DSC thermogram for mesylate TG1- 08 Hit 3. Fig. 7. a. XRPD diffractogram of sodium TGI -08 Hit 1. b. DSC thermogram for mesylate TG1- 08 Hit 1.

[0227] Fig. 8. a. XRPD diffractogram of meglumine TGI -08 Hit 1. b. DSC thermogram for meglumine

[0228] TGI -08 Hit 1.

[0229] EXAMPLES General Methods

[0230] 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), CDCI3 (7.26 ppm), and DMSO-t / e (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).

[0231] Synthesis of BCO ketone

[0232]

[0233] Procedure of step la

[0234] 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 NaHCCh (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).

[0235] Procedure of step lb

[0236] 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).

[0237] Procedure of step 1c 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), NaHCCL (sat., 160 mL), brine (160 mL), dried with IS^SCL and concentrated under reduced pressure to afford (1-4) (13.8 g, crude).JH 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).

[0238] Procedure of step Id

[0239] 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).

[0240] Procedure of step le

[0241] 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).

[0242] Synthesis of INT 1

[0243] BCO Ketone INT 1

[0244] Procedure of step 2a

[0245] 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-(trifhioromethylsulfonyl)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).

[0246] 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).

[0247] Synthesis of INT 2

[0248] Procedure of step 3a

[0249] 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)

[0250] Procedure of step 3b

[0251] 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, ET43896-1202-P1 Al, chloroform-d) 8 ppm 7.31 - 7.41 (m, 5 H) 7.04 (s, l 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)

[0252] Synthesis of INT 3, INT 4

[0253] R1= Br, I, CF3, t-Bu

[0254] Procedure of step 4a

[0255] 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 mL) was stirred at 75 °C for 0.5 hr. After that, to this well stirred reaction was added HC1 (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 HC1 (1 M, 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)

[0256] Procedure of step 4b

[0257] A mixture of INT 3 (R1=Br) (3 g, 8.77 mmol, 1 eq) in SOCI2 (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

[0258] (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).

[0259] Synthesis of INT 5

[0260]

[0261] 5-2 INT 7

[0262] Procedure of step 5a

[0263] (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).

[0264] 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).

[0265] Procedure of step 5c

[0266] 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).

[0267] Synthesis of (INT 5)

[0268] 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-d6) 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).

[0269] Synthesis of (INT 7)

[0270] 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)

[0271] Synthesis of INT 6

[0272]

[0273] Synthesis of (6-1)

[0274] 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)

[0275] 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)

[0276] 1.92 - 2.01 (m, 4 H).

[0277] Synthesis of TGI series

[0278]

[0279] General procedure of step 7a

[0280] To a mixture of (7-1) / (7-1A) (1 eq) and boronic acid (1.5 eq) in DME and water was added K2CO3 (3 eq) and Pd(PPhs)4 (0.05 eq) under N2. Then the mixture was stirred (see details in Table 1) under N2. After the reaction was complete, the mixture was filtered and concentrated in vacuum. The crude was purified by column chromatography or used as is for next step to give (7-2).

[0281] Table 1: Detailed conditions: (all reactions conducted under nitrogen gas)

[0282] cyclopentyl(diphenyl)phosphane;dichloropalladium;iron, K2CO3; E: Cui (1 eq), LiCl (3 eq), Pd(PPhs)4 (0.1 eq); F: Cui, 2-(dimethylamino)acetic acid;hydrochloride, CS2CO3

[0283] General procedure of step 7b-l To a mixture of (7-2) (1 eq) in THF was added Pd(OH)2 (10 wt%, 20% purity). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 Psi) at 20 °C (see details in Table 2). The mixture was filtered and concentrated in vacuum. The crude product was purified by column chromatography or used as it for next step to give (7- 3). General procedure of step 7b-2

[0284] Pd(OAc)2 (0.05 eq), EtsSiH (5 eq) and TEA (3 eq) were stirred in DCM for 15 min. The mixture was added dropwise to (7-2) (1 eq) in DCM under N2 and stirred (see details in Table 2). After the reaction was completed, the mixture was concentrated in vacuum and added THF and TFA (adjust pH = 5). The mixture was stirred for 5 min. The reaction mixture was adjust to pH = 7 by NaHCCF (sat.). The combined organic layers was washed with ethyl acetate, dried over Na2SC>4, filtered and concentrated in vacuum. The crude product was purified by column chromatography or used as is for next step to give (7-3).

[0285] Table 2: Detailed conditions:

[0286]

[0287] Synthesis of (7c-l) To a mixture of (7-3) (1 eq) and INT 7 (1.2 eq) in DCM was added NaHCCh (6 eq) in one portion at 20 °C for 12 h. The reaction mixture was quenched by addition of water. The residue was extracted with DCM. The combined organic layers was washed with brine, dried over Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography or used as is for next step to afford (7c-l).

[0288] Table 3: Detailed conditions:

[0289]

[0290] General procedure of step 7c-l

[0291] To a mixture of (7-3) (1 eq) in DCM was added TEA (3 eq) and E T 4 (1.1 eq). Then the mixture was stirred (see details in Table 4). After the reaction was completed, the reaction mixture was quenched by the addition of water. The residue was extracted with DCM. The combined organic layers was washed with brine, dried over Na2SC>4, filtered and concentrated in vacuum. The crude product was purified by column chromatographyor used as is for next step to give (7-4).

[0292] General procedure of step 7c-2

[0293] To a mixture of ENT 3 (1.1 eq) and (7-3) (1 eq) in DMF was added DIE A (3 eq). Then the mixture was added HATU (1.5 eq) and stirred at M°C for N hours (see details in Table 4). After the reaction was completed, the reaction mixture was quenched by addition of water. The residue was extracted with ethyl acetate. The combined organic layers was washed with brine, dried over Na2SC>4, filtered and concentrated in vacuum. The crude product was purified bycolumn chromatographyor used as is for next step to give (7-4).

[0294] General procedure of step 7c-3

[0295] To a mixture of ( c-l) (1 eq) and 3, 3 -difluoroazetidine hydrochloride (5 eq) in DMA was added DIEA (10 eq). The reaction was stirred at M°C for N hours (see details in Table 4). The mixture was added to water. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography or used as is for next step to afford (7-4).

[0296] Procedure of step 7c-4 To a solution of (7c-l) (0.15 g, 225.25 pmol, 1 eq) in MeOH (4.5 mL) was added NaOMe (60.84 mg, 1.13 mmol, 5 eq), then the mixture was stirred at 70 °C for 12 h. The residue was poured into ice-water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (15 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum to give (7-4) (0.15 g, crude).

[0297] Table 4: Detailed conditions:

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307] General procedure of step 7d

[0308] A mixture of (7-4) (1 eq) in a mixture of solvents (DCM / TFA in a 4: 1 ratio) was stirred (see details in Table 5). After the reaction was completed, the mixture was concentrated and purified by prep- HPLC to give (TGI) (select compounds shown in Table 5).

[0309] Table 5: Detailed conditions:

[0310]

[0311]

[0312]

[0313] Procedure of step 7e

[0314] To a solution of (BCO-Ketone) (5 g, 13.39 mmol, 1 eq) in THF (50 mL) was added LDA (2 M, 16.74 mL, 2.5 eq) at -78 °C. The mixture was stirred at -78 °C for 0.5 hour, then CH3I (3.80 g, 26.78 mmol, 2 eq) was added into the solution and the resulting mixture was stirred at 25°C for

[0315] 0.5 hr. The solution was quenched by NH4CI (sat., 100 mL) and extracted with ethyl acetate (60 mL*3). The combined organic phase was washed with brine (100 mL*2), dried over sodium sulfate, filtered and concentrated to give a residue which was purified by prep-HPLC (column: Welch Xtimate C18 250*100mm* 10um;mobile phase: [water (10 mM NH4HCO3)-ACN]; gradient: 45%-80% B over 20.0 min) to give (7S-1) (4.2 g, 10.84 mmol, 80.96% yield). [M+H]+= 388.1. 'H NMR (400MHz, chloroform-d) 8 ppm 7.40 - 7.29 (m, 5H), 5.99 (br s, 1H), 5.06 (s, 2H), 2.97 - 2.80 (m, 2H), 2.68 (q, J = 7 Hz, 1H), 2.05 - 1.95 (m, 4H), 1.72 - 1.59 (m, 1H), 1.51 - 1.42 (m, 1 OH), 1.16 (d, J = 7 Hz, 3H).

[0316] Procedure of step 7f

[0317] To a mixture of (7S-1) (3.7 g, 9.55 mmol, 1 eq) and 4A MS (2 g, 1.00 eq) in EtOH (50 mL) was added NH2NH2. water (9.26 g, 184.98 mmol, 13.97 eq) in one portion at 20 °C. The mixture was heated to 80 °C and stirred for 60 hours. The mixture was filtered and concentrated in vacuum and purified by prep-HPLC (column: Agela DuraShell Cl 8 250*70mm*10um; mobile phase: [water (10mMNH4HCO3)-ACN]; gradient: 50%-80% B over 17.0 min) to give (7S-2) (0.9 g, 2.24 mmol, 23.47% yield). [M+H]+= 402.3. 'H NMR (400 MHz, chloroform-d) 8 ppm 7.29 - 7.39 (m, 5 H) 6.48 (s, 1 H) 5.05 (s, 4 H) 2.94 (q, J = 6.72 Hz, 1 H) 2.73 - 2.86 (m, 2 H) 2.00 - 2.16 (m, 1 H) 1.83 - 1.97 (m, 2 H) 1.64 - 1.76 (m, 1 H) 1.43 - 1.48 (m, 11 H) 1.18 (d, J = 6.97 Hz, 3 H).

[0318] Procedure of step 7g

[0319] To a solution of (7S-2) (0.9 g, 2.24 mmol, 1 eq) in THF (2.5 mL) and piperidine (3 mL) was added I2 (1.42 g, 5.60 mmol, 2.5 eq) in THE (3.5 mL) at 0 °C under N2. The resulting mixture was stirred at 25°C for 0.5 hr. After the reaction was completed, the mixture was poured into WATER (30 mL) and extracted with ethyl acetate (30 mL*3). The organic phase was washed with brine (20 mL*2), dried over Na2SC>4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 1 / 0 to 9 / 1) to give (7- 1A) (646 mg, 1.30 mmol, 57.94% yield). [M+H]+= 498.1.

[0320] Synthesis of TG15 series Synthesis of 20-1A / B / C

[0321] General procedure of step 20a-l

[0322] To a mixture of (20-1) (1 eq) and DIEA (3 eq) in DMA was added secondary amine (5 eq). The mixture was heated to 100 °C and stirred for 12 h. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography or used as is for next step to give (20-2) (see details in Table 6).

[0323] General procedure of step 20a-2

[0324] To a mixture of (20-1) (1 eq) and (7-31) (1.2 eq) in DMF was added TEA (3 eq) and HATU (1.5 eq). The mixture was stirred at 60 °C for 12 hr. The mixture was added to water. The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried with Na2SC>4 and concentrated in vacuum. The residue was purified by column chromatography or used as is for next step to afford (20-2) (see details in Table 6). Table 6: Detailed conditions:

[0325]

[0326]

[0327]

[0328] General procedure of step 20b

[0329] A solution of (20-2) (1 eq) in a mixture of solvents (DCM / TFA in a 5:1 ratio) was stirred at 25°C for 3 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC to give TG15 series (see details in Table 7).

[0330] Table 7: Detailed conditions:

[0331]

[0332] General procedure of step 20c

[0333] To a mixture of (20S-1) (1 eq) and secondary amine (6 eq) in NMP was added DIEA (5 eq). The mixture was stirred at 100 °C for 12 hr. The mixture was filtered and the filtrate was concentrated in vacuum. The crude product was purified by prep-HPLC to afford (20-1).

[0334] Table 8: Detailed conditions:

[0335]

[0336] General procedure of step 20d

[0337] A mixture (5-1) (1 eq) and l-(3-methoxyphenyl) propan- 1 -one / 1 -(2-methoxyphenyl) propan-1 - one (1 eq) in AcOH was stirred at 75°C for 0.5 hr. After that, HC1 was added to the mixture. The mixture was stirred at M°C (see details in Table 9) for 11.5 hr. After cooled to 25°C, the reaction mixture was poured into HC1 (1 M). The solid was collected by filtration. The filter cake was washed with a mixture of solvents (petroleum ether / ethyl acetate in a 2:1 ratio) and concentrated in vacuum to afford (20-1).

[0338] Table 9: Detailed conditions:

[0339] Synthesis of TG16-01

[0340] Procedure of step 21a

[0341] To a mixture of (21-1) (2 g, 14.70 mmol, 1 eq) and N-methoxymethanamine (1.58 g, 16.17 mmol, 1.1 eq, HC1) in DMF (50 mL) was added TEA (4.46 g, 44.09 mmol, 3 eq). Then the mixture was added HATU (8.38 g, 22.04 mmol, 1.5 eq). The mixture was stirred at 20 °C for 12 h. The mixture was added to WATER (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phase was washed with brine (200 mL*2), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 20 / 1 to 5 / 1) to afford (21-2) (2.1 g, 11.72 mmol, 79.76% yield).

[0342] 'H NMR (400 MHz, chloroform-d) 8 ppm 3.69 (s, 3 H) 3.24 - 3.33 (m, 1 H) 3.22 (s, 3 H) 2.80 - 2.97 (m, 2 H) 2.66 - 2.79 (m, 2 H).

[0343] Procedure of step 21b

[0344] To a mixture of (21-2) (2.1 g, 11.72 mmol, 1 eq) in THF (40 mL) was added bromo (ethyl) magnesium (3 M, 11.72 mL, 3 eq) at 0 °C under N2. The mixture was stirred at 20 °C for 2 h. The mixture was added to water (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL*2). The combined organic phase was washed with brine (100 mL*2), dried with anhydrous Na2S0-i, filtered and concentrated in vacuum. The residue was used directly without purification to afford (21-3) (1.2 g, 8.10 mmol, 69.11% yield). ’H NMR (400 MHz, chloroform-d) 8 ppm 2.99 - 3.16 (m, 1 H) 2.61 - 2.88 (m, 4 H) 2.47 (q, J = 7.25 Hz, 2 H) 1.10 (t, J = 7.25 Hz, 3 H).

[0345] Procedure of step 21c

[0346] To a mixture of (21-3) (100 mg, 674.99 pmol, 1 eq) and (4-1) (152.57 mg, 674.99 pmol, 1 eq) in EtOH (2 mL) was added KOH (37.87 mg, 17.82 mmol, 1 eq). The mixture was stirred at 60 °C for 12 h. The mixture was adjust pH=l with HC1 (1 M). The mixture was filtrated. The filter cake was collected to afford (21-4) (100 mg, crude) which was used directly without purification. [M+H]+= 357.9.

[0347] Procedure of step 21 d

[0348] To a mixture of (21-4) (100 mg, 280.77 pmol, 1 eq) and (7-31) (107.65 mg, 280.77 pmol, 1 eq) in DMF (5 mL) was added DIEA (108.86 mg, 842.31 pmol, 3 eq). Then, the mixture was added HATU (160.14 mg, 421.16 pmol, 1.5 eq). The mixture was stirred at 20 °C for 12 h. The mixture was added to water (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL*2). The combined organic phase was washed with brine (100 mL*2), dried with anhydrous Na2SO-i, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 3:1, Rf = 0.45) to afford (21-5) (50 mg, 69.30 pmol, 24.68% yield). [M+H]+= 723.1. 'H NMR (400 MHz, chloroform-d) 8 ppm 7.87 (d, J = 8.94 Hz, 1 H) 7.68 - 7.72 (m, 1 H) 7.47 - 7.52 (m, 1 H) 7.31 - 7.44 (m, 4 H) 6.46 (s, 1 H) 3.55 - 3.65 (m, 1 H) 3.05 - 3.25 (m, 2 H) 2.85 - 2.96 (m, 2 H) 2.08 - 2.30 (m, 6 H) 1.69 - 1.96 (m, 5 H) 1.51 (s, 9 H).

[0349] Procedure of step 21 e

[0350] To a mixture of (21-5) (50 mg, 69.30 pmol, 1 eq) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC to afford (TG16-01) (5 mg, 7.51 pmol, 10.84% yield). [M+H]+= 667.1.XH NMR (400 MHz, methanol-d4) 8 ppm 7.88 (d, J = 9.01 Hz, 1 H) 7.72 (dd, J = 8.88, 1.88 Hz, 1 H) 7.51 (br d, J = 7.25 Hz, 3 H) 7.38 (br d, J = 4.25 Hz, 2 H) 6.42 (s, 1 H) 3.68 - 3.76 (m, 1 H) 3.01 - 3.13 (m, 2 H) 2.83 - 3.00 (m, 3 H) 2.09 - 2.30 (m, 4 H) 1.91 (br s, 3 H) 1.74 (br d, J = 2.13 Hz, 3 H).

[0351] Synthesis of TG19-01

[0352] Procedure of step 24a

[0353] To a mixture of (24-1) (200 mg, 635.80 pmol, 1 eq) and phenol (59.84 mg, 635.80 pmol, 1 eq) in DMF (4 mL) was added K2CO3 (263.62 mg, 1.91 mmol, 3 eq). The mixture was stirred at 100 °C for 12 h. The mixture was filtrated and the filtrate was concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 3:1, Rf = 0.62) to afford (24-2) (500 mg, 1.34 mmol, 42.26% yield). [M+H]+= 374.1. 'H NMR (400 MHz, chloroform-d) 8 ppm 7.80 (d, J = 2.00 Hz, 1 H) 7.60 - 7.64 (m, 1 H) 7.55 - 7.59 (m, 1 H) 7.42 - 7.49 (m, 2 H) 7.29 (br s, 1 H) 7.23 (br d, J = 7.63 Hz, 2 H) 4.11 (s, 3 H) 2.50 (s, 3 H). Procedure of step 24b

[0354] To a mixture of (24-2) (100 mg, 268.66 pmol, 1 eq) in water (2 mL), MeOH (2 mL) and THF (2 mL) was added LiOH. water (56.37 mg, 1.34 mmol, 5 eq). The mixture was stirred at 30 °C for 12 h. The mixture was concentrated in vacuum to afford (24-3) (80 mg, crude). [M+H]+= 360.1. 'H NMR (400 MHz, methanol-d4) 8 ppm 7.91 (d, J = 2.00 Hz, 1 H) 7.67 (dd, J = 8.94, 2.06 Hz, 1 H) 7.55 (d, J = 9.01 Hz, 1 H) 7.42 - 7.48 (m, 2 H) 7.24 - 7.30 (m, 1 H) 7.21 (dd, J = 8.57, 0.94 Hz, 2 H) 2.53 (s, 3 H).

[0355] Procedure of step 24c

[0356] To a mixture of (24-3) (80 mg, 223.35 pmol, leq) and (7-31) (94.20 mg, 245.68 pmol, 1.1 eq) in DMF (2 mL) was added DIEA (86.60 mg, 670.04 pmol, 3 eq). Then, the mixture was added HATU (127.39 mg, 335.02 pmol, 1.5 eq). The mixture was stirred at 25°C for 12 h. The mixture was added to water (50 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 3:1, Rf = 0.35) to afford (24-4) (80 mg, 110.56 pmol, 49.50% yield). [M+H]+= 725.2. 'H NMR (400 MHz, chloroform-d) 8 ppm 7.54 - 7.58 (m, 1 H) 7.47 - 7.53 (m, 2 H) 7.34 - 7.46 (m, 5 H) 7.22 - 7.26 (m, 2 H) 7.17 (d, J = 7.75 Hz, 2 H) 6.47 (s, 1 H) 2.68 - 3.00 (m, 1 H) 2.19 - 2.31 (m, 3 H) 2.10 - 2.19 (m, 4 H) 1.69 - 1.89 (m, 3 H) 1.52 (s, 9 H).

[0357] Procedure of step 24d

[0358] To a mixture of (24-4) (80 mg, 110.56 pmol, 1 eq) in DCM (2.5 mL) was added TFA (6.16 g, 54.02 mmol, 488.63 eq). The mixture was stirred at 25°C for 1 h. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC to afford (TG19-01) (30 mg, 44.95 pmol, 40.65% yield). [M+H]+= 669.1. 'H NMR (400 MHz, methanol-d4) 8 ppm 7.60 (dd, J = 9.01, 2.13 Hz, 1 H) 7.49 - 7.55 (m, 2 H) 7.43 - 7.49 (m, 2 H) 7.42 (d, J = 0.63 Hz, 1 H) 7.34 - 7.41 (m, 3 H) 7.21 - 7.27 (m, 1 H) 7.14 (d, J = 7.63 Hz, 2 H) 6.43 (s, 1 H) 2.69 - 3.08 (m, 1 H) 2.26 - 2.47 (m, 1 H) 2.14 - 2.25 (m, 2 H) 2.12 - 2.25 (m, 1 H) 2.03 - 2.46 (m, 1 H) 1.86 - 2.03 (m, 1 H) 1.85 - 2.02 (m, 2 H) 1.61 - 1.84 (m, 3 H).

[0359] Table 10: Purification Methods

[0360] Column information for Prep-HPLC and SFC

[0361] Table 11: Purification Conditions

[0362] Biological Activity Assays

[0363] FP receptor myo-inositol 1 phosphate (IP1) accumulation assay

[0364] 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.

[0365] 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- Cryptate antibody (donor).

[0366] 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.

[0367] 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.

[0368] The ratio of 337 nm / 665 nm and 337 nm / 620 nm time-resolved fluorescence readings (RFU) for each well were calculated and multiplied by 10,000 to obtain whole numbers for data analysis. For the IP standard curve, the ratio* 10,000 was plotted on the y-axis versus IP1 concentration on a logarithmic scale on the x-axis. The curve fitting model (Model205), a single-binding site, four parameter concentration response model: (MIN+((MAX-MIN) / ( 1 +((IC>o / 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.

[0369] KB = IC50

[0370] (2 + ([Agonist] I Agonist EC50 )Hi")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.

[0371] EP4 receptor cyclic AMP (cAMP) accumulation assay

[0372] 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.

[0373] 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.

[0374] 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.

[0375] 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.

[0376] 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.

[0377] (REF27) selective: where hEP4 Kb values are listed as >3000 or “no fit”, it was not possible to calculate hEP4 Kb / hFP Kb due to lack of hEP4 activity.

[0378] Mouse parturition model

[0379] The ability of a salt, crystalline salt, crystalline form, compound or 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 salt, crystalline salt, crystalline form, compound or 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. Rat intrauterine pressure (IUP) model

[0380] 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. PGF2ais administered by intravenous (IV) infusion via JVC for 5 minutes in 5 challenges separated by 30 minutes. A salt, crystalline salt, crystalline form, compound or composition of the present disclosure is administered by TV infusion via FVC beginning 5 minutes prior to and during the fourth PGF2a challenge. Thus, salt, crystalline salt, crystalline form, compound or 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.

[0381] Mouse silica-induced pulmonary fibrosis model

[0382] Silica- induced fibrosis mouse model (10 days) is used to assess the in vivo efficacy of a salt, crystalline salt, crystalline form, compound or 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.

[0383] Clinical trial in female human subjects: endometriosis-associated pain

[0384] A salt, crystalline salt, crystalline form, compound or composition of the present disclosure is administered to female human subjects suffering from endometriosis-associated pain. Subject response to the salt, crystalline salt, crystalline form, compound or composition administration is evaluated by a pain Visual Analogue Scale (VAS). Subjects show a positive clinical response to treatment. Clinical trial in female human subjects: dysmenorrhea

[0385] A salt, crystalline salt, crystalline form, compound or composition of the present disclosure is administered to female human subjects suffering from dysmenorrhea. Subject response to the salt, crystalline salt, crystalline form, compound or composition administration is evaluated by a pain Visual Analogue Scale (VAS). Subjects show a positive clinical response to treatment.

[0386] Clinical trial in female human subjects: pre-term birth

[0387] A salt, crystalline salt, crystalline form, compound or 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.

[0388] Clinical trial in human subjects: idiopathic pulmonary fibrosis

[0389] A salt, crystalline salt, crystalline form, compound or composition of the present disclosure is administered to human subjects suffering from idiopathic pulmonary fibrosis. Subject response to the salt, crystalline salt, crystalline form, compound or composition administration is evaluated by change from baseline in Forced Vital Capacity (FVC) at week 24. Subjects show a positive clinical response to treatment.

[0390] Crystallisation and salt screen of TG1-08

[0391] Experimental

[0392] Material

[0393] Solvents

[0394] Solvents used in the crystallisation and salt screens are listed in Table 12, below. All solvents (except water) were dried using molecular sieves before use. Table 12. 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.

[0395] Acid counterions The compounds used as acid counterions in the salt screen are listed in Table 13, below.

[0396] Table 13. Acidic compounds used as counterions in the salt screen

[0397] Basic counterions

[0398] The compounds used as basic counterions in the salt screen are listed in Table 14, below.

[0399] Table 14: Basic compounds used as counterions in the salt screen Material for biorelevant solubility determinations

[0400] The materials used for the biorelevant solubility determinations are listed in Table 15 below.

[0401] Table 15. Materials used for biorelevant solubility determinations

[0402] Instrumentation X-ray powder diffraction (XRPD)

[0403] Instrument: PanAlytical X’Pert Pro

[0404] 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. Measurement parameters:

[0405] Method 1 - 6 minute scan, used for most samples in the salt screen: scan speed of 0. l° / s.

[0406] Method 2 - 20 minute scan used for the starting materials and some of the salt screen experiments: scan speed of 0.03° / s. Method 3 - 20 minute scan, with 3 repetitions, for samples with limited sample amount: scan speed of 0.03%.

[0407] Sample preparation: Solid residues from the walls of the vials of evaporated solutions / suspensions were transferred to zero background wafers of silicon with a spatula. The spatula was then used to flatten the sample. Suspension samples (approximately 5 to 10 mg) were added dropwise to the zero background wafers of silicon and the solvent was allowed to evaporate before the next portion was added or the samples were vacuum filtered, after which analysis was started immediately.

[0408] XRPD diffractogram peak positions were determined using the software Highscore Plus, version 4.9 (Malvern Panalytical B.V).

[0409] 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.

[0410] 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.

[0411] Thermal Gravimetric Analysis (TGA)

[0412] Instrument: PerkinElmer TGA8000

[0413] 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%.

[0414] Method used for crystalline salts: About 2-5 mg of sample were 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 in the range 110 to 350 °C, using a continuous heating rate of 10 K / min and without any intial hold time. In many cases, the analyses were ended manually before the end temperature was reached, depending on the observed weight loss (if sublimation or degradation was suspected).

[0415] Method used for investigation of crystalline forms of TGI -08.- About 2-5 mg of sample were 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 up to 245 °C, using a continuous heating rate of 10 K / min, followed by a 1 -minute isothermal step at 245 °C.

[0416] Differential scanning calorimetry (DSC)

[0417] Instrument: Netzsch DSC 204F1

[0418] 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.

[0419] Method 1 used for analyses of amorphous TGI -08, crystalline TGI -08 and selected promising salts: About 1 mg of sample was gently placed into, and weighed, in Al pans. A lid with a premade pin-hole 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 K. The minimum temperature (start) was 0 °C and the maximum temperature was either 250, 300 or 350°C.

[0420] Method 2a used for investigation of different crystallien forms observed for crystalline TGI -08: About 1 mg of sample was gently placed into, and weighed, in Al pans. A lid with a pre-made pinhole was adapted and crimped onto the pan. The 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 K. The first heating ramp was performed from 0 °C to 250 °C, followed with a conventional cooling step to 0 °C (-5 K / min) and a 15 minutes isothermal step at 0 °C. Finally, in a second heating ramp, the sample was analysed with temperature modulated from 0 °C to 300 °C. Method 2b used for investigation of different crystalline forms observed for crystalline TGI -08: About 1 mg of sample was gently placed into, and weighed, in Al pans. A lid with a pre-made pinhole was adapted and crimped onto the pan. The sample was analysed using conventional DSC temperature profile with an average heating rate of 20 K / min. The minimum temperature (start) was 0 °C and the maximum temperature was 300 °C.

[0421] Method 3: About 1 mg of sample was gently placed into, and weighed, in Al pans. A lid with a pre-made pin-hole was adapted and crimped onto the pan. The sample was analysed using a conventional DSC temperature profile with an average heating rate of 10 K / min. The minimum temperature (start) was 0 °C and the maximum temperature was 350 °C.

[0422] 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.

[0423] FTIR spectroscopy

[0424] Instrument: Shimadzu IRAffinity-1 FTIR instrument with Pike Miracle ATR accessory

[0425] 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 .

[0426] Sample preparation: About 1 -2 mg of sample was applied to the ATR crystal.

[0427] Measurement parameters:

[0428] Gravimetric vapor sorption (GVS)

[0429] Instrument: SMS DVS Advantage

[0430] 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.

[0431] Sample preparation: About 2-5 mg of sample was gently placed into a sample pan.

[0432] Measurement parameters: UV Spectroscopy Instrument: Agilent Cary 8453 spectrophotometer, 1 cm path length

[0433] A system suitability test was carried out before each analysis using a 10 pg / mL sample.

[0434] Method: All quantitative determinations using UV spectroscopy were performed on samples based on a 9:1 methanol: solubility buffer matrix.

[0435] Calibration: UV spectra of analytical standards of 5 pg / mL TGI -08 in 90% MeOH: 10% blank SGF (pH 1.2) and 90% MeOH; 10% SIF buffer (pH 6.8) were obtained. The SIF buffer spectrum had a maximum at 234 nm, while the SGF media spectrum had a local maximum at 240 nm. Based on this, quantification was performed at 234 nm for pH 6.8 samples and at 240 nm for pH 1.2 samples. Calibration curves were constructed based on a series of five samples of different concentrations for each pH.

[0436] Procedures

[0437] Crystallisation of TGI -08

[0438] Samples of 1 mg of amorphous TGI -08 were dissolved in minimal volumes of the solvents listed in Table 12, typically 50 pL. After 24 to 48 hours, the samples were investigated for solid precipitations which indicated crystallisation had occurred. Acetonitrile and ethyl acetate were identified as suitable crystallisation solvents. 20 mg of amorphous TGI -08 was dissolved in 0.5 mL of acetonitrile and 40 mg of amorphous TGI -08 was dissolved in 0.5 mL of ethyl acetate. The acetonitrile experiment precipitated almost immediately after full dissolution. In the case of ethyl acetate, direct precipitation did not occur and the solution was seeded with crystalline solid from the screening experiment after approximately 1 hour. This triggered full precipitation. After precipitation, the solvents were slowly evaporated in ambient conditions. Finally, the obtained solids were further dried at 30 °C for about 24 hours.

[0439] Solvent screen

[0440] Samples of about 1 mg of crystallised TGI -08 were weighed into HPLC vials. Subsequent aliquots of 20, 30, 50, 100, 200, 300 and 500 pL of the solvents listed in Table 12, except for toluene and water, 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 over the weekend, before concluding the result.

[0441] Salt screen experiments

[0442] Salt screen experiments were performed in slurries, composed of about 15 mg amorphous TG1- 08, in 0.1 to 0.4 mL of solvent. Ethyl acetate, ethanol and MEK were selected as solvents based on the results of the initial solubility screen. Ten different counter ions (five acids and five bases, see Tables 13 and 14), were selected. A 1 :1 ratio of acid or base: TGI -08 was used. The experiments were performed in 1.5 ml HPLC-vials which were sealed with screw caps and stirred at ambient conditions. Slurries were analysed up to 7 days after preparation.

[0443] Solubility determination - biorelevant media

[0444] Preparation of solubility media for tests with TGI -08 and different salts thereof:

[0445] Preparation of solubility media:

[0446] 1. “Blank SGF”: 50 mg of NaCl was dissolved in 25.0 mL of water (34 mM) in a volumetric flask. 150 pL concentrated HC1 was added dropwise to pH 1.2.

[0447] 2. SIF (USP): A 1.0 M NaOH solution was prepared by dissolving 4.0 g of NaOH in 100.0 mL water. 340 mg (2.5 mmol) of KH2PO4 and 1.1 mL of the IM NaOH solution was diluted to 50.0 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 according to USP 26. pH was confirmed to be 6.8.

[0448] Preparation of analytical blanks:

[0449] Two analytical matrix solutions with the constitution 9:1 methanol: buffer, one for each pH, were prepared by mixing 6.00 mL of the prepared solubility media solutions above with 54.00 mL of methanol. Preparation of stock standard solutions:

[0450] Two stock standard solutions were prepared by dissolving 4.9 mg of TGI -08, in 1.0 mL of the respective analytical blanks.

[0451] Preparation of diluted samples for calibration:

[0452] Two working standards with concentration 24.5 pg / mL were prepared by dilution of 50 pL of the two stock standards, respectively, to 10.0 mL in volumetric flasks. Series of additional four dilutions to 9.8, 2.94, 0.98 and 0.294 pg / mL at pH 6.8 and to 9.8, 2.94, 0.98 and 0.49 at pH 1.2 were produced by dilution of aliquots of the working standard with appropriate amount of analytical blank solutions using automatic pipettes.

[0453] The obtained calibration curves were assumed to be valid over time and were not repeatedly remeasured for each day of solubility analysis. However, at the start of each analysis a test sample of approximately 10 pg / mL concentration was prepared by dissolution of aliquots of working standard by analytical blank solution and measured with UV. The acceptance criterion for this system suitability test was set to ± 10% of expected result.

[0454] Solubility equilibration

[0455] For each material to be assessed for solubility, approximately 3 mg of sample was weighed into two LC vials and 1 to 2 mL of solubility media was added to the vials, one type of media per vial. The resulting suspensions were magnetically stirred at ambient temperature. After 60 ± 5 minutes, 200 pL of each sample was transferred to an Eppendorf tube and the equilibration quenched by centrifugation for the solubility at 1 hour to be determined. After 24 ± 1 hour, the remaining volumes of the samples were transferred to new Eppendorf tubes and centrifuged to remove the solid.

[0456] Analytical sample preparation Directly after centrifugation, 100 pL of the clear solution was transferred to a vial prefilled with 900 pL of methanol, to obtain a matrix with a ratio of 9:1 methanol: buffer solution. The mixed solution was analysed by UV spectroscopy. For the 24 hours samples, the final pH and end solid form (by XRPD) were also determined.

[0457] Results and discussion

[0458] Characterization of amorphous TGI -08

[0459] This substance is completely amorphous - no crystalline peaks were present in diffractograms taken of the product.

[0460] Two TGA analyses of amorphous TGI -08 were carried out at temperatures of up to 250 °C. The solid started losing weight at 25°C and lost up to about 3% at 250 °C.

[0461] DSC analysis of amorphous TGI -08 was carried out at a temperature of up to 300 °C. The thermogram obtained contained a glass transition in the reversing curve (which shows changes in heat capacity, e.g. glass transitions and melting) with a mid-temperature of about 138 °C and a relaxation endotherm with onset temperature of 132 °C in the total curve. An exothermic event was indicated at an onset temperature of 169 °C in the total curve, representing crystallisation of the substance and at an onset temperature of 249 °C, the substance melts, shown as an endothermic event in the total curve.

[0462] Crystallisation of TGI -08

[0463] An initial screen of suitable solvents was performed using the full list of solvents in Table 12 together with very small amounts of amorphous TGI -08. Solid precipitation was discovered in three of the solubility screen samples after 24 hours: in acetonitrile, ethyl acetate and MTBE and one additional solid form was found later from toluene.

[0464] The solids obtained from the initial screen were characterised with XRPD and TGA. The same, highly crystalline, solid phase was found in both the acetonitrile and ethyl acetate samples (see Fig. 1). TGA indicated low weight loss up to 150 °C and XRPD analysis of the remaining solid showed the form to be unchanged. Thus, the crystalline TGI -08 obtained from acetonitrile or ethyl acetate appears to be an anhydrous crystalline form, suitable for scale-up. This is referred to as Hit 1.

[0465] The solid obtained from MTBE was also crystalline, with a different pattern of signals in its diffractogram relative to crystalline TGI -08 obtained from acetonitrile or ethyl acetate. Based on TGA analysis, this solid appears to be a TGl -08:MTBE [1 : 1]. XRPD analysis of the material formed after TGA analysis indicated the formation of an essentially amorphous material (the diffractogram contained very poorly resolved signals).

[0466] The solid from toluene was very poorly crystalline and was not further evaluated.

[0467] Crystallisation at larger scale (20-50 mg), was carried out in acetonitrile and ethyl acetate. In acetonitrile, precipitation occurred almost immediately, while for ethyl acetate, crystallisation had not occurred after 1 hour, and seeds of the crystalline TGI -08 solid previously obtained from ethyl acetate were added, which triggered crystallisation. Both solids were isolated and dried.

[0468] Crystalline TGI -08 Hit 1 has also been found by the inventors to be isolated from methanol (Merck, > 99.8%) either directly from a highly supersaturated solution (100 mg / mL) or via a reduction of the solubility using water as anti-solvent.

[0469] Characterisation of crystalline TG1-08 Hit 1

[0470] The crystalline materials were confirmed by XRPD to be the expected form (Hit 1) obtained previously by crystallisation in these solvents. The diffractogram comprises peaks at the positions listed in Table 16.

[0471] Table 16. Peak positions and relative intensities of XRPD diffractogram corresponding to crystalline TG1- 08 Hit 1.

[0472] 1Using Cu Ka\ radiation, wavelength 1.5406 A

[0473] TGA confirmed a relative weight loss from 25 to 110 °C of 1.5%, without any distinct step, in line with previous experiments. It was hypothesised that the loss may have been due to some remaining solvent owing to a very mild drying step having been used on the crystalline material isolated from the solvents.

[0474] DSC analysis was performed up to 300 °C. The resultant thermograms are shown in Fig. 2a and 2b and comprise a melting endotherm with an onset temperature of 235 °C (enthalpy 91 J / g), and a second small endotherm (8 J / g) at 263 °C. There being two endotherms suggests that either the original sample is a mixture of two solid forms or, more likely, a partial recrystallisation of a high- temperature crystalline form (Hit 2) occurred during the heating cycle. The second endotherm would then correspond to melting of this high-temperature crystalline form.

[0475] To investigate the hypothesis of a second, high-temperature, crystalline form forming, DSC analysis was carried out with a modified method: in a first heat cycle the sample was heated to 250 °C, lying in between the two identified endotherms. This was followed by a cooling step down to 0 °C, with a slow cooling rate (5 K / min) to facilitate a possible recrystallisation to the hypothesised high temperature crystalline form. Finally, the sample was heated to 300 °C. Both heating cycles of this experiment are shown in Fig. 2b. In the second heating cycle, only one endotherm at 261 °C was detected, with a much larger enthalpy (74 J / g) relative to that of the second endotherm of the first DSC experiment. The increased melting enthalpy of melting at 261-263 °C suggested that a more complete recrystallisation to the high-temperature form (Hit 2) had occurred during the cooling cycle. As previously described, the in situ crystallised solid of amorphous TGI -08 exhibits an onset melting temperature of 249 °C. This might correspond to the presence of Hit 2 in the solid, the reduction of the melting point being due to a lower crystalline quality. In order to isolate Hit 2, Hit 1 was heated up to 245 °C in TGA, and the obtained powder analysed by XRPD. The resultant diffractogram is shown in Fig. 3. The XRPD pattern is different to that of Hit 1 and comprises well-resolved peaks confirming high crystallinity of Hit 2. In a similar experiment, amorphous TGI -08 was heated to 200 °C and then cooled. The XRPD diffractogram of the resultant solid was generally simiar to that of Hit 2, but with less well-resolved peaks, suggesting poorer crystallinity of the material. This confirms that the solid form crystallising at 175 °C on heating amorphous TGI -08, and which then melted at 249 °C, was Hit 2. The XRPD diffractogram corresponding to Hit 2 comprises peaks at the positions listed in Table 17:

[0476] Table 17. Peak positions and relative intensities of XRPD diffractogram corresponding to crystalline TG1- 08 Hit 2.

[0477] 1Using Cu Ka\ radiation, wavelength 1.5406 A

[0478] The humidity interaction and isotherms of Hit 1 are presented in Fig. 4a and Fig. 4b, respectively.

[0479] The sorption values are tabulated in Table 18, below. Table 18. Sorption values (change of mass at the end of each target RH-cycle) of crystalline TG1- 08 Hit l .

[0480] RH = Relative Humidity (% p / po), where p = partial pressure of water vapour and po = saturation pressure of water vapour at the same temperature. The water uptake of crystalline TGI -08 Hit 1 was around 0.3% (w / w) between 0 and 80% RH, confirming that this solid is only slightly hygroscopic. XRPD analysis of the material after GVS analysis confirmed that the structure of Hit 1 was retained after the completed experiment.

[0481] In summary, it was demonstrated that TGI -08 crystallised in acetonitrile, ethyl acetate and methanol to obtain crystalline TGI -08 Hit 1 which is highly crystalline, with a high onset melting point of 235 °C, and a low hygroscopicity of 0.3 % [0 to 80 %RH], DSC experiments have shown that a second crystalline form, with a higher onset melting point, exists.

[0482] Solubility of crystalline TGI -08 Hit 1 in organic solvents

[0483] A solubility screen with crystallised TGI -08 Hit 1 was carried out with ten solvents, with different solvating properties (see Table 12). Toluene and water were not tested owing to the very low solubility of amorphous TGI -08 in these.

[0484] The estimated solubilities, based on visual observation, of crystalline TGI -08 Hit 1 are given in Table 19. Based on these data, it can be concluded that crystalline TGI -08 Hit 1 has poor solubility in many typical solvents. Acetone, ethyl methyl ketone and ethanol and methanol may be suitable solvents for crystallisation development and, as shown from the experiments above, acetonitrile and ethyl acetate are useful solvents for quick crystallisation of small amounts of amorphous material.

[0485] The results indicate that ethyl methyl ketone and ethanol might be suitable solvents for salt screen experiments. Ethyl acetate was also selected, since in situ crystallisation was expected when using this solvent.

[0486] Table 19. Solubility, by visual inspection, of crystalline TG1-08 Hit 1 at room temperature (RT).

[0487] * After 3 days, the substance in these experiments had dissolved, i.e. the solubility is higher than the results reported. ** Carried out with amorphous TG1-08, not repeated with crystalline TG1-08 owing to poor solubility.

[0488] Salt screen of crystalline TG1-08 Hit 1 These were carried out in ethyl acetate, ethanol and ethyl methyl ketone. In certain cases, the solid dissolved completely and precipitation was achieved by first seeding with crystalline TGI -08 Hit 1 and then evaporating the solvent. All solids were analysed by XRPD to evaluate crystallinity and to see if any crystalline forms differed to those already observed for crystalline TGI -08. TGA was also carried out on any crystalline hits, to assess if they contained any volatile component, thereby indicating the hit to be a solvate / hydrate. The results are shown in Table 20.

[0489] 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 (i.e. Hit (1) and Hit (2) have different diffractograms).

[0490] N / A = Not Assessed

[0491] 3Weight loss from TGA

[0492] “Poor Hit” = peaks in diffractogram are not very well-resolved.

[0493] It can be concluded that TGI -08 seems to be most prone to form salts with strong acidic counterions (hydrochloric acid, methanesulfonic acid and toluenesulfonic acid). Scattered hits are also observed when forming salts with basic counterions. No salts were found to form when using weak acids.

[0494] The majority of the salts formed exhibited significant weight loss on TGA, indicating that they contain a volatile component as part of the structure, either solvent (i.e. as a solvate) or water (as a hydrate). Hydrates are more likely than solvates to be developable. Lower weight losses are more likely to be exhibited by hydrates rather than solvates. Both the tosylate and meglumine salts provided crystalline hits with volatile components below 1%. The mesylate salt (Hit 3, obtained from ethyl methyl ketone) and the sodium salt (Hit 1, obtained from ethanol) also exhibited low weight loss on TGA. Since lower weight losses are associated with developable salts, these salts were further characterised, by DSC and solubility determination in biorelevant media. Although the lysine salt isolated from methyl ethyl ketone exhibited a lower weight loss on TGA, this solid exhibited poorer crystallinity and was not further characterised.

[0495] The XRPD diffractograms of lysine TGI -08 isolated from ethyl methyl ketone and of HC1 TG1- 08 isolated from ethyl acetate comprise peaks at the positions listed in the following table:

[0496] 1Using Cu Ka\ radiation, wavelength 1.5406 A

[0497] Further Characterisation of Tosylate TGI -08 Hit 1

[0498] The same crystalline form was obtained from ethyl acetate, ethanol and ethyl methyl ketone.

[0499] Crystal properties (XRPD) The diffractograms of tosylate TGI -08 Hit 1 obtained from ethyl acetate, ethanol or ethyl methyl ketone were compared to the diffractogram of crystalline TGI -08 (without counterion) and the diffractogram of free tosylate counterion. It can be concluded that the same crystalline form was obtained from ethyl acetate, ethanol and ethyl methyl ketone, and that the structure differed from that of crystalline TGI -08 (without counterion).

[0500] The XRPD diffractogram of tosylate TGI -08 Hit 1 is shown in Fig. 5a. The diffractogram comprises peaks at the positions listed in Table 21.

[0501] Table 21. Peak positions and relative intensities of XRPD diffractogram corresponding to Tosylate TG1-

[0502] 08 Hit 1

[0503] 1Using Cu Ka\ radiation, wavelength 1.5406 A

[0504] Thermal properties

[0505] The weight loss of tosylate TGI -08 Hit 1, as analysed by TGA, was determined to be about 0.3 % on heating from 25 to 155 °C. XRPD analysis showed that the structure of the solid was retained after TGA. The results suggest that tosylate TGI -08 Hit 1 is an anhydrate (without volatile component, neither solvate or hydrate). DSC analysis of tosylate TGI -08 Hit 1 was carried out to a maximum temperature of 350 °C. The resultant thermogram is shown in Fig. 5b and comprises a melting endotherm with onset melting point at 318 °C, followed / over lapped by an exothermal event, likely due to decomposition of the material. Humidity interactions (GVS)

[0506] GVS analysis of tosylate TGI -08 Hit 1 indicated a water uptake of 0.5% (w / w) between 0 and 80% RH, see Fig 5c, Fig. 5d, Table 22. XRPD analysis showed that the structure of the solid was retained after GVS. The solid exhibited a larger water uptake in the 80 to 90% RH range (about 0.9% water sorption). No significant hysteresis effect is present in the sorption isotherm graph (Fig. 5d).

[0507] Table 22. Sorption values (change of mass at the end of each target RH-cycle) of tosylate TGI -08 Hit 1.

[0508] RH = Relative Humidity (% p / po), where p = partial pressure of water vapour and po = saturation pressure of water vapour at the same temperature.

[0509] Summary of tosylate TG1-08 Hit 1

[0510] TGI -08 readily forms a crystalline salt with toluenesulfonic acid in all three solvents tested (ethyl acetate, ethanol and ethyl methyl ketone). The same crystalline form (tosylate TGI -08 Hit 1) formed in each case and exhibited negligible weight loss on TGA. The onset melting point of tosylate TGI -08 Hit 1 is high (318 °C), and the water uptake is low (0.5% (0 to 80 %RH)). These properties are beneficial, and tosylate TGI -08 Hit 1 was identified as a suitable candidate for development. Further Characterisation of Mesylate TGI -08 Hit 3

[0511] Different crystalline forms were obtained from ethyl acetate, ethanol and ethyl methyl ketone.

[0512] Crystal properties (XRPD)

[0513] The diffractograms of mesylate TGI -08 Hit 1 , Hit 2 and Hit 3 , obtained from ethyl acetate, ethanol and ethyl methyl ketone, respectively, were compared to the diffractogram of crystalline TGI -08 (without counterion). It can be concluded that different crystalline forms were obtained from ethyl acetate, ethanol and ethyl methyl ketone, and that these forms differed from that of crystalline TGI -08 (without counterion). The mesylate TGI -08 Hit 3 material is highly crystalline with no traces of crystalline TGI -08 Hit 1 in the corresponding diffractogram. The XRPD diffractogram of mesylate TGI -08 Hit 3 is shown in Fig. 6a. The diffractogram comprises peaks at the positions listed in Table 23.

[0514] Table 23. Peak positions and relative intensities of XRPD diffractogram corresponding to Mesylate TG1- 08 Hit 3

[0515] 1Using Cu Ka\ radiation, wavelength 1.5406 A

[0516] Thermal properties

[0517] Preliminary TGA indicated that all the mesylate crystalline forms contained volatile components resulting in weight loss at temperatures below 100 °C. Based on the preliminary data, Hit 3 was selected for further characterisation, as the main peaks of the XRPD diffractogram were retained after TGA and weight loss during TGA was the smallest of all the mesylate hits.

[0518] The weight loss of mesylate TGI -08 Hit 3, as analysed by TGA, was determined to be about 2.4 % on heating from 25 to 165 °C. Theoretically, an 8.8% weight loss would be expected for a stoichiometric TGl-08:mesylate:MEK [1 :1 :1] solvate, and a 10.0% weight loss would be expected for a TGl-08:MEK [1: 1] solvate. The theoretical weight loss of a TGl-08:mesylate:water [1: 1: 1] monohydrate is 2.4%, indicating that Hit 3 is a mesylate monohydrate.

[0519] XRPD analysis showed that the diffractogram pattern was retained after TGA, with some additional minor peaks appearing, which could be an annealing effect of heating. DSC analysis of mesylate TGI -08 Hit 3 was carried out to a maximum temperature of 350 °C. The resultant thermogram is shown in Fig. 6b and comprises a melting endotherm with onset melting temperature of 285 °C. A small exotherm is present at around 262 °C, which could be caused by a transition between two crystalline forms. No significant event corresponding to the weight loss observed on TGA is present in the DSC data.

[0520] Summary of mesylate TG1-08 Hit 3

[0521] TGI -08 readily forms a crystalline salt with methanesulfonic acid in all three solvents tested (ethyl acetate, ethanol and ethyl methyl ketone). Different crystalline forms (Hit 1, Hit 2 and Hit 3) formed in each case and each form exhibited some weight loss on TGA, indicating a volatile component in each. The structure of Hit 3 was stable on heating, and the weight lost indicated a monohydrate material. The DSC curve displayed no major events until the onset melting point at 285 °C.

[0522] Further Characterisation of Sodium TGI -08 Hit 1

[0523] A crystalline form was obtained from ethanol. Crystal properties (XRPD)

[0524] The diffractogram of sodium TGI -08 Hit 1, obtained from ethanol, was compared to the diffractogram of crystalline TGI -08 (without counterion) and sodim hydroxide. It can be concluded that a crystalline form was obtained and differed from that of crystalline TGI -08 (without counterion). After heating the sample to 110 °C during TGA, XRPD was repeated. Several of the peaks that had been present in the diffractogram had disappeared, while other diffraction peaks remained. This was indicative of relaxation of the structure of the solid following evaporation of a volatile component.

[0525] The XRPD diffractogram of sodium TGI -08 Hit 1 after TGA is shown in Fig. 7a. The diffractogram comprises peaks at the positions listed in Table 24. Table 24. Peak positions and relative intensities of XRPD diffractogram corresponding to Sodium TGI -08

[0526] Hit 3

[0527] 1Using Cu Kairadiation, wavelength 1.5406 A

[0528] Thermal properties

[0529] The weight loss of sodium TGI -08 Hit 1, as analysed by TGA, was determined to be about 1% on heating from 25 to 60 °C, followed by a further 2.1% from 60 to 100 °C. Theoretically, a 6.3% weight loss would be expected for a stoichiometric TGl-08:sodium:ethanol [1 :1 :1] solvate, and a 6.6% weight loss would be expected for a TGI -08: ethanol [1 :1] solvate. The theoretical weight loss of a TGl-08:sodium:water [1 :1 :1] monohydrate is 2.5%, indicating that sodium TGI -08 Hit 1 is a monohydrate.

[0530] DSC analysis of sodium TGI -08 Hit 1 was carried out to a maximum temperature of 300 °C. The resultant thermogram is shown in Fig. 7b and comprises a melting endotherm with onset melting temperature of 268 °C and enthalpy of melting of just 9 J / g. This low enthalpy of melting may be indicative of poor crystallinity of this hit, or the structure may have slowly and continuously lost crystallinity during heating, leaving only a small fraction of crystalline sample at the melting point.

[0531] Summary of sodium TG1-08 Hit 1

[0532] TGI -08 readily forms a crystalline salt with sodium hydroxide in ethanol. However, the crystalline phase is only semi-crystalline, and on TGA, exhibits a weight loss of 3.2% in the temperature range 25 to 110 °C. The very low melting enthalpy suggests that the structure of the crystalline form is either weak or unstable on heating.

[0533] Further Characterisation of Meglumine TGI -08 Hit 1

[0534] A crystalline form was obtained from ethyl methyl ketone. Crystal properties (XRPD)

[0535] The diffractogram of meglumine TGI -08 Hit 1, obtained from ethyl methyl ketone, was compared to the diffractogram of crystalline TGI -08 (without counterion). It can be concluded that a semicrystalline form was obtained and differed from that of crystalline TGI -08 (without counterion). The XRPD diffractogram of meglumine TGI -08 Hit 1 is shown in Fig. 8a. The diffractogram comprises peaks at the positions listed in Table 25.

[0536] Table 25. Peak positions and relative intensities of XRPD diffractogram corresponding to Meglumine TG1- 08 Hit 3

[0537] 1Using Cu Ka\ radiation, wavelength 1.5406 A Thermal properties The weight loss of meglumine TGI -08 Hit 1, as analysed by TGA, was determined to be about 0.9% on heating from 25 to 95 °C. Above this temperature, the weight loss accelerated, with the material melting and degrading.

[0538] DSC analysis of meglumine TGI -08 Hit 1 was carried out to a maximum temperature of 250 °C. The resultant thermogram is shown in Fig. 8b and comprises a melting endotherm with onset melting temperature of just 133 °C, indicating that salt formation with meglumine does not enhance stability of TGI -08.

[0539] Summary of meglumine TGI -08 Hit 1

[0540] TGI -08 readily forms a crystalline salt with meglumine in ethyl methyl ketone. However, the crystalline phase is only semi-crystalline, and exhibits a low onset melting temperature of 133 °C and degradation at relatively low temperature, indicating poor stability.

[0541] Summary of DSC analyses

[0542] Table 26. Summary of DSC analyses of different hits of TG1-08

[0543] * also includes non-melting aspects and possibly decomposition Solubility measurements in biorelevant media

[0544] Preparation of solubility media: 1. “Blank SGF”: 200 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.

[0545] 2. SIF (USP): A 1.0 M NaOH solution was prepared by dissolving 4.0 g of NaOH in 100.0 mL water. 640 mg (4.7 mmol) of KH2PO4 and 2.2 mL of the IM NaOH 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+] = 47 mM and [Na+] = 22 mM. pH had to be adjusted to 6.8 using 10 pL of cone. HC1.

[0546] Preparation of analytical blanks:

[0547] Two analytical matrix solutions with the constitution 9:1 methanol: buffer, one for each pH, were prepared by mixing 200 pL of the prepared solubility media solutions with 1.8 mL of methanol.

[0548] Preparation of SST and calibration samples:

[0549] A stock standard solution (51 pg / mL) was prepared by dissolution of 5.1 mg of crystalline TG1- 08 Hit 1 in 100 mL methanol in a volumetric flask. Calibration samples of 15.3, 5.1 and 1.0 pg / mL in MeOH:buffer 9:1 matrix, were prepared for both pH values, by mixing volumes of stock solution, solubility media and pure methanol.

[0550] The 5.1 pg / mL samples for each respective pH were also used as system suitability samples, to assess the original calibration data.

[0551] Solubility equilibration

[0552] 3-6 mg of each of crystalline TGI -08 Hitl and Hit 2 and tosylate TGI -08 Hit 1 was weighed into four separate LC vials and 3 mL of respective solubility media was added to each vial, with each combination of media and Hit tested in duplicate. The resulting suspensions were magnetically stirred at ambient temperature, ca. 23 °C. After 60 ± 5 minutes, 500 pL of each suspension was transferred to an Eppendorf tube and the equilibration quenched by centrifugation for 5 minutes. After 48 ± 1 hour, the remaining volumes of the samples were transferred to new Eppendorf tubes and centrifuged for 5 minutes to remove the solid. Analytical sample preparation

[0553] Directly after centrifugation, 100 pL of each solution was transferred to vials and mixed with 900 pL of methanol, to obtain analytical samples with a matrix of 9:1 methanol :buffer solution. The samples were analysed with UV spectroscopy. For the 48 hours samples, the final pH and end solid form (by XRPD, for one of each duplicate sample) were also determined.

[0554] Results and discussion

[0555] Solubility in different biorelevant media (SGF and SIF) was determined for crystalline TGI -08 Hits 1 and 2 and tosylate TGI -08 Hit 1. Determination of the concentration of the hit by UV spectroscopy was performed after 1 and 24 hours. After 24 hours, the final pH and end solid forms were also determined.

[0556] Table 28. Solubility of different hits of TG1-08 in SGF (pH 1.2, end pH = 1.4)

[0557] 3Dilution factor of 10 is considered when calculating the solubility based on the UV data.

[0558] Table 29. Solubility of different hits of TG1-08 in SIF buffer media (pH 6.8, end pH = 6.9-7.0)

[0559]

[0560] 3Dilution factor of 10 is considered when calculating the solubility based on the UV data.

[0561] For the SGF samples at pH 1.2, there were no significant differences between the different crystalline materials after 48 hours and XRPD analysis of the final solid forms confirmed that all the final solid samples contained crystalline TGI -08 Hit 1 as at least the major form. After 1 hour, tosylate TGI -08 Hit 1 exhibited a noticeably higher solubility than the other samples.

[0562] For the SIF samples, at pH 6.8, higher solubilities were exhibited by both crystalline TGI -08 Hit 2 and tosylate TGI -08 Hit 1 relative to crystalline TGI -08 Hit 1, both after 1 hour and after 48 hours. XRPD analysis of the final solid forms confirmed that all the solids had retained their original structures, thus solubility differences are contributed to the different structures. Solubility increased from 1 hour to 48 hours, indicating slow dissolution, but significantly faster for tosylate TGI -08 Hit 1 relative to the hits without counterions.

[0563] 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.

[0564] CLAUSES By way of further example, the invention will now be described by way of example only, with reference to the following clauses.

[0565] Clause 1. A tosylate salt of a compound of Formula le, optionally in crystalline form: (Formula le) or a stereoisomer, or tautomer thereof, wherein:

[0566] R1is halogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0567] 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;

[0568] W is a bond, -NH-, or -O-; and

[0569] R3Bis (a) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or

[0570] (b) 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or -W-R3BIS -NR3CR3D, -NHC(O)-O(CI-6alkyl), -NHC(O)R3D, or -C(O)NR3CR3D; wherein R3Cis H or Ci-3 alkyl, and R3Dis Ci-6 haloalkyl or C3-4 cycloalkyl; or wherein R3Cand R3D, together with the nitrogen atom to which they are attached, form a 3- to 6-membered ring;

[0571] R4Bis H, C1-3 alkyl, or -OH; and R6is H or C1-6 alkyl; wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).

[0572] Clause 2. The salt of clause 1, wherein R3Bis:

[0573] (i) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy, optionally wherein R3Bis selected from: ; or

[0574] (ii) a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, Ci-6 alkyl, and Ci-6 haloalkoxy, optionally wherein R3Bis selected from:

[0575] Clause 3. The salt of clause 1 or clause 2, wherein R3Bis selected from

[0576] Clause 4. The salt of any one of clauses 1-3, wherein R1is:

[0577] (i) halogen, optionally wherein R1is Br; or

[0578] (ii) C1-6 alkyl, or C1-6 haloalkyl, optionally wherein R1is ethyl or -CHF2.

[0579] Clause 5. The salt of any one of clauses 1-4, wherein R1is Br. Clause 6. The salt of any one of clauses 1-5, wherein R2is:

[0580] (i) phenyl optionally substituted with one to four R2Aindependently selected from halogen, Ci-6 alkyl, and Ci-6 alkoxy, optionally wherein R2is selected from:

[0581] (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, 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, optionally wherein R2is selected from:

[0582] (iii) phenoxy or Ci-6 alkoxy, optionally wherein R2is methoxy.

[0583] Clause 7. The salt of any one of clauses 1-6, wherein R2is Clause 8. The salt of any one of clauses 1-7, wherein W is a bond.

[0584] Clause 9. The salt of any one of clauses 1-8, wherein R4Bis H.

[0585] Clause 10. The salt of clause 1 , wherein the compound is selected from Table A, or a stereoisomer, or tautomer thereof.

[0586] Clause 11. The salt of clause 1 , wherein the compound is selected from:

[0587]

[0588] Clause 12. The salt of clause 1, wherein the compound is: Clause 13. The salt of clause 12, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20 ± 0.2 of:

[0589] 17.0 and 22.1 ; and optionally a further peak at 14.1 ; as measured by X-ray powder diffraction using a Cu K a source.

[0590] Clause 14. The salt of clause 13, wherein the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of: 6.5 and 19.5.

[0591] Clause 15. The salt of clause 13 or clause 14, wherein the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of:

[0592] 8.6, 10.7, 11.2, 11.5, 11.8, 13.5, 14.2, 15.3, 16.7, 16.9, 18.9, 20.1, 20.5, 21.2, 21.3, 22.4,

[0593] 23.1, 23.5, 23.8, 24.6, 25.1, 26.1, 26.4, 27.0, 28.0, 28.1, 28.4, 28.6, 29.6, 31.0, 31.3, 31.6, 32.4, and 32.8, or combinations thereof.

[0594] Clause 16. The salt of any one of clauses 13-15, which comprises an onset melting point of about 315 to 325 °C.

[0595] Clause 17. The salt of any one of clauses 13-16, which has a solubility in Simulated Intestinal Fluid media at a pH of 6.8 after 1 hour of at least about 25 pg / mL, at least about 30 pg / mL, optionally between about 40 and about 70 pg / mL.

[0596] Clause 18. The salt of any one of clauses 13-17, which is anhydrous and / or has a water uptake from 0 to 80%RH of up to about 0.5%.

[0597] Clause 19. A crystalline form of a tosylate salt of a compound of structure: wherein the crystalline form is obtainable by crystallising in any one or a mixture of ethyl acetate, ethanol and methyl ethyl ketone.

[0598] Clause 20. A method of crystallising a tosylate salt of a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of ethyl acetate, ethanol and methyl ethyl ketone, allowing the salt to reprecipitate and isolating the resultant precipitate.

[0599] Clause 21. A crystalline compound of structure:

[0600] Clause 22. The crystalline compound of clause 21, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20 ± 0.2 of:

[0601] 7.6 and 10.7; and optionally a further peak at 28.4; as measured by X-ray powder diffraction using a Cu K a source. Clause 23. The crystalline compound of clause 22, wherein the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of:

[0602] 13.0and 15.1. Clause 24. The crystalline compound of clause 22 or clause 23, wherein the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of:

[0603] 13.4, 14.9, 15.0, 15.5, 18.0, 18.7, 18.9, 19.8, 19.9, 20.0, 20.1, 20.4, 21.0, 21.4, 21.8, 22.1,

[0604] 22.4, 22.5, 22.7, 23.1, 23.4, 24.9, 25.3, 25.7, 26.0, 26.1, 26.2, 26.9, 27.3, 27.7, and 30.5, or combinations thereof. Clause 25. The crystalline compound of any one of clauses 21-24, which comprises an onset melting point of about 230 to 240 °C.

[0605] Clause 26. The crystalline compound of any one of clauses 21-25, which is anhydrous and / or has a water uptake from 0 to 80%RH of up to about 0.5%. Clause 27. A crystalline form of a compound of structure: wherein the crystalline form is obtainable by crystallising in any one or a mixture of acetonitrile, ethyl acetate and methanol.

[0606] Clause 28. A method of crystallising a compound of structure: wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of acetonitrile, ethyl acetate and methanol, allowing the salt to re-precipitate and isolating the resultant precipitate.

[0607] Clause 29. A pharmaceutical composition comprising the salt of any one of clauses 1-19, or the crystalline compound of any one of clauses 21-27, and at least one pharmaceutically acceptable excipient.

[0608] Clause 30. A salt of any one of clauses 1-19, or the crystalline compound of any one of clauses 21-27, or a pharmaceutical composition of clause 29, for use in therapy.

[0609] Clause 31. A salt of any one of clauses 1-19, or the crystalline compound of any one of clauses 21-27, or a pharmaceutical composition of clause 29, for use in:

[0610] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0611] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0612] (iii) preventing or reducing risks of pre-term labor in a subject in need thereof;

[0613] (iv) preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof;

[0614] (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

[0615] (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, epididymitis, 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).

[0616] Clause 32. A method of:

[0617] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0618] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0619] (iii) preventing or reducing risks of pre-term labor in a subject in need thereof;

[0620] (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

[0621] (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, epididymitis, 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 of any one of clauses 1- 19, the crystalline compound of any one of clauses 21 -27, or a pharmaceutical composition of clause 29, optionally in a therapeutically effective amount. Clause 33. Use of a salt of any one of clauses 1-19, the crystalline compound of any one of clauses 21-27, or a pharmaceutical composition of clause 29, in the preparation of a medicament for use in:

[0622] (i) modulating prostaglandin F (FP) receptor activity in a subject in need thereof;

[0623] (ii) treating pre-term labor or reducing risks of pre-term birth in a subject in need thereof;

[0624] (iii) preventing or reducing risks of pre-term labor in a subject in need thereof;

[0625] (iv) preventing or reducing risks of labor prior to cesarean delivery in a subject in need thereof;

[0626] (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

[0627] (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, epididymitis, 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

CLAIMS1. A crystalline tosylate salt of a compound of Formula le:(Formula le) 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;W is a bond, -NH-, or -O-; andR3Bis (a) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or(b) 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the heteroaryl is optionally substituted with one to three substituents independently selected from halogen, -CN, -NH2, -OH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or-W-R3BIS -NR3CR3D, -NHC(O)-O(CI-6alkyl), -NHC(O)R3D, or -C(O)NR3CR3D; wherein R3Cis H or C1-3 alkyl, and R3Dis C1-6 haloalkyl or C3-4 cycloalkyl; or wherein R3Cand R3D, together with the nitrogen atom to which they are attached, form a 3- to 6-membered ring;R4Bis H, C1-3 alkyl, or -OH; and R6is H or C1-6 alkyl; wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).

2. The salt of claim 1 , wherein R3Bis:(i) phenyl optionally substituted with one to four substituents independently selected from halogen, -CN, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy, optionally wherein R3Bis selected from:; or(ii) a 5- to 10-membered heteroaryl containing one or two ring nitrogens, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to three substituentsindependently selected from halogen, C1-6 alkyl, and C1-6 haloalkoxy, optionally wherein R3Bis selected from:

3. The salt of claim 1 or 2, wherein R1is:(i) halogen, optionally wherein R1is Br; or(ii) Ci-6 alkyl, or Ci-6 haloalkyl, optionally wherein R1is ethyl or -CHF2.

4. The salt of any one of claims 1 -3, 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 with one or two substituents independently selected from halogen, optionally wherein R2is selected from:(iii) phenoxy or Ci-6 alkoxy, optionally wherein R2is methoxy.

5. The salt of any one of claims 1-4, wherein:(ii) W is a bond; and / or(in) R4BIS H.

6. The salt of claim 1, wherein the compound is selected from Table A, or a stereoisomer, or tautomer thereof, optionally wherein the compound is selected from:

7. The salt of claim 1, wherein the compound is:; optionally wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at a 20 ± 0.2 of:17.0 and 22.1 ; and optionally a further peak at 14.1 ; as measured by X-ray powder diffraction using a Cu K a source.

8. The salt of claim 7, wherein the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ± 0.2 of:6.5 and 19.5; and optionally wherein: the X-ray powder diffraction pattern comprises further peaks at one or more, or all, of a 20 ±0.2 of:8.6, 10.7, 11.2, 11.5, 11.8, 13.5, 14.2, 15.3, 16.7, 16.9, 18.9, 20.1, 20.5, 21.2, 21.3, 22.4, 23.1, 23.5, 23.8, 24.6, 25.1, 26.1, 26.4, 27.0, 28.0, 28.1, 28.4, 28.6, 29.6, 31.0, 31.3, 31.6, 32.4, and 32.8, or combinations thereof.

9. The salt of claim 7 or 8, which comprises an onset melting point of about 315 to 325 °C.

10. The salt of any one of claims 7-10, which has a solubility in Simulated Intestinal Fluid media at a pH of 6.8 after 1 hour of at least about 25 pg / mL, at least about 30 pg / mL, optionally between about 40 and about 70 pg / mL.

11. The salt of any one of claims 7-11, which is anhydrous and / or has a water uptake from 0 to 80%RH of up to about 0.5%.

12. A crystalline form of a tosylate salt of a compound of structure:wherein the crystalline form is obtainable by crystallising in any one or a mixture of ethyl acetate, ethanol and methyl ethyl ketone.

13. A method of crystallising a tosylate salt of a compound of structure:wherein the method comprises contacting (e.g. dissolving or suspending) the salt with one or a mixture of ethyl acetate, ethanol and methyl ethyl ketone, allowing the salt to reprecipitate 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 risks of pre-term labor in a subject in need thereof;(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(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 idiopathicinterstitial 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, epididymitis, 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).

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