Crystalline compounds of LPAR1 antagonists

Abstract

Crystalline compounds of LPAR1 antagonists, pharmaceutical compositions comprising the crystalline compounds, and methods of treatment using the same are described herein, inter alia.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 481,956, filed on January 27, 2023, which is hereby incorporated by reference in its entirety for all purposes. Background Art

[0003] Lysophosphatidic acid or LPA is a family of bioactive phospholipids associated with a variety of cellular functions. Although family members differ in the length and degree of saturation of their corresponding long-chain fatty acid backbones (Fujiwara et al., J. Biol. Chem., 2005, 280 , 35038-35050), which are all terminated by glycerol-phosphate groups through ester bonds. LPA is biologically produced from membrane phospholipids through a multi-step cascade mediated by enzymes including lysophospholipase D (lysoPLD), autotaxin (ATX), phospholipase A1 (PLA1), phospholipase A2 (PLA2) and acylglycerol kinase (AGK) (Mutoh et al., British J. Pharmacol., 2012, 165 , 829-844). Once formed, LPA regulates numerous cellular signaling pathways by binding to a class of seven membrane-bound G protein-coupled receptors (GPCRs), collectively known as LPA receptors (LPARs), six of which have been characterized: LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 (Choi, JW, Annu. Rev. Pharmacol. Toxicol., 2010, 50 , 157-186). The biological responses caused by LPA binding to LPAR are both broad and context-dependent (Yung et al., J. Lipid Res. 2014, 55 , 1192-1214; Yung et al., Neuron 2015, 85These responses can include induction of cell proliferation, stimulation of cell migration and contraction, promotion of neurite retraction, inhibition of apoptosis, initiation of chemotaxis, closure of gap junctions, etc. (Chun et al. eds., Lysophospholipid Receptors: Signaling and Biochemistry, 2013, Wiley, ISBN: 978-0-470-56905-4). In addition, abnormal upregulation of the LPA pathway has been implicated in a variety of diseases, including cancer, inflammatory diseases, infertility, neuropathic pain, psychiatric and neurodegenerative disorders, atherosclerosis, and fibrosis of the skin, kidney, lung, and liver (Choi, J. W., Annu. Rev. Pharmacol. Toxicol., 2010, 50 , 157-186; Noguchi et al., Curr. Opin Pharmacol., 2009, 9 , 15-23; Yanagida et al., J. Biochem., 2011, 150 , 223-232). Thus, targeting of LPA receptors has been and continues to be an area of intense interest for identifying potential treatments for these disorders. Solutions to these and other problems in the art are specifically disclosed herein. SUMMARY

[0004] In one aspect, a crystalline compound having the formula:

[0005] wherein the crystalline compound has characteristic X-ray powder diffraction peaks at about 5.2° 2Q, about 10.4° 2Q, and about 15.6° 2Q.

[0006] In one aspect, a pharmaceutical composition comprising a crystalline compound described herein and a pharmaceutically acceptable excipient is provided.

[0007] In one aspect, a method of treating a neurodegenerative disorder in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound described herein.

[0008] In one aspect, a method of treating an inflammatory disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound described herein.

[0009] In one aspect, a method of treating a demyelinating disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound described herein.

[0010] In one aspect, a method of treating a fibrotic disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound described herein.

[0011] In one aspect, a method of treating a cancer in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound described herein.

[0012] In one aspect, a method of modulating LPAR1 activity in a subject is provided, the method comprising administering to the subject a crystalline compound described herein. BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 XRPD pattern of Form A crystalline polymorph.

[0014] Figure 2 DSC thermogram of Form A crystalline polymorph.

[0015] Figure 3 TGA thermogram of Form A crystalline polymorph.

[0016] Figure 4 PLM photograph of Form A crystalline polymorph. 1 H-NMR spectrum.

[0017] Figure 5 PLM photograph of Form A crystalline polymorph.

[0018] Figure 6 Simulated XRPD pattern of single crystal grown from slow evaporation.

[0019] Figure 7 XRPD overlay of samples obtained after storage of Form A crystalline polymorph at 25 ℃ / 92% RH, 40 ℃ / 75% RH, and 60 ℃ / 92% RH, 40

[0020] Figures 8A-8B DVS isotherm and DVS isotherm analysis report of Form A crystalline polymorph under test conditions.

[0021] Figure 9 XRPD overlay of Form A crystalline polymorph before (lower figure) and after (upper figure) DVS testing.

[0022] Figure 10 XRPD overlay of samples obtained by compression of Form A crystalline polymorph at 5 MPa and 10 MPa.

[0023] Figure 11XRPD overlay of samples obtained by dry grinding Form A crystalline polymorph manually with a mortar and pestle for 1 min, 3 min, and 5 min.

[0024] Figure 12 XRPD overlay of samples obtained by wet grinding Form A crystalline polymorph with a mortar and pestle in water and ethanol.

[0025] Figure 13 XRPD overlay of samples obtained by equilibrating in methanol, ethanol, isopropanol, acetone, and methyl ethyl ketone at 25 °C for 2 weeks.

[0026] Figure 14 XRPD overlay of samples obtained by equilibrating in ethyl acetate, acetonitrile, IPAc, tetrahydrofuran, and 1,4-dioxane at 25 °C for 2 weeks.

[0027] Figure 15 XRPD overlay of samples obtained by equilibrating in dichloromethane, 2-MeTHF, EtOH / water, acetone / water, and MEK / water at 25 °C for 2 weeks.

[0028] Figure 16 XRPD overlay of samples obtained by equilibrating in ACN / water, 1,4-dioxane / water, THF / water, EA / heptane, and 2-MeTHF / MTBE at 25 °C for 2 weeks.

[0029] Figure 17 XRPD overlay of samples obtained by equilibrating in IPA / heptane at 25 °C for 2 weeks.

[0030] Figure 18 XRPD overlay of samples obtained by equilibrating in methanol, ethanol, isopropanol, acetone, and methyl ethyl ketone at 50 °C for 1 week.

[0031] Figure 19 XRPD overlay of samples obtained by equilibrating in ethyl acetate, acetonitrile, IPAc, tetrahydrofuran, and 1,4-dioxane at 50 °C for 1 week.

[0032] Figure 20 XRPD overlay of samples obtained by equilibrating in MeOH / water, 2-MeTHF, EtOH / water, acetone / water, and MEK / water at 50 °C for 1 week.

[0033] Figure 21 XRPD overlay of samples obtained by equilibrating in ACN / water, 1,4-dioxane / water, THF / water, EA / heptane, and 2-MeTHF / MTBE at 50 °C for 1 week.

[0034] Figure 22XRPD overlay of sample obtained by equilibrating in IPA / heptane at 50 °C for 1 week.

[0035] Figure 23 XRPD overlay of sample obtained by equilibrating in 1,4-dioxane and toluene at 90 °C for 5 days.

[0036] Figure 24 XRPD overlay of sample obtained by equilibrating in methanol, ethanol, isopropanol, acetone and methyl ethyl ketone under temperature cycling.

[0037] Figure 25 XRPD overlay of sample obtained by equilibrating in ethyl acetate, acetonitrile, IPAc, tetrahydrofuran and 1,4-dioxane under temperature cycling.

[0038] Figure 26 XRPD overlay of sample obtained by equilibrating in MeOH / water, 2-MeTHF, EtOH / water, acetone / water and MEK / water under temperature cycling.

[0039] Figure 27 XRPD overlay of sample obtained by equilibrating in ACN / water, 1,4-dioxane / water, THF / water, EA / heptane and 2-MeTHF / MTBE under temperature cycling.

[0040] Figure 28 XRPD overlay of sample obtained by slow cooling in methanol, ethanol, isopropanol, acetone and methyl ethyl ketone.

[0041] Figure 29 XRPD overlay of sample obtained by slow cooling in ethyl acetate, acetonitrile, IPAc, tetrahydrofuran and 2-MeTHF.

[0042] Figure 30 XRPD overlay of sample obtained by fast cooling in methanol, ethanol, isopropanol, acetone and methyl ethyl ketone.

[0043] Figure 31 XRPD overlay of sample obtained by fast cooling in ethyl acetate, acetonitrile, IPAc, tetrahydrofuran and 2-MeTHF.

[0044] Figure 32 XRPD overlay of sample obtained by adding anti-solvent in methanol / water, methyl ethyl ketone / ACN, ethyl acetate / heptane and tetrahydrofuran / water.

[0045] Figure 33 XRPD overlay of sample obtained by adding anti-solvent in tetrahydrofuran / MTBE, DCM / heptane and 2-MeTHF / heptane.

[0046] Figure 34 XRPD overlay of samples obtained by reverse addition of antisolvent in methanol / water, methyl ethyl ketone / ACN, ethyl acetate / heptane, and tetrahydrofuran / water.

[0047] Figure 35 XRPD overlay of samples obtained by reverse addition of antisolvent in methanol / water, methyl ethyl ketone / ACN, ethyl acetate / heptane, and tetrahydrofuran / water.

[0048] Figure 36 XRPD overlay of samples obtained by reverse addition of antisolvent in tetrahydrofuran / MTBE, DCM / heptane, and 2-MeTHF / heptane.

[0049] Figure 37 XRPD overlay of samples obtained by reverse addition of antisolvent in ethyl alcohol / heptane, methyl ethyl ketone / ACN, and 2-MeTHF / ACN.

[0050] Figure 38 XRPD overlay of samples obtained by slow evaporation in methanol, ethyl alcohol, isopropyl alcohol, acetone, and methyl ethyl ketone.

[0051] Figure 39 XRPD overlay of samples obtained by slow evaporation in ethyl acetate, IPAc, tetrahydrofuran, 2-MeTHF, and DCM. DETAILED DESCRIPTION

[0052] I. Definitions

[0053] The abbreviations used herein have their normal chemical and biological meanings. Chemical structures and formulas set forth herein are constructed according to standard rules of chemical valence.

[0054] As used herein, the term“about” means a range of values that a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments,“about” means within standard deviation using measurements generally accepted in the art. In embodiments,“about” means a range extending + / - 10% of the specified value. In embodiments,“about” includes the specified value. In embodiments,“about” includes the specified value (e.g., ± 0.10, ± 0.15, ± 0.20, or ± 0.25).

[0055] The term“polymorph” is used according to its ordinary meaning and refers to a crystalline form of a compound.

[0056] As used herein, the term "crystalline" or "crystalline state" or "crystalline form" means a physical state having a regular, three-dimensional array of atoms, ions, molecules, or molecular assemblies. The crystalline state has a lattice array of structural units arranged in a three-dimensional pattern that is repeated with a well-defined symmetry. In contrast, the term "amorphous" or "amorphous state" or "amorphous form" refers to a non-crystalline solid state. The physical state of a compound can be determined by techniques such as X-ray powder diffraction, polarized light microscopy, and / or differential scanning calorimetry.

[0057] The compounds, salt forms, crystalline polymorphs, therapeutic agents, or other compositions described herein can be referred to as being characterized by "graphical data substantially as depicted in the accompanying figures." Such data can include, but is not limited to, X-ray powder diffraction spectra, NMR spectra, differential scanning calorimetry curves, and thermogravimetric analysis curves, among others. As is known in the art, such graphical data can provide additional technical information to further define the compound, salt form, crystalline polymorph, therapeutic agent, or other composition. As understood by one of skill in the art, such graphical representations of data can be subject to small variations in, for example, peak relative intensities and peak positions, due to factors such as variations in instrument response, as well as variations in sample concentration and purity.

[0058] When substituent groups are described by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0059] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Thus, single stereochemical isomers, as well as enantiomeric and diastereomeric mixtures, of the present compounds are within the scope of the disclosure.

[0060] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids in the administration of an active agent to a subject and facilitates its absorption by the subject, and can be included in the compositions of the present application without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorants, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, carboxymethylcellulose, polyvinylpyrrolidone, and pigments and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents and / or aromatic substances and the like which do not deleteriously react with the compounds of the present application. One skilled in the art will recognize other pharmaceutical excipients that can be used in the present application.

[0061] The term “formulation” is intended to encompass a preparation of the active compound with an encapsulating material as a carrier providing a capsule, with or without other carriers, wherein the active ingredient is surrounded by the carrier which thus binds the active ingredient. Similarly, included are caplets and lozenges. Tablets, powders, capsules, pills, caplets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0062] The term “administration” as used herein is used according to its ordinary and general meaning and includes oral administration, administration in the form of a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a slow-release device (e.g., a microosmotic pump). Administration is by any route, including parenterally and transmucosally (e.g., buccal, sublingual, palatine, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. “Co-administration” means administration of the compositions described herein simultaneously with, just before, or just after, one or more additional therapies (e.g., cancer therapies such as chemotherapy, hormone therapy, radiation therapy, or immunotherapy). The compounds of the present application can be administered to a patient alone or can be co-administered. Co-administration is meant to include simultaneous or sequential administration of the compounds (more than one compound) either separately or in combination. Thus, the formulations can also be combined with other active substances (e.g., to reduce metabolic degradation) if desired. The compositions of the present application can be delivered transdermally, topically, can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0063] As defined herein, the term "inhibition," "inhibit," "inhibiting," and the like in reference to a cell component-inhibitor interaction means negatively affecting (e.g., reducing) the activity or function of a cell component (e.g., reducing a signaling pathway stimulated by a cell component (e.g., a protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the activity or function of the cell component in the absence of the inhibitor. In embodiments, inhibition means negatively affecting (e.g., reducing) the concentration or level of a cell component relative to the concentration or level of the cell component in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction in a disease or a symptom of a disease. In some embodiments, inhibition refers to a reduction in a signaling pathway or signaling pathway activity (e.g., a reduction in a pathway involving a cell component). Thus, inhibition at least partially comprises partially or completely blocking stimulation, reducing, preventing or delaying activation, or inactivating, desensitizing, or down-regulating a signaling pathway or enzyme activity or the amount of a cell component.

[0064] Alternatively, the term "inhibitor," "repressor," "antagonist," or "downregulator" refers to an agent capable of detectably reducing the expression or activity of a given gene or protein. The antagonist can reduce the expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to a control in the absence of the antagonist. In certain instances, the expression or activity is 1 / 1.5, 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 10, or less of the expression or activity in the absence of the antagonist.

[0065] The term "expression" includes any step involved in the production of a polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting proteins (e.g., ELISA, Western Blot, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0066] The term "lysophosphatidic acid receptor 1 antagonist" or "LPAR1 antagonist" refers to any exogenously administered compound or agent capable of partially or completely inhibiting or reversing the effect of an agonist (e.g., lysophosphatidic acid) on a LPAR1 receptor. This term encompasses compounds or agents characterized as, or described as, antagonists, partial antagonists, and negative allosteric modulators.

[0067] The terms "selective" or "selectivity" and the like with respect to a compound or agent refer to the ability of the compound or agent to preferentially cause an increase or decrease in activity of a particular molecular target (e.g., a protein, enzyme, etc.) over one or more different molecular targets (e.g., a compound selective for lysophosphatidic acid receptor 1 (LPAR1) will preferentially inhibit LPAR1 over other lysophosphatidic acid receptors). In embodiments, a "lysophosphatidic acid receptor 1 selective compound" or "LPAR1 selective compound" refers to a compound (e.g., a compound described herein) that is selective for lysophosphatidic acid receptor 1 (LPAR1). In embodiments, a compound (e.g., a compound described herein) is about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or about 100-fold selective for lysophosphatidic acid receptor 1 (LPAR1) over one or more of LPAR2, LPAR3, LPAR4, LPAR5, or LPAR6. In embodiments, a compound (e.g., a compound described herein) is at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or at least 100-fold selective for lysophosphatidic acid receptor 1 (LPAR1) over one or more of LPAR2, LPAR3, LPAR4, LPAR5, or LPAR6.

[0068] A "patient" or "patient in need" or "subject" or "subject in need" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In embodiments, the patient is a human. In embodiments, the patient in need is a human. In embodiments, the subject is a human. In embodiments, the subject in need is a human.

[0069] The terms“treating” or“treatment” refer to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as alleviation; remission; diminishing of symptoms or making the patient more tolerable to the injury, pathology or condition; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. Treatment or amelioration can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or psychometric testing. For example, certain methods presented herein successfully treat cancer by reducing the incidence and / or causing regression of cancer. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. The term“treatment” and conjugations thereof includes preventing an injury, pathology, condition, or disease. In embodiments, treatment is prophylactic. In embodiments, treatment does not include prophylaxis. In embodiments, treating or treatment is not prophylactic treatment.

[0070] An“effective amount” is an amount sufficient to effect at least partial treatment for a purpose for which the compound is administered (e.g., to effect its administration effect, to treat a disease, to decrease enzyme activity, to increase enzyme activity, to decrease a signaling pathway, to reduce one or more symptoms of a disease or condition). An example of an“effective amount” when referred to in this context is an amount sufficient to bring about treatment, prevention, or reduction of one or more symptoms of a disease, which amount can also be referred to as a“therapeutically effective amount.” A“reduction” of one or more symptoms (and grammatical equivalents of this phrase) means decreasing the severity or frequency of the symptom or symptoms, or eliminating the symptom or symptoms altogether. A“prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset of a disease, pathology, or condition (or its recurrence), or reducing the likelihood of the onset (or recurrence) of a disease, pathology, or condition, or its symptoms. A full prophylactic effect need not occur in order for an amount to be deemed prophylactically effective. A prophylactically effective amount can be administered in one or more administrations. As used herein, an“activity reducing amount” refers to the amount of antagonist required to reduce the activity of an enzyme relative to the absence of the antagonist. As used herein, a“function disrupting amount” refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. As used herein, an“activity increasing amount” refers to the amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist. As used herein, a“function increasing amount” refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0071] A "control" or "control experiment" is used according to its plain ordinary meaning and refers to an experiment in which subjects or reagents of an experiment are treated as in a parallel experiment except that a procedure, reagent, or variable of the experiment is omitted. In some cases, a control is used as a standard for comparison in assessing the effect of an experiment. In some embodiments, a control is a measure of the activity of a protein (e.g., a signaling pathway) in the absence of a compound as described herein (including embodiments, examples, figures, or tables).

[0072] "Disease" or "disorder" refers to a state or health condition of a patient or subject that can be treated with a compound or method provided herein. In some embodiments, the disease is a disease associated with (caused by) a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microbe, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is a neurodegenerative disease. In embodiments, the disease is an inflammatory disease. In embodiments, the disease is posthemorrhagic encephalitis. In embodiments, the disease is a demyelinating disease. In embodiments, the disease is multiple sclerosis. In embodiments, the disease is a fibrotic disease. In embodiments, the disease is pulmonary fibrosis. In embodiments, the disease is idiopathic pulmonary fibrosis. In embodiments, the disease is cancer. In embodiments, the disease is glioblastoma.

[0073] As used herein, the term "neurodegenerative disease" or "neurodegenerative disorder" refers to a disease or condition in which a subject's nervous system function is impaired. Examples of neurodegenerative diseases that can be treated with a compound, pharmaceutical composition, or method described herein include Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Guillain-Barre syndrome, Huntington's disease, inclusion body myositis, Kennedy's disease, Lewy body dementia, multiple sclerosis, multiple system atrophy, myoclonus epilepsy ragged red fiber syndrome, Niemann-Pick disease, Parkinson's disease, Pelizaeus-Merzbacher disease, progressive supranuclear palsy, prion diseases, and spinocerebellar ataxia.

[0074] (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Guillain-Barre syndrome, Huntington's disease, inclusion body myositis, Kennedy's disease, Lewy body dementia, multiple sclerosis, multiple system atrophy, myoclonus epilepsy ragged red fiber syndrome, Niemann-Pick disease, Parkinson's disease, Pelizaeus-Merzbacher disease, progressive supranuclear palsy, prion diseases, and spinocerebellar ataxia. -Scheinker syndrome), Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum's disease, Sandhoff's disease, Schilder's disease disease), subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (several types with varying features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

[0075] As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation (eg, increased levels of inflammation compared to a control, such as compared to a healthy individual without the disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison's disease, and disease), vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.

[0076] As used herein, the term "demyelinating disease" refers to any disease or disorder characterized by damage to the protective covering (e.g., myelin sheath) surrounding nerve fibers (e.g., in the brain, optic nerve, or spinal cord). In embodiments, the demyelinating disease is a demyelinating disease of the central nervous system. In embodiments, the demyelinating disease is multiple sclerosis. In embodiments, the demyelinating disease is a demyelinating disease of the peripheral nervous system.

[0077] As used herein, the terms "fibrotic disease" and "fibrosis" refer to any disease or disorder characterized by the formation of excess fibrous connective tissue. The formation of excess fibrous connective tissue can be in response to a reparative or reactive process. Fibrotic diseases include, but are not limited to, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)), liver fibrosis (e.g., nonalcoholic steatohepatitis (NASH)), myelofibrosis, skin fibrosis (e.g., scleroderma), ocular fibrosis, intramedullary fibrosis, cardiac fibrosis, renal fibrosis, stromal fibrosis, epidural fibrosis, epithelial fibrosis, or idiopathic fibrosis.

[0078] As used herein, the terms "cardiovascular disorder" or "cardiovascular disease" are used according to their plain ordinary meaning. In embodiments, cardiovascular diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include, but are not limited to, stroke, heart failure, hypertension, hypertensive heart disease, myocardial infarction, angina pectoris, tachycardia, cardiomyopathy, rheumatic heart disease, myocardial disease, arrhythmia, congenital heart disease, valvular heart disease, myocarditis, aortic aneurysm, peripheral arterial disease, thromboembolic disease, and venous thrombosis.

[0079] As used herein, the term "cancer" refers to all types of cancer, tumor, or malignant tumor found in mammals (e.g., humans), including leukemias, lymphomas, carcinomas, and sarcomas. Exemplary cancers that can be treated with the compounds or methods provided herein include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, medulloblastoma, colorectal cancer, or pancreatic cancer. Additional examples include: Hodgkin's disease, Non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, carcinoma, malignant pancreatic insulanoma, malignant carcinoid carcinoma, bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortex cancer, endocrine or exocrine pancreatic tumor, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular cancer, or prostate cancer.

[0080] The term "leukemia" broadly refers to a progressive, malignant disease of the blood-forming organs, and is generally characterized by the unregulated growth and development of leukocytes and their precursors in the blood and bone marrow. Clinical classifications of leukemia are generally based on (1) the duration and characteristics of the disease - acute or chronic; (2) the type of cells involved; myeloid (myelocytic), lymphoid (lymphoblastic), or monocytic; and (3) the increase or non-increase in the number of abnormal cells in the leukemia or non-leukemia (subleukemia). Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, aleukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphoid leukemia, lymphosarcellar cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblast leukemia, monocyte leukemia, myeloblastocytic leukemia, myelocytic leukemia, myelogenous leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0081] As used herein, the term "lymphoma" refers to a group of cancers that affect the hematopoietic and lymphoid tissues. It begins in lymphocytes, which are blood cells primarily found in lymph nodes, the spleen, the thymus, and the bone marrow. The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for about 15% of all diagnosed lymphomas. It is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the rate of growth of the cancer and the type of cell involved. There are aggressive (high-grade) and indolent (low-grade) types of NHL. Based on the type of cell involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoma extranodal (MALT), nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0082] The term "sarcoma" generally refers to a tumor composed of substance similar to embryonic connective tissue and is usually composed of closely packed cells embedded in a fibrous or homogeneous substance. Sarcomas that can be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanoma sarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, lipomatous sarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, interstitial sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0083] The term "melanoma" is understood to mean a tumor derived from the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

[0084] The term "cancer" refers to a malignant new growth composed of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary cancers that can be treated with the compounds or methods provided herein include, for example, medullary carcinoma of the thyroid, familial medullary carcinoma of the thyroid, acinar carcinoma, alveolar carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenocarcinoma, carcinoma of the adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid cell tumor, basal cell-like carcinoma, basal squamous cell carcinoma, bronchiolar alveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirasse, carcinoma en cuirscroti), signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, potato carcinoma, globular cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, fusiform carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or villoglandular carcinoma.

[0085] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" are used interchangeably and refer to the spread of a proliferative disease or disorder (e.g., a cancer) from one organ or another non-adjacent organ or body part. A "metastatic cancer" is also referred to as a "stage IV cancer." Cancer arises at a primary site (e.g., the breast), which is referred to as a primary tumor, e.g., a primary breast cancer. Some cancer cells in the primary tumor or site of origin acquire the ability to penetrate and infiltrate the surrounding normal tissue, and / or the ability to penetrate the wall of the lymphatic system or the vascular system that circulates through the body to other sites and tissues within the body. A second clinically detectable tumor formed from cancer cells of the primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, it is presumed that the metastatic tumor and its cells are similar to the primary tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the breast site is composed of abnormal lung cells, not abnormal breast cells. The secondary tumor in the breast refers to metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrase non-metastatic cancer or a subject with non-metastatic cancer refers to a disease in which a subject has a primary tumor but does not have one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject who has a primary lung tumor or has a history of a primary lung tumor and has one or more secondary tumors at a second location or locations (e.g., in the breast).

[0086] The term "cutaneous metastasis" or "skin metastasis" refers to the growth of secondary malignant cells in the skin, where the malignant cells originate from a primary cancer site (e.g., the breast). In cutaneous metastasis, cancer cells from the primary cancer site can migrate to the skin, where these cells divide and cause lesions. Cutaneous metastasis can result from the migration of cancer cells from a breast cancer tumor to the skin.

[0087] The term "visceral metastasis" refers to secondary malignant cell growth in an internal organ (e.g., heart, lung, liver, pancreas, intestine) or body cavity (e.g., pleural, peritoneal), where the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In a visceral metastasis, cancer cells from a primary cancer site can migrate to an internal organ, where these cells divide and cause a lesion. Visceral metastasis can result from migration of cancer cells from a liver cancer tumor or a head and neck tumor to an internal organ.

[0088] As used herein, the term "LPAR1 -associated disease" refers to any disease or disorder caused by abnormal activity or signaling of LPAR1. In embodiments, the LPAR1 -associated disease is a neurodegenerative disease. In embodiments, the LPAR1 -associated disease is an inflammatory disease. In embodiments, the LPAR1 -associated disease is hemorrhagic postencephalitis. In embodiments, the LPAR1 -associated disease is a demyelinating disease. In embodiments, the LPAR1 -associated disease is multiple sclerosis. In embodiments, the LPAR1 -associated disease is a fibrotic disease. In embodiments, the LPAR1 -associated disease is pulmonary fibrosis. In embodiments, the LPAR1 -associated disease is idiopathic pulmonary fibrosis. In embodiments, the LPAR1 -associated disease is a cancer. In embodiments, the LPAR1 -associated disease is a glioblastoma.

[0089] The term "drug" is used according to its ordinary meaning and refers to a substance that has a physiological effect (e.g., a beneficial effect, useful in the treatment of a subject) when introduced into the body of or onto a subject (e.g., in or on a subject or patient). A drug moiety is a group of a drug.

[0090] In therapeutic uses for treating a disease, the compounds used in the pharmaceutical compositions of the present application can be administered at an initial dose of about 0.001 mg / kg to about 1000 mg / kg per day. The daily dose can range from about 0.01 mg / kg to about 500 mg / kg, or from about 0.1 mg / kg to about 200 mg / kg, or from about 1 mg / kg to about 100 mg / kg, or from about 10 mg / kg to about 50 mg / kg. However, the dose can vary according to the needs of the patient, the severity of the condition being treated, and the compound or drug employed. For example, the dose can be empirically determined based on the type and stage of disease (e.g., multiple sclerosis, fibrotic disease, encephalitis, or cancer) diagnosed in a particular patient. In the context of the present application, the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose will also depend on the existence, nature, and extent of any adverse side effects that accompany the administration of the compound in a particular patient. Determining the appropriate dose for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect is achieved. For convenience, the total daily dosage can be divided and administered in portions during the day as required. The compounds of the present application can be administered in a form suitable to be delivered to the lungs, including, but not limited to, as an aerosol. The aerosol can be delivered in a pressurized pack or a nebulizer and can also be obtained by means of a dry powder inhaler. The compounds of the present application can also be administered in the form of suppositories for rectal administration.

[0091] In the context of a substance or substance activity or function associated with a disease (e.g., a protein-related disease, a disease associated with a cellular component), the term “associated” or “associated with” means that the disease (e.g., multiple sclerosis, fibrotic disease, encephalitis, or cancer) is caused, in whole or in part, by the substance or substance activity or function, or that the symptoms of the disease are caused, in whole or in part, by the substance or substance activity or function, or that the disease or symptoms of the disease can be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component). As used herein, a pathogen is described as being associated with a disease if it can be a target for treating the disease.

[0092] As used herein, the term “abnormal” means different from normal. When used to describe enzymatic activity, abnormal refers to an activity that is greater or less than the average of a normal control or normal non-diseased control sample. An abnormal activity can refer to an amount of activity that causes a disease, wherein returning the abnormal activity to a normal or non-disease associated amount (e.g., by administering a compound or using a method as described herein) results in a reduction in the disease or one or more symptoms of the disease.

[0093] The term “lysophosphatidic acid receptor” or “LPAR” refers to one or more of the family of G protein-coupled receptors for lysophosphatidic acid (LPA). In embodiments, LPAR includes LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6.

[0094] The term "lysophosphatidic acid receptor 1" or "LPAR1" refers to a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA) (including homologs, isoforms, and functional fragments thereof). The term includes any recombinant or naturally occurring variant of LPAR1 that maintains LPAR1 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type LPAR1). In embodiments, the LPAR1 protein encoded by the LPAR1 gene has the amino acid sequence set forth in or corresponding to Entrez 1902, UniProt Q92633, RefSeq (protein) NP_001392.2, or RefSeq (protein) NP_476500.1. In embodiments, the LPAR1 gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_001401.3 or RefSeq (mRNA) NM_057159.2. In embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing this application.

[0095] II. Compounds

[0096] In one aspect, a crystalline compound of trans-4-(3-(2-(difluoromethoxy)-6- methoxypyridin-3-yl)-1-(2-isopropylphenyl)ureido)cyclohexane-1-carboxylic acid having the structure:

[0097]

[0098] In one aspect, a crystalline compound having the formula:

[0099] wherein the crystalline compound has characteristic X-ray powder diffraction peaks at about 5.2° 2Θ, about 10.4° 2Θ, and about 15.6° 2Θ.

[0100] In embodiments, the crystalline compound has additional characteristic X-ray powder diffraction peaks at about 11.3° 2Θ, about 12.6° 2Θ, about 18.4° 2Θ, about 20.9° 2Θ, about 22.4° 2Θ, about 26.1° 2Θ, about 27.4° 2Θ, and about 27.6° 2Θ.

[0101] In embodiments, the crystalline compound has additional characteristic X-ray powder diffraction peaks at about 6.7° 2Θ, about 7.3° 2Θ, about 8.6° 2Θ, about 9.4° 2Θ, about 11.3° 2Θ, about 12.0° 2Θ, about 12.6° 2Θ, about 13.6° 2Θ, about 14.9° 2Θ, about 16.8° 2Θ, about 17.4° 2Θ, about 18.4° 2Θ, about 18.8° 2Θ, about 19.5° 2Θ, about 20.1° 2Θ, about 20.9° 2Θ, about 21.8° 2Θ, about 22.4° 2Θ, about 22.7° 2Θ, about 23.1° 2Θ, about 24.1° 2Θ, about 24.4° 2Θ, about 24.9° 2Θ, about 25.4° 2Θ, about 26.1° 2Θ, about 27.4° 2Θ, about 27.6° 2Θ, about 28.0° 2Θ, about 28.4° 2Θ, about 28.7° 2Θ, about 29.2° 2Θ, about 29.5° 2Θ, about 30.0° 2Θ, about 30.2° 2Θ, about 31.3° 2Θ, about 31.8° 2Θ, about 32.0° 2Θ, about 32.9° 2Θ, about 33.9° 2Θ, about 34.5° 2Θ, about 36.3° 2Θ, about 36.9° 2Θ, about 37.5° 2Θ, about 38.0° 2Θ, and about 39.6° 2Θ.

[0102] The peaks of the X-ray powder diffraction pattern of the crystalline compound are provided in Table 1.

[0103] Table 1. XRPD Peak Listing for Crystalline Compound

[0104]

[0105]

[0106] In embodiments, the X-ray powder diffraction pattern of the crystalline compound has one or more of the peaks shown in Table 1.

[0107] In embodiments, the crystalline compound is further characterized by having a differential scanning calorimetry endotherm onset at about 188.6 °C.

[0108] In one aspect, a compound having the following formula is provided:

[0109] wherein the compound is in crystalline form and the crystalline form has characteristic X-ray powder diffraction peaks at about 5.2° 2Θ, about 10.4° 2Θ, and about 15.6° 2Θ.

[0110] In embodiments, the crystalline form has additional characteristic X-ray powder diffraction peaks at about 6.7° 2Θ, about 7.3° 2Θ, about 8.6° 2Θ, about 9.4° 2Θ, about 11.3° 2Θ, about 12.0° 2Θ, about 12.6° 2Θ, about 13.6° 2Θ, about 14.9° 2Θ, about 16.8° 2Θ, about 17.4° 2Θ, about 18.4° 2Θ, about 18.8° 2Θ, about 19.5° 2Θ, about 20.1° 2Θ, about 20.9° 2Θ, about 21.8° 2Θ, about 22.4° 2Θ, about 22.7° 2Θ, about 23.1° 2Θ, about 24.1° 2Θ, about 24.4° 2Θ, about 24.9° 2Θ, about 25.4° 2Θ, about 26.1° 2Θ, about 27.4° 2Θ, about 27.6° 2Θ, about 28.0° 2Θ, about 28.4° 2Θ, about 28.7° 2Θ, about 29.2° 2Θ, about 29.5° 2Θ, about 30.0° 2Θ, about 30.2° 2Θ, about 31.3° 2Θ, about 31.8° 2Θ, about 32.0° 2Θ, about 32.9° 2Θ, about 33.9° 2Θ, about 34.5° 2Θ, about 36.3° 2Θ, about 36.9° 2Θ, about 37.5° 2Θ, about 38.0° 2Θ, and about 39.6° 2Θ.

[0111] In embodiments, the crystalline form has additional characteristic X-ray powder diffraction peaks at about 6.7° 2Θ, about 7.3° 2Θ, about 8.6° 2Θ, about 9.4° 2Θ, about 11.3° 2Θ, about 12.0° 2Θ, about 12.6° 2Θ, about 13.6° 2Θ, about 14.9° 2Θ, about 16.8° 2Θ, about 17.4° 2Θ, about 18.4° 2Θ, about 18.8° 2Θ, about 19.5° 2Θ, about 20.1° 2Θ, about 20.9° 2Θ, about 21.8° 2Θ, about 22.4° 2Θ, about 22.7° 2Θ, about 23.1° 2Θ, about 24.1° 2Θ, about 24.4° 2Θ, about 24.9° 2Θ, about 25.4° 2Θ, about 26.1° 2Θ, about 27.4° 2Θ, about 27.6° 2Θ, about 28.0° 2Θ, about 28.4° 2Θ, about 28.7° 2Θ, about 29.2° 2Θ, about 29.5° 2Θ, about 30.0° 2Θ, about 30.2° 2Θ, about 31.3° 2Θ, about 31.8° 2Θ, about 32.0° 2Θ, about 32.9° 2Θ, about 33.9° 2Θ, about 34.5° 2Θ, about 36.3° 2Θ, about 36.9° 2Θ, about 37.5° 2Θ, about 38.0° 2Θ, and about 39.6° 2Θ.

[0112] III. Methods of Making Crystalline Compound

[0113] In one aspect, a method of making a crystalline compound is provided, the method comprising:

[0114] (i) preparing a blend comprising a solvent component and a compound having the formula: and

[0115] (ii) obtaining the crystalline compound.

[0116] In embodiments, the solvent component comprises one or more selected from the group consisting of methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, 2-methyltetrahydrofuran, water, heptane, and methyl tert-butyl ether. In embodiments, the solvent component is methanol. In embodiments, the solvent component is ethanol. In embodiments, the solvent component is isopropanol. In embodiments, the solvent component is acetone. In embodiments, the solvent component is methyl ethyl ketone. In embodiments, the solvent component is ethyl acetate. In embodiments, the solvent component is acetonitrile. In embodiments, the solvent component is isopropyl acetate. In embodiments, the solvent component is tetrahydrofuran. In embodiments, the solvent component is 1,4-dioxane. In embodiments, the solvent component is dichloromethane. In embodiments, the solvent component is 2-methyltetrahydrofuran. In embodiments, the solvent component is a mixture of ethanol and water. In embodiments, the solvent component is a mixture of methyl ethyl ketone and water. In embodiments, the solvent component is a mixture of acetonitrile and water. In embodiments, the solvent component is a mixture of 1,4-dioxane and water. In embodiments, the solvent component is a mixture of tetrahydrofuran and water. In embodiments, the solvent component is a mixture of ethyl acetate and heptane. In embodiments, the solvent component is a mixture of 2-methyltetrahydrofuran and methyl tert-butyl ether. In embodiments, the solvent component is a mixture of isopropanol and heptane.

[0117] In embodiments, the solvent component and the compound are mixed at 25 °C for two weeks. In embodiments, the solvent component and the compound are mixed at 50 °C for one week. In embodiments, the solvent component and the compound are mixed at 90 °C for five days. In embodiments, the solvent component and the compound are mixed at a temperature cycling between 5 °C and 50 °C at a cooling rate of 0.1 °C / minute for ten cycles.

[0118] In embodiments, step (ii) comprises filtering the admixture. In embodiments, step (ii) comprises filtering the admixture by centrifugation.

[0119] In embodiments, step (ii) comprises centrifuging the admixture and filtering through a 0.45 pm nylon membrane filter. In embodiments, step (ii) comprises centrifuging the admixture at 14,000 rpm and filtering through a 0.45 pm nylon membrane filter.

[0120] In embodiments, step (ii) comprises slow evaporation of the solvent component.

[0121] In one aspect, there is provided a method of preparing a crystalline compound, the method comprising:

[0122] (i) preparing an admixture comprising a solvent component and a compound having the formula:

[0123] (ii) heating the blend to a first temperature;

[0124] (iii) filtering the blend to obtain a filtrate;

[0125] (iv) cooling the filtrate to a second temperature to obtain a precipitate; and

[0126] (v) filtering the precipitate to obtain a crystalline compound.

[0127] In embodiments, the first temperature ranges from about 40 °C to about 60 °C. In embodiments, the first temperature is about 40 °C. In embodiments, the first temperature is about 45 °C. In embodiments, the first temperature is about 50 °C. In embodiments, the first temperature is about 55 °C. In embodiments, the first temperature is about 60 °C.

[0128] In embodiments, the second temperature ranges from about 0 °C to about 10 °C. In embodiments, the second temperature is about 0 °C. In embodiments, the second temperature is about 5 °C. In embodiments, the first temperature is about 10 °C.

[0129] In embodiments, the method further comprises, after step (iv), further cooling the blend to about -20 °C.

[0130] In embodiments, the solvent component comprises one or more selected from the group consisting of: methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, isopropyl acetate, tetrahydrofuran, and 2-methyltetrahydrofuran. In embodiments, the solvent component is methanol. In embodiments, the solvent component is ethanol. In embodiments, the solvent component is isopropanol. In embodiments, the solvent component is acetone. In embodiments, the solvent component is methyl ethyl ketone. In embodiments, the solvent component is ethyl acetate. In embodiments, the solvent component is acetonitrile. In embodiments, the solvent component is isopropyl acetate. In embodiments, the solvent component is tetrahydrofuran. In embodiments, the solvent component is 2-methyltetrahydrofuran.

[0131] In one aspect, a method of making a crystalline compound is provided, the method comprising:

[0132] (i) preparing a blend comprising a solvent component and a compound having the formula:

[0133] (ii) filtering the blend to obtain a filtrate;

[0134] (iii) adding an antisolvent component to the filtrate to obtain a precipitate; and

[0135] (iv) filtering the precipitate to obtain a crystalline compound.

[0136] In embodiments, the method further comprises, after step (iii), cooling the blend to about -20 °C.

[0137] In embodiments, the solvent component comprises one or more selected from the group consisting of methanol, ethanol, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, and 2-methyltetrahydrofuran. In embodiments, the solvent component is methanol. In embodiments, the solvent component is ethanol. In embodiments, the solvent component is acetone. In embodiments, the solvent component is methyl ethyl ketone.

[0138] In embodiments, the solvent component is ethyl acetate. In embodiments, the solvent component is tetrahydrofuran. In embodiments, the solvent component is 1,4-dioxane. In embodiments, the solvent component is dichloromethane. In embodiments, the solvent component is 2-methyltetrahydrofuran.

[0139] In embodiments, the antisolvent component comprises one or more selected from the group consisting of water, heptane, methyl tert-butyl ether, and acetonitrile.

[0140] In embodiments, the antisolvent component is water. In embodiments, the antisolvent component is heptane. In embodiments, the antisolvent component is methyl tert-butyl ether. In embodiments, the antisolvent component is acetonitrile.

[0141] In one aspect, there is provided a method of preparing a crystalline compound, the method comprising:

[0142] (i) preparing a blend comprising a solvent component and a compound having the formula:

[0143] (ii) filtering the blend to obtain a filtrate;

[0144] (iii) adding the filtrate to an antisolvent component to obtain a precipitate; and

[0145] (iv) filtering the precipitate to obtain the crystalline compound.

[0146] In embodiments, step (iii) comprises rapidly adding the filtrate to the antisolvent component.

[0147] In embodiments, the method further comprises, after step (iii), cooling the blend to about -20 °C.

[0148] In embodiments, the solvent component comprises one or more selected from the group consisting of methanol, ethanol, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, and 2-methyltetrahydrofuran. In embodiments, the solvent component is methanol. In embodiments, the solvent component is ethanol. In embodiments, the solvent component is acetone. In embodiments, the solvent component is methyl ethyl ketone.

[0149] In embodiments, the solvent component is ethyl acetate. In embodiments, the solvent component is tetrahydrofuran. In embodiments, the solvent component is 1,4-dioxane. In embodiments, the solvent component is dichloromethane. In embodiments, the solvent component is 2-methyltetrahydrofuran.

[0150] In embodiments, the anti-solvent component comprises one or more selected from the group consisting of water, heptane, methyl tert-butyl ether, and acetonitrile. In embodiments, the anti-solvent component is water. In embodiments, the anti-solvent component is heptane. In embodiments, the anti-solvent component is methyl tert-butyl ether. In embodiments, the anti-solvent component is acetonitrile.

[0151] IV. Pharmaceutical Compositions

[0152] In one aspect, a pharmaceutical composition comprising a crystalline compound of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1-carboxylic acid having the structure:

[0153] and a pharmaceutically acceptable excipient.

[0154] In one aspect, a pharmaceutical composition comprising a crystalline compound described herein and a pharmaceutically acceptable excipient is provided.

[0155] In embodiments, the pharmaceutical composition does not comprise a compound in a crystalline form other than the crystalline compound described herein. In embodiments, the pharmaceutical composition does not comprise the compound in any amorphous form.

[0156] In embodiments, the pharmaceutical composition does not comprise a compound in a crystalline form other than the crystalline form described herein.

[0157] In embodiments, the pharmaceutical composition comprises an effective amount of the crystalline compound as described herein. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the crystalline compound as described herein.

[0158] In embodiments, the crystalline compound is further processed to provide a more uniform particle size or to control the particle size or to reduce the particle size. For example, the initial crystalline material can be subjected to mechanical impact means, such as crushing, grinding, milling (such as ball milling and jet milling), etc., to provide particles with a desired particle size distribution.

[0159] In embodiments, the crystalline compound described herein is substantially pure in that it contains less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as contaminating intermediates or by-products produced in one or more of the steps of the synthesis method. In embodiments, the crystalline compound described herein is substantially pure in that it contains less than about 5% of other small organic molecules, such as contaminating intermediates or by-products produced in one or more of the steps of the synthesis method. In embodiments, the crystalline compound described herein is substantially pure in that it contains less than about 1% of other small organic molecules, such as contaminating intermediates or by-products produced in one or more of the steps of the synthesis method. In embodiments, the crystalline compound described herein is substantially pure in that it contains less than about 0.1% of other small organic molecules, such as contaminating intermediates or by-products produced in one or more of the steps of the synthesis method.

[0160] These pharmaceutical compositions include those suitable for oral, rectal, topical, buccal, parenteral (eg, subcutaneous, intramuscular, intradermal, or intravenous), vaginal, ophthalmic, or aerosol administration.

[0161] Exemplary pharmaceutical compositions are used in the form of pharmaceutical preparations, such as solid, semisolid or liquid forms, which contain the crystalline compound as an active ingredient in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral application. In embodiments, the crystalline compound is mixed with a generally non-toxic pharmaceutically acceptable carrier, such as for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. The crystalline compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0162] In embodiments for preparing solid compositions such as tablets, the crystalline compound is mixed with a pharmaceutical carrier, for example, conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums and other pharmaceutical diluents (e.g., water) to form a solid preformulated composition containing a homogeneous mixture of the crystalline compound described herein. When referring to these preformulated compositions as homogeneous, it is meant that the crystalline compound is evenly dispersed throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0163] In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, and the like), a crystalline compound is mixed with one or more pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate and / or any of the following: (1) fillers or extenders such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders such as, for example, carboxymethylcellulose, hydroxypropylmethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and / or acacia; (3) humectants such as glycerol; (4) disintegrating agents such as polyvinylpyrrolidinone, croscarmellose sodium, sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, sodium lauryl sulfate, cetostearyl alcohol, and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the compositions also comprise buffering agents. In some embodiments, similar types of solid compositions are also used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose, and high molecular weight polyethylene glycols, and the like.

[0164] In embodiments, tablets are prepared by compression or molding, optionally with one or more accessory ingredients. In embodiments, compressed tablets are prepared by compressing, in a suitable machine, the crystalline compound in the presence of at least one additive, binder (such as gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (such as sodium starch glycolate or crosscarmellose sodium), surface active or dispersing agent. In embodiments, molded tablets are prepared by molding, in a suitable machine, a mixture of the crystalline compound moistened with an inert liquid diluent. In embodiments, tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, are optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings.

[0165] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the crystalline compounds, in some embodiments the liquid dosage forms contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butyleneglycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0166] In embodiments, suspensions contain, in addition to the crystalline compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0167] In embodiments, formulations for rectal or vaginal administration are presented as suppositories, which are prepared by mixing the crystalline compounds with one or more suitable non-irritating excipients or carriers such as, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which are solid at room temperature, but liquid at body temperature, and therefore melt in the body cavity and release the active agent.

[0168] Dosage forms for transdermal administration of the crystalline compounds include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In embodiments, the crystalline compounds are mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants as can be required.

[0169] In embodiments, ointments, pastes, creams and gels contain, in addition to the crystalline compounds, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0170] In embodiments, powders and sprays contain, in addition to the crystalline compounds, excipients such as lactose, talc, aluminim hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Sprays, in addition to the aforementioned excipients, can also contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0171] In embodiments, the crystalline compounds described herein are formulated as eye drops for ocular administration.

[0172] The compositions and crystalline compounds disclosed herein are alternatively administered by aerosol. In embodiments, this is achieved by preparing an aqueous aerosol, a liposome preparation, or a solid particle containing the crystalline compound. In embodiments, non-aqueous (e.g., fluorocarbon propellants) suspensions are used. In embodiments, ultrasonic nebulizers are used. Typically, aqueous aerosols are prepared by dispensing a solution or suspension of the crystalline compound in an aqueous carrier with the conventional pharmaceutically acceptable adjuvants and stabilizers. The carrier and stabilizers vary with the needs of the specific subject composition, but generally include non-ionic surfactants (e.g., Tween, pluronic or polyethylene glycol), innocuous proteins, such as serum albumul, sorbitol esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. The aerosol is typically prepared from an isotonic solution.

[0173] Pharmaceutical compositions adapted for parenteral administration include one or more crystalline compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into sterile injectable solutions or dispersions just prior to use, which in embodiments contain anti-oxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0174] Examples of suitable aqueous and nonaqueous carriers for pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof; vegetable oils, such as olive oil; and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

[0175] Also contemplated are enteric pharmaceutical formulations comprising the crystalline compound and an enteric material; and pharmaceutically acceptable carriers or excipients thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and are primarily soluble in the intestinal fluid at a particular pH. The small intestine is the part of the gastrointestinal tract (the intestine) between the stomach and the large intestine, and includes the duodenum, the jejunum, and the ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the distal ileum is about 7.5. Thus, the enteric material is not dissolvable until, for example, a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, succinylated hydroxypropyl methylcellulose, cellulose acetate succinate, hexahydrocellulose acetate phthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methyl methacrylate and methacrylic acid methyl ester, copolymer of methyl acrylate, methyl methacrylate and methacrylic acid, copolymer of methyl vinyl ether and maleic anhydride (Gantrez ES series), methyl methacrylate-ethyl methacrylate-chlorotrityl acrylate copolymer, natural resins such as zein, shellac and copalcollophorium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is known or readily determined in vitro.

[0176] The dosage of the compositions comprising the crystalline compounds described herein varies depending on the patient (e.g., human)’s condition, i.e., the stage of the disease, the overall state of health, age, and other factors.

[0177] The pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or to be prevented). The appropriate dose, and the appropriate duration of administration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration, among others. Generally, a suitable dose and treatment regimen provides the composition in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., improvement in clinical outcome, such as complete or partial remission more frequently, or no disease and / or longer overall survival or lessening of severity of symptoms). Optimal doses usually are determined using experimental models and / or clinical trials. In some embodiments, the optimal dose depends on the body mass, weight, or blood volume of the patient.

[0178] Oral dosages generally range from about 1.0 mg to about 1000 mg per day in one to four or more divided doses.

[0179] The crystalline compounds described herein are administered to a subject or patient (animal and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the actual dose required for any particular application will vary depending on the patient, not only on the particular composition selected, but also on the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent or special diets then being followed by the patient, and other factors, where appropriate, the determination of the appropriate dose being made by the attending physician. For the treatment of the clinical conditions and diseases described above, the crystalline compounds disclosed herein are administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration includes subcutaneous injection, intravenous or intramuscular injection or infusion techniques.

[0180] V. Methods of Treatment

[0181] In one aspect, there is provided a method of treating a neurodegenerative disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1-carboxylic acid having the structure:

[0182]

[0183] In one aspect, there is provided a method of treating a neurodegenerative disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound described herein.

[0184] In an aspect, a method of treating an inflammatory disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1-carboxylic acid having the structure:

[0185]

[0186] In an aspect, a method of treating an inflammatory disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound described herein.

[0187] In embodiments, the inflammatory disease is encephalitis. In embodiments, the inflammatory disease is posthemorrhagic encephalitis. In embodiments, the inflammatory disease is ocular inflammation. In embodiments, the inflammatory disease is conjunctivitis. In embodiments, the inflammatory disease is allergic conjunctivitis. In embodiments, the inflammatory disease is vernal keratoconjunctivitis. In embodiments, the inflammatory disease is papillary conjunctivitis. In embodiments, the inflammatory disease is Sjogren’s syndrome. In embodiments, the inflammatory disease is an inflammatory disease with dry eye.

[0188] In an aspect, a method of treating a demyelinating disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1-carboxylic acid having the structure:

[0189]

[0190] In an aspect, a method of treating a demyelinating disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound described herein.

[0191] In embodiments, the demyelinating disease is a demyelinating disease of the central nervous system. In embodiments, the demyelinating disease is multiple sclerosis. In embodiments, the demyelinating disease is a demyelinating disease of the peripheral nervous system.

[0192] In an aspect, a method of treating a fibrotic disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1-carboxylic acid having the structure:

[0193]

[0194] In an aspect, a method of treating a fibrotic disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound described herein.

[0195] In embodiments, the fibrotic disease is pulmonary fibrosis. In embodiments, the fibrotic disease is dermal fibrosis. In embodiments, the fibrotic disease is liver fibrosis. In embodiments, the fibrotic disease is ocular fibrosis. In embodiments, the fibrotic disease is idiopathic pulmonary fibrosis. In embodiments, the fibrotic disease is scleroderma. In embodiments, the fibrotic disease is nonalcoholic steatohepatitis. In embodiments, the fibrotic disease is ocular fibrosis. In embodiments, the fibrotic disease is hypertrophic scarring or keloids (e.g., burn-induced or surgical, sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener’s granulomatosis, mixed connective tissue disease, or Peyronie’s disease). In embodiments, the fibrotic disease is iatrogenic pulmonary fibrosis. In embodiments, the fibrotic disease is radiation-induced fibrosis. In embodiments, the fibrotic disease is silicosis-induced pulmonary fibrosis. In embodiments, the fibrotic disease is asbestos-induced pulmonary fibrosis. In embodiments, the fibrotic disease is pleural fibrosis. In embodiments, the fibrotic disease is pulmonary fibrosis associated with SARS-CoV-2 infection and / or COVID-19. In embodiments, the fibrotic disease is pulmonary fibrosis secondary to a systemic inflammatory disease. In embodiments, the fibrotic disease is pulmonary fibrosis secondary to sarcoidosis. In embodiments, the fibrotic disease is intestinal fibrosis. In embodiments, the fibrotic disease is head and neck fibrosis. In embodiments, the fibrotic disease is cirrhosis. In embodiments, the fibrotic disease is alcohol-induced liver fibrosis. In embodiments, the fibrotic disease is endometriosis. In embodiments, the fibrotic disease is spinal cord fibrosis. In embodiments, the fibrotic disease is myelofibrosis. In embodiments, the fibrotic disease is cardiac fibrosis. In embodiments, the fibrotic disease is perivascular fibrosis. In embodiments, the fibrotic disease is Peyronie’s disease. In embodiments, the fibrotic disease is abdominal or intestinal adhesions. In embodiments, the fibrotic disease is bladder fibrosis. In embodiments, the fibrotic disease is fibrosis of the nasal passages. In embodiments, the fibrotic disease is fibrosis mediated by fibrocytes. In embodiments, the fibrotic disease is kidney fibrosis associated with chronic kidney disease (CKD).

[0196] In one aspect, a method of treating cancer in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1-carboxylic acid having the structure:

[0197]

[0198] In one aspect, a method of treating cancer in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound described herein.

[0199] In embodiments, the cancer is a brain cancer. In embodiments, the cancer is a glioblastoma. In embodiments, the cancer is a solid tumor (e.g., a solid tumor of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (e.g., lymphoma), ovary, pancreas, or other endocrine organ (e.g., thyroid), prostate, skin (e.g., melanoma or basal cell carcinoma), or a blood tumor (e.g., leukemia) with or without metastasis at any stage of the disease. In embodiments, the cancer is acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical tumor, anal cancer, appendix cancer, astrocytic tumor, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (e.g., osteosarcoma or malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt’s lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymal

[0200] In an aspect, a method of treating an LPAR1 -associated disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1-carboxylic acid having the structure:

[0201]

[0202] In an aspect, a method of treating an LPAR1 -associated disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound described herein.

[0203] In embodiments, the LPAR1 -associated disease is a neurodegenerative disease. In embodiments, the LPAR1 -associated disease is an inflammatory disease. In embodiments, the LPAR1 -associated disease is posthemorrhagic encephalitis. In embodiments, the LPAR1 -associated disease is a demyelinating disease. In embodiments, the LPAR1 -associated disease is multiple sclerosis. In embodiments, the LPAR1 -associated disease is a fibrotic disease. In embodiments, the LPAR1 -associated disease is pulmonary fibrosis. In embodiments, the LPAR1 -associated disease is idiopathic pulmonary fibrosis. In embodiments, the LPAR1 -associated disease is ocular fibrosis. In embodiments, the LPAR1 -associated disease is a cancer (e.g., brain cancer, ovarian cancer, colon cancer, prostate cancer, breast cancer, melanoma, head and neck cancer, intestinal cancer, colorectal cancer, or thyroid cancer). In embodiments, the LPAR1 -associated disease is pain (e.g., neuropathic pain, acute pain, or chronic pain). In embodiments, the LPAR1 -associated disease is neuropathic pain. In embodiments, the LPAR1 -associated disease is acute pain. In embodiments, the LPAR1 -associated disease is chronic pain.

[0204] In embodiments, the LPAR1 -associated disease is a respiratory or allergic disorder. In embodiments, the respiratory or allergic disorder is asthma, peribronchiolar fibrosis, bronchiolitis obliterans, or chronic obstructive pulmonary disease (COPD). In embodiments, the COPD is chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis, and / or bronchitis, or cystic fibrosis. In embodiments, the respiratory disease is adult respiratory distress syndrome or allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, and hypoxia.

[0205] In embodiments, the LPARl -associated disease is a neurological disorder. In embodiments, the neurological disorder is Alzheimer's disease, brain edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's disease, neurological conditions found after blunt or surgical trauma (including postoperative cognitive dysfunction and spinal or bone marrow stem injury), degenerative disc disease, or sciatica.

[0206] In embodiments, the LPARl -associated disease is a cardiovascular disorder. In embodiments, the cardiovascular disorder is cardiac arrhythmia (e.g., atrial or ventricular); atherosclerosis and its sequelae; angina; heart rhythm disorders; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis; stroke; peripheral occlusive arterial disorders of a limb, organ or tissue; reperfusion injury following ischemia of the brain, heart, or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension; valvular heart disease; heart failure; abnormal blood pressure; shock; vasoconstriction (including that associated with migraine); vascular abnormality or cardiovascular insufficiency (limited to a single organ or tissue).

[0207] In embodiments, the LPARl -associated disease is pulmonary fibrosis, renal fibrosis, liver fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension, interstitial pulmonary fibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative disorder, or inflammatory condition.

[0208] In embodiments, the LPARl -associated disease is a liver disease. In embodiments, the liver disease is hepatitis C, liver cancer, familial combined hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), progressive familial intrahepatic cholestasis, primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC). In embodiments, the liver disease is primary sclerosing cholangitis (PSC). In embodiments, the liver disease includes portal hypertension. In embodiments, the liver cancer includes hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma, or hemangiosarcoma. In embodiments, the NAFLD includes steatosis. In embodiments, the NAFLD includes NASH. In embodiments, the NAFLD or NASH includes liver fibrosis. In embodiments, the NAFLD or NASH includes cirrhosis. In embodiments, the NAFLD or NASH includes compensated cirrhosis. In embodiments, the NAFLD or NASH includes decompensated liver fibrosis. In embodiments, the NAFLD includes hepatocellular carcinoma (HCC). In embodiments, the liver disease is NASH.

[0209] In one aspect, a method of modulating LPAR1 activity in a subject is provided, the method comprising administering to the subject a crystalline compound of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1-carboxylic acid having the structure:

[0210]

[0211] In one aspect, a method of modulating LPAR1 activity in a subject is provided, the method comprising administering to the subject a crystalline compound described herein.

[0212] VI. Embodiments

[0213] Embodiment 1. A crystalline compound having the formula:

[0214]

[0215] wherein the crystalline compound has characteristic X-ray powder diffraction peaks at about 5.2° 2Q, about 10.4° 2Q, and about 15.6° 2Q.

[0216] Embodiment 2. The crystalline compound of embodiment 1, wherein the crystalline compound has additional characteristic X-ray powder diffraction peaks at about 11.3° 2Q, about 12.6° 2Q, about 18.4° 2Q, about 20.9° 2Q, about 22.4° 2Q, about 26.1° 2Q, about 27.4° 2Q, and about 27.6° 2Q.

[0217] Embodiment 3. The crystalline compound of embodiment 1, wherein the crystalline compound has additional characteristic X-ray powder diffraction peaks at about 6.7° 2Θ, about 7.3° 2Θ, about 8.6° 2Θ, about 9.4° 2Θ, about 11.3° 2Θ, about 12.0° 2Θ, about 12.6° 2Θ, about 13.6° 2Θ, about 14.9° 2Θ, about 16.8° 2Θ, about 17.4° 2Θ, about 18.4° 2Θ, about 18.8° 2Θ, about 19.5° 2Θ, about 20.1° 2Θ, about 20.9° 2Θ, about 21.8° 2Θ, about 22.4° 2Θ, about 22.7° 2Θ, about 23.1° 2Θ, about 24.1° 2Θ, about 24.4° 2Θ, about 24.9° 2Θ, about 25.4° 2Θ, about 26.1° 2Θ, about 27.4° 2Θ, about 27.6° 2Θ, about 28.0° 2Θ, about 28.4° 2Θ, about 28.7° 2Θ, about 29.2° 2Θ, about 29.5° 2Θ, about 30.0° 2Θ, about 30.2° 2Θ, about 31.3° 2Θ, about 31.8° 2Θ, about 32.0° 2Θ, about 32.9° 2Θ, about 33.9° 2Θ, about 34.5° 2Θ, about 36.3° 2Θ, about 36.9° 2Θ, about 37.5° 2Θ, about 38.0° 2Θ, and about 39.6° 2Θ.

[0218] Embodiment 4. The crystalline compound of one of embodiments 1 to 3, wherein the crystalline compound is further characterized as having a differential scanning calorimetry endotherm onset at about 188.6 °C.

[0219] Embodiment 5. A pharmaceutical composition comprising the crystalline compound of one of embodiments 1 to 4 and a pharmaceutically acceptable excipient.

[0220] Embodiment 6. The pharmaceutical composition of embodiment 5, wherein the pharmaceutical composition does not comprise a compound of Formula I in a crystalline form other than the crystalline compound.

[0221] Embodiment 7. A method of treating a neurodegenerative disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the crystalline compound of one of embodiments 1 to 4.

[0222] Embodiment 8. A method of treating an inflammatory disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the crystalline compound of one of embodiments 1 to 4.

[0223] Embodiment 9. The method of embodiment 8, wherein the inflammatory disease is encephalitis.

[0224] Embodiment 10. The method of embodiment 9, wherein the encephalitis is hemorrhagic postencephalitis.

[0225] Embodiment 11. A method of treating a demyelinating disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound according to one of embodiments 1 to 4.

[0226] Embodiment 12. The method of embodiment 11, wherein the demyelinating disease is a demyelinating disease of the central nervous system.

[0227] Embodiment 13. The method of embodiment 12, wherein the demyelinating disease is multiple sclerosis.

[0228] Embodiment 14. The method of embodiment 11, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.

[0229] Embodiment 15. A method of treating a fibrotic disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound according to one of embodiments 1 to 4.

[0230] Embodiment 16. The method of embodiment 15, wherein the fibrotic disease is pulmonary fibrosis, cutaneous fibrosis, liver fibrosis, or ocular fibrosis.

[0231] Embodiment 17. The method of embodiment 15, wherein the fibrotic disease is idiopathic pulmonary fibrosis, scleroderma, nonalcoholic steatohepatitis, or ocular fibrosis.

[0232] Embodiment 18. A method of treating a cancer in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound according to one of embodiments 1 to 4.

[0233] Embodiment 19. The method of embodiment 18, wherein the cancer is a brain cancer.

[0234] Embodiment 20. The method of embodiment 19, wherein the cancer is a glioblastoma.

[0235] Embodiment 21. A method of treating an LPAR1 -associated disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline compound according to one of embodiments 1 to 4, wherein the LPAR1 -associated disease is neuropathic pain.

[0236] Embodiment 22. A method of modulating LPAR1 activity in a subject, the method comprising administering to the subject a crystalline compound according to one of embodiments 1 to 4.

[0237] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in view thereof will be suggested to those skilled in the art and are to be included within the spirit and scope of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes. Example

[0238] Polymorph Screening

[0239] Polymorph screening was performed using the free acid form of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2-isopropylphenyl)ureido)cyclohexane-1-carboxylic acid. The polymorphic behavior of the free acid form was investigated using equilibrium, slow cooling, fast cooling, slow evaporation, antisolvent addition, and reverse antisolvent addition experiments.

[0240] Despite approximately 100 polymorph screening experiments in 15 solvents and their combinations with different crystallization methods, only one crystalline polymorph was identified, which was designated Pattern A.

[0241] Characterization of Crystalline Compound

[0242] Pattern A is anhydrous. It is obtained from most solvent systems by equilibration, slow cooling, fast cooling, antisolvent addition, and reverse antisolvent addition experiments. Pattern A has high crystallinity ( Figure 1 ). DSC showed a T of 188.6°C. 起始 The melting peak at Figure 2 ). Decomposition occurs during melting. TGA shows a weight loss of about 0.4% at about 180°C ( Figure 3 ). 1 H-NMR showed no detectable residual solvent ( Figure 4 ). PLM showed that the crystal morphology was plate-like and the particle size ranged from 1 μm to 20 μm ( Figure 5 ). Pattern A is a stable polymorph.

[0243] Compared with the typical XRPD pattern of mode A and the single crystal data of mode A ( Figure 6 ), some of the screening samples obtained from equilibrium, rapid cooling, and slow volatilization contained a small additional peak at 10.0° 2θ, which might be caused by some unknown impurities.

[0244] Bulk Stability for Pattern A

[0245] The bulk stability of Pattern A was evaluated over a period of 1 week at 25°C / 92% RH in an open container, at 40°C / 75% RH in an open container, and at 60°C in a closed container. Pattern A was found to be physically and chemically stable over a period of 1 week under these conditions. Figure 7 ).

[0246] Hygroscopicity for Pattern A

[0247] The hygroscopicity of Pattern A was evaluated by dynamic vapor sorption (DVS) testing at 25°C with a mass change rate of 0.002% / min per time unit at a cycle of 40% → 0% → 95% → 0% → 40% RH. Pattern A was found to be slightly hygroscopic at 80% RH and hygroscopic at 95% RH. At 25°C, it absorbed about 1.2% of water at 80% RH and 3.1% of water at 95% RH (Figure 8). After the DVS test, the obtained sample was still Pattern A ( Figure 9 ).

[0248] Feasibility of Formulation Process for Pattern A

[0249] Compression, grinding and granulation simulation experiments were performed to evaluate the feasibility of the formulation process of Pattern A. Pattern A showed good compression resistance, no form change, and only a slight decrease in crystallinity ( Figure 10 Upon manual grinding, Pattern A rapidly lost its crystallinity and transformed into an almost amorphous form after 3 minutes of grinding with a mortar and pestle ( Figure 11 Similarly, upon wet granulation with ethanol or water, the crystallinity of pattern A was significantly reduced, and partial amorphization was observed ( Figure 12 ).

[0250] Polymorph Screening Experiments

[0251] Equilibration at 25 °C for 2 weeks

[0252] Approximately 50 mg of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2-isopropylphenyl)ureido)cyclohexane-1-carboxylic acid was equilibrated in 0.4 mL to 1.0 mL of solvent at 25° C. with a stirring bar on a magnetic stirrer at a rate of 300 to 400 rpm for 2 weeks.

[0253] The resulting suspension was centrifuged at 14,000 rpm and then filtered through a 0.45 μm nylon membrane filter. The solid portion (wet cake) was studied by XRPD. The results are summarized in Table 2.

[0254] Table 2. Summary of Equilibration Experiments at 25 °C for 2 Weeks

[0255] Solvent XRPD Figure 13 , Figure 14 , Figure 15 , Figure 16 , Figure 17 ) Methanol Pattern A Ethanol Pattern A Isopropanol Pattern A Acetone Pattern A Methyl ethyl ketone Pattern A Ethyl acetate Pattern A Acetonitrile Pattern A IPAc Pattern A Tetrahydrofuran Pattern A 1,4-Dioxane Pattern A Dichloromethane Pattern A 2-MeTHF Pattern A EtOH / water (50:50, v:v) Pattern A Acetone / water (40:60, v:v) Pattern A MEK / water (30:70, v:v) Pattern A ACN / water (30:70, v:v) Pattern A 1,4-Dioxane / water (20:80, v:v) Pattern A THF / water (10:90, v:v) Pattern A EA / heptane (50:50, v:v) Pattern A 2-MeTHF / MTBE (50:50, v:v) Pattern A IPA / heptane (25:75, v:v) Pattern A

[0256] Equilibration at 50 °C for 1 week

[0257] About 50 mg of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1 -carboxylic acid was equilibrated in 0.2 mL to 1 mL of solvent at 50 °C with a stir bar on a magnetic stirrer at a rate of 300 rpm to 400 rpm for 1 week.

[0258] The resulting suspension was centrifuged at 14,000 rpm and then filtered through a 0.45 pm nylon membrane filter. The solid fraction (wet cake) was investigated by XRPD. The results are summarized in Table 3.

[0259] Table 3. Summary of Equilibration Experiments at 50 °C for 1 Week

[0260]

[0261]

[0262] Equilibration at 90 °C for 5 days

[0263] About 50 mg of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1 -carboxylic acid was equilibrated in 0.2 mL to 0.6 mL of solvent at 90 °C with a stir bar on a magnetic stirrer at a rate of 300 rpm to 400 rpm for 5 days.

[0264] The resulting suspension was centrifuged at 14,000 rpm and then filtered through a 0.45 pm nylon membrane filter. The solid fraction (wet cake) was investigated by XRPD. The results are summarized in Table 4.

[0265] Table 4. Summary of Equilibration Experiments at 90 °C for 5 Days

[0266] Solvent XRPD Figure 23 ) 1,4-Dioxane Pattern A + one small extra peak at 10.0 °2q Toluene Pattern A + one small extra peak at 10.0 °2q

[0267] Equilibration under temperature cycling

[0268] About 50 mg of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1 -carboxylic acid was equilibrated in 0.2 mL to 1 mL of solvent at a temperature cycle between 5 °C to 50 °C with a heating / cooling rate of 0.1 °C / min for 10 cycles. The equilibration was performed with a stir bar on a magnetic stirrer at a rate of 400 rpm.

[0269] The obtained suspension was centrifuged at 14,000 rpm and then filtered through a 0.45 pm nylon membrane filter. The solid fraction (wet cake) was investigated by XRPD. The results are summarized in Table 5.

[0270] Table 5. Summary of Equilibration Experiments under Temperature Cycling

[0271]

[0272]

[0273] Crystallization from hot saturated solution by slow cooling

[0274] About 30 mg of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1 -carboxylic acid was dissolved in a minimum amount of the selected solvent at 50 °C. The obtained solution was then filtered through a 0.45 pm syringe membrane filter. The clear solution was cooled to 5 °C at 0.1 °C / min. Samples that did not show precipitation at 5 °C were further cooled to -20 °C.

[0275] The precipitate was collected after centrifugation at 14,000 rpm and filtration through a 0.45 pm nylon membrane filter. The solid fraction (wet cake) was investigated by XRPD. The results are summarized in Table 6.

[0276] Table 6. Summary of Crystallization Experiments from Hot Saturated Solution by Slow Cooling

[0277]

[0278] Crystallization from hot saturated solution by rapid cooling

[0279] About 30 mg of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1 -carboxylic acid was dissolved in a minimum amount of the selected solvent at 50 °C. The obtained solution was then filtered through a 0.45 pm syringe membrane filter. The clear solution was placed in a 0 °C ice bath and stirred. Samples that did not show precipitation at 0 °C were further cooled to -20 °C.

[0280] The precipitate was collected after centrifugation at 14,000 rpm and filtration through a 0.45 pm nylon membrane filter. The solid fraction (wet cake) was investigated by XRPD. The results are summarized in Table 7.

[0281] Table 7. Summary of Crystallization Experiments from Hot Saturated Solution by Rapid Cooling

[0282]

[0283] Crystallization by slow addition of antisolvent to homogeneous solution

[0284] About 30 mg of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1 -carboxylic acid was dissolved in a minimum amount of the selected solvent at ambient temperature (about 25 °C). The obtained solution was then filtered through a 0.45 pm syringe membrane filter. Two-fold to four-fold of the anti-solvent was slowly added to the clear solution. Samples that did not show precipitation at 25 °C were further cooled to -20 °C.

[0285] The precipitate was collected after centrifugation at 14,000 rpm by filtration through a 0.45 pm nylon membrane filter. The solid fraction (wet cake) was investigated by XRPD. The results are summarized in Table 8.

[0286] Table 8. Summary of Crystallization Experiments by Slow Addition of Antisolvent

[0287]

[0288]

[0289] Crystallization by rapid addition of antisolvent to homogeneous solution

[0290] About 30 mg of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1 -carboxylic acid was dissolved in a minimum amount of the selected solvent at ambient temperature (about 25 °C). The obtained solution was then filtered through a 0.45 pm syringe membrane filter. The clear solution was quickly added to four-fold of the anti-solvent. Samples that did not show precipitation at 25 °C were further cooled to -20 °C.

[0291] The precipitate was collected after centrifugation at 14,000 rpm by filtration through a 0.45 pm nylon membrane filter. The solid fraction (wet cake) was investigated by XRPD. The results are summarized in Table 9.

[0292] Table 9. Summary of Crystallization Experiments by Rapid Reverse Addition of Antisolvent

[0293]

[0294] Crystallization by slow evaporation at room temperature

[0295] About 30 mg of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1 -carboxylic acid was dissolved in 0.2 mL to 5.0 mL of solvent. The obtained solution was then filtered through a 0.45 pm syringe membrane filter. The clear solution was slowly evaporated under ambient conditions (about 10 °C to 25 °C, 20% to 30% RH).

[0296] The solid residue was investigated by XRPD. The results are summarized in Table 10.

[0297] Table 10. Summary of Crystallization Experiments by Slow Evaporation at Room Temperature

[0298] Solvent XRPD Figure 38 , Figure 39 ) Methanol Pattern A + one small extra peak at 10.0 °2q Ethanol Pattern A + one small extra peak at 10.0 °2q Isopropanol Pattern A + one small extra peak at 10.0 °2q Acetone Pattern A + one small extra peak at 10.0° 2Θ Methyl ethyl ketone Pattern A + one small extra peak at 10.0° 2Θ Ethyl acetate Pattern A + one small extra peak at 10.0° 2Θ IPAc Pattern A Tetrahydrofuran Pattern A 2-MeTHF Pattern A + one small extra peak at 10.0° 2Θ DCM Pattern A + one small extra peak at 10.0° 2Θ

[0299] Characterization of crystalline compound experiments

[0300] Bulk stability determination experiments

[0301] Form A crystalline polymorph was placed in open containers at 25°C / 92% RH, in open containers at 40°C / 75% RH, and in closed containers at 60°C for 1 week. The samples after stress were characterized by XRPD and HPLC, and color change was detected. The results are summarized in Table 11.

[0302] Table 11. Overview of bulk stability experiments under check conditions

[0303]

[0304] Water sorption and desorption experiments

[0305] The water sorption and desorption behavior of Form A crystalline polymorph was investigated by DVS at 25°C with a cycle of 40%-0%-95%-0%-40% RH, dm / dt 0.002, shortest equilibration time 60 min and longest equilibration time 360 min. XRPD was measured after the DVS test to determine form change. The results are summarized in Table 12.

[0306] Table 12. Overview of water sorption and desorption experiments

[0307]

[0308] Compression simulation experiments

[0309] Approximately 10 mg of Form A crystalline polymorph was compressed with a hydraulic press at 5 MPa and 10 MPa for 5 minutes. Potential form change and crystallinity were evaluated by XRPD. The results are summarized in Table 13.

[0310] Table 13. Overview of compression simulation experiments

[0311] Pressure XRPD Figure 10 ) Remarks 5 MPa Pattern A The crystallinity is slightly reduced. The peaks become broader. 10 MPa Pattern A The crystallinity is slightly reduced. The peaks become broader.

[0312] Dry milling simulation experiments

[0313] About 20 mg of Form A crystalline polymorph was hand ground with a mortar and pestle for 1 min, 3 min, and 5 min. The potential form changes and crystallinity were evaluated by XRPD. The results are summarized in Table 14.

[0314] Table 14. Overview of dry milling simulation experiments

[0315]

[0316] Wet granulation simulation experiments

[0317] Water or ethanol was added dropwise to about 20 mg of Form A crystalline polymorph until the sample was fully wetted. The wet sample was gently ground with a mortar and pestle. The post-granulation sample was dried at ambient conditions for 3 min. The potential form changes and crystallinity were evaluated by XRPD. The results are summarized in Table 15.

[0318] Table 15. Overview of wet granulation simulation experiments

[0319]

[0320] Preparation of polymorphs

[0321] Preparation of Pattern A

[0322] Into a 40 mL glass vial was weighed 1.0 g of trans-4-(3-(2-(difluoromethoxy)-6- methoxypyridin-3-yl)-1-(2-isopropylphenyl)ureido)cyclohexane-1-carboxylic acid (see below). To the vial was added 10 mL of ACN and stirred at 50 °C for about 1 min to obtain a suspension.

[0323] After stirring at 50 °C for 4 days, the solids were collected by filtration through a 0.45 pm nylon membrane filter after centrifugation at 4,000 rpm and then vacuum dried at 25 °C for about 20 h.

[0324] 748 mg of Form A was obtained in 76% yield as an off-white solid.

[0325] Preparation of trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1-carboxylic acid Biological evaluation: in vitro functional assay for lysophosphatidic acid receptor 1 activity

[0326]

[0327] Preparation of intermediate amine 1: trans-4-((2-isopropylphenyl)amino)cyclohexane-1- carboxylic acid ethyl ester: In a dry round-bottom flask, equipped with a magnetic stirrer, 6-methoxy-3-nitropyridin-2-ol (1 equiv, Combi-Blocks) was suspended in acetonitrile (0.10 M). Sodium hydride (60% w / w dispersion in paraffin oil, 2.8 equiv, Sigma-Aldrich) was then added in one portion, rapidly, to this and the resulting mixture was stirred at RT for 10 min, to give a brown-yellow suspension. Then, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.8 equiv, Sigma-Aldrich) was added neat and dropwise over a period of 5 min, during which a slight exotherm was observed. After stirring for 16 h, another aliquot of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.8 equiv, Sigma-Aldrich) was added neat and dropwise over a period of 5 min. After stirring at RT for a further 48 h, the crude reaction mixture was carefully quenched with water and then diluted with a 1 : 1 (v / v) solution of ethyl acetate and hexanes. The organic layer was then separated and washed successively with saturated aqueous NaHC03, water and brine, dried over MgS04, filtered and the filtrate concentrated in vacuo. The crude product thus obtained was purified by column chromatography (Si02, gradient elution: Hex -» 1 : 1 (v / v) Hex: EtOAc) to give 2-(difluoromethoxy)-6-methoxy-3-nitropyridine as a yellow solid (75% yield).

[0328] Biological evaluation: in vitro functional assay for lysophosphatidic acid receptor 1 activity : In a dry round-bottom flask, equipped with a magnetic stirrer, 2-(difluoromethoxy)-6-methoxy-3-nitropyridine from the previous step (1 equiv) was dissolved in methanol (0.17 M). The resulting yellow solution was then deoxygenated by sub-surface sparging with nitrogen for 10 min, before the addition of palladium (10% w / w on activated carbon, dry, 0.08 equiv, Sigma-Aldrich) in one portion, rapidly. The resulting black suspension was then sub-surface sparged with hydrogen for 10 min, before being stirred at RT under a static atmosphere of hydrogen (maintained with a balloon) for 90 min. The reaction was then diluted with EtOAc and filtered through a bed of dichloromethane-wetted Celite. The insolubles were further washed with EtOAc. The filtrate thus obtained was concentrated in vacuo to give 2-(difluoromethoxy)-6-methoxypyridin-3-amine as a brown-red solid (>99% yield).

[0329] ​: In a dry round-bottom flask, equipped with a magnetic stirrer, 2-(difluoromethoxy)-6- methoxypyridin-3 -amine (1 equiv) and pyridine (3 equiv, Sigma-Aldrich) from the previous step were combined in anhydrous dichloromethane (0.086 M). Phosgene (15% w / w in toluene, 1.5 equiv, Sigma-Aldrich) was then added dropwise to this at RT and the resulting solution stirred at RT for 15 min. Volatiles were then removed in vacuo and the crude product (2-(difluoromethoxy)-6-methoxypyridin-3-yl)carbamoyl chloride thus obtained was redissolved in anhydrous dichloromethane (0.12 M). This solution was then added dropwise to trans-4-((2-isopropylphenyl)amino)cyclohexane-1 -carboxylic acid ethyl ester (1 equiv, Intermediate Amine 1, see below), pyridine (3 equiv, Sigma-Aldrich) and freshly activated 4 A molecular sieves (1.5 equiv) at RT. The resulting mixture was stirred at RT for 24 h, then the reaction was quenched with water. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were dried over MgS04, filtered and the filtrate concentrated in vacuo. The crude product thus obtained was purified by column chromatography (Si02, gradient elution: Hex → 7:3 (v / v) Hex:EtOAc) to give trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1 -(2- isopropylphenyl)ureido)cyclohexane-1 -carboxylic acid ethyl ester as a white foam (81 % yield). : In a dry round-bottom flask, equipped with a magnetic stirrer, 2-(difluoromethoxy)-6- methoxypyridin-3 -amine (1 equiv) and pyridine (3 equiv, Sigma-Aldrich) from the previous step were combined in anhydrous dichloromethane (0.086 M). Phosgene (15% w / w in toluene, 1.5 equiv, Sigma-Aldrich) was then added dropwise to this at RT and the resulting solution stirred at RT for 15 min. Volatiles were then removed in vacuo and the crude product (2-(difluoromethoxy)-6-methoxypyridin-3-yl)carbamoyl chloride thus obtained was redissolved in anhydrous dichloromethane (0.12 M). This solution was then added dropwise to trans-4-((2-isopropylphenyl)amino)cyclohexane-1 -carboxylic acid ethyl ester (1 equiv, Intermediate Amine 1, see below), pyridine (3 equiv, Sigma-Aldrich) and freshly activated 4 A molecular sieves (1.5 equiv) at RT. The resulting mixture was stirred at RT for 24 h, then the reaction was quenched with water. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were dried over MgS04, filtered and the filtrate concentrated in vacuo. The crude product thus obtained was purified by column chromatography (Si02, gradient elution: Hex → 7:3 (v / v) Hex:EtOAc) to give trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1 -(2- isopropylphenyl)ureido)cyclohexane-1 -carboxylic acid ethyl ester as a white foam (81 % yield).

[0330] ​ : In a dry round-bottom flask, equipped with a magnetic stirrer, 2-(difluoromethoxy)-6- methoxypyridin-3 -amine (1 equiv) and pyridine (3 equiv, Sigma-Aldrich) from the previous step were combined in anhydrous dichloromethane (0.086 M). Phosgene (15% w / w in toluene, 1.5 equiv, Sigma-Aldrich) was then added dropwise to this at RT and the resulting solution stirred at RT for 15 min. Volatiles were then removed in vacuo and the crude product (2-(difluoromethoxy)-6-methoxypyridin-3-yl)carbamoyl chloride thus obtained was redissolved in anhydrous dichloromethane (0.12 M). This solution was then added dropwise to trans-4-((2-isopropylphenyl)amino)cyclohexane-1 -carboxylic acid ethyl ester (1 equiv, Intermediate Amine 1, see below), pyridine (3 equiv, Sigma-Aldrich) and freshly activated 4 A molecular sieves (1.5 equiv) at RT. The resulting mixture was stirred at RT for 24 h, then the reaction was quenched with water. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were dried over MgS04, filtered and the filtrate concentrated in vacuo. The crude product thus obtained was purified by column chromatography (Si02, gradient elution: Hex → 7:3 (v / v) Hex:EtOAc) to give trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1 -(2- isopropylphenyl)ureido)cyclohexane-1 -carboxylic acid ethyl ester as a white foam (81 % yield). + ; 1H NMR (DMSO-d6): δ = 8.08 (d, J = 8.7 Hz, 1H), 7.56-7.49 (m, 2H), 7.36 (t, J = 72.9 Hz, 1H), 7.35 (td, J = 7.2, 1.8 Hz, 1H), 7.25 (dd, J = 8.1, 1.2 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 6.29 (s, 1H), 4.30-4.21 (m, 1H), 3.82 (s, 3H), 3.22 (sept, J = 6.9 Hz, 1H), 2.24-1.85 (m, 5H), 1.62-1.46 (m, 3H), 1.29 (d, J = 6.9 Hz, 3H), 1.22-1.05 (m, 4H).

[0331] ​

[0332]

[0333] In a thick-walled glass reaction vessel equipped with a magnetic stirrer and a Teflon screw cap, trans-4-aminocyclohexanecarboxylic acid ethyl ester hydrochloride (1 eq, ChemScene), 1-iodo-2-isopropylbenzene (1.4 eq, Combi-Blocks), tris(dibenzylideneacetone)dipalladium(0) (0.1 eq, Sigma-Aldrich), 2-cyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl (0.2 eq, Combi-Blocks) and cesium carbonate (4 eq, Sigma-Aldrich) were combined in 1,4-dioxane (0.12 M). The resulting purple suspension was then deoxygenated by sub-surface sparging with nitrogen for 10 min, the reaction vessel was then tightly sealed and heated at 90 °C for 48 h. The resulting orange-brown suspension was cooled to RT, diluted with methyl tert-butyl ether and washed sequentially with water and brine. The organic extract thus obtained was then dried over MgS04, treated with charcoal, filtered through a bed of celite and the filtrate was concentrated in vacuo. The crude product thus obtained was purified by column chromatography (Si02, gradient elution: Hex → 4:1 (v / v) Hex:EtOAc) to give the title compound as a golden yellow oil (67% yield). ℃

[0334] ​

[0335] Primary compound plates were prepared in 100% DMSO (Sigma-Aldrich), secondary compound plates were prepared at 10x concentration in DMEM (Invitrogen), and tertiary compound plates were prepared in HBSS (without Ca +2 / Mg +2 ​Threel compound plates were prepared at 3x concentration in assay buffer of Fluo-4 NW calcium assay dye (Invitrogen) and 0.1% BSA (Sigma-Aldrich) and 0.1% DMSO. Fluo-4 NW calcium assay dye (Invitrogen) was prepared in assay buffer according to manufacturer’s recommendations. B103 cells stably expressing human LPAR1 (J. Chun lab, UCSD) were grown to confluency in DMEM media (Invitrogen) containing 10% FBS (ATCC), 10% penicillin-streptomycin (Sigma-Aldrich), and 50 pg of geneticin (Sigma-Aldrich) and dissociated with Accutase (Sigma-Aldrich) prior to assay. Freshly dissociated cells were resuspended in growth media and plated at a density of 5 x 10 4 cells / well in black clear bottom 96-well plates (Costar, i.e., secondary compound plates) containing compounds. Once plated, cells were left at room temperature for 30 minutes and then transferred to a 37 °C, 5% CO2 incubator for 24 hours. After 24 hours, growth media was removed and freshly prepared Fluo-4 NW calcium assay dye was added to the cells. Compounds (i.e., tertiary compound plates) were then added back to the dye / cells, returned to the incubator for 30 minutes, and then left at room temperature for an additional 30 minutes. Finally, EC 80 concentrations of lysophosphatidic acid (18:1) were added and calcium flux was measured using a FlexStation 3 (Molecular Devices). S-shaped dose response curves were generated by measuring luminescence over 45 seconds and calculating area under the curve. Dose response curves and IC 50 values were generated using Prism (GraphPad). Compounds were tested in a range of final concentrations from 100 pM to 10 mM in 0.1% DMSO.

[0336] The lysophosphatidic acid receptor 1 IC 50 for trans-4-(3-(2-(difluoromethoxy)-6-methoxypyridin-3-yl)-1-(2- isopropylphenyl)ureido)cyclohexane-1-carboxylic acid was found to be 10 nM.

[0337] While the foregoing has been described in some detail for purposes of clarity and the understanding, it will be apparent to those skilled in the art that numerous and various modifications can be made without departing from the essence of the disclosure. Accordingly, it is to be understood that the forms disclosed herein are illustrative and not restrictive, and that all modifications and alternative arrangements are intended to be included within the true scope thereof.

Claims

1. A crystalline compound having the formula: The crystalline compound has characteristic X-ray powder diffraction peaks at about 5.2°2θ, about 10.4°2θ, and about 15.6°2θ.

2. The crystalline compound of claim 1 , wherein the crystalline compound has additional characteristic X-ray powder diffraction peaks at about 11.3°2θ, about 12.6°2θ, about 18.4°2θ, about 20.9°2θ, about 22.4°2θ, about 26.1°2θ, about 27.4°2θ, and about 27.6°2θ.

3. The crystalline compound of claim 1 , wherein the crystalline compound has a crystalline phase at about 6.7°2θ, about 7.3°2θ, about 8.6°2θ, about 9.4°2θ, about 11.3°2θ, about 12.0°2θ, about 12.6°2θ, about 13.6°2θ, about 14.9°2θ, about 16.8°2θ, about 17.4°2θ, about 18.4°2θ, about 18.8°2θ, about 19.5°2θ, about 20.1°2θ, about 20.9°2θ, about 21.8°2θ, about 22.4°2θ, about 22.7°2θ, about 23.1°2θ, about 24.1°2θ, about 24.4°2θ, about The X-ray powder diffraction peaks are approximately 24.9°2θ, approximately 25.4°2θ, approximately 26.1°2θ, approximately 27.4°2θ, approximately 27.6°2θ, approximately 28.0°2θ, approximately 28.4°2θ, approximately 28.7°2θ, approximately 29.2°2θ, approximately 29.5°2θ, approximately 30.0°2θ, approximately 30.2°2θ, approximately 31.3°2θ, approximately 31.8°2θ, approximately 32.0°2θ, approximately 32.9°2θ, approximately 33.9°2θ, approximately 34.5°2θ, approximately 36.3°2θ, approximately 36.9°2θ, approximately 37.5°2θ, approximately 38.0°2θ, and approximately 39.6°2θ.

4. The crystalline compound of claim 1, wherein the crystalline compound is further characterized by having a differential scanning calorimetry endotherm onset at about 188.6°C.

5. A pharmaceutical composition comprising the crystalline compound according to one of claims 1 to 4 and a pharmaceutically acceptable excipient.

6. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition does not comprise a crystalline form of the compound of formula I other than the crystalline compound.

7. A method of treating a neurodegenerative disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the crystalline compound according to one of claims 1 to 4.

8. A method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the crystalline compound according to one of claims 1 to 4.

9. The method of claim 8, wherein the inflammatory disease is encephalitis.

10. The method of claim 9, wherein the encephalitis is post-hemorrhagic encephalitis.

11. A method of treating a demyelinating disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the crystalline compound according to one of claims 1 to 4.

12. The method of claim 11, wherein the demyelinating disease is a demyelinating disease of the central nervous system.

13. The method of claim 12, wherein the demyelinating disease is multiple sclerosis. The method according to claim 11 , wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.

15. A method of treating a fibrotic disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the crystalline compound according to one of claims 1 to 4.

16. The method of claim 15, wherein the fibrotic disease is pulmonary fibrosis, skin fibrosis, liver fibrosis, or ocular fibrosis.

17. The method of claim 15, wherein the fibrotic disease is idiopathic pulmonary fibrosis, scleroderma, nonalcoholic steatohepatitis, or ocular fibrosis.

18. A method of treating cancer in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the crystalline compound according to one of claims 1 to 4.

19. The method of claim 18, wherein the cancer is brain cancer.

20. The method of claim 19, wherein the cancer is glioblastoma.

21. A method of treating an LPAR1-related disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the crystalline compound according to one of claims 1 to 4, wherein the LPAR1-related disease is neuropathic pain.

22. A method of modulating LPAR1 activity in a subject, the method comprising administering to the subject a crystalline compound according to one of claims 1 to 4.

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