CRF receptor antagonists and methods of use

Abstract

Provided herein are compounds, as well as related formulations, compositions, and methods for treating diseases and / or conditions that would benefit from the compounds, such as congenital adrenal hyperplasia (CAH).

Description

background Technical Field

[0001] The present disclosure generally relates to compounds, compositions related thereto, and methods, such as methods for treating congenital adrenal hyperplasia (CAH).

[0002] Description of Related Technology

[0003] CRF is a hypothalamic hormone that acts as a key regulator of the hypothalamus-pituitary-adrenal (HPA) axis. Classic congenital adrenal hyperplasia (CAH) is a disease that includes a group of autosomal recessive disorders, which results in an enzyme deficiency that alters adrenal steroid production due to a 21-hydroxylase deficiency, which results in little or no biosynthesis of cortisol. A clinical manifestation of lack of cortisol is a lack of feedback inhibition of CRF, causing an HPA axis disorder. In addition, a 21-hydroxylase deficiency causes a shunting of cortisol precursor steroids, resulting in excessive androgen (e.g., 17-hydroxyprogesterone, androstenedione, and testosterone) production.

[0004] At present, exogenous corticosteroids are the standard treatment for the treatment of patients with typical CAH. This treatment is used to correct cortisol deficiency and reduce androgen excess. However, the dosage of the corticosteroid used is usually much higher than the normal physiological level (such as in patients suffering from Addison's disease) that is used alone for cortisol replacement. This increase in corticosteroid exposure can lead to iatrogenic Cushing's syndrome, increased cardiovascular risk factors, glucose intolerance, reduced growth rate and reduced bone mineral density in CAH patients. Therefore, it is necessary to avoid the treatment of CAH with the serious complications associated with current corticosteroid treatment.

[0005] Certain CRF1 antagonist compounds have been demonstrated in clinical trials to provide significant reductions in CAH-related steroid biomarkers (eg, 17-hydroxyprogesterone and androstenedione) compared to placebo in patients with CAH.

[0006] There remains a need to identify new CRF1 antagonists for the treatment of CAH. As will be apparent by reference to the following disclosure, the present disclosure satisfies these and other needs. Summary of the invention

[0007] Compounds that are CRF antagonists are provided herein. In specific embodiments, compounds that are CRF1 antagonists are provided. In addition, compounds that are prodrugs of compounds that are CRF antagonists are provided herein. Therefore, such compounds and prodrugs can be used to treat CAH.

[0008] Some embodiments provide a pharmaceutical composition comprising a compound of formula (Ia):

[0009]

[0010] or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein:

[0011] Each R 1a Independently C(R A )3 or C(R A )2R B ;

[0012] Each R A independently hydrogen or deuterium;

[0013] R B Yes-OR C ;

[0014] R C is hydrogen or deuterium;

[0015] Each R 2a independently hydrogen or deuterium;

[0016] Each R 3a independently hydrogen or deuterium;

[0017] R 4a yes

[0018] R 5a is hydrogen or deuterium;

[0019] R 6a is C(R A )3; and

[0020] R 7a is C(R A )3 or C(R A )2R B ,

[0021] Where R 1a and R 7a At least one of them is C(R A )2R B .

[0022] Some embodiments provide formulations of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0023]

[0024] in:

[0025] Each R 1a Independently C(R A )3 or C(R A )2R B ;

[0026] Each R A independently hydrogen or deuterium;

[0027] R B Yes – OR C ;

[0028] R C is hydrogen or deuterium;

[0029] Each R 2a independently hydrogen or deuterium;

[0030] Each R 3a independently hydrogen or deuterium;

[0031] R 4a yes

[0032] R 5a is hydrogen or deuterium;

[0033] R 6a is C(R A )3; and

[0034] R 7a is C(R A )3 or C(R A )2R B ,

[0035] Where R 1a and R 7a At least one of them is C(R A )2R B .

[0036] In some embodiments, the compound of formula (Ia) is a compound of the formula:

[0037]

[0038] or a pharmaceutically acceptable salt thereof.

[0039] Some embodiments provide a method of treating congenital adrenal hyperplasia in an individual in need thereof, comprising administering a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof.

[0040] Some embodiments provide a method of treating congenital adrenal hyperplasia in an individual in need thereof, comprising administering a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP); (b) testosterone; and (c) androstenedione in the individual.

[0041] In some embodiments, the method comprises administering a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof in an amount sufficient to reduce the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP); (b) testosterone; and (c) androstenedione in the individual.

[0042] Some embodiments provide a method for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and growth impairment in an individual with classic congenital adrenal hyperplasia, the method comprising administering a compound of formula (Ia) or a pharmaceutically acceptable salt thereof in an amount sufficient to reduce the level of androstenedione in the individual.

[0043] Some embodiments provide a method of reducing the level of one or more biomarkers in an individual with congenital adrenal hyperplasia, the method comprising administering to the individual a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof.

[0044] Some embodiments provide a method of managing congenital adrenal hyperplasia by reducing the dose of a corticosteroid administered to a subject having congenital adrenal hyperplasia, the method comprising administering to the subject a compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

[0045] Some embodiments provide a method of reducing the severity of one or more side effects of glucocorticoid treatment in an individual with congenital adrenal hyperplasia, the method comprising administering to the individual a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein the side effect is selected from osteoporosis, ischemic osteonecrosis, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushing's-like features, growth inhibition, adrenal suppression, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis, hypertension , coronary artery disease, ischemic heart disease, heart failure, dermatoprosis, skin atrophy, ecchymoses, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, alopecia, mood changes, depression, euphoria, emotional lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic eye infections, central serous chorioretinopathy, cell-mediated immunosuppression, predisposition to infection, reactivation of latent infection.

[0046] Some embodiments provide compounds of formula (I):

[0047]

[0048] or a pharmaceutically acceptable salt thereof, wherein:

[0049] Each R 1 Independently C(R A )3 or C(R A )2R B ;

[0050] Each R A independently hydrogen or deuterium;

[0051] R B Yes-OR C ;

[0052] R C is hydrogen or deuterium;

[0053] Each R 2 independently hydrogen or deuterium;

[0054] Each R 3 independently hydrogen or deuterium;

[0055] R 4 yes

[0056] R 5 is hydrogen or deuterium;

[0057] R 6 is C(R A )3; and

[0058] R 7 is C(R A )3 or C(R A )2R B ,

[0059] Where R A , R 2 , R 3 and R 5 At least one of them is deuterium, and R 1 and R 7 At least one of them is C(R A )2R B .

[0060] Some embodiments provide compounds of formula (III):

[0061]

[0062] or a pharmaceutically acceptable salt thereof, wherein:

[0063] R 11 is a)-P(=O)(OR 33 )2 or -P(=O)(OR 33 )(N(R 33 )2);

[0064] b) -C(=O)R 50 ;

[0065] c)-C(=O)N(R 33 )R 50 ;

[0066] d) -C(=O)OR 50 ;or

[0067] e)R 50 ;

[0068] Each R 33 are independently hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl or aryl, wherein the C1-C6 alkyl and the aryl are each optionally substituted by R 10 replace;

[0069] R 50 is C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more R 10 and / or R 20 replace;

[0070] Each R 10 are independently halogen, halogenated C1-C6 alkyl, cyano, nitro, trimethylsilyl, -O(oxy), -OR 30 、-SR 30 、-OC(O)-R 30 、-OC(O)OR 30 、-N(R 30 )2. -C(O)R 30 、-C(O)OR 30 、-OC(O)N(R 30 )2、-C(O)N(R 30 )2、-N(R 30 )C(O)OR 31 、-N(R 30 )C(O)R 31 、-N(R 30 )C(=NR 31 )N(R 32 )2、-N(R 30 )S(O) t R 31 、-S(O) t OR 30 、-S(O) p R 30 、-S(O) t N(R 30)2.-OP(=O)(OR 30 )2, or optionally two R 10 The groups come together to form an oxo group on a single atom;

[0071] Each t is independently 1 or 2;

[0072] Each p is independently 1, 2 or 3;

[0073] Each R 20 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl or heteroaryl, wherein each R 20 Optionally R 10 and / or R 22 replace;

[0074] Each R 22 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl or heteroaryl, wherein each R 22 Optionally R 10 Replacement; and

[0075] Each R 30 , R 31 and R 32 are independently hydrogen, halogenated C1-C6 alkyl or C1-C6 alkyl;

[0076] Each R 1a Independently C(R A )3;

[0077] Each R A independently hydrogen or deuterium;

[0078] Each R 2a independently hydrogen or deuterium;

[0079] Each R 3a independently hydrogen or deuterium;

[0080] R 4a yes

[0081] R 5a is hydrogen or deuterium; and R 6a is C(R A )3.

[0082] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I) or Formula (III) or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.

[0083] Some embodiments provide a method of treating congenital adrenal hyperplasia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (I) or Formula (III) or a pharmaceutically acceptable salt thereof.

[0084] Some embodiments provide a method of treating congenital adrenal hyperplasia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of (S)-{4-[1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methanol (Compound 2), wherein Compound 2 is produced under physiological conditions or by solvolysis following administration of a prodrug of Compound 2 or a pharmaceutically acceptable salt thereof to the individual, wherein the prodrug of Compound 2 or a pharmaceutically acceptable salt thereof is not 4-(2-chloro-4-methoxy-5-methylphenyl)-N-((1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-2-propyn-1-yl-2-thiazolamine or a pharmaceutically acceptable salt thereof.

[0085] Some embodiments provide a method of treating congenital adrenal hyperplasia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of (S)-{4-[1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methanol (Compound 2), wherein Compound 2 is produced by a metabolic chemical reaction following administration of a prodrug of Compound 2 or a pharmaceutically acceptable salt thereof to the individual, wherein the prodrug of Compound 2 or a pharmaceutically acceptable salt thereof is not 4-(2-chloro-4-methoxy-5-methylphenyl)-N-((1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-2-propyn-1-yl-2-thiazolamine or a pharmaceutically acceptable salt thereof.

[0086] Some embodiments provide a method of treating congenital adrenal hyperplasia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a prodrug of (S)-{4-[1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methanol (Compound 2) or a pharmaceutically acceptable salt thereof, wherein the prodrug of Compound 2 or a pharmaceutically acceptable salt thereof is not 4-(2-chloro-4-methoxy-5-methylphenyl)-N-((1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-2-propyn-1-yl-2-thiazolamine or a pharmaceutically acceptable salt thereof.

[0087] These and other embodiments will become apparent upon reference to the following detailed description.To this end, various references are listed herein that describe in more detail certain background information, methods, compounds and compositions, and each reference is hereby incorporated by reference in its entirety. Specific implementation plan

[0088] Compound

[0089] Provided herein are compounds useful for treating diseases and / or conditions treatable by modulation of CRF1.

[0090] The present invention provides a compound of formula (I):

[0091]

[0092] or a pharmaceutically acceptable salt thereof, wherein:

[0093] Each R 1 Independently C(R A )3 or C(R A )2R B ;

[0094] Each R A independently hydrogen or deuterium;

[0095] R B Yes-OR C ;

[0096] R C is hydrogen or deuterium;

[0097] Each R 2 independently hydrogen or deuterium;

[0098] Each R 3 independently hydrogen or deuterium;

[0099] R 4 yes

[0100] R 5 is hydrogen or deuterium;

[0101] R 6 yes 13 C(R A )3 or C(R A )3; and

[0102] R 7 is C(R A )3 or C(R A )2R B ,

[0103] Where R A , R 2 , R 3 and R 5 At least one of them is deuterium, and R 1 and R 7 At least one of them is C(R A )2R B .

[0104] In some embodiments, the present invention provides compounds of formula (I):

[0105]

[0106] or a pharmaceutically acceptable salt thereof, wherein:

[0107] Each R 1 Independently C(R A )3 or C(R A )2R B ;

[0108] Each R A independently hydrogen or deuterium;

[0109] R B Yes-OR C ;

[0110] R C is hydrogen or deuterium;

[0111] Each R 2 independently hydrogen or deuterium;

[0112] Each R 3 independently hydrogen or deuterium;

[0113] R 4 yes

[0114] R 5 is hydrogen or deuterium;

[0115] R 6 is C(R A )3; and

[0116] R 7 is C(R A )3 or C(R A )2R B ,

[0117] Where R A , R 2 , R 3 and R 5 At least one of them is deuterium, and R 1 and R 7At least one of them is C(R A )2R B .

[0118] In some embodiments, R 6 yes 13 CD3.

[0119] In some embodiments, R 6 is CD3; and R 7 It is CH3.

[0120] In some embodiments, R 6 is CH3; and R 7 It's CD3.

[0121] In some embodiments, R 6 is CD3; and R 7 It's CD3.

[0122] In some embodiments, R 1 It's CD3.

[0123] In some embodiments, each R A It's hydrogen.

[0124] In some embodiments, each R 2 It's hydrogen.

[0125] In some embodiments, each R 3 It's hydrogen.

[0126] In some embodiments, the present invention relates to compounds of formula (Ia):

[0127]

[0128] or a pharmaceutically acceptable salt thereof, wherein:

[0129] Each R 1a Independently C(R A )3 or C(R A )2R B ;

[0130] Each R A independently hydrogen or deuterium;

[0131] R B Yes-OR C ;

[0132] R C is hydrogen or deuterium;

[0133] Each R 2a independently hydrogen or deuterium;

[0134] Each R 3a independently hydrogen or deuterium;

[0135] R 4a yes R 5a is hydrogen or deuterium;

[0136] R 6a yes 13 C(R A )3 or C(R A )3; and

[0137] R 7a is C(R A )3 or C(R A )2R B ,

[0138] Where R 1a and R 7a At least one of them is C(R A )2R B .

[0139] In some embodiments, the present invention relates to compounds of formula (Ia):

[0140]

[0141] or a pharmaceutically acceptable salt thereof, wherein:

[0142] Each R 1a Independently C(R A )3 or C(R A )2R B ;

[0143] Each R A independently hydrogen or deuterium;

[0144] R B Yes-OR C ;

[0145] R C is hydrogen or deuterium;

[0146] Each R 2a independently hydrogen or deuterium;

[0147] Each R 3a independently hydrogen or deuterium;

[0148] R 4a yes

[0149] R 5a is hydrogen or deuterium;

[0150] R 6ais C(R A )3; and

[0151] R 7a is C(R A )3 or C(R A )2R B ,

[0152] Where R 1a and R 7a At least one of them is C(R A )2R B .

[0153] In some embodiments, R 7a is C(R A )2R B ; and R C It's hydrogen.

[0154] In some embodiments, R 7a It is CH2OH.

[0155] In some embodiments, the present invention relates to compounds of formula (IIa):

[0156]

[0157] or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, R 6a Is CD3 or R 6a It is CH3.

[0159] In some embodiments, R 6a It's CD3.

[0160] In some embodiments, each R 2a It's hydrogen.

[0161] In some embodiments, R 7a It's CD2OH.

[0162] In some embodiments, the present invention provides compounds having the formula:

[0163]

[0164] or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the present invention provides compounds having the formula:

[0166]

[0167] or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the present invention relates to compounds having the following formula:

[0169]

[0170] or a pharmaceutically acceptable salt thereof.

[0171] It should also be understood that, for the sake of clarity, certain features described in the context of separate implementations may also be provided in combination in a single embodiment. Conversely, for the sake of brevity, various features described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0172] Compounds described herein can be asymmetric (for example, having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers are expected. It should be understood that in any compound described herein with one or more chiral centers, if absolute stereochemistry is not clearly indicated, each center can independently have an R configuration or an S configuration or a mixture thereof. Therefore, compounds provided herein can be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure, diastereomerically enriched or stereoisomer mixtures. The preparation of enantiomerically pure or enantiomerically enriched forms can be achieved by splitting a racemic mixture or by using enantiomerically pure or enantiomerically enriched raw materials or by stereoselective or stereospecific synthesis. Stereochemical definitions can be obtained in EL Elliel, SH Wilen & L. N. Mander "Stereochemistry of Organic Compounds" John Wiley & Sons, Inc., New York, NY, 1994, which is incorporated herein by reference as a whole. In some embodiments, where the compounds of the invention are chiral or otherwise contain one or more stereocenters, compounds having an enantiomeric excess (ee) or diastereomeric excess (de) of greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 99% can be prepared. As will be apparent from the context, a compound of the invention may refer to a single molecule or to a plurality of molecules.

[0173] The resolution of the racemic mixture of compound can be carried out by any of a variety of methods known in the art. Exemplary methods include the fractional recrystallization using chiral resolution acid, which is an optically active salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids in D and L forms. Other resolving agents suitable for fractional crystallization methods include methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. in stereoisomerically pure form (e.g., S and R form, or diastereoisomerically pure form).

[0174] Resolution of the racemic mixture can also be performed by elution on a column filled with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

[0175] In some embodiments, compounds of the invention can be prepared having an enantiomeric excess of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 99.9%, or an enantiomeric excess within the range defined by any of the foregoing numbers.

[0176] Compounds described herein also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomeric forms include proton transfer tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary proton transfer tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or spatially locked into one form by appropriate substitution.

[0177] The compounds described herein and their pharmaceutically acceptable salts may exist in the form of hydrates or solvates together with other substances such as water and solvents. When in the solid state, the compounds described herein and their salts may exist in various forms and may, for example, take the form of solvates, including hydrates. The compound may be in any solid state form, such as a crystalline form, an amorphous form, a solvated form, etc., so unless otherwise expressly stated, reference to the compound and its salt in the specification should be understood as an interpretation of any solid state form of the compound.

[0178] As used herein, the term "solvate" refers to a solid form of a compound of the invention (or a pharmaceutically acceptable salt thereof) that includes one or more solvent molecules in stoichiometric or non-stoichiometric amounts. In the case where the solvent is water, the solvate is a hydrate.

[0179] In some embodiments, the compounds described herein or their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which the compound is formed or detected. Partial separation can include, for example, a composition enriched with the compounds of the present invention. Substantially isolated can include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of a compound disclosed herein or its salt.

[0180] As used herein, "about" means ±20% of the stated value, and more specifically includes values ​​of ±10%, ±5%, ±2%, and ±1% of the stated value.

[0181] Additionally, it is understood that when the compounds described herein contain one or more double bonds (e.g., C=C, C=N, etc.) or other centers of geometric asymmetry, unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers (e.g., cis or trans). Cis and trans geometric isomers of the compounds described herein can be isolated as a mixture of isomers or as separated isomeric forms.

[0182] isotope

[0183] The compounds disclosed and described herein allow the atoms at each position of the compound to independently have an isotopic distribution of chemical elements in an amount proportional to those elements commonly found in nature, or an isotopic distribution of an amount proportional to those elements commonly found in nature, unless the context clearly dictates otherwise. A specific chemical element has an atomic number defined by the number of protons in the nucleus. Each atomic number identifies a specific element, but does not identify an isotope; an atom of a given element can have a wide range in the number of neutrons. The number of protons and neutrons in the nucleus is the mass number of the atom, and each isotope of a given element has a different mass number. Compounds in which one or more atoms have an isotopic distribution of chemical elements in a proportional amount different from those elements commonly found in nature are generally referred to as isotope-labeled compounds. Each chemical element as represented in the compound structure may include any isotopic distribution of the element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position in a compound where a hydrogen atom may be present, the hydrogen atom may be in an isotopic distribution of hydrogen including, but not limited to, amounts of protons in proportion to those normally found in nature and amounts of protons in proportions different from those normally found in nature ( 1 H) and deuterium ( 2 H). Thus, references to compounds herein encompass all possible isotopic distributions of each atom, unless the context clearly dictates otherwise. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. As will be appreciated by those skilled in the art, any compound as disclosed and described herein may include radioactive isotopes. Thus, also contemplated are the uses of compounds as disclosed and described herein in which one or more atoms have an isotopic distribution different from those normally found in nature, such as having a greater proportion of 2 H or 3 H, or proportions greater than those found in nature 11 C. 13 C or 14 C. By way of general example, and without limitation, isotopes of hydrogen include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Carbon isotopes include carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C) and carbon-14 ( 14 C). Nitrogen isotopes include nitrogen-13 ( 13 N), nitrogen-14 ( 14 N) and nitrogen-15( 15 N). Oxygen isotopes include oxygen-14 ( 14 O), oxygen-15 ( 15O), oxygen-16 ( 16 O), oxygen-17 ( 17 O) and oxygen-18 ( 18 O). Fluorine isotopes include fluorine-17 ( 17 F), fluorine-18 ( 18 F) and fluorine-19 ( 19 F). Phosphorus isotopes include phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), phosphorus-34 ( 34 P), phosphorus-35 ( 35 P) and phosphorus-36 ( 36 P). Sulfur isotopes include sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S) and sulfur-38 ( 38 S). Chlorine isotopes include chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl) and chlorine-37( 37 Cl). Isotopes of bromine include bromine-75 ( 75 Br), bromine-76( 76 Br), bromine-77( 77 Br), bromine-79( 79 Br), bromine-81( 81 Br) and bromine-82( 82 Br). Iodine isotopes include iodine-123 ( 123 I), iodine-124( 124 I), iodine-125( 125 I), iodine-131( 131 I) and iodine-135( 135I). In some embodiments, atoms at each position of the compound have an isotopic distribution of each chemical element in an amount proportional to those commonly found in nature. In some embodiments, atoms at at least one position of the compound have an isotopic distribution of chemical elements in amounts different from those commonly found in nature (the remaining atoms have an isotopic distribution of chemical elements in amounts proportional to those elements commonly found in nature). In some embodiments, atoms at at least two positions of the compound independently have an isotopic distribution of chemical elements in amounts different from those commonly found in nature (the remaining atoms have an isotopic distribution of chemical elements in amounts proportional to those commonly found in nature). In some embodiments, atoms at at least three positions of the compound independently have an isotopic distribution of chemical elements in amounts different from those commonly found in nature (the remaining atoms have an isotopic distribution of chemical elements in amounts proportional to those commonly found in nature). In some embodiments, atoms at at least four positions of a compound independently have an isotopic distribution of chemical elements in amounts proportional to those commonly found in nature (the remaining atoms have an isotopic distribution of chemical elements in amounts proportional to those commonly found in nature). In some embodiments, atoms at at least five positions of a compound independently have an isotopic distribution of chemical elements in amounts proportional to those commonly found in nature (the remaining atoms have an isotopic distribution of chemical elements in amounts proportional to those commonly found in nature). In some embodiments, atoms at at least six positions of a compound independently have an isotopic distribution of chemical elements in amounts proportional to those commonly found in nature (the remaining atoms have an isotopic distribution of chemical elements in amounts proportional to those commonly found in nature). As will be apparent from the context, a compound of the invention may refer to a single molecule or a plurality of molecules.

[0184] Certain compounds, such as those with radioactive elements (e.g., 3 H and 14 C) are also useful for drug or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) isotopes because they are easy to prepare and detect. Isotopes such as deuterium ( 2H) compounds may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotope-labeled compounds can generally be prepared by following procedures routinely practiced in the art. Such isotope perturbations or enrichments are easily measured using methods such as mass spectrometry, and for isotopes that are radioactive isotopes, additional methods such as radioactive detectors used in conjunction with HPLC or GC can be used.

[0185] As used herein, "isotopic variant" refers to a compound that contains an unnatural ratio of isotopes at one or more atoms that constitute the compound. In certain embodiments, an "isotopic variant" of a compound contains an unnatural ratio of one or more isotopes, including but not limited to protium ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131I). In certain embodiments, an "isotopic variant" of a compound is a stable form, i.e., non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including but not limited to protium ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 O), oxygen-17 ( 17 O) and oxygen-18 ( 18 In certain embodiments, an "isotopic variant" of a compound is an unstable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including but not limited to tritium ( 3 H), carbon-11 ( 11 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 O) and oxygen-15( 15 O). It is understood that in the compounds provided herein, any hydrogen may include 2 H as the major isotopic form, as an example, or any carbon including 13 C as the major isotopic form, as an example, or any nitrogen may include 15 N as the major isotopic form, as an example, and any oxygen may include 18 O as the major isotopic form, as an example. In certain embodiments, an "isotopic variant" of a compound contains an unnatural proportion of deuterium ( 2 H).

[0186] With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D" or "d", it is understood that the abundance of deuterium at that position is significantly greater than the natural abundance of deuterium, which is about 0.015%. In certain embodiments, positions designated as having deuterium typically have a minimum isotopic enrichment factor at each designated deuterium position of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0187] Synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds of the present invention and are well known in the art. For example, these synthetic methods for incorporating activity levels of tritium into target molecules are as follows:

[0188] A. Catalytic Reduction with Tritium Gas: This procedure generally produces high specific activity products and requires halogenated or unsaturated precursors.

[0189] B. Use borohydride 3 H] Sodium reduction: This procedure is fairly cheap and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, etc.

[0190] C. Using hydrogen 3 Lithium aluminum reduction: This procedure provides products with nearly theoretical specific activities. Precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, etc. are also required.

[0191] D. Tritium Gas Labeling: This procedure involves exposing a precursor containing exchangeable protons to tritium gas in the presence of a suitable catalyst.

[0192] E. Use of methyl 3 H] iodine for N-methylation: This procedure is usually used to synthesize a methyl group with high specific activity ( 3 H) Iodine treatment of appropriate precursors to prepare O-methyl or N-methyl ( 3 H) Product. This method generally allows higher specific activities, for example, about 70-90 Ci / mmol.

[0193] To increase the activity level 125 Synthetic methods for incorporating I into target molecules include:

[0194] A. Sandmeyer and similar reactions: This procedure converts an aryl or heteroaryl amine into a diazonium salt, such as diazonium tetrafluoroborate, followed by the use of Na 125 I is converted to 125 I-labeled compounds. A representative procedure was reported by Zhu, GD. and co-workers in J. Org. Chem., 2002, 67, 943-948.

[0195] B. The ortho position of phenol 125 Iodination: This procedure allows the introduction of iodine at the ortho position of the phenol. 125 I, as reported by Collier, TL and co-workers in J. Labelled Compd. Radiopharm., 1999, 42, S264-S266.

[0196] C. Use 125I exchange with aryl bromides and heteroaryl bromides: This method is generally a two-step process. The first step is to convert the aryl bromide or heteroaryl bromide into the corresponding trialkyltin intermediate using, for example, a Pd-catalyzed reaction [i.e., Pd(Ph3P)4], or by aryl or heteroaryl lithium in the presence of a trialkyltin halide or hexaalkylditin [e.g., (CH3)3SnSn(CH3)3]. Le Bas, M.-D. and co-workers reported a representative procedure in J. Labelled Compd. Radiopharm. 2001, 44, S280-S282.

[0197] Chemical Definition

[0198] Unless otherwise defined, all technical terms and scientific terms used herein have the same meanings as those generally understood by those of ordinary skill in the art to which the present disclosure belongs. All patents, applications, published applications and other publications are incorporated herein by reference in their entirety. Where multiple definitions exist for a term in this article, those definitions in this section shall prevail unless otherwise stated.

[0199] Whenever a group is described as "optionally substituted", the group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as "unsubstituted or substituted", if substituted, the substituents may be selected from one or more of the indicated substituents. It should be understood that substitution at a given atom is limited by valence.

[0200] As used herein, “C a -C b " (wherein "a" and "b" are integers) refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in the ring of a heterocyclyl, heteroaryl, cycloalkyl, cycloalkenyl, or aryl group. That is, these groups can contain from "a" to "b" (inclusive) carbon atoms. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. If "a" and "b" are not specified for an alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl, cycloalkyl, cycloalkenyl, or aryl group, the broadest range described in these definitions is assumed.

[0201] In addition to the foregoing, as used in the specification and appended claims, unless otherwise indicated, the following terms have the designated meanings:

[0202] The term "alkenyl" refers to a hydrocarbon group containing one or more double bonds in a straight or branched hydrocarbon chain. Examples of alkenyl groups include allenyl, vinylmethyl and vinyl. In some embodiments, the alkenyl group may be unsubstituted or substituted. In some embodiments, the alkenyl group may have 2 to 6 carbon atoms. The alkenyl group of a compound may be designated as "C2-C6 alkenyl" or similarly designated.

[0203] The term "alkynyl" refers to a hydrocarbon group containing one or more triple bonds in a straight or branched hydrocarbon chain. Examples of alkynyl groups include ethynyl and propynyl. Alkynyl groups may be unsubstituted or substituted. In some embodiments, alkynyl groups may be unsubstituted or substituted. In some embodiments, alkynyl groups may have 2 to 6 carbon atoms. The alkenyl group of a compound may be designated as "C2-C6 alkynyl" or similarly designated.

[0204] The term "aryl" refers to an aromatic ring system containing 6, 10 or 14 carbon atoms, which may contain a single ring, two fused rings or three fused rings, such as phenyl, naphthyl and phenanthrenyl. In some embodiments, the aryl group may have 6 or 10 carbon atoms (i.e., C6 or C7). 10 When one or more substituents are present on an "aryl" ring, the substituents may be bonded at any available ring carbon. In some embodiments, aryl may be substituted or unsubstituted. In some embodiments, aryl is phenyl.

[0205] The term "alkyl" refers to a fully saturated straight or branched hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears in this article, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms. In some embodiments, the alkyl group may have 1 to 6 carbons (i.e., "C1-C6 alkyl"). Some embodiments are 1 to 5 carbons (i.e., C1-C5 alkyl), some embodiments are 1 to 4 carbons (i.e., C1-C4 alkyl), some embodiments are 1 to 3 carbons (i.e., C1-C3 alkyl), and some embodiments are 1 or 2 carbons. By way of example only, " "C1-C4 alkyl" means that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, 1-methylbutyl [i.e., -CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -CH2CH(CH3)CH2CH3], n-hexyl, and the like. When one or more substituents are present on the alkyl group, the substituents may be bonded at any available carbon atom. In some embodiments, the alkyl group may be substituted or unsubstituted.

[0206] The term "haloalkyl" refers to an alkyl group as defined herein, wherein one or more of the hydrogen atoms of the alkyl group has been replaced by a halogen atom (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). In some embodiments, the haloalkyl group may have from 1 to 6 carbon atoms (i.e., "haloC1-C6 alkyl"). The haloC1-C6 alkyl group may be fully substituted, in which case it may be represented by the formula C n L 2n+1 , wherein L is a halogen and "n" is 1, 2, 3, 4, 5 or 6. When there are more than one halogen, they may be the same or different and are selected from: fluorine, chlorine, bromine and iodine. In some embodiments, the haloalkyl contains 1 to 5 carbons (i.e., halogenated C1-C5 alkyl). In some embodiments, the haloalkyl contains 1 to 4 carbons (i.e., halogenated C1-C4 alkyl). In some embodiments, the haloalkyl contains 1 to 3 carbons (i.e., halogenated C1-C3 alkyl). In some embodiments, the haloalkyl contains 1 or 2 carbons. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, etc.

[0207] The term "carbonyl" refers to the group -C(=O)-.

[0208] The term "oxo" refers to a =0 substituent.

[0209] The term "oxy" refers to an -O- group (oxy).

[0210] The term "cycloalkyl" refers to a fully saturated all carbon monocyclic or polycyclic ring system. In some embodiments, a cycloalkyl is a monocyclic ring containing 3 to 7 carbon atoms (i.e., "C3-C7 cycloalkyl"). Some embodiments contain 3 to 6 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When one or more substituents are present on an alkyl, the substituents may be bonded at any available carbon atom. In some embodiments, a cycloalkyl may be substituted or unsubstituted.

[0211] "Cycloalkenyl" refers to a monocyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if there are more than one ring, the double bonds cannot form a completely delocalized π electron system (i.e., an aromatic system) in all rings, otherwise the group will be an "aryl" as defined herein. When consisting of two or more rings, the rings may be connected together in a fused, bridged, or spiro-connected manner. The cycloalkenyl group may contain 3 to 12 atoms in the ring or 3 to 8 atoms in the ring. In some embodiments, the cycloalkenyl group may be unsubstituted or substituted. In some embodiments, the cycloalkenyl group may have 4 to 8 carbon atoms (i.e., "C4-C8 cycloalkenyl"). An example is cyclohexenyl.

[0212] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system and has at least one heteroatom in the ring system, i.e., an element other than carbon, including but not limited to nitrogen, oxygen and sulfur. Some embodiments are "5-6 membered heteroaryl" and refer to an aromatic ring containing 5 to 6 ring atoms in a single ring and having at least one heteroatom in the ring system. Examples of heteroaryl rings include, but are not limited to, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, isoindolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, dibenzo [b, d] furan, dibenzo [b, d] thiophene, phenanthridinyl, benzimidazolyl, pyrrolyl, quinolyl, isoquinolyl, benzisoxazolyl, imidazo [1,2-b] thiazolyl, etc. Heteroaryl can be substituted or unsubstituted. In some embodiments, heteroaryl has 5 to 10 ring members or 5 to 7 ring members. Heteroaryl groups may be designated as "5-7 membered heteroaryl", "5-10 membered heteroaryl" or similar designations. In some embodiments, heteroaryl groups may be substituted or unsubstituted C1-C 13A five-, six-, seven-, eight-, nine-, ten-, up to 14-membered monocyclic, bicyclic or tricyclic ring system, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, heteroaryl can be a substituted or unsubstituted C1-C5 five- or six-membered monocyclic ring, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, heteroaryl can be a substituted or unsubstituted C5-C9 eight-, nine- or ten-membered bicyclic ring system, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, heteroaryl is a substituted or unsubstituted C5-C9 eight-, nine- or ten-membered heteroaryl. In some embodiments, the C5-C9 eight-membered, nine-membered or ten-membered bicyclic heteroaryl is imidazo[2,1-b]thiazolyl, 1H-indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzisoxazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, quinoxalinyl, pyrido[3,4-b]pyrazinyl or pyrido[4,3-d]pyrimidinyl. In some embodiments, the heteroaryl is a substituted or unsubstituted C8-C 13 13-membered or 14-membered tricyclic ring system, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, heteroaryl can be oxazolyl, such as imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,2,4-thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl, each of which can be substituted or unsubstituted. In some embodiments, heteroaryl is C1-C4 5-membered heteroaryl. In some embodiments, C1-C4 5-membered heteroaryl is furanyl, thienyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, isothiazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl. In some embodiments, heteroaryl is C3-C5 6-membered heteroaryl. In some embodiments, C3-C5 6-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl. In some embodiments, "5-10-membered heteroaryl" refers to: furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl, triazinyl, benzofuranyl, 1H-indolyl, benzo [b] thienyl, etc. In some embodiments, "5-10-membered heteroaryl" refers to: pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, 1H-indolyl, quinoxalinyl, thiadiazolyl, etc. In some embodiments, heteroaryl can be substituted or unsubstituted.

[0213] The term "heterocyclyl" refers to a three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system, wherein carbon atoms together with 1 to 5 heteroatoms constitute the ring system and optionally contain one or more unsaturated bonds, however, the unsaturated bonds exist in such a way that a completely delocalized π electron system (aromatic system) is not present in a monocyclic ring or in at least one ring in a bicyclic and tricyclic system. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur and nitrogen. When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro manner, wherein heteroatoms may be present in a non-aromatic ring or aromatic ring in the ring system. In some embodiments, a heterocyclyl may be a 3-7-membered saturated non-aromatic ring system containing 3 to 7 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, a "3-6-membered heterocyclyl" refers to a saturated non-aromatic ring group containing 3 to 6 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, "4-6 membered heterocyclyl" refers to a saturated non-aromatic ring group containing 4 to 6 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, one or two heteroatoms in the ring system are independently selected from: O (oxygen) and N (nitrogen). In some embodiments, the heterocyclyl may include a carbonyl (C=O) adjacent to a heteroatom, i.e., substituted by oxo on the carbon adjacent to the heteroatom, wherein the substituted ring system is a lactam, a lactone, a cyclic imide, a cyclic thioimide, or a cyclic carbamate.Examples of unsubstituted or oxo-substituted "heterocyclyl" include, but are not limited to, aziridinyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolyl, 1,3-dioxolyl, 1,4-dioxolyl, 1,3-oxathiolanyl, 1,4-oxathiolanyl, 1,3-oxathiolanyl, 1,3-dithiolanyl, 1,4-oxathiolanyl, tetrahydro-1,4-thiazinyl, 2H-1,2-oxazinyl, maleimido, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolidinyl, isoxazolidinyl, isoindolinyl, indolinyl, oxazolinyl, oxazolidinyl, oxazolidinone, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidinone, pyrrolidinedione, 4-piperidone, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopyranyl, 1,4-diazabicyclo[2.2.2]octane, 1,4-diazabicyclo[3.1.1]heptane, 2-azaspiro[3,3]heptane, 2,6-diazaspiro[3,3]heptane, 2-oxa-6-azaspiro[3,3]heptane and benzo-fused analogs thereof (e.g., benzimidazolidinone, tetrahydroquinolinyl and 3,4-methylenedioxyphenyl). A heterocyclyl group may be designated as a "3-10 membered heterocyclyl" or similar designation. In some embodiments, a heterocyclyl group may be C2-C. 12 A three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 13-membered monocyclic, bicyclic or tricyclic ring system, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocyclyl group can be a substituted or unsubstituted C2-C6 three-, four-, five-, six- or seven-membered monocyclic ring, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocyclyl group can be a substituted or unsubstituted C2-C6 three-, four-, five-, six- or seven-membered monocyclic ring. 10 A four-, five-, six-, seven-, eight-, nine-, ten-, or eleven-membered bicyclic ring system comprising 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl group may be a substituted or unsubstituted C7-C 12A 12-membered or 13-membered tricyclic ring system including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroatoms of the six-membered monocyclic heterocyclic group are selected from one to three O (oxygen), N (nitrogen) or S (sulfur), and the heteroatoms of the five-membered monocyclic heterocyclic group are selected from one or two heteroatoms selected from O (oxygen), N (nitrogen) or S (sulfur). In some embodiments, the heterocyclic group can be aziridine, azetidinyl, tetrahydrofuranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolyl, 1,3-dioxolyl, 1,3-oxathiolanyl, 1,4-oxathiolanyl, 1,3-oxathiolanyl, 1,3-dith ... thiolanyl, 1,4-oxathiolanyl, tetrahydro-1,4-thiazinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolyl, indolyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, morpholinyl, oxirane, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-diazabicyclo[2.2 .2] octane, 1,4-diazabicyclo[3.1.1]heptane, 2-azaspiro[3,3]heptane, 2,6-diazaspiro[3,3]heptane, tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydro-2,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,7-naphthyridinyl, 1,2,3,4-tetrahydro-1,7-naphthyridinyl, 1,2,3,4-tetrahydro- , 1,6-naphthyridinyl, 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl, [1,3]dioxol[4,5-c]pyridinyl, [1,3]dioxol[4,5-b]pyridinyl, [1,3]dioxol[4,5-d]pyrimidinyl or 3,4-methylenedioxyphenyl. In some embodiments, the unsubstituted or substituted heterocyclic group can be selected from aziridine, azetidinyl, piperidinyl, morpholinyl, oxetanyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, 2-piperidone, 1,1-dioxothiomorpholinyl, oxolanyl (tetrahydrofuranyl) and oxhexyl (tetrahydropyranyl). When one or more substituents are present on the heterocyclic group, the substituents may be bonded at any available carbon atom and / or heteroatom. In some embodiments, the heterocyclic group may be substituted or unsubstituted.

[0214] The term "cyano" refers to the group -CN.

[0215] The term "halogen" or "halo" refers to a fluorine, chlorine, bromine or iodine group. In some embodiments, the halogen or halo is fluorine, chlorine or bromine. In some embodiments, the halogen or halo is fluorine or chlorine. In some embodiments, the halogen or halo is fluorine.

[0216] The term "nitro" refers to a -NO2 group.

[0217] The term "halogenating agent" refers to a compound that provides a halogen atom to a reactant compound, such as converting an alcohol reactant compound into an alkyl halide product compound. Examples of halogenating agents include, but are not limited to, thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, methanesulfonyl chloride and NaI, p-toluenesulfonyl chloride and NaI, phosphorus tribromide, dibromotriphenylphosphine, phosphorus pentabromide or thionyl bromide, etc.

[0218] The term "coupling agent" refers to a compound that promotes amide bond formation, where carboxylic acid activation is required to promote coupling with amines. Examples of amide coupling agents include, but are not limited to, thionyl chloride, oxalyl chloride, phosphoryl chloride, Vilsmeier reagent, propylphosphonic anhydride, ethylmethylphosphinic anhydride (EMPA), Ac2O, pivaloyl chloride, ethyl chloroformate (ECF), isobutyl chloroformate (IBCF), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), pentafluorophenyl trifluoroacetate, cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM) , 1-tert-butyl-3-ethylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC), 1,3-di-p-tolylcarbodiimide, benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyClock), (7-azabenzotriazol-1-yloxy)tripyrrole Alkylphosphonium hexafluorophosphate (PyAOP), 1-cyano-2-ethoxy-2-oxoethylideneaminooxy-tripyrrolidino-phosphonium hexafluorophosphate (PyOxim), 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate (COMU), 3-(diethoxy-phosphoryloxy)-1,2,3-benzo[d]triazine-4(3H)-one (DEPBT), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), O-(2-oxo-1(2H)pyridinyl)-N,N,N',N'-tetramethyluronium 1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TPTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU), N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate (HSTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(6-chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium hexafluorophosphate (HCTU), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU).

[0219] The term "base" refers to a compound that is an electron pair donor in an acid-base reaction.

[0220] The base may be an inorganic base or an organic base.

[0221] The term "organic base" refers to a base (e.g., an amine base) comprising at least one C—H bond. In some embodiments, the amine base can be a primary amine, a secondary amine, or a tertiary amine. Examples of amine bases include, but are not limited to, methylamine, dimethylamine, diethylamine, diphenylamine, trimethylamine, triethylamine, N,N-diisopropylethylamine, diisopropylamine, piperidine, 2,2,6,6-tetramethylpiperidine, pyridine, 2,6-lutidine, 4-methylmorpholine, 4-ethylmorpholine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-bis (dimethylamino) naphthalene, 4- (dimethylamino) pyridine, etc.

[0222] The term "inorganic base" refers to a base that does not include at least one C—H bond and includes at least one alkali metal or alkaline earth metal. Examples of inorganic bases include, but are not limited to, sodium hydride, potassium hydride, lithium hydride, calcium hydride, barium carbonate, calcium carbonate, cesium carbonate, lithium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, cesium bicarbonate, potassium bicarbonate, sodium bicarbonate, barium hydroxide, calcium hydroxide, cesium hydroxide, lithium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, etc.

[0223] For compounds disclosed herein or pharmaceutically acceptable salts thereof in which a variable appears more than once, each variable may be a different moiety independently selected from the group defining the variable. For example, in the case of describing a structure with two R groups present simultaneously on the same compound, the two R groups may represent different moieties independently selected from the group defined for R.

[0224] As used herein, unless otherwise indicated, abbreviations for any protecting groups, amino acids, and other compounds are in accordance with their commonly used, recognized abbreviations or the IUPAC-IUB Biochemical Nomenclature Commission (see Biochem. 11:942-944 (1972)).

[0225] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0226] The compounds described herein can be used in neutral forms such as free acid or free base forms. Alternatively, the compounds can be used in the form of acid addition salts or base addition salts. The term "pharmaceutically acceptable salt" refers to a salt of a compound having an acidic or basic portion that is not biologically or otherwise undesirable for use in medicine. In many cases, the compounds disclosed herein can form acid salts and / or basic salts by the presence of an acidic or basic portion (e.g., an amino group and / or a carboxyl group or a group similar thereto). Pharmaceutically acceptable acid addition salts can be formed by combining a compound having a basic portion with an inorganic acid and an organic acid. Inorganic acids that can be used to prepare salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids that can be used to prepare salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed by combining compounds with acidic moieties with inorganic and organic bases. Inorganic bases that can be used to prepare salts include, for example, hydroxides, carbonates, bicarbonates, phosphates, etc. of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, and aluminum; particularly preferred are hydroxides, carbonates, bicarbonates, or phosphates of ammonium, potassium, sodium, calcium, and magnesium. Organic bases that can be used to prepare salts include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, particularly, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with at least a stoichiometric amount of a suitable base or acid in water or in an organic solvent or in a mixture of the two; typically, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts are found in WO 87 / 05297, Johnston et al., published September 11, 1987; Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; and Berge, J. Pharm. Sci., 66, 2 (1977), each of which is incorporated herein by reference in its entirety. A reference for the preparation and selection of pharmaceutically acceptable salts of the present disclosure is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002, which is incorporated herein by reference in its entirety.

[0227] preparation

[0228] The present invention also relates to preparations of the compounds of the present invention or their salts. As used herein, a "preparation" is a product of a method, for example, for preparing or purifying the compounds of the present invention or their salts. In some embodiments, the preparation may optionally include one or more impurities, residual solvents, or a combination thereof. The preparation may be liquid or solid.

[0229] In some embodiments, the present invention relates to a formulation of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0230]

[0231] in:

[0232] Each R 1a Independently C(R A )3 or C(R A )2R B ;

[0233] Each R A independently hydrogen or deuterium;

[0234] R B Yes-OR C ;

[0235] R C is hydrogen or deuterium;

[0236] Each R 2a independently hydrogen or deuterium;

[0237] Each R 3a independently hydrogen or deuterium;

[0238] R 4a yes

[0239] R 5a is hydrogen or deuterium;

[0240] R 6a yes 13 C(R A )3 or C(R A )3; and

[0241] R 7a is C(R A )3 or C(R A )2R B ,

[0242] Where R 1a and R 7a At least one of them is C(R A )2RB .

[0243] In some embodiments, the present invention relates to a formulation of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0244]

[0245] in:

[0246] Each R 1a Independently C(R A )3 or C(R A )2R B ;

[0247] Each R A independently hydrogen or deuterium;

[0248] R B Yes-OR C ;

[0249] R C is hydrogen or deuterium;

[0250] Each R 2a independently hydrogen or deuterium;

[0251] Each R 3a independently hydrogen or deuterium;

[0252] R 4a yes

[0253] R 5a is hydrogen or deuterium;

[0254] R 6a is C(R A )3; and

[0255] R 7a is C(R A )3 or C(R A )2R B ,

[0256] Where R 1a and R 7a At least one of them is C(R A )2R B .

[0257] In some embodiments, R 7a is C(R A )2R B ; and R C It's hydrogen.

[0258] In some embodiments, R 7aIt is CH2OH.

[0259] In some embodiments, the present invention relates to a formulation of a compound of formula (IIa) or a pharmaceutically acceptable salt thereof:

[0260]

[0261] In some embodiments, R 6a Is CD3 or R 6a It is CH3.

[0262] In some embodiments, R 6a It's CD3.

[0263] In some embodiments, each R 2a It's hydrogen.

[0264] In some embodiments, R 7a It's CD2OH.

[0265] In some embodiments, the compound of the formulation is a compound having the formula:

[0266]

[0267] or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, the compound of the formulation is a compound having the formula:

[0269]

[0270] or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the compound of the formulation is a compound having the formula:

[0272]

[0273] or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the compound of the formulation has an enantiomeric excess of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 99.9%, or an enantiomeric excess within the range defined by any of the foregoing numbers.

[0275] In some embodiments, the formulation includes at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 99.9% by weight of the compound, or a weight percentage within the range defined by any of the foregoing numbers.

[0276] In some embodiments, the formulation comprises at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 99.9% by weight of the compound, or a weight percent within the range defined by any of the foregoing numbers.

[0277] In some embodiments, the formulation comprises at least about 50% by weight of the compound.

[0278] In some embodiments, the formulation comprises at least about 75% by weight of the compound.

[0279] In some embodiments, the formulation comprises at least about 90% by weight of the compound.

[0280] In some embodiments, the formulation comprises at least about 95% by weight of the compound.

[0281] In some embodiments, the formulation is in solid form, ie, a solid formulation.

[0282] In some embodiments, the formulation is used to prepare a pharmaceutical composition.

[0283] Prodrug

[0284] "Prodrug" is intended to mean a compound that can be converted to a biologically active compound described herein (e.g., Compound 2) under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a metabolic precursor of a compound described herein that is pharmaceutically acceptable. A prodrug may be inactive when administered to an individual in need thereof, but is converted in vivo to an active compound described herein. Prodrugs are typically rapidly converted in vivo (e.g., by hydrolysis in the blood) to produce the parent compound described herein. Prodrug compounds often provide advantages of solubility, tissue compatibility or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, pp. 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACSSymposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

[0285] In one embodiment, the compounds of Formula (IIIaa), (IIIbb), (IIIcc), (IIIdd), (IIIee) and (IIIff) are used as prodrugs of Compound 2; that is, the compounds can be converted to Compound 2 under physiological conditions. In another embodiment, the compounds of Formula (IIIaa), (IIIbb), (IIIcc), (IIIdd), (IIIee) and (IIIff) are themselves CRF1 inhibitors.

[0286] Some embodiments provide compounds of formula (III):

[0287]

[0288] or a pharmaceutically acceptable salt thereof, wherein:

[0289] R 11 is a)-P(=O)(OR 33 )2 or -P(=O)(OR 33 )(N(R 33 )2);

[0290] b) -C(=O)R 50 ;

[0291] c)-C(=O)N(R 33 )R 50 ;

[0292] d) -C(=O)OR 50 ;or

[0293] e)R 50 ;

[0294] Each R 33 are independently hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl or aryl, wherein the C1-C6 alkyl and the aryl are each optionally substituted by R 10 replace;

[0295] R 50 is C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more R 10 and / or R 20 replace;

[0296] Each R 10 are independently halogen, halogenated C1-C6 alkyl, cyano, nitro, trimethylsilyl, -O(oxy), -OR 30 、-SR 30 、-OC(O)-R 30 、-OC(O)OR 30 、-N(R 30 )2. -C(O)R 30 、-C(O)OR 30 、-OC(O)N(R 30 )2、-C(O)N(R 30 )2、-N(R 30 )C(O)OR 31 、-N(R 30 )C(O)R 31 、-N(R 30 )C(=NR 31 )N(R 32 )2、-N(R 30 )S(O) t R 31 、-S(O) t OR 30 、-S(O) p R 30 、-S(O) t N(R 30 )2.-OP(=O)(OR 30 )2, or optionally two R 10 The groups come together to form an oxo group on a single atom;

[0297] Each t is independently 1 or 2;

[0298] Each p is independently 1, 2 or 3;

[0299] Each R 20 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl or heteroaryl, wherein each R 20 Optionally R 10 and / or R 22 replace;

[0300] Each R 22 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl or heteroaryl, wherein each R 22 Optionally R 10 Replacement; and

[0301] Each R 30 , R 31 and R 32 are independently hydrogen, halogenated C1-C6 alkyl or C1-C6 alkyl;

[0302] Each R 1a Independently C(R A )3;

[0303] Each R A independently hydrogen or deuterium;

[0304] Each R 2a independently hydrogen or deuterium;

[0305] Each R 3a independently hydrogen or deuterium;

[0306] R 4a yes

[0307] R 5a is hydrogen or deuterium;

[0308] R 6a is C(R A )3; and

[0309] R 7a is C(R A )3.

[0310] In some embodiments, each R 33 R is independently hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl or aryl; 50is C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl or heterocyclic; each R 20 are independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl or heteroaryl; each R 22 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl or heteroaryl; and each R 30 , R 31 and R 32 are independently hydrogen, halogenated C1-C6 alkyl or C1-C6 alkyl.

[0311] In some embodiments, the compound is of formula (IIIa):

[0312] or a pharmaceutically acceptable salt thereof.

[0313] In some embodiments, the compound is of Formula (IIIaa):

[0314] or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the compound is of formula (IIIb):

[0316] or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the compound is of formula (IIIbb):

[0318] or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, the compound is of formula (IIIc):

[0320] or a pharmaceutically acceptable salt thereof.

[0321] In some embodiments, the compound is of formula (IIIcc):

[0322] or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments, the compound is of formula (IIId):

[0324] or a pharmaceutically acceptable salt thereof.

[0325] In some embodiments, the compound is of formula (IIIdd):

[0326] or a pharmaceutically acceptable salt thereof.

[0327] In some embodiments, the compound is of formula (IIIe):

[0328] or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the compound is of formula (IIIee):

[0330] or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, the compound is of formula (IIIf):

[0332] or a pharmaceutically acceptable salt thereof.

[0333] In some embodiments, the compound is of formula (IIIff):

[0334] or a pharmaceutically acceptable salt thereof.

[0335] In some embodiments, R 11 Choose one of the following:

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342] In some embodiments, R 11 Selected from

[0343]

[0344] In some embodiments, the compound is of the formula:

[0345] or a pharmaceutically acceptable salt thereof.

[0346] In some embodiments, the compound is the hydrochloride salt of a compound of the formula:

[0347]

[0348] In some embodiments, the compound is of the formula:

[0349] or a pharmaceutically acceptable salt thereof.

[0350] In some embodiments, the compound is the sodium salt of a compound of the formula:

[0351]

[0352] In some embodiments, the compound is a compound of the formula:

[0353] or a pharmaceutically acceptable salt thereof.

[0354] In some embodiments, the compound is the sodium salt of a compound of the formula:

[0355]

[0356] In some embodiments, the compound is the disodium salt of a compound of the formula:

[0357]

[0358] The compound of formula (III) can be prepared according to the synthesis method described in International Publication No. WO 2016 / 127133 A1. For example, the compound of formula (IIIaa), (IIIbb), (IIIcc), (IIIdd), (IIIee) and (IIIff) can be prepared according to the synthesis method described in International Publication No. WO 2016 / 127133 A1 using compound 2 as a starting material instead of [(2R, 3S, 11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H, 2H, 3H, 4H, 6H, 7H, 11bH-pyrido [2, 1-a] isoquinolin-2-yl] methanol.

[0359] In some embodiments, the starting material compound 2 can be reacted with R in the presence of a coupling agent (e.g., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)) and a base (e.g., an amine base such as dimethylaminopyridine (DMAP)) in a solvent such as dichloromethane. 50 The compound of formula (IIIaa) can be prepared by reacting C(=O)OH. In some embodiments, the compound 2 as a starting material can be reacted with R 50C(=O)X (X is Cl, Br or I) in a solvent such as dichloromethane to prepare a compound of formula (IIIaa), wherein R 50 C(=O)X can be purchased when commercially available or by using R 50 C(=O)OH can be prepared by reacting a halogenating agent (e.g., thionyl chloride). In some embodiments, the compound of formula (IIIaa) can be prepared by reacting compound 2 as a starting material with R 50 C(=O)OC(=O)R 60 Reaction to prepare, where R 50 C(=O)OC(=O)R 60 It can be purchased when commercially available, or by using R 50 C(=O)OH and R 60 C(=O)X is prepared by reacting in a solvent in the presence of a base, wherein R 60 It is C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more substituents selected from halogen, C1-C6 alkyl, halo-substituted C1-C6 alkyl, cyano and nitro.

[0360] In some embodiments, the compound 2 as a starting material can be reacted with p-nitrophenyl chloroformate, 1,1-bis[6-(trifluoromethyl)benzotriazolyl]carbonate, di(2-pyridyl)carbonate, N,N'-disuccinimidyl carbonate, 4,5-dichloro-6-oxopyridazine-1(6H)-phenylcarboxylate, CDI, phosgene or triphosgene, optionally in the presence of a base (e.g., DMAP) in a solvent, followed by reaction with R 50 OH treatment to prepare the compound of formula (IIIbb).

[0361] In some embodiments, the compound 2 as a starting material can be reacted with p-nitrophenyl chloroformate, 1,1-bis[6-(trifluoromethyl)benzotriazolyl]carbonate, di(2-pyridyl)carbonate, N,N'-disuccinimidyl carbonate, 4,5-dichloro-6-oxopyridazine-1(6H)-phenylcarboxylate, CDI, phosgene or triphosgene, optionally in the presence of a base (e.g., DIPEA or DMAP) in a solvent, followed by reaction with R 50 R 33 The compound of formula (IIIcc) is prepared by NH treatment.

[0362] In some embodiments, the compound 2 as a starting material can be reacted with (R 33Compounds of formula (IIIdd) are prepared by reacting 2-(4-(2-nitropropene)-2-nitropropene (=O ...X) (X is Cl, Br or I) in a solvent such as pyridine or a solvent such as dichloromethane and a base such as DIPEA.

[0363] In some embodiments, R 50 R 33 NH and (R 33 O)P(=O)(X)2 (X is Cl, Br or I) is reacted in a solvent such as dichloromethane and optionally a base such as TEA or N-methylimidazole to provide a chlorophosphoramidate intermediate ((R 33 O)(R 50 R 33 N)P(=O)(X)), which can then be treated with compound 2 as a starting material to prepare a compound of formula (IIIee).

[0364] In some embodiments, the starting material compound 2 can be reacted with a base (eg, NaH) or in the presence of a base (eg, K2CO3) in a solvent (eg, DMF or DMSO), and then reacted with R 50 X (X is Cl, Br or I) or R 50 S(=O)2R 60 To prepare a compound of formula (IIIff), wherein R 60 It is C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more substituents selected from halogen, C1-C6 alkyl, halo-substituted C1-C6 alkyl, cyano and nitro.

[0365] In some embodiments, the starting material compound 2 can be reacted with a halogenating agent (p-toluenesulfonyl chloride (TsCl) or methanesulfonyl chloride (MsCl)) optionally in the presence of a base (e.g., K2CO3) in a solvent (e.g., DMF), and then reacted with R in the presence of a base (e.g., K2CO3) in a solvent (e.g., DMF). 50 OH combination, or by making R 50 R prepared by reacting OH with a base (such as NaH) in a solvent (such as DMF or DMSO) 50 The compound of formula (IIIff) is prepared by combining an alkoxide of OH.

[0366] How to use

[0367] Provided herein is a method for treating congenital adrenal hyperplasia (CAH), comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to an individual in need thereof. In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 4 or 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7 or 8, or a pharmaceutically acceptable salt thereof.

[0368] Provided herein is a method for treating congenital adrenal hyperplasia (CAH), comprising administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 2, 4 or 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7 or 8, or a pharmaceutically acceptable salt thereof.

[0369] Provided herein is a method for treating congenital adrenal hyperplasia (CAH), comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to normalize or partially normalize the level of a biomarker associated with congenital adrenal hyperplasia. In some embodiments, normalizing or partially normalizing the level of a biomarker comprises reducing the level of an elevated biomarker or increasing the level of a reduced biomarker compared to an individual not suffering from CAH. In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 4 or 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7 or 8, or a pharmaceutically acceptable salt thereof.

[0370] Provided herein is a method for treating congenital adrenal hyperplasia (CAH), comprising administering a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient to normalize or partially normalize the level of a biomarker associated with congenital adrenal hyperplasia. In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 2, 4 or 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7 or 8, or a pharmaceutically acceptable salt thereof.

[0371] Provided herein is a method for treating congenital adrenal hyperplasia in an individual in need thereof, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount sufficient to reduce the level of one or more biomarkers associated with congenital adrenal hyperplasia. In some embodiments, the biomarker is selected from (a) 17-hydroxyprogesterone (17-OHP) in an individual; (b) testosterone; and (c) androstenedione. In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 4 or 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7 or 8, or a pharmaceutically acceptable salt thereof.

[0372] Provided herein is a method for treating congenital adrenal hyperplasia in an individual in need thereof, the method comprising administering a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in an amount sufficient to reduce the level of one or more biomarkers associated with congenital adrenal hyperplasia. In some embodiments, the biomarker is selected from (a) 17-hydroxyprogesterone (17-OHP) in an individual; (b) testosterone; and (c) androstenedione. In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 2, 4 or 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7 or 8, or a pharmaceutically acceptable salt thereof.

[0373] In some embodiments, the reduction in the level of any biomarker (e.g., any one of 17-OHP, testosterone, and androstenedione) is determined by comparing the level of the biomarker measured during the rhythmic release of the day before the administration of the compound of the present invention or its pharmaceutically acceptable salt with the level of the biomarker measured during the rhythmic release of the day after the administration of the compound of the present invention or its pharmaceutically acceptable salt. One day before the administration of the compound of the present invention or its pharmaceutically acceptable salt is applicable to individuals who have not previously administered the compound of the present invention or its pharmaceutically acceptable salt within at least the past 24 hours.

[0374] In some embodiments, the rhythmic release of biomarkers associated with CAH occurs between 2 AM and 10 AM. In some embodiments, the rhythmic release of biomarkers associated with CAH occurs between 6 AM and 10 AM.

[0375] In some embodiments of any method disclosed herein, the compound of the present invention or its pharmaceutically acceptable salt is applied to an individual at night or before sleep (i.e., before bedtime). In some embodiments, the compound of the present invention or its pharmaceutically acceptable salt is applied three to eight hours before the rhythmic release of the biomarker. In some embodiments, the compound of the present invention or its pharmaceutically acceptable salt is applied six to eight hours before the rhythmic release of the biomarker. Application before rhythmic release can be suitable for shift workers (e.g., those workers who work at night and sleep during the day), in which case it is not necessary to apply at night. Therefore, application depends on the expected rhythmic release of the biomarker, and can be changed according to the specific work and sleep patterns of the individual (i.e., individual, patient).

[0376] In some embodiments of the methods provided herein, the level of 17-hydroxyprogesterone in an individual is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 55%, or at least about 60% from the level before administration. In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least about 25%. In some embodiments, the level of 17-hydroxyprogesterone is reduced by at least 50%. In some embodiments of the methods provided herein, the level of 17-hydroxyprogesterone is reduced by about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 50% to about 90%, about 55% to about 90%, or about 60% to about 90% from the level before administration.

[0377] In some embodiments, the level of 17-hydroxyprogesterone is reduced to a level within the range of 17-hydroxyprogesterone expected for individuals not having CAH, ie, less than 1,000 ng / dL or less than 200 ng / dL.

[0378] In some embodiments of the methods provided herein, the level of testosterone is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 55% or at least about 60% from the level before administration. In some embodiments, the level of testosterone is reduced by at least about 25%. In some embodiments, the level of testosterone is reduced by at least about 40%. In some embodiments, the level of testosterone is reduced by at least about 50%.

[0379] In some embodiments of the methods provided herein, the level of testosterone is reduced by an amount from about 10% to about 90%, from about 15% to about 90%, from about 20% to about 90%, from about 25% to about 90%, from about 30% to about 90%, from about 35% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 55% to about 90%, or from about 60% to about 90% from the pre-administration level.

[0380] In some embodiments, testosterone levels are reduced to levels within the testosterone range expected for individuals not suffering from CAH.

[0381] In some embodiments of the methods provided herein, the level of androstenedione is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 55% or at least about 60% from the level before administration. In some embodiments, the level of androstenedione is reduced by at least about 25%. In some embodiments, the level of androstenedione is reduced by at least about 30%. In some embodiments, the level of androstenedione is reduced by at least about 50%.

[0382] In some embodiments of the methods provided herein, the level of androstenedione is reduced by an amount from about 10% to about 90%, from about 15% to about 90%, from about 20% to about 90%, from about 25% to about 90%, from about 30% to about 90%, from about 35% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 55% to about 90%, or from about 60% to about 90% from pre-administration levels.

[0383] In some embodiments, the level of androstenedione is reduced to a level within the range of androstenedione expected for individuals not suffering from CAH, ie, less than 200 ng / dL.

[0384] In some embodiments of the methods provided herein, the level of 17-hydroxyprogesterone is reduced by at least about 50% from the level before administration, and the level of androstenedione is reduced by at least about 50% from the level before administration. In some embodiments of the methods provided herein, the level of 17-hydroxyprogesterone is reduced by at least about 50% from the level before administration, and the level of androstenedione is reduced by at least about 30% from the level before administration.

[0385] Also provided herein is a method for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne and growth impairment in an individual with classic congenital adrenal hyperplasia, the method comprising administering a compound of the invention or a pharmaceutically acceptable salt thereof in an amount sufficient to reduce one or more CAH biomarkers in the individual, e.g., reducing androstenedione in the individual. Growth impairment can refer to, for example, accelerated height velocity, accelerated weight velocity and / or accelerated bone age.

[0386] Provided herein is a method for reducing the level of one or more biomarkers in an individual with congenital adrenal hyperplasia, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, one or more biomarkers are selected from (a) 17-hydroxyprogesterone (17-OHP); (b) testosterone; and (c) androstenedione. In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 2, 4 or 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7 or 8, or a pharmaceutically acceptable salt thereof.

[0387] Provided herein is a method for reducing the level of one or more biomarkers in an individual with congenital adrenal hyperplasia, the method comprising administering to the individual a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In some embodiments, one or more biomarkers are selected from (a) 17-hydroxyprogesterone (17-OHP); (b) testosterone; and (c) androstenedione. In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 2, 4 or 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7 or 8, or a pharmaceutically acceptable salt thereof.

[0388] Provided herein is a method for reducing the dosage of a corticosteroid applied to an individual suffering from congenital adrenal hyperplasia to control congenital adrenal hyperplasia, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the corticosteroid is a glucocorticoid. In some embodiments, the glucocorticoid is hydrocortisone, dexamethasone, prednisone or prednisolone. In some embodiments, the corticosteroid is a mineralocorticoid. In some embodiments, the mineralocorticoid is fludrocortisone.

[0389] Provided herein is a method for reducing the dosage of corticosteroids applied to an individual with congenital adrenal hyperplasia to control congenital adrenal hyperplasia, the method comprising administering to the individual a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the corticosteroid is a glucocorticoid. In some embodiments, the glucocorticoid is hydrocortisone, dexamethasone, prednisone or prednisolone. In some embodiments, the corticosteroid is a mineralocorticoid. In some embodiments, the mineralocorticoid is fludrocortisone. In some embodiments, the compound is compound 2, 4 or 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7 or 8, or a pharmaceutically acceptable salt thereof.

[0390] Also provided herein is a method for reducing the severity of one or more side effects of the glucocorticoid treatment in the individual with congenital adrenal hyperplasia, the method comprising applying the compound of the present invention or its pharmaceutically acceptable salt to the individual. The long-term effect of glucocorticoid treatment is fully documented in the art (see, e.g., Oray, M. et al., (2016): Long-term effect of glucocorticoids, Expert Opinion on DrugSafety.DOI:10.1517 / 14740338.2016.1140743). Such side effects are related to each biological system, such as the musculoskeletal system (e.g., osteoporosis, ischemic osteonecrosis, and myopathy), the endocrine and metabolic systems (e.g., hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth inhibition, adrenal suppression), the gastrointestinal system (e.g., gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis), the cardiovascular system (e.g., hypertension, coronary heart disease, ischemic heart disease, heart failure), the skin system (e.g., rough skin, eczema, leukemia), and the inflammatory system (e.g., inflammatory bowel disease ... In some embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid is hydrocortisone, dexamethasone, prednisone or prednisolone. In some embodiments, the compound is compound 2, 4 or 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound 6, 7, or 8, or a pharmaceutically acceptable salt thereof.

[0391] Also provided herein is a method for reducing the severity of one or more side effects of glucocorticoid treatment in an individual with congenital adrenal hyperplasia, the method comprising administering to the individual a pharmaceutical composition comprising a compound of the present invention or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient. In some embodiments, the compound is a compound of formula (I) or its pharmaceutically acceptable salt. In some embodiments, the compound is a compound of formula (Ia) or its pharmaceutically acceptable salt. In some embodiments, the compound is a compound of formula (III) or its pharmaceutically acceptable salt. In some embodiments, glucocorticoid is hydrocortisone, dexamethasone, prednisone or prednisolone. In some embodiments, the compound is compound 2, 4 or 5, or its pharmaceutically acceptable salt. In some embodiments, the compound is compound 6, 7 or 8, or its pharmaceutically acceptable salt.

[0392] Thus, in some embodiments, the side effects of glucocorticoid therapy are selected from osteoporosis, ischemic osteonecrosis, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth inhibition, adrenal suppression, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis, hypertension, coronary heart disease, ischemic heart disease, heart failure, rough cutis, cutaneous atrophy, ecchymoses, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, alopecia, mood changes, depression, euphoria, emotional lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic eye infections, central serous chorioretinopathy, cell-mediated immunosuppression, predisposition to infection, reactivation of latent infection, and any combination thereof.

[0393] Provided herein are methods of treating congenital adrenal hyperplasia in an individual comprising

[0394] (i) measuring the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP); (b) testosterone; and (c) androstenedione in a biological sample obtained from an individual;

[0395] (ii) analyzing the level of one or more biomarkers measured in step (i) to determine whether the level of the one or more biomarkers is elevated compared to a healthy individual not suffering from congenital adrenal hyperplasia; and

[0396] (iii) if the individual is determined to have elevated levels of one or more biomarkers, administering to the individual a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0397] In some embodiments, the method further comprises (iv) after administering the compound of the present invention or its pharmaceutically acceptable salt, measuring the level of one or more biomarkers in a biological sample obtained from the individual, and determining whether the individual has a reduced level of one or more biomarkers compared to the measurement of step (i). In some embodiments, the method further comprises (v) if the individual has a reduced level of one or more biomarkers, continuing to administer the compound of the present invention or its pharmaceutically acceptable salt.

[0398] In some embodiments, steps (i) and (iv) are performed on biological samples collected from an individual in a similar manner and within the same time window. In some embodiments, steps (i) and (iv) are performed on biological samples collected from an individual within a time window of 2 a.m. to 10 a.m. In some embodiments, steps (i) and (iv) are performed on biological samples collected from an individual within a time window of 6 a.m. to 10 a.m.

[0399] In some embodiments, steps (i) and (iv) comprise measuring the levels of at least two biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP); (b) testosterone; and (c) androstenedione.

[0400] In some embodiments, steps (i) and (iv) comprise measuring the levels of (a) 17-hydroxyprogesterone (17-OHP); (b) testosterone; and (c) androstenedione.

[0401] In some embodiments, step (i) comprises measuring the level of 17-hydroxyprogesterone (17-OHP), wherein the level of 17-hydroxyprogesterone (17-OHP) is elevated when it is greater than or equal to 1,000 ng / dL.

[0402] In some embodiments, step (i) comprises measuring the level of androstenedione, wherein the level of androstenedione is elevated when it is greater than 200 ng / dL.

[0403] In some embodiments of the methods of the present disclosure, the compound of the present invention or its pharmaceutically acceptable salt is administered in an amount equivalent to about 25 mg to about 150 mg of the free base compound. In some embodiments, the compound of the present invention or its pharmaceutically acceptable salt is administered in an amount equivalent to about 50 mg or about 100 mg of the free base compound.

[0404] In some embodiments of the methods disclosed herein, the compounds of the invention are administered in free base form.

[0405] In some embodiments of the methods disclosed herein, the compound of the invention, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day.

[0406] In some embodiments of the methods disclosed herein, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the methods disclosed herein, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments of the methods disclosed herein, the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0407] In some embodiments of the methods disclosed herein, the compound of the invention is administered as a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0408] In some embodiments of the methods disclosed herein, the compound is a compound of formula (Ia) having the following structure:

[0409]

[0410] or a pharmaceutically acceptable salt thereof.

[0411] Some embodiments provide a method of treating congenital adrenal hyperplasia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of (S)-{4-[1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methanol (Compound 2)

[0412]

[0413] Wherein Compound 2 is produced under physiological conditions or by solvolysis after administration of a prodrug of Compound 2 or a pharmaceutically acceptable salt thereof to a subject, wherein the prodrug of Compound 2 or a pharmaceutically acceptable salt thereof is not 4-(2-chloro-4-methoxy-5-methylphenyl)-N-((1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-2-propyn-1-yl-2-thiazolamine or a pharmaceutically acceptable salt thereof.

[0414] Some embodiments provide a method of treating congenital adrenal hyperplasia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of (S)-{4-[1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methanol (Compound 2)

[0415]

[0416] Wherein Compound 2 is produced by a metabolic chemical reaction following administration of a prodrug of Compound 2 or a pharmaceutically acceptable salt thereof to an individual, wherein the prodrug of Compound 2 or a pharmaceutically acceptable salt thereof is not 4-(2-chloro-4-methoxy-5-methylphenyl)-N-((1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-2-propyn-1-yl-2-thiazolamine or a pharmaceutically acceptable salt thereof.

[0417] Some embodiments provide a method of treating congenital adrenal hyperplasia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a prodrug of (S)-{4-[1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methanol (Compound 2)

[0418]

[0419] or a pharmaceutically acceptable salt thereof, wherein the prodrug of Compound 2 or a pharmaceutically acceptable salt thereof is not 4-(2-chloro-4-methoxy-5-methylphenyl)-N-((1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-2-propyn-1-yl-2-thiazolamine or a pharmaceutically acceptable salt thereof.

[0420] In some embodiments of the methods disclosed herein, the CAH is typical CAH. In some embodiments of the methods disclosed herein, the CAH is atypical CAH.

[0421] As used herein, the term "individual" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, and most preferably people. In the case of clinical trials or screening or activity experiments, individuals can be healthy volunteers or healthy participants without potential CRF1-mediated disorders or conditions, or volunteers or participants who have received a diagnosis of a disorder or condition that requires medical treatment as determined by a health care professional. In the case of clinical trials outside, individuals who have received a diagnosis of a disorder or condition under the care of a health care professional are generally described as patients. In some embodiments, individuals have experienced and / or shown at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, individuals have been identified or diagnosed as suffering from congenital adrenal hyperplasia (CAH). In some embodiments, individuals are suspected of suffering from CAH. In some embodiments, individuals have clinical records indicating that individuals suffer from CAH (and optionally, clinical records indicate that individuals apply any composition provided herein for treatment). In some embodiments, individuals are children.

[0422] As used herein, the term "pediatric subject" refers to an individual who is less than 21 years old at the time of diagnosis or treatment. The term "child" can be further divided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years); children (2 years to 12 years); and adolescents (12 years to 21 years (up to, but not including, the 22nd birthday)). Berhman et al., Textbook of Pediatrics, 15th ed., Philadelphia: WB Saunders Company, 1996; Rudolph et al., Rudolph's Pediatrics, 21st ed., New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd ed., Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric subject is from birth to the first 28 days of life, from 29 days to less than 2 years of age, from 2 years to less than 12 years of age, or from 12 years to 21 years of age (up to, but not including, the 22nd birthday). In some embodiments, a pediatric subject is from birth to the first 28 days of life, from 29 days to less than 1 year of age, from one month to less than four months, from three months to less than seven months, from six months to less than 1 year of age, from 1 year to less than 2 years of age, from 2 years to less than 3 years of age, from 2 years to less than 7 years of age, from 3 years to less than 5 years of age, from 5 years to less than 10 years of age, from 6 years to less than 13 years of age, from 10 years to less than 15 years of age, or from 15 years to less than 22 years of age.

[0423] As used herein, the terms "treat" and "treatment" refer to the medical management of a disease, disorder or condition of an individual (i.e., a patient) (see, e.g., Stedman's Medical Dictionary). Generally, appropriate dosages and treatment regimens provide an amount of CRF1 antagonist sufficient to provide therapeutic and / or preventive benefit. Therapeutic benefits for individuals to whom a CRF1 antagonist compound of a compound described herein is administered include, for example, improved clinical outcomes, where the goal is to prevent or slow or delay (mitigate) undesirable physiological changes associated with a disease, or to prevent or slow or delay (mitigate) the extension or severity of such a disease. As discussed herein, the effects of one or more CRF1 antagonists can include beneficial or desired clinical results, including, but not limited to, reduction, alleviation or relief of symptoms produced by or associated with the disease to be treated; reduction in the incidence of symptoms; improvement in quality of life; prolonged disease-free state (i.e., reduction in the likelihood or propensity that an individual will exhibit symptoms on the basis of which a disease diagnosis is made); reduction in the extent of the disease; stabilization (i.e., non-worsening) of the disease state; delay or slowing of disease progression; improvement or alleviation of the disease state; and remission (whether partial or complete), whether detectable or undetectable; and / or overall survival.

[0424] "Treatment" can also mean prolonging survival when compared to the expected survival if the individual does not receive treatment. Individuals in need of treatment include those already suffering from the disease or disorder as well as those susceptible to or at risk of developing the disease or disorder, and those in which the disease, condition or disorder is to be prevented (i.e., the likelihood of occurrence or recurrence of the disease or disorder is reduced).

[0425] As used herein, the term "preventing" or "preventing" means preventing, in whole or in part, the onset, recurrence, or spread of a disease or condition as described herein, or symptoms thereof.

[0426] The term "administration" or "administering" refers to a method of giving a dose of a compound or pharmaceutical preparation to a vertebrate or invertebrate (including mammals, birds, fish or amphibians). The preferred method of administration may vary depending on various factors, such as the components of the pharmaceutical preparation, the site of the disease, and the severity of the disease.

[0427] As used herein, a "therapeutically effective amount" is an amount of a compound of the present invention or its pharmaceutically acceptable salt that is sufficient to achieve the desired effect and that can vary depending on the nature and severity of the disease condition and the efficacy of the compound, or the amount of a pharmaceutical composition comprising a compound of the present invention or its pharmaceutically acceptable salt. The therapeutic effect is to alleviate one or more symptoms of the disease to some extent, and may include curing the disease. "Cure" means eliminating the symptoms of active disease. However, some long-term or permanent effects of the disease may still exist even after a cure is achieved (e.g., extensive tissue damage).

[0428] As used herein, "time window" refers to a time period defined by a window start time and a window stop time. These times all refer to the local time when the sample is collected. The phrase "same time window" when referring to samples collected from an individual means, for example, that a sample collected at 8:15 a.m. and a sample collected at 9:15 a.m. are considered to be collected within the same time window of, for example, 2 a.m. to 10 a.m. or 6 a.m. to 10 a.m.

[0429] Various indicators for determining the effectiveness of the method for treating CAH are known to those skilled in the art. Examples of suitable indicators include, but are not limited to, a reduction in the amount of 17-OHP and androstenedione compared to non-treatment or a glucocorticoid (e.g., hydrocortisone, dexamethasone, prednisone or prednisolone) administered daily.

[0430] In some embodiments, the compounds of the present invention or its pharmaceutically acceptable salts can cause the 17-OHP plasma level during 6 am to 10 am in the individual to be reduced by at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100 times or more relative to the pre-treatment level, as measured after the completion of the treatment regimen (e.g., 1 week after completion). In some embodiments, the compounds of the present invention or its pharmaceutically acceptable salts can cause the androstenedione plasma level during 6 am to 10 am to be reduced by about 2 times to about 5 times, about 10 times to about 20 times, about 15 times to about 40 times or about 50 times to about 100 times relative to the pre-treatment level. In some embodiments, the compounds of the present invention or its pharmaceutically acceptable salts can cause the testosterone plasma level during 6 am to 10 am to be reduced by 2 times to 5 times, 10 times to 20 times, 15 times to 40 times or 50 times to 100 times relative to the pre-treatment level. In some embodiments, administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, can result in a reduction in the daily glucocorticoid (e.g., hydrocortisone, dexamethasone, prednisone, or prednisolone) administered compared to the current standard of care for CAH, or can achieve the same plasma level of at least one of 17-OHP, androstenedione, and testosterone plasma levels between 6 a.m. and 10 a.m. compared to glucocorticoid (e.g., hydrocortisone, dexamethasone, prednisone, or prednisolone) monotherapy as measured after completion of the treatment regimen (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks after completion).

[0431] In some embodiments, the compounds of the present invention or a pharmaceutically acceptable salt thereof can reduce the percentage of individuals experiencing complications of CAH compared to the percentage of individuals experiencing complications in the case of treatment with a glucocorticoid (e.g., hydrocortisone, dexamethasone, prednisone or prednisolone) monotherapy. For example, the percentage of individuals experiencing complications in the case of treatment with a compound of the present invention or a pharmaceutically acceptable salt thereof can be 10%, 25%, 40%, 50%, 60%, 70%, 80% and 90% less than individuals treated with a glucocorticoid (e.g., hydrocortisone, dexamethasone, prednisone or prednisolone).

[0432] In another embodiment, a method for antagonizing CRF1 in a cell is provided, comprising contacting the cell with a compound of the invention or a pharmaceutically acceptable salt thereof (including specific compounds described herein) for a sufficient time and under appropriate conditions sufficient to allow interaction between the cell and the compound. In certain embodiments, the cell is in an individual in need of treatment with a compound disclosed herein.

[0433] Combination therapy

[0434] The compound of the present invention or its pharmaceutically acceptable salt can be used for joint therapy, wherein the compound of the present invention or its pharmaceutically acceptable salt is co-administered with other treatments (such as the administration of one or more other therapeutic agents). Other therapeutic agents are generally those therapeutic agents commonly used to treat a specific condition to be treated. Other therapeutic agents may include glucocorticoids (for example, hydrocortisone, dexamethasone, prednisone or prednisolone) or mineralocorticoids (for example, fludrocortisone). The example of other therapeutic agents includes but is not limited to glucocorticoids (for example, hydrocortisone, dexamethasone, prednisone or prednisolone) and mineralocorticoids (for example, fludrocortisone). Other treatments that can be co-administered with the compound of the present invention or its pharmaceutically acceptable salt include but are not limited to surgical intervention.

[0435] A compound of the invention, or a pharmaceutically acceptable salt thereof, may be administered with one or more additional agents in a single pharmaceutical composition, or as two or more separate pharmaceutical compositions.

[0436] The order of administration of the compound of the invention, or a pharmaceutically acceptable salt thereof, can be simultaneous with any / all additional agents, or sequentially with any / all additional agents in any order (e.g., the compound of the invention, or a pharmaceutically acceptable salt thereof, can be administered before or after any / all additional agents).

[0437] Pharmaceutical compositions, preparations and dosage forms

[0438] The present disclosure also provides a composition for use in a method of treating CAH, the composition comprising any compound disclosed and described herein (e.g., a compound of Formula (I), Formula (Ia), or Formula (III), including specific compounds described herein) or a pharmaceutically acceptable salt thereof and an excipient (e.g., a pharmaceutically acceptable excipient). A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non-toxic and inactive material or ingredient that does not interfere with the activity of the drug substance; an excipient may also be referred to as a carrier. The formulation methods and excipients described herein are exemplary and in no way limiting. Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Edition, 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition, Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used.

[0439] In some embodiments, the pharmaceutical composition comprises a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a preparation of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a preparation of a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having the following structure:

[0440]

[0441] or a pharmaceutically acceptable salt thereof.

[0442] For compositions formulated as liquid solutions, acceptable carriers and / or diluents include saline and sterile water, and may optionally include antioxidants, buffers, antibacterial agents and other common additives. The compositions may also be formulated as pills, capsules, granules or tablets, containing diluents, dispersants and surfactants, adhesives and lubricants in addition to the CRF1 antagonist. Those skilled in the art may also formulate the CRF1 antagonist in an appropriate manner and in accordance with generally accepted practices such as those disclosed in Remington above.

[0443] The administration method includes systemic administration of the CRF1 antagonists described herein (preferably in the form of the pharmaceutical compositions discussed above). As used herein, systemic administration includes oral and parenteral administration methods. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets and capsules, as well as liquids, syrups, suspensions and emulsions. These compositions may also include flavoring agents, preservatives, suspending agents, thickeners and emulsifiers, as well as other pharmaceutically acceptable additives. For parenteral administration, the compounds of the present invention may be prepared in the form of aqueous injections, which may contain buffers, antioxidants, antibacterial agents and other additives commonly used in such solutions in addition to the CRF1 antagonists.

[0444] As described herein, experimental models and / or clinical trials are generally used to determine the optimal dose. The optimal dose of a CRF1 antagonist may depend on the individual's body weight, weight, blood volume or other personal characteristics. For example, a person skilled in the art of medicine may consider the individual's condition, i.e., the stage of the disease, the severity of the symptoms caused by the disease, the general state of health, and age, sex and weight, as well as other factors that are apparent to a person skilled in the art of medicine. Generally, the amount of the compound described herein present in one dose is about 0.1 mg to about 2 mg / kg of the individual's body weight. In certain embodiments, the daily dose is about 10-150 mg. It is generally preferred to use the minimum dose sufficient to provide effective treatment. The effectiveness of the treatment of an individual may generally be monitored by clinical assessment and using a test suitable for the condition to be treated or prevented, which is familiar to a person skilled in the art and is described herein. The level of the compound applied to an individual is monitored by determining the level of the compound in a biological fluid (e.g., blood, blood fraction (e.g., plasma, serum) and / or urine) and / or other biological sample from the individual. Any method of detecting a compound implemented in the art can be used to measure the level of the compound during the treatment regimen.

[0445] Pharmaceutical compositions comprising CRF1 antagonists can be formulated for timed release (also referred to as extended release, sustained release, controlled release or slow release). Such compositions can generally be prepared using well-known techniques and administered, for example, by oral, rectal or subcutaneous implantation or by implantation at a desired target site. Sustained release formulations can contain compounds dispersed in a carrier matrix and / or compounds contained in a container surrounded by a rate-controlling membrane. The excipients used in such formulations are biocompatible and can also be biodegradable; preferably, the formulation provides a relatively constant level of release of the active ingredient. The amount of active compound contained in the sustained release formulation depends on the implantation site, the release rate and the expected duration of release and the nature of the condition to be treated or prevented.

[0446] The pharmaceutical compositions described herein, comprising at least one CRF1 antagonist compound described herein, can be administered to an individual in need thereof by any of several routes that are effective for delivering an effective amount of the compound. Such routes of administration include, for example, oral, parenteral (e.g., subcutaneous, intravenous, intramuscular, intrasternal, intracavernous), enteral, rectal, intranasal, buccal, sublingual, intramuscular, and transdermal.

[0447] Pharmaceutical compositions for oral administration can be obtained by any suitable method, generally by uniformly mixing the compound with a liquid or finely divided solid carrier or both in the desired proportion and then, after adding suitable auxiliaries, if desired, processing the mixture into the desired shape to obtain tablets or dragee cores.

[0448] Conventional excipients, such as adhesives, fillers, adjuvants, carriers, acceptable wetting agents, tablet lubricants and disintegrants can be used for tablets and capsules for oral administration. Liquid compositions for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, oral compositions can be in the form of dry powders, which can be reconstituted with water or other suitable liquid vehicles before use. Additional additives, such as suspending agents or emulsifiers, non-aqueous vehicles (including edible oils), preservatives and flavoring agents and coloring agents can be added to liquid preparations. Parenteral dosage forms can be prepared by dissolving the compound of the present invention in a suitable liquid vehicle and filtering and sterilizing the solution before lyophilization, or simply filling and sealing a suitable vial or ampoule.

[0449] As used herein, "drug substance" defined in the context of a "pharmaceutical composition" refers to the component of the pharmaceutical composition that provides the primary pharmacological effect, such as a compound of the present invention (e.g., a compound of Formula (I), Formula (Ia) or Formula (III), including specific compounds described herein) and pharmaceutically acceptable salts thereof, as opposed to "inactive ingredients" that are generally considered to provide no therapeutic benefit.

[0450] As used herein, "excipient" refers to a substance added to a composition to provide (but not limited to) volume, consistency, stability, binding ability, lubricity, disintegration ability, etc. to the composition. "Diluent" is a type of excipient, and refers to a pharmaceutical composition that lacks pharmacological activity but may be a necessary or desired component of the drug. For example, a diluent may be used to increase the volume of an effective drug, the mass of which is too small for manufacture and / or administration. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically stable, nontoxic, and inactive material or component that does not interfere with the activity of a drug substance. Pharmaceutically acceptable excipients are well known in the pharmaceutical field and are described in the following literature, for example, Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th edition, 2006, and Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers, etc. can be provided in pharmaceutical compositions. In addition, antioxidants and suspending agents can also be used. For compositions formulated as liquid solutions, acceptable carriers and / or diluents, saline and sterile water are included, and antioxidants, buffers, antibacterial agents and other common additives can be optionally included. In some embodiments, the diluent can be a buffered aqueous solution, such as but not limited to phosphate buffered saline. Compositions can also be formulated as capsules, granules or tablets, except for compounds disclosed and described herein, which contain diluents, dispersants and surfactants, adhesives and lubricants. Those skilled in the art can further prepare compounds disclosed and described herein in an appropriate manner and according to generally accepted practices (such as those disclosed in Remington above).

[0451] In preparing pharmaceutical compositions containing the compounds of the invention and their pharmaceutically acceptable salts, the drug substance is usually mixed with an excipient, diluted by an excipient or enclosed in such a carrier in the form of, for example, a capsule, paper or other container. When the excipient serves as a diluent, it can be a solid, semisolid or liquid material that serves as a vehicle, carrier or medium for the active ingredient. Thus, the composition can be in the form of tablets, powders, lozenges, capsules, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0452] For preparing solid form pharmaceutical compositions, such as powders, tablets, capsules, cachets, suppositories and dispersible granules, the excipient may be one or more substances which may also be used as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials. Also included are solid form compositions intended to be converted into liquid form preparations for oral administration shortly before use. Such liquid forms include solutions, suspensions and emulsions. In addition to the drug substance, these compositions may contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0453] To prepare suppositories, a low melting point wax (such as a mixture of fatty acid glycerides or cocoa butter) is first melted and the drug substance is dispersed uniformly therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0454] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the drug substance such carriers as are known in the art to be appropriate.

[0455] Liquid form compositions include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, parenteral injection liquid compositions can be formulated into solutions in aqueous polyethylene glycol solutions. Suitable dispersants or wetting agents and suspending agents can be used to prepare injectable compositions, such as sterile injectable aqueous or oily suspensions, according to known techniques. Sterile injectable compositions can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils are generally used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. In addition, it is found that fatty acids such as oleic acid can be used for the preparation of injections.

[0456] The pharmaceutical composition may be in the form of a suspension, solution or emulsion, for example, in an oily or aqueous vehicle, and may contain a formulation agent, such as a suspending agent, a stabilizer and / or a dispersant. Alternatively, the pharmaceutical composition may be in the form of a powder obtained by aseptic isolation of a sterile solid or by lyophilization from a solution for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0457] The pharmaceutical composition can be formulated into an aqueous solution, a water-alcohol solution, a solid suspension, an emulsion, a liposomal suspension, or a lyophilized powder for reconstruction. Such pharmaceutical compositions can be administered directly or as a mixture for further dilution / reconstruction. The route of administration includes intravenous push, intravenous infusion, lavage, and infusion. Suitable solvents include water, alcohol, PEG, propylene glycol, and lipids; pH adjustment using an acid (e.g., HCl or citric acid) can be used to increase solubility and subject the resulting composition to suitable sterilization procedures known in the art, such as sterile filtration. In some embodiments, the pH of the aqueous solution is about 2.0 to about 4.0. In some embodiments, the pH of the aqueous solution is about 2.5 to about 3.5.

[0458] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the drug substance in water and adding suitable colorants, flavoring agents, stabilizers and thickening agents as needed.

[0459] Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided drug substance in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0460] For topical application to the epidermis, the compounds of the present invention and their pharmaceutically acceptable salts can be formulated into gels, ointments, creams or lotions, or into transdermal patches. In addition, preparations suitable for topical application in the mouth include lozenges (lozenge) containing drug substances in flavoring bases (usually sucrose and gum arabic or gum tragacanth); lozenges (pastille) containing drug substances in inert bases (e.g., gelatin and glycerol or sucrose and gum arabic); and mouthwashes containing drug substances in suitable liquid carriers. Ointments and creams can be formulated, for example, with aqueous or oily bases, adding suitable thickeners and / or gelling agents. Lotions can be formulated with aqueous or oily bases, and usually also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or colorants. In some embodiments, topical preparations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ethers, propylene glycol, white vaseline, etc. The carrier composition of the cream can be based on a combination of water with glycerol and one or more other components, such as glyceryl monostearate, PEG-glyceryl monostearate and cetyl stearyl alcohol. Gels can be formulated using isopropyl alcohol and water, appropriately combined with other components such as glycerol, hydroxyethylcellulose, etc. In some embodiments, the topical formulation contains at least 0.1% by weight, at least 0.25% by weight, at least 0.5% by weight, at least 1% by weight, at least 2% by weight or at least 5% by weight of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0461] The solution or suspension can be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or sprayer. The preparation can be provided in a single dose or multiple dose form. In the latter case of a dropper or pipette, this can be achieved by the patient administering a solution or suspension of an appropriate predetermined volume. In the case of a sprayer, this can be achieved, for example, by a metered atomizing spray pump.

[0462] Administration to the respiratory tract can also be achieved by aerosol formulations, in which the drug substance is provided in a pressurized package together with a suitable propellant. If the compound of the present invention and its pharmaceutically acceptable salt or a pharmaceutical composition comprising them is administered as an aerosol (e.g., as a nasal aerosol) or by inhalation, this can be performed, for example, using a sprayer, atomizer, a pump atomizer, an inhalation device, a metered-dose inhaler or a dry powder inhaler. The pharmaceutical form of the compound of the present invention administered as an aerosol can be prepared by methods well known to those skilled in the art. For their preparation, for example, a solution or dispersion of the compound of the present invention in water, a water / alcohol mixture or a suitable saline solution can be used, using conventional additives, such as benzyl alcohol or other suitable preservatives, absorption enhancers for increasing bioavailability, solubilizers, dispersants, etc., and if appropriate, conventional propellants include, for example, carbon dioxide, CFC, such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane; Etc. Aerosols can also conveniently contain surfactants, such as lecithin. The dosage of the drug can be controlled by providing a metering valve.

[0463] Alternatively, the pharmaceutical composition may be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dosage form, for example in capsules or cartridges of, for example, gelatin, or in blister packs from which the powder can be administered by an inhaler.

[0464] The compounds of the present invention and their pharmaceutically acceptable salts can also be administered via a fast dissolving or sustained release composition, wherein the composition comprises a biodegradable fast dissolving or sustained release carrier (e.g., a polymer carrier, etc.) and a compound of the present invention. Fast dissolving or sustained release carriers are well known in the art and are used to form complexes in which the drug substance is captured and rapidly or slowly degraded / dissolved in a suitable environment (e.g., aqueous, acidic, alkaline, etc.).

[0465] The pharmaceutical composition is preferably in unit dosage form. In this form, the composition is subdivided into unit doses containing appropriate quantities of the drug substance. The unit dosage form can be a packaged composition containing discrete quantities of the composition, such as packaged tablets, capsules, and powders in vials or ampoules. Additionally, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these unit dosage forms in packaged form.

[0466] Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.

[0467] The composition can be formulated in unit dosage form, each dose containing 1 to 1,000 mg (1 g), more usually 5 mg to 200 mg of the drug substance, or an equivalent mass of the drug substance. The term "unit dosage form" refers to physically discrete unit preparations suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable excipient, as described herein.

[0468] The compositions described herein can be formulated to provide immediate and / or timed release (also referred to as extended release, sustained release, controlled release or slow release) of the drug substance after being applied to an individual by using procedures known in the art. For example, tablets containing the compounds of the present invention or their pharmaceutically acceptable salts can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action. For example, a tablet can include an inner dosage component and an outer dosage component, the latter being in the form of a coating on the former. The two components can be separated by an enteric layer, which is used to resist disintegration in the stomach and allow the inner component to enter the duodenum intact or delay release. Various materials can be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids and such materials (e.g., shellac, cetyl alcohol and cellulose acetate).

[0469] Pharmaceutical compositions comprising drug substances can be formulated for timed release. Such compositions can be prepared using well-known techniques and administered by, for example, oral, rectal or subcutaneous implantation or implantation at a desired target site. Sustained release formulations can include compounds dispersed in a carrier matrix and / or contained in a reservoir surrounded by a rate-controlling membrane. The excipients used in such formulations are biocompatible and can also be biodegradable; preferably, the formulation provides a relatively constant level of active ingredient release. The amount of drug substance contained in a sustained release formulation depends on the nature of the implantation site, release rate and expected duration and the condition to be treated or prevented.

[0470] Liquid forms containing the drug substance which may be incorporated for oral or injectable administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions and emulsions flavored with edible oils (eg, cottonseed oil, sesame oil, coconut oil or peanut oil), and similar excipients.

[0471] The pharmaceutical compositions described herein can be sterilized by conventional sterilization techniques, or can be aseptically filtered. The aqueous solution can be packaged for use as is, or lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier before administration. The pH of the composition is generally 3 to 11, more preferably 5 to 9 and most preferably 7 to 8. It should be understood that the use of some of the aforementioned excipients can result in the formation of pharmaceutically acceptable salts.

[0472] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable excipients as described herein. In some embodiments, the composition is administered by oral or nasal respiratory route for local or systemic effect. The composition may be atomized using an inert gas. The atomized solution may be inhaled directly from an atomizing device, or the atomizing device may be attached to a mask or intermittent positive pressure breathing machine. The solution, suspension or powder composition may be administered orally or nasally from a device that delivers the preparation in an appropriate manner.

[0473] If desired, the composition may be present in a package or dispenser device, which may contain one or more unit dosage forms containing a drug substance. The package may, for example, include a metal or plastic foil, such as a blister package. The package or dispenser device may be accompanied by instructions for use. The package or dispenser may also be accompanied by a notice related to the container that is specified by a government agency that manages the manufacture, use or sale of the drug, which reflects the drug form approved by the agency for human or veterinary administration. Such a notice, for example, may be a label for a prescription drug approved by the U.S. Food and Drug Administration, or an approved product instruction sheet. A composition comprising a compound as described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of a specified condition.

[0474] As used herein, "dose" or "dosage" means the measured amount of a drug substance taken by a patient at one time. In certain embodiments, where the drug substance is not a free base or free acid, the amount is a molar equivalent to the corresponding amount of the free base or free acid.

[0475] In order to prepare solid compositions, such as tablets, the drug substance can be mixed with an excipient to form a solid preformulated composition containing a uniform mixture of components. When these preformulated compositions are mentioned as uniform, the drug substance is usually evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets and capsules. The solid preformulation is then subdivided into unit dosage forms of the above type containing, for example, 0.001 mg to 5000 mg of the drug substance. In certain embodiments, where the drug substance is not a free alkali or free acid of a compound of the present invention, such as a salt or a hydrate, the amount of the unit dosage form is 0.001 mg to 5000 mg, which is a molar equivalent to the corresponding amount of the free alkali or free acid of the compound of the present invention. Representative amounts of the drug substance in a unit dosage form include, but are not limited to, 0.01 mg, 0.1 mg, 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg, 5000 mg, or an amount within the range defined by any of the foregoing amounts. In certain embodiments, where the drug substance is not a free base or free acid, the molar equivalent of the drug substance corresponding to the free base or free acid in the unit dosage form includes, but is not limited to, 0.01 mg, 0.1 mg, 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 , 500 mg, 2000 mg, 2500 mg, 3000 mg, 4000 mg, 4500 mg, 5000 mg, or an amount within the range defined by any of the foregoing amounts.

[0476] Multiple doses may be administered during the day, particularly when relatively large amounts are deemed necessary, such as 2, 3 or 4 doses. It may be necessary to deviate upward or downward from the doses described herein, as deemed appropriate by the individual and the patient's physician or caregiver.

[0477] The amount of the drug substance required for treatment will vary not only with the specific salt selected, but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be determined by the attending physician or clinician. Generally, those skilled in the art understand how to extrapolate the in vivo data obtained in a model system (usually an animal model) to other model systems, such as people. In some cases, these extrapolations can be based only on the weight of the animal model compared to other models (e.g., mammals, preferably people), however, more often, these extrapolations are not simply based on weight, but combine a variety of factors. Representative factors include the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations (e.g., the activity, efficacy, pharmacokinetic and toxicological characteristics of the specific compound used), whether a drug delivery system is used, whether an acute or chronic disease state is being treated or prevented, or whether other active compounds are administered in addition to the compounds described herein and whether other active compounds are used as part of a drug combination. The dosage regimen for treating a disease state with a compound and / or composition described herein is selected according to the various factors mentioned above. Thus, the actual dosage regimen used may vary widely and therefore may deviate from the preferred dosage regimen, and one skilled in the art will recognize that doses and dosage regimens outside of these typical ranges can be tested and, where appropriate, used in the methods described herein.

[0478] As described herein, experimental models and / or clinical trials are generally used to determine the optimal dose. The optimal dose of a compound as disclosed and described herein may depend on the body mass, body weight, blood volume or other individual characteristics of the individual. For example, a person skilled in the art of medicine may consider the individual's condition, i.e., the stage of the disease, the severity of the symptoms caused by the disease, general health, and age, sex and body weight, as well as other factors apparent to a person skilled in the art of medicine. Typically, the amount of the compound described herein is present in a dose of about 0.1 mg to about 2 mg / kg of individual body weight. In certain embodiments, the daily dose is about 10 mg to 150 mg. It is generally preferred to use a minimum dose sufficient to provide effective treatment. The effectiveness of individual treatment can generally be monitored by clinical evaluation and using a test suitable for the condition to be treated or prevented, and the method will be familiar to a person of ordinary skill in the art and is described herein. The compound level applied to an individual can be monitored by measuring the compound level in a biological fluid (e.g., blood, blood fraction (e.g., plasma, serum) and / or urine) and / or other biological sample from the individual. The compound level during the treatment regimen can be measured using any method of measuring the compound practiced in the art.

[0479] Kits with unit doses of one or more compounds described herein, typically oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use of the drug in treating the target pathological condition and the attendant benefits, and optionally an implement or device for delivering the composition.

[0480] Dosage regimen / dose

[0481] The compounds of the present invention or their pharmaceutically acceptable salts can be effective in a wide dosage range and are generally administered in a therapeutically effective amount. However, it should be understood that the amount of the compound actually administered will generally be determined by the physician based on relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight and response of a single individual, the severity of individual symptoms, etc.

[0482] The amount of the compound or composition administered to an individual will also vary depending on the substance being administered, the purpose of the administration (e.g., prevention or treatment), the state of the individual, the mode of administration, etc. In therapeutic applications, the composition can be administered to an individual already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms and / or pathology of the disease and its complications. The therapeutically effective dose will depend on the disease condition being treated and the judgment of the attending clinician based on factors such as the severity of the disease, the age, weight, and general condition of the individual.

[0483] Some typical dosage ranges are 1 μg / kg to 1 g / kg body weight of the drug substance per day, or an equivalent mass of the drug substance when administered in a form such as a salt or hydrate. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight of the drug substance per day, or an equivalent mass of the drug substance. Representative amounts in a dose of a drug substance include, but are not limited to, 0.01 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.4 mg / kg, 0.6 mg / kg, 0.8 mg / kg, 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, or any amount within the range defined per day of body weight of the foregoing. In certain embodiments, wherein the drug substance is not a free base or free acid of a compound of the invention, such as a salt or hydrate, the molar equivalent of the drug substance corresponding to the free base or free acid of the compound of the invention in a unit dosage form includes but is not limited to 0.01 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.4 mg / kg, 0.6 mg / kg, 0.8 mg / kg, 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg. g / kg, 14mg / kg, 16mg / kg, 18mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, 100mg / kg, or any amount within the range defined by each body weight.

[0484] Depending on individual needs, dosage can be a single dose or a series of two or more doses given over a one-day or multi-day time course. In some embodiments, the compound will be administered for a period of time, such as a week or longer, or for months or years. The effective dose can be extrapolated from dose-response curves from in vitro or animal model test systems and human clinical trials.

[0485] In cases where human dosages for compounds have been determined for at least some conditions, those same dosages may be used, or dosages ranging from 0.1% to 500%, more preferably from about 25% to 250%, of the determined human dosages. In cases where human dosages have not been determined, such as in the case of newly discovered pharmaceutical compositions, the ED may be derived. 50 Suitable human doses can be extrapolated from values ​​obtained by in vitro or in vivo studies, such as those obtained by toxicity studies and efficacy studies in animals.

[0486] In the case of administering a pharmaceutically acceptable salt, the dosage can be calculated as a free form (e.g., free base or free acid). Typically, the drug is packaged in salt form, and the dosage strength refers to the mass of the salt form or the equivalent mass of the corresponding free base or free acid. As will be appreciated by those skilled in the art, in some cases, it may be necessary to administer the compounds disclosed herein in an amount exceeding or even far exceeding the above-mentioned preferred dosage range in order to effectively and actively treat particularly aggressive diseases or infections.

[0487] Dosage and interval can be adjusted individually to provide a plasma level of the active part sufficient to maintain the modulatory effect or minimum effective concentration (MEC). For each compound, MEC will vary, but can be estimated from in vitro data. The dosage necessary to achieve MEC will depend on individual characteristics and route of administration. However, HPLC determination or bioassay can be used to determine plasma concentration. MEC values ​​can also be used to determine dosage intervals. The composition should be administered using a regimen that maintains plasma levels above MEC for 10% to 90%, preferably 30% to 90% and most preferably 50% to 90% of the time. In the case of local administration or selective uptake, the effective local concentration of the drug may be independent of plasma concentration.

[0488] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a specific compound or a subset of compounds sharing certain chemical moieties can be established by determining the in vitro toxicity to a cell line (e.g., a mammalian cell line, preferably a human cell line). The results of such studies often predict the toxicity to animals (e.g., mammals, or more specifically, humans). Alternatively, the toxicity of a specific compound in an animal model (e.g., mouse, rat, rabbit, or monkey) can be determined using known methods. Several recognized methods, such as in vitro methods, animal models, or human clinical trials can be used to determine the efficacy of a specific compound. When a model is selected to determine efficacy, those skilled in the art can select a suitable model, dosage, route of administration, and / or regimen by prior art guidance.

[0489] It is obvious to those skilled in the art that the dosage forms described herein may include a compound described herein or a pharmaceutically acceptable salt thereof as a drug substance. In addition, various hydrates and solvates of the compounds described herein and their salts may be used as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for preparing and identifying suitable hydrates and solvates other than those mentioned herein are well known to those skilled in the art; see, for example, KJ Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," in: Polymorphism in Pharmaceutical Solids, Harry G. Britain, ed., Vol. 95, Marcel Dekker, Inc., New York, 1999, pp. 202-209, which is incorporated herein by reference in its entirety. Therefore, one aspect of the present invention relates to a method of administering hydrates and solvates of the compounds described herein and / or pharmaceutically acceptable salts thereof, which can be separated and characterized by methods known in the art, such as thermogravimetric analysis (TGA), TGA-mass spectrometry, TGA-infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high resolution X-ray diffraction, and the like.

[0490] Compound synthesis

[0491] Detailed methods for synthesizing the compounds are described herein in the Examples. One of ordinary skill in the chemical arts will be able to prepare compounds of the disclosure, including the specific compounds described herein, by these or similar methods or other methods practiced by those skilled in the art.

[0492] Generally, the compounds used in the reactions described herein can be prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" can be obtained from standard commercial sources, including Acros Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester PA), Crescent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher Scientific Co. (Pittsburgh PA), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), ICN Biomedicals, Inc. (Costa Mesa CA), Key Organics (Cornwall UK), Lancaster Synthesis (Windham NH), Maybridge Chemical Co. Ltd. (Cornwall UK), Parish Chemical Co. (Orem UT), Pfaltz & Bauer, Inc. (Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co. (Rockford IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland OR), Trans World Chemicals, Inc. (Rockville MD) and Wako Chemicals USA, Inc. (Richmond VA).

[0493] Methods known to those of ordinary skill in the art can be determined by various reference books and databases. Suitable reference books and monographs that explain in detail the synthesis of the reactants used in the preparation of the compounds of the present disclosure or provide references to articles describing the preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," Second Edition, Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions," Second Edition, WA Benjamin, Inc. Menlo Park, Calif. 1972; TL Gilchrist, "Heterocyclic Chemistry," Second Edition, John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," Fourth Edition, Wiley-Interscience, New York, 1992. Additional suitable reference books and monographs that detail the synthesis of reactants used in preparing the compounds of the present disclosure or provide references to articles describing the preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" Second Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4th Edition (1992), John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (Editor), "Modern Carbonyl Chemistry" (2000), Wiley-VCH, ISBN: 3-527-29871-1; Patai, S., "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992), Interscience, ISBN: 0-471-93022-9; Quin, L.D. et al., "A Guide to Organophosphorus Chemistry" (2000), Wiley-Interscience, ISBN: 0-471-31824-8; Solomons, T.W.G., "Organic Chemistry", 7th Edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry", 2nd Edition (1993), Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999), John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942 - 2019), John Wiley & Sons, in over 95 volumes; and "Chemistry of Functional Groups", John Wiley & Sons, in hardcover volumes (86) and electronic volumes (26).

[0494] Specific and similar reactants may also be identified by indexing known chemicals prepared by the Chemical Abstracts service of the American Chemical Society, which is available in most public and university libraries, or through online databases (the American Chemical Society, Washington, DC may be contacted for further details). Chemicals known in the catalog but not commercially available may be prepared by custom chemical synthesis facilities according to known methods, many of which provide custom synthesis services, such as those listed above.

[0495] Abbreviations

[0496] This specification contains a number of abbreviations, the definitions of which are listed in the following table:

[0497]

[0498]

[0499] Example

[0500] The following examples are included to illustrate embodiments of the present disclosure. However, those skilled in the art will appreciate, in light of the present disclosure, that many changes can be made to the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present disclosure.

[0501] Example 1: Preparation of racemic {4-[1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methanol (Compound 1)

[0502] The preparation of racemic {4-[1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methanol (Compound 1) is shown in Scheme 1:

[0503] Solution 1

[0504]

[0505] Step 1: Preparation of ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (Compound 1-B)

[0506]

[0507] A mixture of (4-bromo-2-fluorophenyl)methanol (20g, 98mmol) and imidazole (7.31g, 107mmol) in dichloromethane (100mL) was treated with a solution of tert-butyldimethylsilyl chloride (16.17g, 107mmol) in dichloromethane (100mL) at room temperature for 10 minutes. A white precipitate was formed immediately, which was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in heptane (100mL). The organic phase was washed with water (2×40mL), brine (2×40mL), dried over NaSO4 and concentrated under reduced pressure. The residue was dissolved in cyclohexane and passed through a silica pad (100g), then the solvent was removed under reduced pressure to obtain compound 1-B (30.51g, 98% yield) in a light yellow oil. 1 H NMR (400MHz, CDCl3) δppm 0.12(s,6H),0.95(s,9H),4.74(s,2H),7.14-7.22(m,1H),7.28–7.32(m,1H),7.34-7.42(m,1H).

[0508] Step 2: Preparation of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)-2-cyclopropylethan-1-one (Compound 3-B)

[0509]

[0510] Magnesium turnings (2.34 g, 97 mmol, 1.38 equiv) are suspended in anhydrous THF (39 mL). The mixture is maintained at 35 ° C and treated with diisobutylaluminum hydride (1M in heptane, 201 mL, 0.03 equiv) under stirring. The resulting mixture is treated with a small amount of ((4-bromo-2-fluorobenzyl)oxy) (tert-butyl) dimethylsilane (1-B, 3.01 g, 9.4 mmol, a total of 0.1 wt %), and the resulting suspension is stirred for 15 minutes. The remaining ((4-bromo-2-fluorobenzyl)oxy) (tert-butyl) dimethylsilane (1-B, 27.09 g, 84.6 mmol, a total of 0.9 wt %) is dissolved in THF (81 mL), and the resulting product is added to the previously prepared suspension within 1 hour. The resulting mixture is heated to 40 ° C and stirred for 3 hours. Subsequently, the Grignard suspension was cooled to 15 ° C, and then treated with a solution of 2-cyclopropyl-N-methoxy-N-methylacetamide (2-B, 10g, 70mmol) in THF (60.2mL) for 50 minutes. The resulting mixture was stirred at 20 ° C for 2 hours, then cooled to 5 ° C and treated with 3NHCl (60.2mL) to keep the internal temperature below 20 ° C for 30 minutes. After the addition was completed, the mixture was stirred at 20 ° C for 2 hours. The mixture was allowed to stand overnight to consume any residual magnesium. The mixture was merged with heptane (120mL) and each layer was distributed. The organic layer was washed with saturated NaHCO3 aqueous solution (30mL) and brine (30mL), dried over Na2SO4 and filtered to remove solids. The solvent was removed under reduced pressure, and the crude product was passed through a silica gel pad (100g) and eluted with cyclohexane / AcOEt (98:2). The solvent was removed under reduced pressure to give a mixture of compound 3-B (16.5 g, 73% corrected) and the debrominated compound (3.7 g), which was used in the next step without isolation. 1 H NMR (400 MHz, CDCl3) δ ppm-0.01-0.34 (m, 10H), 0.52-0.70 (m, 2H), 0.91-1.06 (m, 12H), 1.07-1.24 (m, 1H), 2.86 (d, J = 7.03 Hz, 2H), 4.81 (s, 1H), 4.85 (s, 2H), 6.92-7.05 (m, 1H), 7.11-7.18 (m, 1H), 7.19-7.26 (m, 1H), 7.44-7.54 (m, 1H), 7.56-7.66 (m, 2H), 7.74 (dd, J = 7.90, 1.32 Hz, 1H) residual debrominated compound was present.

[0511] Step 3: Preparation of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)-2-cyclopropylethan-1-amine (Compound 4-B)

[0512]

[0513] A mixture of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)-2-cyclopropylethan-1-one (3-B, 10 g, 31 mmol, 1 eq) and ammonium acetate (11.95 g, 155 mmol, 5 eq) in methanol (50 mL) was stirred for 3 minutes and then treated with sodium cyanoborohydride (2.92 g, 47 mmol). The resulting mixture was stirred at room temperature for 30 minutes and then heated to 50 ° C and stirred overnight. The solvent was removed under reduced pressure and the residue was combined with 2M NaOH (50 mL). The resulting aqueous mixture was extracted with methyl tert-butyl ether (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 4-B (10.4 g, assumed quantitative) as a waxy solid. 1 H NMR (400 MHz, DMSO-d6) δ-0.03 (m, 2H), 0.08 (s, 13H), 0.20-0.43 (m, 4H), 0.77-0.97 (m, 19H), 1.10 (s, 3H), 1.51 (d, J = 5.71 Hz, 3H), 4.00 (t, J = 6.81 Hz, 1H), 4.70-4.74 (m, 3H), 6.88-7.13 (m, 1H), 6.88-7.11 (m, 1H), 7.13-7.24 (m, 2H), 7.30-7.46 (m, 2H) There was residual debrominated compound.

[0514] Step 4: Preparation of N-(1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)-2-cyclopropylethyl)-4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-amine (Compound 6-B)

[0515]

[0516] A suspension of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (5-B, 5.84 g, 22 mmol, 1 equivalent) in heptane (50 mL) was heated to 85 ° C, then treated with a solution of compound 4-B in heptane (30 mL) for 35 minutes. The resulting mixture was stirred overnight at 85 ° C and then cooled to room temperature. The solvent was removed under reduced pressure, and the crude material was purified by flash chromatography twice (100 g, cyclohexane / AcOEt 100: 0 to 96: 4 and cyclohexane / MTBE 100: 0 to 80: 20), and the solvent was removed under reduced pressure to obtain compound 6-B (5.50 g, 44% yield) as a light yellow oil after the second run.1 H NMR (400MHz,CDCl3)δppm-0.04-0.19(m,3H),0.12(s,6H),0.39-0.58(m,2H),0.61-0.76(m,1H),0.87-1.00(m,1H),0.95(s,9H),1.44(s),1.69-1.78(m,2H),2.09(s,3H),2.17(s,3H),3.84(s,3H),4.35-4.46(m,1H),4.80(s,2H),5.48-5.63(m,1H),6.78-7.22(m,2H),6.86(s,1H),7.13(s,1H),7.47(s,1H)Residual solvent is present. LCMS:[M] + =575.

[0517] Step 5: Preparation of N-(1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)-2-cyclopropylethyl)-4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound 7-B)

[0518]

[0519] A mixture of N-(1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)-2-cyclopropylethyl)-4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-amine (6-B, 5 g, 9 mmol) and TBAB (420 mg, 1 mmol) in methyl tert-butyl ether (10 mL) was stirred at room temperature for 10 minutes. The mixture was then cooled to -10°C and treated with aqueous KOH (64%, 1.8 mL) at a rate to keep the temperature below 5°C (1 hour) to give a mixture. The resulting mixture was treated with a solution of propargyl bromide in toluene (80%, 1.16 mL) at a rate to keep the temperature below 5°C (30 minutes) to give a mixture. The resulting mixture was stirred at 5°C for 20 hours and then combined with methyl tert-butyl ether (10 mL) and water (10 mL). After vigorous shaking, the layers were partitioned. The organic layer was washed with water (2×40 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give compound 7-B as a residue, which was used directly in the next step without further purification.

[0520] Step 6: Preparation of racemic {4-[1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methanol (Compound 1)

[0521]

[0522] Compound 7-B is dissolved in anhydrous THF (50mL) and a solution of 1M TBAF in THF (10.4mL) is added. The resulting mixture is stirred at room temperature for 3 hours, and then the solvent is removed under reduced pressure to obtain a residue. The residue is merged with water (10mL) and the resulting aqueous mixture is extracted with methyl tert-butyl ether (2×25mL). The combined organic layer is dried over Na2SO4, filtered to remove solids and concentrated under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (50g, cyclohexane / AcOEt 100: 0 to 80: 20) to obtain the first isolate (2g, 46%) in an orange foam shape. The second purification (50g, cyclohexane / AcOEt 100: 0 to 80: 20) obtains the final product (1.5g) in an orange foam shape. 1 HNMR(400MHz,CDCl3)δppm 0.15(m,2H),0.38(m,2H),0.72(m,1H),1.4(s),1.85-1.95(m,1H),2.11(s,3H), 2.11(s,3H),2.10-2.15(m,1H),2.31(s,1H),3.13(s,1H),3.26-3.36(m,2H),3. 32 (s, 2H), 3.84 (s, 3H) 4.00-4.18 (m, 2H), 4.44-4.57 (m, 2H), 5.16-5.31 (m, 2H), 7.01-7.09 (m, 1H), 7.12-7.18 (m, 1H) 7.19-7.31 (m, 2H) 7.36-7.49 (m, 1H) Residual solvent is present. LCMS: [M] + =499.

[0523] Example 2: Preparation of (S)-{4-[1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methanol (Compound 2) The preparation of (S)-{4-[1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methanol (Compound 2) is shown in Scheme 2.

[0524] Solution 2

[0525]

[0526] Step 1: Preparation of 4-bromo-2-fluoro-1-((methoxymethoxy)methyl)benzene (Compound 1-D)

[0527]

[0528] A mixture of (4-bromo-2-fluorophenyl)methanol (20 g, 98 mmol) and DIPEA (25.5 mL, 107 mmol) in dichloromethane (100 mL) was treated with a solution of methoxymethyl chloride (8.17 mL, 107 mmol) in dichloromethane (20 mL) at 4 ° C for 20 minutes. The resulting mixture was stirred for 48 hours. The mixture was washed with 5% NaHCO3 aqueous solution (50 mL), dried over NaSO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel 100 g, cyclohexane / AcOEt 100: 0 to 95: 5) to obtain compound 1-D (23.5 g, 88% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s), 3.28 (s, 3H), 4.54 (d, J = 1.32 Hz, 2H), 4.65 (s, 2H), 7.37-7.48 (m, 2H), 7.50-7.60 (m, 1H) Residual solvent was present.

[0529] Step 2: Preparation of 2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethan-1-one (Compound 3-D)

[0530]

[0531] Magnesium turnings (2.34 g, 97 mmol, 1.2 eq) were suspended in anhydrous THF (40 mL). The mixture was treated with iodine (410 mg, 1.6 mmol, 0.02 eq). The resulting mixture was treated with a small amount of 4-bromo-2-fluoro-1-((methoxymethoxy)methyl)benzene (1-D, 2 g, 8 mmol, 0.1 wt % in total), and the resulting suspension was gently heated with a heat gun until a color change occurred. The remaining 4-bromo-2-fluoro-1-((methoxymethoxy)methyl)benzene (18 g, 72 mmol, 0.9 wt % in total) was dissolved in THF (120 mL), and the resulting solution was added to the previously prepared suspension within 1.5 hours. The resulting mixture was stirred at room temperature for 1 hour. Subsequently, the Grignard suspension was cooled to 5 ° C. and then treated with a solution of 2-cyclopropyl-N-methoxy-N-methylacetamide (2-B, 17.25 g, 120 mmol) in THF (20 mL) for 20 minutes. The resulting mixture was stirred at room temperature overnight, then cooled to 5 ° C. and treated with saturated NH4Cl (66 mL). The mixture was extracted with methyl tert-butyl ether (2 × 170 mL). The combined organic layer was washed with brine (170 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, 100 g, cyclohexane / AcOEt 100: 0 to 80: 20) to obtain compound 3-D (8.0 g, 39% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δppm 0.15(dd,J=4.83,1.32Hz,2H),0.50(d,J=6.59Hz,2H),0.92–1.14(m,1H),2.95(d,J=6.59Hz,2H),3.3 0(s,3H),3.31(s),4.64(s,2H),4.68(s,2H),7.56-7.66(m,1H),7.68-7.76(m,1H),7.77-7.85(m,1H).

[0532] Step 3: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)-N-(1-phenylethyl)ethane-1-imine (Compound 4-D)

[0533]

[0534] A mixture of 2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethan-1-one (3-D, 1.8 g, 7 mmol, 1 eq), (S)-(-)-phenylethylamine (2.59 g, 21 mmol, 3.0 eq) and PTSA.H2O (70 mg, 0.37 mmol, 0.05 eq) in toluene (9 mL) was refluxed for 24 h with a Dean-Stark condenser attached to the apparatus. The mixture was cooled to room temperature and then washed with 10% Na2CO3 (3.6 mL) and 26% NaCl (3.6 mL). The organic solvent was removed under reduced pressure to give crude compound 4-D (2.54 g, assumed quantitative) which was used directly in the next step.

[0535] Step 4: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5-D)

[0536]

[0537] Raney nickel (50% wet, 2.38g, 20mmol) is washed with anhydrous ethanol (4×6mL) and transferred to HEL autoclave to provide a catalyst suspension. Compound 4-D (2.4g, 6.8mmol) is added to the catalyst suspension, and ethanol is added to provide a final volume of 30mL. The mixture is subjected to three vacuum / nitrogen cycles and two hydrogen purge cycles. The mixture is then stirred at 25°C for 6 hours and at 60°C for 24 hours under hydrogen (initial pressure: 10 bar). The mixture is filtered and the solid is washed with ethanol (20ml). The collected ethanol solution is concentrated, and the residue is purified by column chromatography (25g cyclohexane / AcOEt 100: 0 to 80: 20), to obtain compound 5-D (2g, 83% yield) in a light oily state. 1 H NMR (400MHz, DMSO-d6) δppm-0.36--0.02 (m, 2H), 0.10-0.43 (m, 2H), 0.54-0.67 (m, 1H), 1.00-1.20 (m, 3H), 1.22-1.38 (m, 1H), 1.42-1.65 (m, 1H), 2.60-2.72 (m, 1H), 3.22-3.42 (m, 6H), 4.54 (s, 2H), 4.65 (s, 2H), 6.91-7.02 (m, 1H), 7.05-7.13 (m, 1H), 7.14-7.42 (m, 7H)) There is a residual solvent peak. LCMS: [M+H] + =358.

[0538] Step 5: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethan-1-amine (Compound 6-D)

[0539]

[0540] A steel autoclave was charged with a solution of (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)-N-((S)-1-phenylethyl)ethan-1-amine (5-D, 2 g, 6 mmol) and Pd / C (10% wet, 100 mg) in methanol (40 mL). The steel autoclave was purged with nitrogen for 2 minutes. The autoclave was then mounted on a HEL hydrogenation system and the mixture was stirred at 60° C. for 10 hours under hydrogen (initial pressure: 8 bar), then cooled to 20° C. and stirred overnight. The mixture was stirred overnight with 4% ethanol. The pad was filtered and the filtrate was concentrated to give crude compound 6-D (1.42 g, assumed quantitative), which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δppm-0.12-0.06 (m, 2H), 0.23-0.43 (m, 2H), 0.52-0.69 (m, 1H), 1.31-1.52 (m, 2H), 1.89 (br s, 2H), 3.28 (s, 3H), 3.87 (t, J = 6.81 Hz, 1H), 4.52 (s, 2H), 4.63 (s, 2H), 7.11-7.23 (m, 2H), 7.34 (t, J = 7.69 Hz, 1H)) Residual solvent peaks exist. LCMS: [M+H] + =254.

[0541] Step 6: Preparation of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethyl)-5-methylthiazol-2-amine (Compound 7-D)

[0542]

[0543] A suspension of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (5-B, 1.51 g, 6 mmol, 1 equivalent) in heptane (15 mL) was heated to 90 ° C and then treated with a solution of compound 6-D (1.42 g, 6 mmol, 1 equivalent) in heptane (7 mL) for 15 minutes. The resulting mixture was stirred at 85 ° C for 3 hours and then cooled to room temperature. The solvent was removed under reduced pressure to provide a crude product. The crude product was purified by flash chromatography (50 g, cyclohexane / AcOEt 100: 0 to 90: 10). The solvent was removed under reduced pressure to obtain compound 7-D (4.46 g, 94% yield) in a yellow foamy state. MS: [M] + =505.

[0544] Step 7: Preparation of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound 8-D)

[0545]

[0546] A mixture of compound 7-D (2.5 g, 5 mmol) and TBAB (240 mg, 0.15 mmol) in methyl tert-butyl ether (6.25 mL) was treated with KOH aqueous solution (64%, 4.5 mL) at -10 ° C for 5 minutes. The resulting mixture was treated with a solution of bromopropyne in toluene (80%, 0.66 mL) for 5 minutes. The resulting mixture was stirred at 5 ° C for 5 hours, then merged with methyl tert-butyl ether (10 mL) and water (10 mL). Each layer was distributed. The aqueous layer was washed with methyl tert-butyl ether (10 mL) and the combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain compound 8-D as a residue, which was directly used in the next step without further purification.

[0547] Step 8: Preparation of (S)-{4-[1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methanol (Compound 2)

[0548]

[0549] Compound 8-D is dissolved in acetone (30mL) and 37% HCl aqueous solution (1.7g) is added. The resulting mixture is stirred at 55 ° C for 45 minutes. The mixture is cooled to room temperature and merged with saturated Na2CO3 aqueous solution (5mL), then merged with water (10mL). Volatiles are removed under reduced pressure, and the aqueous mixture is merged with methyl tert-butyl ether (20mL). The organic layer is collected, and the aqueous phase is washed with methyl tert-butyl ether (2×10mL). The combined organic layer is dried over Na2SO4, filtered to remove solids and concentrated under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (50g, DCM / MTBE, 100:0 to 95:5) to obtain the first isolate (1.4g, 91% HPLC purity) in a light yellow foam shape. Purification is repeated under the same conditions as the first isolate to obtain the second isolate (1.1g, 95% HPLC purity, as light yellow foam). The third purification (50 g, n-hexane / MTBE 100:0 to 60:40) gave compound 2 (1 g, 98% HPLC purity, 80% ee) as off-white foam. MS: [M] + =499. According to Example 1, 1 H NMR matched compound 1.

[0550] Example 2A. Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-(1-phenylethyl)ethane-1-imine

[0551]

[0552] The title compound can be prepared in a similar manner to the preparation of compound 4-D using 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one instead of compound 3-D in step 3.

[0553] Example 2B. Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine

[0554]

[0555] The title compound can be prepared in a similar manner to the preparation of compound 5-D using (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-(1-phenylethyl)ethan-1-imine instead of compound 4-D in step 4.

[0556] Example 3. (S)-(4-(1-((4-(2-chloro-4-(methoxy- 13Preparation of (C-d3)-5-methylphenyl)-5-methylthiazol-2-yl)(prop-2-yn-1-yl)amino)-2-cyclopropylethyl)-2-fluorophenyl)methanol (Compound 3)

[0557] (S)-(4-(1-((4-(2-chloro-4-(methoxy- 13 The preparation of (C-d3)-5-methylphenyl)-5-methylthiazol-2-yl)(prop-2-yn-1-yl)amino)-2-cyclopropylethyl)-2-fluorophenyl)methanol (Compound 3) is shown in Scheme 3.

[0558] Solution 3

[0559]

[0560] Step 1: 4-chloro-2-(methoxy- 13 Preparation of C-d3)-1-methylbenzene (Compound 1-F)

[0561]

[0562] A mixture of 5-chloro-2-methylphenol (9 g, 63 mmol) and potassium carbonate (13.21 g, 69 mmol, 1.1 eq.) was stirred in acetone (60 mL) at 20 °C for 15 min. 13 A solution of C,d3 (10.13 g, 69 mmol, 1.1 equiv) in acetone (30 mL) was added to the stirred mixture over 30 minutes (slight exotherm observed, +1 °C). The mixture was stirred at room temperature for 24 hours, then diluted with DMF (30 mL) and stirred for another 15 hours at room temperature. Acetone was removed at atmospheric pressure until all acetone was distilled off (80 °C). The residue was combined with water (250 mL) and the resultant was extracted with pentane (3 × 50 mL). The combined organic fractions were dried over Na2SO4, filtered to remove solids, and concentrated under reduced pressure to give crude compound 1-F (10.6 g, assumed quantitative) as a yellow oil, which was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s, 3H), 6.88 (dd, J = 7.91, 2.20 Hz, 1H), 6.98 (d, J = 2.20 Hz, 1H) 7.14 (dd, J = 7.90, 0.88 Hz, 1H) There is a residual solvent peak.

[0563] Step 2: 1-(2-chloro-4-(methoxy- 13 Preparation of C-d3)-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 2-F)

[0564]

[0565] Aluminum chloride (9.55 g, 72 mmol, 1.15 equivalents) was loaded into a 500 mL jacketed glass reactor, and DCM (40 mL) was then added and the resulting mixture was stirred at room temperature. Compound 1-F (10 g, 62 mmol, 1 equivalent) was added to the stirred mixture at room temperature within 10 minutes. The addition line was washed with DCM (10 mL) to ensure the complete addition of compound 1-F. The dark suspension was heated and stirred at 30 ° C for 10 minutes until almost completely dissolved. Subsequently, the mixture was cooled to 0 ° C and treated with pure 2-bromopropionyl chloride (12.27 g, 72 mmol, 1.15 equivalents) for 30 minutes; The addition line was washed with DCM (10 mL) to ensure the complete addition of 2-bromopropionyl chloride. The resulting mixture was stirred at 0 ° C for 20 hours. Subsequently, the mixture was cooled to -5 ° C and treated with water (50 mL) for 15 minutes. The resulting mixture was stirred at 0 ° C for 30 minutes. The mixture was then combined with cyclohexane (300mL), and the resulting suspension was stirred overnight. Each layer was then distributed, and the organic layer was washed with water (2×100mL) and a 1:1 mixture (100mL, pH of the washings was calculated to be 8) of 13% NaCl aqueous solution + 5% NaHCO3 aqueous solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was suspended in cyclohexane (100mL) and filtered. The solution was concentrated (90mL) and diluted with DCM (10mL). In a round-bottom flask, KSCN (9.68g, 100mmol.1.6 equivalents) and TBAB (0.30g, 0.93mmol.0.015 equivalents) were dissolved in water (10mL). The aqueous mixture was heated to 55°C and then treated with a pre-prepared solution containing a bromine intermediate for 1 hour. The resulting mixture was stirred for 3.5 hours, and then water (10mL) was added. The obtained mixture was stirred for 10 minutes, and each layer was distributed at 50°C. The organic layer was concentrated under reduced pressure, and the residue was merged with methanol (60mL). A white solid was precipitated, and the mixture was stirred at room temperature for 30 minutes, then stirred at 0°C for 1 hour. The solid was collected by filtration and washed with cold methanol (10mL) to obtain compound 2-F (10.3g, 60% yield) in a white powder. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (d, J = 6.59 Hz, 3H), 2.16 (s, 3H), 5.28 (q, J = 6.73 Hz, 1H), 7.15 (s, 1H) 7.74 (s, 1H) There is a residual solvent peak.

[0566] Step 3: (S)-4-(2-chloro-4-(methoxy- 13Preparation of C-d3)-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethyl)-5-methylthiazol-2-amine (Compound 3-F)

[0567]

[0568] 1-(2-chloro-4-(methoxy- 13 A suspension of (2-F, 2.16 g, 8 mmol, 1 equivalent) in heptane (20 mL) was heated to 90 ° C and then treated with a solution of compound 6-D (2 g, 8 mmol, 1 equivalent) in heptane (10 mL) for 20 minutes. The resulting mixture was stirred at 85 ° C for 5 hours and then cooled to room temperature. The solvent was removed under reduced pressure to provide a crude product. The crude product was purified by flash chromatography (100 g, n-hexane / methyl tert-butyl ether 95: 5 to 60: 40). The solvent was removed under reduced pressure to obtain compound 3-F (3.5 g, 87% yield) in a yellow foamy state. 1 H NMR(400MHz,DMSO-d6)δppm-0.03-0.16(m,2H),0.27-0.45(m,2H),0.63-0.76(m,1H),0. 82-0.89(m),1.20-1.30(m),1.42-1.54(m,1H),1.72-1.83(m,1H),2.00(s,3H),2.10(s,3 H), 3.28 (s, 3H), 3.32 (s), 4.52 (s, 2H), 4.63 (s, 2H), 4.55-4.68 (m, 1H), 7.00 (s, 1H), 7.05 (d, J = 0.88 Hz, 1H), 7.16-7.25 (m, 1H), 7.33-7.42 (m, 1H), 7.93 (d, J = 7.91 Hz, 1H) There is a residual solvent peak. LCMS: [M] + =575.

[0569] Step 4: (S)-(4-(1-((4-(2-chloro-4-(methoxy- 13 Preparation of C-d3)-5-methylphenyl)-5-methylthiazol-2-yl)(prop-2-yn-1-yl)amino)-2-cyclopropylethyl)-2-fluorophenyl)methanol (Compound 3)

[0570]

[0571] A mixture of compound 3-F (3.2 g, 6.3 mmol) and TBAB (300 mg, 0.93 mmol, 0.15 equiv) in methyl tert-butyl ether (15 mL) was treated with aqueous KOH (64%, 5.76 mL) at -10 ° C for 15 minutes. The resulting mixture was kept at 0 ° C and treated with a solution of bromopropynyl in toluene (80%, 0.84 mL) for 10 minutes. The resulting mixture was stirred at 5 ° C overnight and then stirred at room temperature for 1 hour. The mixture was combined with methyl tert-butyl ether (10 mL) and water (10 mL). The layers were distributed. The aqueous layer was washed with methyl tert-butyl ether (10 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was dissolved in acetone (30 mL) and 37% aqueous HCl (2.3 g) was added. The resulting mixture was stirred at 55 ° C for 1 hour. The mixture is cooled to room temperature and merged with saturated NaCOThe aqueous solution (10mL) is merged, then merged with water (10mL).Volatile matter is removed under reduced pressure, and aqueous mixture is merged with methyl tert-butyl ether (20mL).Collected organic layer, and aqueous phase is washed with methyl tert-butyl ether (2×20mL).The combined organic layer is through NaSODry, filter to remove solid and concentrate under reduced pressure, to obtain the first isolate.The first isolate is purified by column chromatography (100g, n-hexane / MTBE 100:0 to 60:40) to provide the second isolate.Purification for the second time (100g, DCM / MTBE 100:0 to 95:5) obtains compound 3 (1.6g, 99.5%HPLC purity, 93%ee) in off-white foam. 1 H NMR (600 MHz, DMSO-d6) δ ppm 0.15 (m, 2H), 0.38 (m, 2H), 0.72 (m, 1H), 1.90 (dt, J = 14.2, 7.1 Hz, 1H), 2.0–2.2 (overlapping, 1H), 2.11 (s, 3H), 2.14 (s, 3H), 2.31 (s, 1H), 3.12 (t, J = 2.3 Hz, 1H), 4.09 (m, 2H) ,4.52(d,J=5.6Hz,2H),5.23(t,J=5.8Hz,1H),5.27(t,J=7.6Hz,1H),7.05(s,1H) ,7.17(s,1H)7.22(d,J=11.5Hz,1H)7.26(d,J=7.9Hz,1H),7.43(t,J=7.9Hz,1H). MS:98.1% 13 CD3 purity.

[0572] Example 3A. Preparation of enantiomerically enriched (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethan-1-amine (Compound 6-D) used in Step 3 of Example 3.

[0573] Step 1A: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5-D)

[0574]

[0575] Compound 4-D (5.61 g, 15.8 mmol) was hydrogenated with Raney nickel (3 eq.) for 30 hours according to the procedure described in step 3 of Example 2. After separation, the crude product was eluted by three consecutive column chromatography (100 g, hexane / AcOEt 100:0 to 90:10; 2×100 g, cyclohexane / IPA 100:0 to 95:5) to give compound 5-D (3.1 g, 55% yield) with a diastereoisomer ratio of about 97:3 ( 1 H-NMR, DMSO-d6, 94% de). Selected mixed chromatographic fractions were combined to give an additional sample of compound 5-D (1.43 g, 25% yield), where the diastereomeric ratio was calculated to be 85:15 d.r. ( 1 H-NMR, DMSO-d6, 70% de).

[0576] Step 2A: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethan-1-amine (Compound 6-D)

[0577]

[0578] Compound 5-D (3.1 g, 8.7 mmol, 94% de) was hydrogenated over Pd / C (initial pressure: 10 bar) at 60° C. for 10 h following the procedure described in Step 4 of Example 2. The reaction was worked up as described in Step 4 of Example 2 to give crude compound 6-D (2.2 g, assumed quantitative), which was used directly in Step 3 of Example 3.

[0579] Example 4. The preparation of (S)-(4-(1-((4-(2-chloro-4-(methoxy-d3)-5-methylphenyl)-5-methylthiazol-2-yl)(prop-2-yn-1-yl)amino)-2-cyclopropylethyl)-2-fluorophenyl)methanol (Compound 4) is shown in Scheme 4.

[0580] Solution 4

[0581]

[0582] Step 1: Preparation of 4-chloro-2-(methoxy-d3)-1-methylbenzene (Compound 1-G)

[0583]

[0584] A mixture of 5-chloro-2-methylphenol and potassium was stirred in acetone at 20°C for 15 minutes. A solution of iodomethane-d3 in acetone was added to the stirred mixture within 30 minutes. The mixture was stirred at room temperature for 24 hours, then diluted with DMF and stirred for another 15 hours at room temperature. Acetone was removed at atmospheric pressure until all acetone was distilled out (80°C). The residue was merged with water, and the resulting product was extracted with pentane. The combined organic fractions were dried over Na2SO4, filtered to remove solids, and concentrated under reduced pressure to obtain compound 1-G.

[0585] Step 2: Preparation of 1-(2-chloro-4-(methoxy-d3)-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 2-G)

[0586]

[0587] Aluminum chloride is loaded into a 500mL jacketed glass reactor, DCM is then added, and the resulting mixture is stirred at room temperature. Compound 1-G is added to the stirred mixture within 10 minutes at room temperature. The resulting mixture is heated to 30 ° C and stirred for 10 minutes. Subsequently, the mixture is cooled to 0 ° C and treated with pure 2-bromopropionyl chloride for 30 minutes. The resulting mixture is stirred at 0 ° C for 20 hours. Subsequently, the mixture is cooled to -5 ° C and treated with water for 15 minutes. The resulting mixture is maintained at 0 ° C and stirred for 30 minutes. The mixture is then merged with cyclohexane and stirred overnight. Each layer is then distributed, and the organic layer is washed with a 1: 1 mixture of water and a 13% NaCl aqueous solution + 5% NaHCO3 aqueous solution. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure to provide a bromine intermediate. The bromine intermediate is suspended in cyclohexane and filtered. The solution is concentrated and diluted with DCM. In a round-bottomed flask, KSCN and TBAB are dissolved in water. The aqueous mixture was heated to 55 ° C and then treated with a solution containing the bromine intermediate for 1 hour. The resulting mixture was stirred for 3.5 hours and then water was added. The resulting mixture was stirred for 10 minutes and the layers were distributed at 50 ° C. The organic layer was concentrated under reduced pressure and the residue was combined with methanol. The mixture was stirred at room temperature for 30 minutes and then stirred at 0 ° C for 1 hour. The solid was collected by filtration and washed with cold methanol to obtain compound 2-G.

[0588] Step 3: Preparation of (S)-4-(2-chloro-4-(methoxy-d3)-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethyl)-5-methylthiazol-2-amine (Compound 3-G)

[0589]

[0590]

[0591] The mixture of compound 2-G in heptane is heated to 90 ° C, and then treated with a solution of compound 6-D in heptane for 20 minutes. The resulting mixture is stirred at 85 ° C for 5 hours and then cooled to room temperature. The solvent is removed under reduced pressure to provide a crude product. The crude product is purified by flash chromatography (100g, n-hexane / methyl tert-butyl ether 95: 5 to 60: 40). The solvent is removed under reduced pressure to obtain compound 3-G.

[0592] Step 4: Preparation of (S)-(4-(1-((4-(2-chloro-4-(methoxy-d3)-5-methylphenyl)-5-methylthiazol-2-yl)(prop-2-yn-1-yl)amino)-2-cyclopropylethyl)-2-fluorophenyl)methanol (Compound 4)

[0593]

[0594] The mixture of compound 3-G and TBAB in methyl tert-butyl ether (15mL) was treated with KOH aqueous solution (64%) for 15 minutes at -10°C. The resulting mixture was maintained at 0°C and treated with a solution of propargyl bromide in toluene (80%) for 10 minutes. The resulting mixture was stirred overnight at 5°C and then stirred at room temperature for 1 hour. The mixture was combined with methyl tert-butyl ether and water. Each layer was distributed and the aqueous layer was extracted with methyl tert-butyl ether. The combined organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure to obtain an intermediate product. The intermediate product was dissolved in acetone and a 37% HCl aqueous solution was added. The resulting mixture was stirred at 55°C for 1 hour. The mixture was cooled to room temperature and combined with saturated Na2CO and water, and then combined with water. Volatiles were removed under reduced pressure, and the aqueous mixture was combined with methyl tert-butyl ether. The organic layer was collected and the aqueous phase was extracted with methyl tert-butyl ether. The combined organic layer was dried over Na2SO4, filtered to remove solids and concentrated under reduced pressure to obtain the first isolate. The first isolate was purified by column chromatography (100 g, n-hexane / MTBE 100:0 to 60:40) to give a second isolate. The second isolate was purified by column chromatography (DCM / MTBE 100:0 to 95:5) to give compound 4.

[0595] Example 5. The preparation of (S)-(4-(1-((4-(2-chloro-4-(methoxy-d3)-5-methylphenyl)-5-methylthiazol-2-yl)(prop-2-yn-1-yl)amino)-2-cyclopropylethyl-2,2-d2)-2-fluorophenyl)methanol (Compound 5) is shown in Scheme 5.

[0596] Solution 5

[0597]

[0598] A mixture of compound 3-G and TBAB in methyl tert-butyl ether (15mL) was treated with KOH aqueous solution (64%) at -10°C for 15 minutes. The resulting mixture was maintained at 0°C and treated with 3-bromoprop-1-yne-3,3-d2 for 10 minutes. The resulting mixture was stirred overnight at 5°C and then stirred at room temperature for 1 hour. The mixture was merged with methyl tert-butyl ether and water. Each layer was distributed and the aqueous layer was extracted with methyl tert-butyl ether. The combined organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure to obtain an intermediate product. The intermediate product was dissolved in acetone and 37% HCl aqueous solution was added. The resulting mixture was stirred at 55°C for 1 hour. The mixture was cooled to room temperature and merged with saturated Na2CO3 and then merged with water. Volatiles were removed under reduced pressure, and the aqueous mixture was merged with methyl tert-butyl ether. The organic layer was collected and the aqueous phase was extracted with methyl tert-butyl ether. The organic layer merged is through Na2SO4 drying, filtered to remove solid and concentrated under reduced pressure, to obtain the first isolate. The first isolate is purified by column chromatography (100g, normal hexane / MTBE 100:0 to 60:40) to obtain the second isolate. The second isolate is purified by column chromatography (DCM / MTBE 100:0 to 95:5) to obtain compound 5.

[0599] LC-MS analysis was performed using the following method:

[0600] Method: A

[0601] Platform: Agilent 1260UPLC with Thermo MSQ mass detector and Agilent DAD (220 and 254 nm);

[0602] HPLC column: Waters BEH C18 XP, 2.5μM, 50x3.0mm;

[0603] HPLC gradient: 1.5 mL / min, 40% acetonitrile (with 0.025% TFA) in water (with 0.025% TFA) for 6 seconds, then increase to 100% acetonitrile for 1.5 minutes. Hold at 100% acetonitrile for 18 seconds. Return to 10% acetonitrile in 6 seconds and hold at 10% for 30 seconds.

[0604] Method: B

[0605] Platform: Agilent 1260UPLC with Thermo MSQ mass detector and Agilent DAD (220 and 254 nm);

[0606] HPLC column: Waters BEH C18 XP, 2.5μM, 50x3.0mm;

[0607] HPLC gradient: 1.5 mL / min, 10% acetonitrile (with 0.025% TFA) in water (with 0.025% TFA) for 6 seconds, then increase to 90% acetonitrile for 6.5 minutes. Increase to 99% acetonitrile for 6 seconds, then hold at 99% acetonitrile for 12 seconds. Return to 10% acetonitrile in 6 seconds and hold at 10% for 30 seconds.

[0608] Example 6. The preparation of {4-[(1S)-1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methyl (2S)-2-amino-3-methylbutanoate (Compound 6) is shown in Scheme 6.

[0609] Solution 6

[0610]

[0611] The mixture of compound 2 (50 mg) and Boc-valine (26 mg) in MeCN (2 mL) was treated with DIC (19 mg, diisopropylcarbodiimide) and then treated with DMAP (1 mg). The resulting mixture was stirred at room temperature overnight. The solvent was removed, and the mixture was purified by chromatography on silica gel, eluted with EtOAc / Hex, to obtain an oily Boc-protected intermediate. The material was dissolved in DCM (2 mL), and the resulting mixture was treated with a solution of 4M HCl in dioxane (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum, and the resulting residue was ground with MTBE. A solid precipitate was formed, filtered and dried by suction to obtain compound 6 (50 mg) as a white powder for HCl salt. The LCMS (method: A) of the intermediate protected by Boc: m / z (M+H) = 698.3; tR = 1.99 minutes. LCMS of compound 6 (method: B): m / z (M+H) = 598.2; tR = 4.48 min.

[0612] Example 7. The preparation of 5-({4-[(1S)-1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methoxy)-5-oxopentanoic acid (Compound 7) is shown in Scheme 7.

[0613] Solution 7

[0614]

[0615] The mixture of compound 2 (50mg) and glutaric anhydride (23mg) in MeCN (2mL) is treated with DMAP (1mg). The resulting mixture is stirred at room temperature overnight. The solvent is removed, and the mixture is purified by chromatography on silica gel, eluted with EtOAc / Hex, to obtain the first separation in an oily state. The first separation is dissolved in THF / water (1:1, 5mL), and the resulting mixture is treated with sodium bicarbonate until pH 7 (about 1 equivalent) is reached. The solvent is removed under vacuum, and the resulting residue is placed under vacuum overnight to obtain compound 7 (31mg) as a sodium salt in the form of a white powder. LCMS (method: B) of compound 7: m / z (M+H) = 613.2; tR = 5.05 minutes.

[0616] Example 8. The preparation of ({4-[(1S)-1-{[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl](prop-2-yn-1-yl)amino}-2-cyclopropylethyl]-2-fluorophenyl}methoxy)phosphonic acid (Compound 8) is shown in Scheme 8.

[0617] Solution 8

[0618]

[0619] The mixture of compound 2 (50mg) in MeCN (2mL) is slowly treated with diphosphoryl chloride (50mg, 2 equivalents) at room temperature and stirred for 30 minutes. Subsequently, the mixture is added to excessive K under agitation PO In the aqueous solution (2mL). After stirring for 30 minutes, the solvent is removed under vacuum and 20% phosphoric acid aqueous solution (1mL) is added to obtain a strongly acidic mixture. The mixture is extracted with DCM, and the DCM extract is dried over MgSO, and concentrated under vacuum to obtain the first isolate. The first isolate is purified by HPLC (water / MeCN with 0.025% TFA) to obtain the second isolate in an oily state. The second isolate is dissolved in water / MeCN (1mL) and treated with the 1M NaOH aqueous solution under agitation until the mixture reaches pH 7 (about 2 equivalents). Subsequently, the solvent is removed under vacuum to obtain compound 8 (15mg) as a disodium salt in an off-white powder. LCMS (Method: B): m / z = 579.0; tR = 4.13 min.

[0620] Example 9. CRF1 receptor antagonist activity

[0621] As reported by Fleck et al. (J. Pharmacology and Experimental Therapeutics, 341(2):518-531, 2012) (hereinafter, "Fleck et al.", and incorporated by reference in its entirety), the activity of CRF1 receptor antagonists can be expressed as the association (k1) and dissociation (k2) by the following equation: -1 ) rate constants calculated from the kinetically derived affinity (K i ):

[0622] K i =k -1 / k1

[0623] Compound 1 was evaluated according to these procedures, and the kinetic K was determined. i is 1.14.

[0624] Example 10. Dissociation half-life (t 1 / 2 )

[0625] The dissociation half-life of compound 1 (t 1 / 2 ) were also estimated by the technique described by Fleck et al. As described herein, the dissociation rate constants for labeled and unlabeled ligands are expressed as k -1, whereas the drug dissociation half-life from the receptor (t 1 / 2 ) is given by the dissociation rate constant (k -1 ) is calculated by the following equation.

[0626] t 1 / 2 =0.693 / k -1 .

[0627] Compound 1 was evaluated according to these procedures and the dissociation half-life (t 1 / 2 ) is 63 minutes.

[0628] These and other changes can be made to the embodiments in light of the above detailed description. Generally, in the following claims, the terms used should not be interpreted as limiting the claims to the specific embodiments disclosed in the specification and claims, but should be interpreted to include all possible embodiments along with the full range of equivalents provided by such claims. Therefore, the claims are not limited by the present disclosure.

[0629] Incorporation by Reference

[0630] Various references, such as patents, patent applications, and publications, are cited herein, the disclosures of which are incorporated by reference in their entireties.

Claims

1. A pharmaceutical composition comprising a compound of formula (IIa): or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein: Each R 2a independently hydrogen or deuterium; R 4a yes R 6a is C(R A )3; and Each R A is independently hydrogen or deuterium.

2. The pharmaceutical composition of claim 1, wherein R 6a Is CD3 or R 6a It is CH3.

3. The pharmaceutical composition of claim 1, wherein R 6a It's CD3.

4. The pharmaceutical composition of claim 1, wherein each R 2a It's hydrogen.

5. The pharmaceutical composition according to claim 1, wherein the compound of formula (IIa) is a compound of the following formula: or a pharmaceutically acceptable salt thereof.

6. A preparation of a compound of formula (IIa) or a pharmaceutically acceptable salt thereof, in: Each R 2a independently hydrogen or deuterium; R 4a yes R 6a is C(R A )3; and Each R A is independently hydrogen or deuterium.

7. The preparation of claim 6, wherein R 6a Is CD3 or R 6a It is CH3.

8. The preparation of claim 6, wherein R 6a It's CD3.

9. The preparation of claim 6, wherein each R 2a It's hydrogen.

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