CRF receptor antagonists and methods of use

Abstract

To provide compounds, as well as related preparations, compositions and methods for treating diseases and / or disorders that would benefit from the same such as congenital adrenal hyperplasia (CAH).SOLUTION: Provided herein are compounds that are CRF antagonists. In particular embodiments, compounds are provided that are CRF1 antagonists. Also, provided herein are compounds that are prodrugs of compounds that are CRF antagonists. Accordingly, such compounds and prodrugs are useful in the treatment of CAH.SELECTED DRAWING: None

Description

[Technical field]

[0001] background Technical Field The present disclosure relates generally to compounds, compositions and methods relating thereto for treating congenital adrenal hyperplasia (CAH), including methods for treating congenital adrenal hyperplasia (CAH). [Background technology]

[0002] 2. Description of Related Art CRF is a hypothalamic hormone that acts as a critical regulator of the hypothalamic-pituitary-adrenal (HPA) axis. Classical congenital adrenal hyperplasia (CAH) is a condition in which little or no cortisol biosynthesis occurs, a group of autosomal recessive genetic disorders resulting in an enzyme deficiency that alters the production of adrenal steroids due to 21-hydroxylase deficiency. One clinical manifestation of the lack of cortisol is the lack of feedback inhibition of CRF, which causes dysregulation of the HPA axis. 21-hydroxylase deficiency also causes shunting of the production pathway of cortisol precursor steroids, resulting in excess androgen (e.g., 17-hydroxyprogesterone, androstenedione, and testosterone) production.

[0003] Currently, exogenous corticosteroids are the standard of care for treating patients with classical CAH. This treatment is used to correct cortisol deficiency and reduce androgen excess. However, the doses of corticosteroids used are typically well above normal physiological levels used alone for cortisol replacement (as in patients with Addison's disease). This increased exposure to corticosteroids can lead to iatrogenic Cushing's syndrome, increased cardiovascular risk factors, impaired glucose tolerance, reduced growth rate, and reduced bone mineral density in CAH patients. Thus, there is a need for a treatment for CAH that avoids the severe complications associated with current corticosteroid therapy.

[0004] In clinical trials, certain CRF1 antagonist compounds have been demonstrated to significantly reduce CAH-associated steroid biomarkers (eg, 17-hydroxyprogesterone and androstenedione) in patients with CAH compared to placebo.

[0005] There remains a need to identify new CRF1 antagonists for use in the treatment of CAH. The present disclosure meets these and other needs, as will become apparent upon reference to the disclosure below. Summary of the Invention [Means for solving the problem]

[0006] overview Provided herein is a compound that is a CRF antagonist.In certain embodiments, provided herein is a compound that is a CRF1 antagonist.Also provided herein is a compound that is a prodrug of a compound that is a CRF antagonist.Therefore, such compounds and prodrugs are useful in treating CAH.

[0007] Some embodiments include a compound of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, Each R 1a are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2aare independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2R B [is].

[0008] Some embodiments include a compound of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof, wherein Each R 1a are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2R B [is].

[0009] In some embodiments, the compound of formula (Ia) is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0010] Some embodiments provide a method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering a compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

[0011] Some embodiments provide a method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof in an amount sufficient to reduce a level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) testosterone, and (c) androstenedione in the subject.

[0012] In some embodiments, the method includes administering a compound of formula (Ia) or a pharma- ceutically 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 subject.

[0013] Some embodiments provide a method for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and growth disorders in a subject with classical congenital adrenal hyperplasia, comprising administering a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof in an amount sufficient to reduce androstenedione levels in the subject.

[0014] Some embodiments provide a method of reducing the level of one or more biomarkers in a subject having congenital adrenal hyperplasia, comprising administering to the subject a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof.

[0015] Some embodiments provide a method of reducing the dosage of corticosteroids administered to a subject having congenital adrenal hyperplasia to control the congenital adrenal hyperplasia, comprising administering to the subject a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof.

[0016] Some embodiments relate to a method of reducing the severity of one or more side effects of glucocorticoid treatment in a subject with congenital adrenal hyperplasia, comprising administering to the subject a compound of Formula (Ia) or a pharma- ceutically acceptable salt thereof, wherein the side effects are osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth suppression, adrenal suppression, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, fatty liver, pancreatitis, hypertension, coronary heart disease, ischemic heart disease, heart failure, dermatoprosis, atrophy of the skin, ecchymoses, purpura, erosions, striae, delayed wound healing, monokinesis, vasculitis ... The symptoms are selected from easy bruising, acne, hirsutism, hair loss, mood changes, depression, euphoria, emotional lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, predisposition to infection, and reactivation of latent infection.

[0017] Some embodiments include a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, Each R 1 are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2 are independently hydrogen or deuterium; Each R 3 are independently hydrogen or deuterium; R 4 teeth, [ka] and R 5 is hydrogen or deuterium, R 6 is C(R A )3, R 7 is C(R A )3 or C(R A )2R B and Here, R A , R 2 , R3 and R 5 At least one of is deuterium, and R 1 and R 7 At least one of C(R A )2R B [is].

[0018] Some embodiments include a compound of formula (III) [ka] or a pharma- ceutically acceptable salt thereof, R 11 teeth, a)-P(=O)(OR 33 )2 or -P(=O)(OR 33 )(N(R 33 )2) b) -C(=O)R 50 , c) -C(=O)N(R 33 )R 50 , d) -C(=O)OR 50 ,or e)R 50 and Each R 33 are independently hydrogen, C1-C6 alkyl, haloC1-C6 alkyl or aryl, where C1-C6 alkyl and aryl are each independently R 10 where appropriate, 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 selected from one or more R 10 and / or R 20 where appropriate, Each R 10 are independently halo, haloC1-C6 alkyl, cyano, nitro, trimethylsilanyl, -O · (oxyl radical), -OR 30 , -SR30 , -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 two R's as required 10 the groups taken together on a single atom form oxo, each t is independently 1 or 2; each p is independently 1, 2, or 3; Each R 20 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl, or heteroaryl, where each R 20 is R 10 and / or R 22 where appropriate, Each R 22 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl, or heteroaryl, where each R 22 is R 10 where appropriate, Each R 30 , R 31 and R 32are independently hydrogen, haloC1-C6 alkyl, or C1-C6 alkyl; Each R 1a are independently A )3, Each R A are independently hydrogen or deuterium; Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, and R 6a is C(R A )3].

[0019] Some embodiments provide pharmaceutical compositions comprising a compound of Formula (I) or Formula (III), or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0020] Some embodiments provide a method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (III), or a pharma- ceutically acceptable salt thereof.

[0021] Some embodiments provide a method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject 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 generated under physiological conditions or by solvolysis following administration of a prodrug of compound 2 or a pharma- ceutically acceptable salt thereof to the subject, and wherein the prodrug of compound 2 or a pharma- ceutically 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 pharmaceutical salt thereof.

[0022] Some embodiments provide a method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject 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 generated as a result of a metabolic chemical reaction following administration of a prodrug of Compound 2 or a pharma- ceutically acceptable salt thereof to the subject, and wherein the prodrug of Compound 2 or a pharma- ceutically 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 pharmaceutical salt thereof.

[0023] Some embodiments provide a method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject 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 pharma- ceutically acceptable salt thereof, wherein the prodrug of Compound 2 or a pharma- ceutically 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 pharmaceutical salt thereof.

[0024] These and other embodiments will become evident upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and compositions, each of which is hereby incorporated by reference in its entirety. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Detailed Description compound Provided herein are compounds useful for treating diseases and / or disorders treatable by modulating CRF1.

[0026] The present invention relates to a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, Each R 1 are independently A )3 or C(R A )2R B and Each R Aare independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2 are independently hydrogen or deuterium; Each R 3 are independently hydrogen or deuterium; R 4 teeth, [ka] and R 5 is hydrogen or deuterium, R 6 teeth, 13 C(R A )3 or C(R A )3, R 7 is C(R A )3 or C(R A )2R B and Here, R A , R 2 , R 3 and R 5 At least one of is deuterium, and R 1 and R 7 At least one of C(R A )2R B [is].

[0027] In some embodiments, the present invention provides a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, Each R 1 are independently A )3 or C(R A )2R B and Each RA are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2 are independently hydrogen or deuterium; Each R 3 are independently hydrogen or deuterium; R 4 teeth, [ka] and R 5 is hydrogen or deuterium, R 6 is C(R A )3, R 7 is C(R A )3 or C(R A )2R B and Here, R A , R 2 , R 3 and R 5 At least one of is deuterium, and R 1 and R 7 At least one of C(R A )2R B [is].

[0028] In some embodiments, R 6 teeth 13 It's CD3.

[0029] In some embodiments, R 6 is CD3 and R 7 is CH3.

[0030] In some embodiments, R 6 is CH3 and R 7 is CD3.

[0031] In some embodiments, R 6 is CD3 and R 7 is CD3.

[0032] In some embodiments, R 1 is CD3.

[0033] In some embodiments, each R A is hydrogen.

[0034] In some embodiments, each R 2 is hydrogen.

[0035] In some embodiments, each R 3 is hydrogen.

[0036] In some embodiments, the present invention provides a compound of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof, Each R 1a are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5ais hydrogen or deuterium, R 6a teeth, 13 C(R A )3 or C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2R B [is].

[0037] In some embodiments, the present invention provides a compound of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof, Each R 1a are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2R B [is].

[0038] In some embodiments, R 7a is C(R A )2R B and R C is hydrogen.

[0039] In some embodiments, R 7a is CHOH.

[0040] In some embodiments, the present invention provides a compound of formula (IIa) [ka]

[0041] or a pharma- ceutically acceptable salt thereof.

[0042] In some embodiments, R 6a is CD3 or R 6a is CH3.

[0043] In some embodiments, R 6a is CD3.

[0044] In some embodiments, each R 2a is hydrogen.

[0045] In some embodiments, R 7a is CD2OH.

[0046] In some embodiments, the present invention provides a compound having the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0047] In some embodiments, the present invention provides a compound having the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0048] In some embodiments, the present invention provides a compound having the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0049] It will be further understood that certain features that are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0050] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are intended. In any compound described herein having one or more chiral centers, if the absolute stereochemistry is not explicitly indicated, it is understood that each center may be independently in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure, diastereomerically enriched, or stereoisomeric mixtures. The preparation of enantiomerically pure or enantiomerically enriched forms may be achieved by resolution of racemic mixtures, or by using enantiomerically pure or enriched starting materials, or by stereoselective or stereospecific synthesis. The definition of stereochemistry is set forth in EL Eliel, SH Wilen & LN Mander "Stereochemistry of Organic Compounds" John Wiley & Sons, Inc., incorporated herein by reference in its entirety. New York, NY, 1994. The compounds of the invention are chiral or In some embodiments, or which otherwise contain one or more stereocenters, the compounds can be prepared in 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%. As the context makes clear, the compounds of the invention can refer to single molecules or multiple molecules.

[0051] The resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using chiral resolving acids, which are organic acids that form optically active salts. Suitable resolving agents for fractional recrystallization are optically active acids, such as, for example, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the D and L forms of various optically active camphorsulfonic acids. Other suitable resolving agents for fractional crystallization include stereoisomerically pure forms of methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0052] Resolution of racemic mixtures can also be achieved by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The composition of an appropriate elution solvent can be determined by one skilled in the art.

[0053] 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 within a range defined by any of the foregoing values.

[0054] The compounds described herein also include tautomeric forms. Tautomeric forms arise from the exchange of a single bond with an adjacent double bond, with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-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 the heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium, or may be sterically fixed in one form by appropriate substitution.

[0055] The compounds described herein and their pharmaceutically acceptable salts can be found together with water and other substances such as solvents, for example in the form of hydrate or solvate.The compounds described herein and their salts can occur in various forms when in solid state, for example in the form of solvate, including hydrate.The compounds can be in any solid state form, such as crystalline form, amorphous form, solvate form, and therefore, unless otherwise clearly indicated, the references herein to the compounds and their salts should be understood to read any solid state form of the compounds.

[0056] As used herein, the term "solvate" refers to a solid form of a compound of the invention (or a pharma- ceutically acceptable salt thereof) that contains one or more molecules of a solvent in a stoichiometric or non-stoichiometric amount. When the solvent is water, the solvate is a hydrate.

[0057] In some embodiments, the compound or salt thereof described herein is substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation may include, for example, a composition enriched in the compound of the present invention. Substantial separation may 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 the compound or salt thereof disclosed herein.

[0058] 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.

[0059] Additionally, it is understood that the compounds described herein contain one or more double bonds (e.g., C=C, C=N, etc.) or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers (e.g., cis or trans). The cis and trans geometric isomers of the compounds described herein may be isolated as a mixture of isomers or as separated isomeric forms. Isotopes

[0060] In the compounds disclosed and described herein, the atoms at each position of the compound can independently have an isotopic distribution for a chemical element in a proportionate amount relative to the amount normally found in nature, or a proportionate amount different from the amount normally found in nature, unless otherwise specified by the context. A particular chemical element has an atomic number defined by the number of protons in the atomic nucleus. Each atomic number is an identification of a particular element, not an isotope, and atoms of a given element may have a wide range of their number of neutrons. The number of both 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 for a chemical element in a proportionate amount different from the amount normally found in nature are generally referred to as isotopically labeled compounds. Each chemical element can include any isotopic distribution of said element as represented in the compound structure. For example, a hydrogen atom in a compound structure may be specifically disclosed or understood to be present in the compound. At any position of the compound where a hydrogen atom may be present, the hydrogen atom may be present in an amount proportional to the amount normally found in nature and in an amount different from the amount normally found in nature, including, but not limited to, protium ( 1 H) and deuterium ( 2 The isotope distribution of hydrogen, including H). Thus, reference to a compound herein includes all possible isotope distributions for each atom, unless otherwise indicated by the context. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine. As will be recognized by those skilled in the art, any of the compounds disclosed and described herein may contain radioisotopes. Thus, one or more atoms may have an isotope distribution different from that normally found in nature, for example, a higher percentage than that found in nature. 2 H or 3 H, or 11 C. 13 C or 14 Also contemplated is the use of compounds disclosed and described herein having 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 The isotopes of oxygen include oxygen-14 ( 14 O), oxygen-15( 15 O), 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 The 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 ( 82Br). Iodine isotopes include iodine-123 ( 123 I), iodine-124( 124 I), iodine-125( 125 I), iodine-131( 131 I) and iodine-135( 135 I). In some embodiments, the atoms at all positions of the compound have an isotopic distribution for each chemical element in a proportionate amount relative to the amount normally found in nature. In some embodiments, the atoms at at least one position of the compound have an isotopic distribution for a proportionate amount of chemical elements different from the amount normally found in nature (the remaining atoms have an isotopic distribution for a proportionate amount of chemical elements relative to the amount normally found in nature). In some embodiments, the atoms at at least two positions of the compound independently have an isotopic distribution for a proportionate amount of chemical elements different from the amount normally found in nature (the remaining atoms have an isotopic distribution for a proportionate amount of chemical elements relative to the amount normally found in nature). In some embodiments, the atoms at at least three positions of the compound independently have an isotopic distribution for a proportionate amount of chemical elements different from the amount normally found in nature (the remaining atoms have an isotopic distribution for a proportionate amount of chemical elements relative to the amount normally found in nature). In some embodiments, the atoms in at least four positions of the compound independently have an isotopic distribution for a proportional amount of a chemical element different from the amount normally found in nature (the remaining atoms have an isotopic distribution for a proportional amount of a chemical element relative to the amount normally found in nature). In some embodiments, the atoms in at least five positions of the compound independently have an isotopic distribution for a proportional amount of a chemical element different from the amount normally found in nature (the remaining atoms have an isotopic distribution for a proportional amount of a chemical element relative to the amount normally found in nature). In some embodiments, the atoms in at least six positions of the compound independently have an isotopic distribution for a proportional amount of a chemical element different from the amount normally found in nature (the remaining atoms have an isotopic distribution for a proportional amount of a chemical element relative to the amount normally found in nature). As the context makes clear, the compound of the present invention can refer to a single molecule or multiple molecules.

[0061] Certain compounds, such as radioisotopes, e.g. 3 H and 14 Compounds incorporating C are also useful in drug or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) isotopes are particularly preferred due to their ease of preparation and detection. Proportional amounts of isotopes greater than those normally found in nature, such as deuterium ( 2 Compounds having the formula (H) have several therapeutic advantages that derive from their higher metabolic stability, e.g. It may result in increased half-life in vivo or reduced dosage requirements.Isotopically labeled compounds can generally be prepared by carrying out routine procedures in the art.Methods such as mass spectrometry are readily available for measuring the perturbation or enrichment of such isotopes, and for isotopes that are radioisotopes, additional methods such as HPLC or GC with radio-detectors are available.

[0062] As used herein, an "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. In certain embodiments, an "isotopic variant" of a compound includes, but is 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( 131 In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., non-radioactive. In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., non-radioactive. In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., non-radioactive. 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 is an unstable form, i.e., radioactive, including, but not limited to, tritium ( 3 H), Carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14O), and oxygen-15 ( 15 In the compounds provided herein, any hydrogen may be, for example, any one of, for example, 1 to 3. 2 H as the predominant isotopic form, or any carbon, e.g. 13 C as the major isotopic form, or any nitrogen, e.g. 15 N as the major isotopic form, any oxygen, e.g. 18 It is understood that the isotope may contain 1,2,3,4,5,6,7,8,8 as the predominant isotopic form. In certain embodiments, an "isotopic variant" of a compound may contain unnatural proportions of deuterium ( 2 H).

[0063] 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 substantially greater than the natural abundance of deuterium, which is about 0.015%. 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), in certain embodiments.

[0064] Synthetic methods for incorporating radioisotopes into organic compounds can be applied 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:

[0065] A. Catalytic Reduction with Tritium Gas: This procedure usually yields high specific activity products and requires halogenated or unsaturated precursors.

[0066] B. Sodium borohydride [ 3 Reduction with [H]: This procedure is somewhat less expensive and requires precursors that contain reducible functional groups such as aldehydes, ketones, lactones, esters, and the like.

[0067] C. Lithium aluminum hydride [ 3 Reduction with [H]: This procedure provides products at nearly theoretical specific activities. It also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, etc.

[0068] D. Tritium Gas Exposure Labeling: This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.

[0069] E. Methyl iodide [ 3 N-Methylation using [H]: This procedure typically involves converting the appropriate precursor to a highly specific activity methyl iodide ( 3 H) to give O-methyl or N-methyl ( 3 H) to prepare the product. This method generally allows for higher specific activities, for example, about 70-90 Ci / mmol.

[0070] Activity level 125 Synthetic methods for incorporating I into target molecules include the following: A. Sandmeyer reaction and similar reactions: This procedure converts aryl or heteroaryl amines to diazonium salts, such as tetrafluoroborate diazonium salts, followed by the addition of Na 125 Using I 125 A typical procedure is described by Zhu, GD. and coworkers in J. Org. Chem., 2002, 67, 943-948. It was reported that B. Phenol ortho 125 Iodination: This procedure was reported by Collier, TL and coworkers in J. Labelled Compd. Radiopharm., 1999, 42, S264-S266. As reported in 125 It becomes possible to incorporate I. C. 125 Exchange of aryl and heteroaryl bromides with I: This method is generally a two-step process. The first step is the conversion of an aryl or heteroaryl bromide to the corresponding tri-alkyltin intermediate using, for example, Pd catalysis [i.e., Pd(Ph3P)4] in the presence of tri-alkyltin halides or hexaalkylditins [e.g., (CH3)3SnSn(CH3)3] or via an aryl or heteroaryl lithium. A representative procedure is described by Le Bas, M.-D. and and coworkers in J. Labelled Compd. Radiopharm. 2001, 44, S280-S282. chemical definition

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by those skilled in the art to which this disclosure belongs.All patents, applications, published applications and other publications are incorporated herein by reference in their entirety.If there are multiple definitions for a term in this specification, the definition in this section shall prevail unless otherwise stated.

[0072] Whenever a group is described as "optionally substituted," the group may be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as "unsubstituted or substituted," if it is substituted, the substituents may be selected from one or more of the indicated substituents. It is understood that substitution at a given atom is limited by valence.

[0073] As used herein, "C a ~C b (where "a" and "b" are integers) refer to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a ring of a heterocyclyl, heteroaryl, cycloalkyl, cycloalkenyl, or aryl group; that is, these groups can contain from "a" to "b" carbon atoms, inclusive. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having one to four carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "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 to be assumed.

[0074] In addition to the above, as used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated.

[0075] The term "alkenyl" refers to an alkyl group that contains one or more double bonds in the straight or branched hydrocarbon chain. Examples of alkenyl groups include arenyl, vinylmethyl, and ethenyl. In some embodiments, an alkenyl group can be unsubstituted or substituted. In some embodiments, an alkenyl group can have from 2 to 6 carbon atoms. The alkenyl group of a compound can be designated as "C2-C6 alkenyl" or a similar designation.

[0076] The term "alkynyl" refers to an alkyl group containing one or more triple bonds in the straight or branched hydrocarbon chain. Examples of alkynyl include ethynyl and propynyl. Alkynyl groups can be unsubstituted or substituted. In some embodiments, alkynyl groups can be unsubstituted or substituted. In some embodiments, alkynyl groups can have from 2 to 6 carbon atoms. The alkenyl group of a compound can be designated as "C2-C6 alkynyl" or a similar designation.

[0077] The term "aryl" refers to an aromatic ring system containing 6, 10 or 14 carbon atoms, e.g., phenyl, naphthalenyl and phenanthrenyl, which may contain a single ring, two fused rings or three fused rings. In some embodiments, an aryl group may have 6 or 10 carbon atoms (i.e., C6 or C7). 10 Aryl). When one or more substituents are present on an "aryl" ring, the substituents may be attached at any available ring carbon. In some embodiments, the aryl group may be substituted or unsubstituted. In some embodiments, the aryl group is phenyl.

[0078] The term "alkyl" refers to a fully saturated straight or branched chain hydrocarbon radical. An alkyl group can have 1-20 carbon atoms (wherever an alkyl group appears herein, a numerical range such as "1-20" refers to each integer in the given range, e.g., "1-20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. In some embodiments, an alkyl group can have 1-6 carbons (i.e., "C1-C6 alkyl"). Some embodiments are 1-5 carbons (i.e., C1-C5 alkyl), some embodiments are 1-4 carbons (i.e., C1-C4 alkyl), some embodiments are 1-3 carbons (i.e., C1-C3 alkyl), and some embodiments are 1 or 2 carbons. By way of example only, "C1-C4 alkyl" is a substituted or unsubstituted alkyl group. "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neo-pentyl, 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 an alkyl group, the substituents may be attached at any available carbon atom. In some embodiments, the alkyl group may be substituted or unsubstituted.

[0079] The term "haloalkyl" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms of the alkyl group are replaced by halogen atoms (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). In some embodiments, a haloalkyl group can have 1-6 carbons (i.e., "haloC1-C6 alkyl"). A haloC1-C6 alkyl can be fully substituted, in which case it can be represented by the formula C n L 2n+1 (L is a halogen and "n" is 1, 2, 3, 4, 5, or 6). When more than one halogen is present, the halogens may be the same or different and may be selected from fluorine, chlorine, bromine, and iodine. In some embodiments, the haloalkyl contains 1-5 carbons (i.e., haloC1-C5 alkyl). In some embodiments, the haloalkyl contains 1-4 carbons (i.e., haloC1-C4 alkyl). In some embodiments, the haloalkyl contains 1-3 carbons (i.e., haloC1-C3 alkyl). In some embodiments, the haloalkyl contains 1 or 2 carbons. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, and the like.

[0080] The term "carbonyl" refers to the group -C(=O)-.

[0081] The term "oxo" refers to a ═O substituent.

[0082] The term "oxyl" means -O · Refers to the group (oxyl radical).

[0083] The term "cycloalkyl" refers to a fully saturated, all-carbon, monocyclic or polycyclic ring system. In some embodiments, the cycloalkyl is a monocyclic ring containing 3-7 carbon atoms (i.e., "C3-C7 cycloalkyl"). Some embodiments contain 3-6 carbons. Some embodiments contain 3-5 carbons. Some embodiments contain 5-7 carbons. Some embodiments contain 3-4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When one or more substituents are present on an alkyl group, the substituents may be attached at any available carbon atom. In some embodiments, the cycloalkyl group may be substituted or unsubstituted.

[0084] The term "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, but if more than one is present, the double bonds cannot form a completely delocalized π-electron system (i.e., aromatic system) through all rings, otherwise the group can be "aryl" as defined herein. When composed of two or more rings, the rings can be fused, bridged, or joined together in a spiro fashion. Cycloalkenyls can contain 3-12 atoms in the rings or 3-8 atoms in the rings. In some embodiments, cycloalkenyl groups can be unsubstituted or substituted. In some embodiments, cycloalkenyl groups can have 4-8 carbon atoms (i.e., "C4-C8 cycloalkenyl"). An example is cyclohexenyl.

[0085] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system having 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," which refers to an aromatic ring containing 5-6 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, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, isoindolyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, dibenzo[b,d]furan, dibenzo[b,d]thiophene, phenanthridinyl, benzimidazolyl, pyrrolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, and the like. Heteroaryl groups can be substituted or unsubstituted. In some embodiments, heteroaryl groups have 5-10 ring members or 5-7 ring members. Heteroaryl groups may be designated as "5- to 7-membered heteroaryl," "5- to 10-membered heteroaryl," or similar designations. In some embodiments, heteroaryl is a substituted or unsubstituted C1-C6 heteroaryl having 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 13In some embodiments, the heteroaryl may be a substituted or unsubstituted C1-C5 5- or 6-membered monocyclic ring containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl may be a substituted or unsubstituted C5-C9 8-, 9-, or 10-membered bicyclic ring system containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl is a substituted or unsubstituted C5-C9 8-, 9-, or 10-membered heteroaryl. In some embodiments, the C5-C9 8-, 9-, or 10-membered bicyclic heteroaryl is imidazo[2,1-b]thiazolyl, 1H-indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzisoxazolyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyrido[3,4-b]pyrazinyl, or pyrido[4,3-d]pyrimidinyl. In some embodiments, the heteroaryl is a substituted or unsubstituted C8-C aryl ring with 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur. 13In some embodiments, the heteroaryl is a 13- or 14-membered tricyclic ring system. In some embodiments, the heteroaryl can be azolyl, 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, the heteroaryl is a C1-C4 5-membered heteroaryl. In some embodiments, the C1-C4 5-membered heteroaryl is furanyl, thienyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, isothiazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, pyrrolyl, triazolyl, or tetrazolyl. In some embodiments, the heteroaryl is a C3-C5 6-membered heteroaryl. In some embodiments, the C3-C5 6-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments, the "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]thiophenyl, and the like. In some embodiments, the "5-10-membered heteroaryl" refers to pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, 1H-indolyl, quinoxalinyl, thiadiazolyl, and the like. In some embodiments, the heteroaryl group may be substituted or unsubstituted.

[0086] The term "heterocyclyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and up to 18-membered monocyclic, bicyclic, and tricyclic ring systems, in which carbon atoms together with 1-5 heteroatoms make up said ring system, and which optionally contain one or more unsaturated bonds, but which are positioned so as not to result in a completely delocalized π-electron system (aromatic system) in the monocyclic ring or in at least one ring of the bicyclic or tricyclic ring 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 can be fused, bridged, or joined together in a spiro fashion, where the heteroatom can be in either the non-aromatic or aromatic ring in the ring system. In some embodiments, the heterocyclyl can be a 3-7 membered saturated non-aromatic ring system containing 3-7 ring atoms, where at least one ring atom is a heteroatom. In some embodiments, "3- to 6-membered heterocyclyl" refers to a saturated non-aromatic ring radical containing 3 to 6 ring atoms, where at least one ring atom is a heteroatom. In some embodiments, "4- to 6-membered heterocyclyl" refers to a saturated non-aromatic ring radical containing 4 to 6 ring atoms, where 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 can contain a carbonyl (C=O) group adjacent to the heteroatom, i.e., substituted by oxo on the carbon adjacent to the heteroatom, where the substituted ring system is a lactam, lactone, cyclic imide, cyclic thioimide, or cyclic carbamate.Examples of unsubstituted or oxo-substituted "heterocyclyl" groups include, but are not limited to, aziridinyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,3-oxathiolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, 1,4-oxathianyl, tetrahydro-1,4-thiazinyl, 2H-1,2-oxazinyl, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolinyl, indolinyl, oxaz ... Zolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, 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 their benzo-fused analogs (e.g., benzimidazolidinonyl, tetrahydroquinolinyl, and 3,4-methylenedioxyphenyl). Heterocyclyl groups may be designated as "3- to 10-membered heterocyclyl" or similar designations. In some embodiments, heterocyclyl is a C-C ring system containing 1-5 heteroatoms selected from nitrogen, oxygen and sulfur. 12In some embodiments, the heterocyclyl may be a substituted or unsubstituted C2-C6 3-, 4-, 5-, 6-, or 7-membered monocyclic ring containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl may be a substituted or unsubstituted C2-C6 3-, 4-, 5-, 6-, or 7-membered monocyclic ring containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur. 10 In some embodiments, the heterocyclyl is a substituted or unsubstituted C7-C cyclic ring system containing 1-5 heteroatoms selected from nitrogen, oxygen and sulfur. 12In some embodiments, the heteroatoms of a 6-membered monocyclic heterocyclyl are selected from 1 to 3 of O (oxygen), N (nitrogen) or S (sulfur), and the heteroatoms of a 5-membered monocyclic heterocyclyl are selected from 1 or 2 heteroatoms selected from O (oxygen), N (nitrogen) or S (sulfur). In some embodiments, the heterocyclyl is selected from aziridinyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl, 1,3-dioxolanyl, 1,3-oxathiyl, 1,4-oxathiyl, 1,3-oxathiolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, 1,4-oxathiyl, tetrahydro-1,4- Thiazinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolinyl, indolinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, 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, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,7-naphthyridinyl, 1,2,3,4-tetrahydro-1,7-naphthyridinyl, It can be 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]dioxolo[4,5-c]pyridinyl, [1,3]dioxolo[4,5-b]pyridinyl, [1,3]dioxolo[4,5-d]pyrimidinyl or 3,4-methylenedioxyphenyl.In some embodiments, the unsubstituted or substituted heterocyclyl can be selected from aziridinyl, azetidinyl, piperidinyl, morpholinyl, oxetanyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, 2-piperidone, 1,1-dioxidothiomorpholinyl, oxolanyl (tetrahydrofuranyl), and oxanyl (tetrahydropyranyl). When one or more substituents are present on the heterocyclyl group, the substituents can be attached at any available carbon atom and / or heteroatom. In some embodiments, the heterocyclyl group can be substituted or unsubstituted.

[0087] The term "cyano" refers to the group -CN.

[0088] The term "halogen" or "halo" refers to a fluoro, chloro, bromo, or iodo group. In some embodiments, the halogen or halo is fluoro, chloro, or bromo. In some embodiments, the halogen or halo is fluoro or chloro. In some embodiments, the halogen or halo is fluoro.

[0089] The term "nitro" refers to the group --NO.sub.2.

[0090] The term "halogenating agent" refers to a compound that provides a halogen atom to a reactant compound, e.g., converts an alcohol reactant compound to 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, triphenylphosphine dibromide, phosphorus pentabromide, or thionyl bromide.

[0091] The term "coupling agent" refers to a compound that promotes the formation of an amide bond, where activation of a carboxylic acid is required to facilitate coupling with an amine. Examples of amide coupling agents include, but are not limited to, thionyl chloride, oxalyl chloride, phosphorus oxychloride, 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-triazin-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-dimethylphenyl)-2-propanediol (DMTMM), (ethylaminopropyl)-N'-ethylcarbodiimide (EDC), 1,3-di-p-tolylcarbodiimide, benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyClock) , (7-azabenzotriazol-1-yloxy)trispyrrolidinophosphonium hexafluorophosphate (PyAOP), 1-cyano-2-ethoxy-2-oxoethylideneaminooxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyOxim), 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate (COMU), 3-(diethoxy-phosphoryloxy)-1,2,3-Benzo[d]triazin-4(3H)-one (DEPBT), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), O-(2-oxo-1(2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), N,N,N',N'-tetramethyl-O-(N-succinimide) imidyl)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-tetramethylaminium hexafluorophosphate (HCTU), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU).

[0092] The term "base" refers to a compound that is an electron pair donor in an acid-base reaction.

[0093] The base may be an inorganic base or an organic base.

[0094] The term "organic base" refers to a base (e.g., an amine base) that contains at least one C-H bond. In some embodiments, the amine base may be a primary, secondary, or 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, and the like.

[0095] The term "inorganic base" refers to a base that does not contain at least one C-H bond and that contains 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, and the like.

[0096] For compounds disclosed herein or pharma- ceutically acceptable salts thereof in which a variable occurs more than once, each variable may be a different moiety independently selected from the group defining that variable. For example, when a structure is described having two R groups co-occurring on the same compound, the two R groups may represent different moieties independently selected from the group defined for R.

[0097] As used herein, abbreviations for any protecting groups, amino acids and other compounds follow their common usage, accepted abbreviations, or those of the IUPAC-IUB Biochemical Nomenclature Commission (see Biochem. 11:942-944 (1972)) unless otherwise specified.

[0098] The phrase "pharmacologically acceptable" is used herein to refer to compounds, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0099] The compounds described herein may be used in neutral form, such as free acid or free base form. Alternatively, the compounds may be used in the form of acid or base addition salts. The term "pharmaceutically acceptable salt" refers to a salt of a compound having an acidic or basic moiety that is biologically or otherwise desirable for use in medicine. In many cases, the compounds disclosed herein can form acid salts and / or base salts due to the presence of an acidic or basic moiety (e.g., amino and / or carboxyl groups or groups similar thereto). Pharmaceutically acceptable acid addition salts can be formed by combining compounds having a basic moiety with inorganic and organic acids. Inorganic acids that can be used to prepare salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. 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 a compound having an acidic moiety with an inorganic base and an organic base. Inorganic bases that can be used to prepare salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, aluminum hydroxide, carbonate, bicarbonate, phosphate, etc., and particularly preferred are hydroxide, carbonate, bicarbonate, or phosphate salts of ammonium, potassium, sodium, calcium, and magnesium. Organic bases which 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, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with at least a stoichiometric amount of a suitable base or acid in water or an organic solvent, or a mixture of the two, generally with non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) being preferred. Lists of suitable salts can be found in WO87 / 05297, published September 11, 1987, by Johnston et al., 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. References for the preparation and selection of pharmaceutical salts of the present disclosure include PH Stahl & CG Wermuth "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002, which is incorporated herein by reference in its entirety. preparation

[0100] The present invention further relates to the preparation of the compound of the present invention or its salt.As used herein, "preparation" is, for example, the product of the process used to make or purify the compound of the present invention or its salt.In some embodiments, the preparation may optionally contain one or more impurities, residual solvent, or a combination thereof.The preparation may be liquid or solid.

[0101] In some embodiments, the present invention provides a compound of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof, Each R1a are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a teeth, 13 C(R A )3 or C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2R B [is].

[0102] In some embodiments, the present invention provides a compound of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof, Each R 1a are independently A )3 or C(R A )2R Band Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2R B [is].

[0103] In some embodiments, R 7a is C(R A )2R B and R C is hydrogen.

[0104] In some embodiments, R 7a is CH2OH.

[0105] In some embodiments, the present invention provides a compound of formula (IIa) [ka] or a pharma- ceutically acceptable salt thereof.

[0106] In some embodiments, R 6a is CD3 or R 6a is CH3.

[0107] In some embodiments, R 6a is CD3.

[0108] In some embodiments, each R 2a is hydrogen.

[0109] In some embodiments, R 7a is CD2OH.

[0110] In some embodiments, the compound of the preparation is a compound having the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0111] In some embodiments, the compound of the preparation is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0112] In some embodiments, the compound of the preparation is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0113] In some embodiments, the compounds of the preparation are in 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 a range defined by any of the foregoing values.

[0114] In some embodiments, the preparation comprises 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 a range defined by any of the preceding numeric values.

[0115] In some embodiments, the preparation 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 percentage within a range defined by any of the preceding numeric values.

[0116] In some embodiments, the preparation comprises at least about 50% by weight of the compound.

[0117] In some embodiments, the preparation comprises at least about 75% by weight of the compound.

[0118] In some embodiments, the preparation comprises at least about 90% by weight of the compound.

[0119] In some embodiments, the preparation comprises at least about 95% by weight of the compound.

[0120] In some embodiments, the preparation is in solid form, ie, a solid preparation.

[0121] In some embodiments, the preparation is used to prepare a pharmaceutical composition. Prodrug

[0122] "Prodrug" is meant to indicate a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound, such as compound 2 described herein. Thus, the term "prodrug" refers to a metabolic precursor of a compound described herein that is pharma- ceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo into an active compound described herein. A prodrug is typically rapidly converted in vivo, for example by hydrolysis in blood, to yield the parent compound described herein. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; Both of which are incorporated herein by reference in their entireties.

[0123] In one embodiment, the compounds of formula (IIIaa), (IIIbb), (IIIcc), (IIIdd), (IIIee) and (IIIff) act as prodrugs of compound 2, i.e., 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.

[0124] Some embodiments include a compound of formula (III) [ka] or a pharma- ceutically acceptable salt thereof, R 11 teeth, a)-P(=O)(OR 33 )2 or -P(=O)(OR 33 )(N(R 33 )2) b) -C(=O)R 50 , c) -C(=O)N(R 33 )R 50 , d) -C(=O)OR 50 ,or e)R 50 and Each R 33 are independently hydrogen, C1-C6 alkyl, haloC1-C6 alkyl or aryl, where C1-C6 alkyl and aryl are each independently R 10 where appropriate, 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 one or more R 10 and / or R 20 where appropriate, Each R 10are independently halo, haloC1-C6 alkyl, cyano, nitro, trimethylsilanyl, -O · (oxyl radical), -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 two R's as required 10 the groups taken together on a single atom form oxo, each t is independently 1 or 2; each p is independently 1, 2, or 3; Each R 20 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl, or heteroaryl, where each R 20 is R 10 and / or R 22 where appropriate, Each R 22 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl, or heteroaryl, where each R 22 is R10 where appropriate, Each R 30 , R 31 and R 32 are independently hydrogen, haloC1-C6 alkyl, or C1-C6 alkyl; Each R 1a are independently A )3, Each R A are independently hydrogen or deuterium; Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3, R 7a is C(R A )3].

[0125] In some embodiments, each R 33 are independently hydrogen, C1-C6 alkyl, haloC1-C6 alkyl or aryl; R 50 is C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, or heterocyclyl, and each R 20 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl, or heteroaryl, and 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 is independently hydrogen, haloC1-C6 alkyl, or C1-C6 alkyl.

[0126] In some embodiments, the compound is a compound of formula (IIIa) [ka] or a pharma- ceutically acceptable salt thereof.

[0127] In some embodiments, the compound is a compound of formula (IIIaa) [ka] or a pharma- ceutically acceptable salt thereof.

[0128] In some embodiments, the compound is a compound of formula (IIIb) [ka] or a pharma- ceutically acceptable salt thereof.

[0129] In some embodiments, the compound is a compound of formula (IIIbb) [ka] or a pharma- ceutically acceptable salt thereof.

[0130] In some embodiments, the compound is a compound of formula (IIIc) [ka] or a pharma- ceutically acceptable salt thereof.

[0131] In some embodiments, the compound is a compound of formula (IIIcc) [ka] or a pharma- ceutically acceptable salt thereof.

[0132] In some embodiments, the compound is a compound of formula (IIId) [ka] or a pharma- ceutically acceptable salt thereof.

[0133] In some embodiments, the compound is a compound of formula (IIIdd) [ka] or a pharma- ceutically acceptable salt thereof.

[0134] In some embodiments, the compound is a compound of formula (IIIe) [ka] or a pharma- ceutically acceptable salt thereof.

[0135] In some embodiments, the compound is a compound of formula (IIIee) [ka] or a pharma- ceutically acceptable salt thereof.

[0136] In some embodiments, the compound is a compound of formula (IIIf) [ka] or a pharma- ceutically acceptable salt thereof.

[0137] In some embodiments, the compound is a compound of formula (IIIff) [ka] or a pharma- ceutically acceptable salt thereof.

[0138] In some embodiments, R 11 is selected from one of the following: [ka] [ka] [ka] [ka] [ka] [ka]

[0139] In some embodiments, R 11 teeth, [ka] is selected from.

[0140] In some embodiments, the compound is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0141] In some embodiments, the compound is the hydrochloride salt of a compound of the formula: [ka]

[0142] In some embodiments, the compound is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0143] In some embodiments, the compound is the sodium salt of a compound of the formula: [ka]

[0144] In some embodiments, the compound is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof.

[0145] In some embodiments, the compound is the sodium salt of a compound of the formula: [ka]

[0146] In some embodiments, the compound is a bis-sodium salt of a compound of the formula: [ka]

[0147] The compound of formula (III) can be prepared according to the synthesis method described in International Publication WO2016 / 127133A1.For example, the compounds of formula (IIIaa), (IIIbb), (IIIcc), (IIIdd), (IIIee) and (IIIff) can be prepared according to the synthesis method described in International Publication WO2016 / 127133A1, using compound 2 as 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.

[0148] In some embodiments, the compound of formula (IIIaa) can be prepared by reacting compound 2 as the starting material with 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 methylene chloride, with R 50 In some embodiments, the compound of formula (IIIaa) can be prepared by reacting compound 2 as the starting material with R 50 C(═O)X (X is Cl, Br, or I), where R 50 C(=O)X can be purchased if commercially available or can be prepared by the method R 50 C(═O)OH can be prepared by reacting with a halogenating agent (e.g., thionyl chloride). In some embodiments, the compound of formula (IIIaa) can be prepared by reacting compound 2 as the starting material with R 50 C(=O)OC(=O)R 60 where R 50 C(=O)OC(=O)R 60 can be purchased if commercially available or 50 C(=O)OH is reacted with R 60 C(=O)X, where R 60is C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, haloC1-C6 alkyl, cyano, and nitro.

[0149] In some embodiments, the compound of formula (IIIbb) can be prepared by reacting compound 2 as the starting material with p-nitrophenyl chloroformate, 1,1-bis[6-(trifluoromethyl)benzotriazolyl]carbonate, di(2-pyridyl)carbonate, N,N′-disuccinimidyl carbonate, phenyl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylate, CDI, phosgene, or triphosgene in a solvent, optionally in the presence of a base (e.g., DMAP), followed by reaction with R 50 It can be prepared by treatment with OH.

[0150] In some embodiments, the compound of formula (IIIcc) can be prepared by reacting compound 2 as starting material with p-nitrophenyl chloroformate, 1,1-bis[6-(trifluoromethyl)benzotriazolyl]carbonate, di(2-pyridyl)carbonate, N,N′-disuccinimidyl carbonate, phenyl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylate, CDI, phosgene, or triphosgene in a solvent, optionally in the presence of a base (e.g., DIPEA or DMAP), followed by reaction with R 50 R 33 It can be prepared by treatment with NH.

[0151] In some embodiments, the compound of formula (IIIdd) can be prepared by reacting compound 2 as the starting material with (R 33 O)2P(=O)X (X is Cl, Br, or I) by reaction with

[0152] In some embodiments, the compound of formula (IIIee) is R 50 R 33 NH in a solvent (e.g., methylene chloride) and optionally a base (e.g., TEA or N-methylimidazole) to form (R 33 O)P(═O)(X)2 (wherein X is Cl, Br, or I) to give a chlorophosphoramidate intermediate ((R 33 O)(R 50 R 33 N)P(=O)(X)), which can then be treated with compound 2 as the starting material.

[0153] In some embodiments, the compound of formula (IIIff) can be prepared by reacting compound 2 as the starting material with a base (e.g., NaH) or in the presence of a base (e.g., KCO) in a solvent (e.g., DMF or DMSO), followed by reaction with R 50 X (wherein X is Cl, Br, or I) or R 50 S(=O)2R 60 (where R 60 is a C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, haloC1-C6 alkyl, cyano, and nitro.

[0154] In some embodiments, the compound of formula (IIIff) can be prepared by reacting compound 2 as the starting material with a halogenating agent (p-toluenesulfonyl chloride (TsCl) or methanesulfonyl chloride (MsCl)) in a solvent (e.g., DMF) optionally in the presence of a base (e.g., KCO), followed by reacting R 50 Combine with OH or R 50 R prepared by reacting OH with a base (e.g., NaH) in a solvent (e.g., DMF or DMSO).50 It can be prepared by combining OH with an alkoxide. How to use

[0155] Provided herein is a method of treating congenital adrenal hyperplasia (CAH), comprising administering a therapeutically effective amount of a compound of the present invention or a pharma- ceutically acceptable salt thereof to a subject in need of treating congenital adrenal hyperplasia (CAH). In some embodiments, the compound is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 4 or 5, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7, or 8, or a pharma- ceutically acceptable salt thereof.

[0156] Provided herein is a method of treating congenital adrenal hyperplasia (CAH), comprising administering to a subject in need of treating congenital adrenal hyperplasia (CAH) a therapeutically effective amount of a pharmaceutical composition comprising a compound of the present invention or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient. In some embodiments, the compound is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 2, 4, or 5, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7, or 8, or a pharma- ceutically acceptable salt thereof.

[0157] Provided herein is a method of treating congenital adrenal hyperplasia (CAH), comprising administering a compound of the present invention or a pharma- ceutically acceptable salt thereof to normalize or partially normalize the levels of biomarkers associated with congenital adrenal hyperplasia. In some embodiments, normalizing or partially normalizing the levels of biomarkers comprises reducing the levels of elevated biomarkers or increasing the levels of reduced biomarkers compared to subjects without CAH. In some embodiments, the compound is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 4 or 5, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7, or 8, or a pharma- ceutically acceptable salt thereof.

[0158] 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 pharma- ceutically acceptable salt thereof and at least one pharma- ceutically 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 pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 2, 4, or 5, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7, or 8, or a pharma- ceutically acceptable salt thereof.

[0159] Provided herein is a method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering a compound of the present invention or a pharma- ceutically 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 biomarkers are selected from (a) 17-hydroxyprogesterone (17-OHP), (b) testosterone, and (c) androstenedione in the subject. In some embodiments, the compound is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 4 or 5, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7, or 8, or a pharma- ceutically acceptable salt thereof.

[0160] Provided herein is a method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering a pharmaceutical composition comprising a compound of the present invention or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient in an amount sufficient to reduce the level of one or more biomarkers associated with congenital adrenal hyperplasia. In some embodiments, the biomarkers are selected from (a) 17-hydroxyprogesterone (17-OHP), (b) testosterone, and (c) androstenedione in the subject. In some embodiments, the compound is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 2, 4, or 5, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7, or 8, or a pharma- ceutically acceptable salt thereof.

[0161] In some embodiments, the reduction of any of the biomarkers (e.g., any of 17-OHP, testosterone, and androstenedione) levels is determined by comparing the level of the biomarker measured during circadian release on the day before administering the compound of the present invention or a pharmaceutically acceptable salt thereof with the level of the biomarker measured during circadian release on the day after administering the compound of the present invention or a pharmaceutically acceptable salt thereof.The day before administering the compound of the present invention or a pharmaceutically acceptable salt thereof applies to subjects who have not previously administered the compound of the present invention or a pharmaceutically acceptable salt thereof within at least the past 24 hours.

[0162] In some embodiments, the circadian release of biomarkers associated with CAH occurs between 2:00 a.m. and 10:00 a.m. In other embodiments, the circadian release of biomarkers associated with CAH occurs between 6:00 a.m. and 10:00 a.m.

[0163] In some embodiments of any of the methods disclosed herein, the compound of the present invention or a pharma- ceutically acceptable salt thereof is administered to the subject at night or before sleep (i.e., at bedtime). In some embodiments, the compound of the present invention or a pharma- ceutically acceptable salt thereof is administered 3-8 hours before the circadian release of the biomarker. In some embodiments, the compound of the present invention or a pharma- ceutically acceptable salt thereof is administered 6-8 hours before the circadian release of the biomarker. Administration before the circadian release may be accommodated for shift workers (e.g., workers who work at night and sleep during the day), in which case administration does not necessarily have to occur at night. Thus, administration depends on the predicted circadian release of the biomarker and may vary depending on the particular work and sleep patterns of the individual (i.e., subject, patient).

[0164] In some embodiments of the methods provided herein, the 17-hydroxyprogesterone level in the subject 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 pre-administration level. In some embodiments, the 17-hydroxyprogesterone level is reduced by at least about 25%. In some embodiments, the 17-hydroxyprogesterone level is reduced by at least 50%. In some embodiments of the methods provided herein, 17-hydroxyprogesterone levels are reduced by an amount from pre-administration levels of 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%.

[0165] In some embodiments, 17-hydroxyprogesterone levels are reduced to a level within the range of 17-hydroxyprogesterone expected in a subject free of CAH, ie, below 1,000 ng / dL or below 200 ng / dL.

[0166] In some embodiments of the methods provided herein, testosterone levels are 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 pre-administration levels. In some embodiments, testosterone levels are reduced by at least about 25%. In some embodiments, testosterone levels are reduced by at least about 40%. In some embodiments, testosterone levels are reduced by at least about 50%.

[0167] In some embodiments of the methods provided herein, testosterone levels are reduced by an amount from pre-administration levels of 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%.

[0168] In some embodiments, testosterone levels are reduced to a level within the range of testosterone expected in a subject free of CAH.

[0169] In some embodiments of the methods provided herein, androstenedione levels are 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 pre-administration levels. In some embodiments, androstenedione levels are reduced by at least about 25%. In some embodiments, androstenedione levels are reduced by at least about 30%. In some embodiments, androstenedione levels are reduced by at least about 50%.

[0170] In some embodiments of the methods provided herein, androstenedione levels are reduced by an amount from pre-administration levels of 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%.

[0171] In some embodiments, androstenedione levels are reduced to a level within the range of androstenedione expected in a subject without CAH, i.e., below 200 ng / dL.

[0172] In some embodiments of the methods provided herein, 17-hydroxyprogesterone levels are reduced by at least about 50% from pre-administration levels and androstenedione levels are reduced by at least about 50%. In some embodiments of the methods provided herein, 17-hydroxyprogesterone levels are reduced by at least about 50% from pre-administration levels and androstenedione levels are reduced by at least about 30%.

[0173] Also provided herein is a method for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and impaired growth in a subject with classical congenital adrenal hyperplasia, comprising administering a compound of the present invention or a pharma- ceutically acceptable salt thereof in an amount sufficient to reduce one or more biomarkers of CAH in the subject, e.g., to reduce androstenedione in the subject. Impaired growth can refer to, for example, accelerated height growth velocity, accelerated weight growth velocity, and / or accelerated bone age.

[0174] Provided herein is a method for reducing the level of one or more biomarkers in a subject with congenital adrenal hyperplasia, comprising administering to the subject a compound of the present invention or a pharma- ceutically acceptable salt thereof. In some embodiments, the 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 pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 2, 4, or 5, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7, or 8, or a pharma- ceutically acceptable salt thereof.

[0175] Provided herein is a method for reducing the level of one or more biomarkers in a subject with congenital adrenal hyperplasia, comprising administering to the subject a pharmaceutical composition comprising a compound of the present invention or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient. In some embodiments, the 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 pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 2, 4, or 5, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7, or 8, or a pharma- ceutically acceptable salt thereof.

[0176] Provided herein is a method for reducing the dosage of a corticosteroid administered to a subject with congenital adrenal hyperplasia to control the congenital adrenal hyperplasia, comprising administering to the subject a compound of the present invention or a pharma- ceutically 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.

[0177] Provided herein is a method for reducing the dosage of a corticosteroid administered to a subject with congenital adrenal hyperplasia to control the congenital adrenal hyperplasia, comprising administering to the subject a pharmaceutical composition comprising a compound of the present invention or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient. In some embodiments, the compound is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7, or 8, or a pharma- ceutically acceptable salt thereof.

[0178] Also provided herein is a method of reducing the severity of one or more side effects of glucocorticoid treatment in a subject with congenital adrenal hyperplasia, comprising administering to the subject a compound of the present invention or a pharma- ceutically acceptable salt thereof. The long-term effects of glucocorticoid treatment are well documented in the art (see, e.g., Oray, M. et al. (2016): Long-term effect of glucocorticoids, Expert Opinion on (See Drug Safety. DOI: 10.1517 / 14740338.2016.1140743.) Such side effects may affect all biological systems, including musculoskeletal (e.g., osteoporosis, avascular necrosis of bone, and myopathy), endocrine and metabolic (e.g., hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth suppression, adrenal suppression), gastrointestinal (e.g., gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, fatty liver, pancreatitis), cardiovascular (e.g., hypertension, coronary heart disease, ischemic heart disease, heart failure), dermatological (e.g., dermatoporosis, dermatomal inflammatory disease, and osteoporosis), and osteoporosis. Skin atrophy, ecchymoses, purpura, erosions, striae, delayed wound healing, simple purpura, acne, hirsutism, and hair loss), neuropsychiatric (e.g., mood changes, depression, euphoria, emotional lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, and delirium), ophthalmology (e.g., cataracts, glaucoma, ptosis, mydriasis, opportunistic ocular infections, and central serous chorioretinopathy), and immune system (e.g., suppression of cell-mediated immunity, predisposition to infection, and reactivation of latent infections). 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.

[0179] Also provided herein is a method of reducing the severity of one or more side effects of glucocorticoid treatment in a subject with congenital adrenal hyperplasia, comprising administering to the subject a pharmaceutical composition comprising a compound of the present invention or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient. In some embodiments, the compound is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III) or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof. In some embodiments, the compound is compound 6, 7, or 8, or a pharma- ceutically acceptable salt thereof.

[0180] Thus, in some embodiments, the side effects of glucocorticoid treatment are selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth suppression, adrenal suppression, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, fatty liver, pancreatitis, hypertension, coronary heart disease, ischemic heart disease, heart failure, dermatoporosis, atrophoderma, ecchymosis, purpura, erosions, striae, delayed wound healing, purpura simplex, acne, hirsutism, hair loss, mood changes, depression, euphoria, emotional lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cellular immunity, predisposition to infection, reactivation of latent infection, and any combination thereof.

[0181] Provided herein is a method of treating congenital adrenal hyperplasia in a subject, comprising: (i) measuring in a biological sample obtained from the subject the level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) testosterone, and (c) androstenedione; (ii) analyzing the level of the one or more biomarkers measured in step (i) to determine whether the level of the one or more biomarkers is elevated compared to healthy subjects who do not have congenital adrenal hyperplasia; (iii) if the subject is determined to have elevated levels of one or more biomarkers, administering to the subject a compound of the invention or a pharma- ceutically acceptable salt thereof; A method is provided that includes:

[0182] In some embodiments, the method further comprises the step of (iv) measuring the level of one or more biomarkers in a biological sample obtained from the subject after administering the compound of the invention or a pharma- ceutically acceptable salt thereof to determine whether the subject has a reduced level of the one or more biomarkers compared to the measurement of step (i). In some embodiments, the method further comprises the step of (v) continuing administration of the compound of the invention or a pharma- ceutically acceptable salt thereof if the subject has a reduced level of the one or more biomarkers.

[0183] In some embodiments, steps (i) and (iv) are performed on biological samples taken from the subject in a similar manner within the same time of day window. In some embodiments, steps (i) and (iv) are performed on biological samples taken from the subject between 2:00 AM and 10:00 AM within the time window. In some embodiments, steps (i) and (iv) are performed on biological samples taken from the subject between 6:00 AM and 10:00 AM within the time window.

[0184] 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.

[0185] In some embodiments, steps (i) and (iv) comprise measuring levels of (a) 17-hydroxyprogesterone (17-OHP), (b) testosterone, and (c) androstenedione.

[0186] In some embodiments, step (i) comprises measuring 17-hydroxyprogesterone (17-OHP) levels, and 17-hydroxyprogesterone (17-OHP) levels are elevated if they are equal to or greater than 1,000 ng / dL.

[0187] In some embodiments, step (i) comprises measuring androstenedione levels, and androstenedione levels are elevated if greater than 200 ng / dL.

[0188] In some embodiments of the disclosed methods, the compound of the invention or a pharma- ceutically acceptable salt thereof 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 invention or a pharma- ceutically acceptable salt thereof is administered in an amount equivalent to about 50 mg or about 100 mg of the free base compound.

[0189] In some embodiments of the methods disclosed herein, the compounds of the invention are administered in free base form.

[0190] In some embodiments of the methods disclosed herein, the compound of the invention, or a pharma- ceutically acceptable salt thereof, is administered once per day or twice per day.

[0191] 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.

[0192] In some embodiments of the methods disclosed herein, the compounds of the invention are administered in a pharmaceutical composition comprising the compound or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0193] In some embodiments of the methods disclosed herein, the compound is a compound of formula (Ia) having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0194] Some embodiments include a method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject 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). [ka] administering The method includes the step of: generating compound 2 under physiological conditions or by solvolysis following administration of a prodrug of compound 2 or a pharma- ceutically acceptable salt thereof to a subject; and wherein the prodrug of compound 2 or a pharma- ceutically 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 pharmaceutical salt thereof.

[0195] Some embodiments include a method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject 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). [ka] administering The method provides a method in which compound 2 is produced as a result of a metabolic chemical reaction following administration of a prodrug of compound 2, or a pharma- ceutically acceptable salt thereof, to a subject, and the prodrug of compound 2, or a pharma- ceutically 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 pharmaceutical salt thereof.

[0196] Some embodiments include a method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject 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). [ka] or a pharma- ceutically acceptable salt thereof, wherein the prodrug of Compound 2 or a pharma- ceutically 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 pharmaceutical salt thereof.

[0197] In some embodiments of the methods disclosed herein, the CAH is classical CAH. In some embodiments of the methods disclosed herein, the CAH is non-classical CAH.

[0198] As used herein, the term "subject" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, most preferably humans. In the context of clinical trials or screening or activity experiments, the subject may be a healthy volunteer or participant without an underlying CRF1-mediated disorder or condition, or a volunteer or participant who has been diagnosed with a disorder or condition that requires medical treatment, as determined by a health care professional. In the context of non-clinical trials, a subject who has been diagnosed with a disorder or condition and is under the care of a health care professional is typically described as a patient. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject is identified or diagnosed as having congenital adrenal hyperplasia (CAH). In some embodiments, the subject is suspected of having CAH. In some embodiments, the subject has clinical records indicating that the subject has CAH (optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject.

[0199] The term "pediatric subject," as used herein, refers to a subject under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subpopulations, including neonates (birth to 1 month of age), infants (1 month to 2 years of age), children (2 to 12 years of age), and adolescents (12 to 21 years of age (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 embodiments, the 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 less than 21 years of age (up to but not including the 22nd birthday). In some embodiments, the pediatric subject is from birth to the first 28 days of life, from 29 days to less than 1 year of age, from 1 month to less than 4 months of age, from 3 months to less than 7 months of age, from 6 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.

[0200] As used herein, the terms "treat" and "treatment" refer to the medical management of a disease, disorder, or condition of a subject (i.e., a patient) (see, for example, Stedman's Medical Dictionary). In general, an appropriate dosage and treatment regimen provides a CRF1 antagonist in an amount sufficient to provide therapeutic and / or prophylactic benefit. The therapeutic benefit for a subject to whom a CRF1 antagonist compound described herein is administered includes, for example, improved clinical outcome, the purpose of which is to prevent or slow or delay (reduce) undesirable physiological changes associated with a disease, or to prevent or slow or delay (reduce) the spread or severity of such a disease. As discussed herein, the efficacy of one or more CRF1 antagonists may include beneficial or desired clinical outcomes, including, but not limited to, amelioration, reduction or alleviation of symptoms resulting from or associated with the disease to be treated; reduction in the occurrence of symptoms; improvement in quality of life; prolonged disease-free state (i.e., reduction in the likelihood or propensity of a subject to develop symptoms based on a diagnosis of the disease being made); reduction in the extent of disease; stabilization of the disease state (i.e., not worsening); delay or slowing of disease progression; alleviation or remission of disease symptoms; and remission (whether partial or complete), whether detectable or undetectable; and / or overall survival.

[0201] "Treatment" can also mean prolonging survival as compared to expected survival if the subject had not received treatment. Subjects in need of treatment include those already with the disease or disorder, as well as those prone to having 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).

[0202] The term "preventing" as used herein means preventing, in whole or in part, the onset, recurrence or spread of a disease or condition as described herein, or a symptom thereof.

[0203] The term "administration" or "administering" refers to a method of giving a dosage of a compound or pharmaceutical formulation to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian. The preferred method of administration can vary depending on various factors, such as the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.

[0204] As used herein, a "therapeutically effective amount" is an amount of the compound of the present invention or a pharma- ceutically acceptable salt thereof, or an amount of a pharmaceutical composition containing the compound of the present invention or a pharma- ceutically acceptable salt thereof, sufficient to achieve a desired effect, and may vary according to the nature and severity of the disease state and the potency of the compound. The therapeutic effect is some degree of relief of one or more symptoms of the disease, and may include curing the disease. "Cure" means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after the cure is obtained (such as, for example, extensive tissue damage).

[0205] As used herein, "time frame" refers to the period defined by the start time of the frame and the stop time of the frame.These times all refer to the local time when the sample is taken.The phrase "same time frame" means that when referring to samples taken from a subject, for example, a sample taken at 8:15 am and a sample taken at 9:15 am are considered to be taken in the same time frame, for example, 2 am to 10 am or 6 am to 10 am.

[0206] 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, the reduction of 17-OHP and androstenedione compared with no treatment, or the reduction of the amount of glucocorticoid (e.g., hydrocortisone, dexamethasone, prednisone or prednisolone) administered per day.

[0207] In some embodiments, the compounds of the present invention or pharma- ceutically acceptable salts thereof can provide a reduction in 17-OHP plasma levels in a subject between 6:00 a.m. and 10:00 a.m. relative to pre-treatment levels, as determined after completion of the treatment regimen (e.g., one week after completion). In some embodiments, the compounds of the present invention or pharma- ceutically acceptable salts thereof can provide a reduction in androstenedione plasma levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold relative to pre-treatment levels, as determined after completion of the treatment regimen (e.g., one week after completion). In some embodiments, the compounds of the invention, or pharma- ceutically acceptable salts thereof, can provide a reduction in testosterone plasma levels between 6:00 AM and 10:00 AM that is in the range of 2-5 fold, 10-20 fold, 15-40 fold, or 50-100 fold relative to pre-treatment levels. In some embodiments, administration of a compound of the present invention or a pharma- ceutically acceptable salt thereof can result in a reduction in the amount of glucocorticoid (e.g., hydrocortisone, dexamethasone, prednisone, or prednisolone) administered per day compared to the current standard of care for CAH, or can achieve at least one plasma level selected from 17-OHP, androstenedione, and testosterone plasma levels between 6:00 AM and 10:00 AM that is the same as glucocorticoid (e.g., hydrocortisone, dexamethasone, prednisone, or prednisolone) monotherapy, as determined 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).

[0208] In some embodiments, the compounds of the present invention or pharma- ceutically acceptable salts thereof can reduce the percentage of subjects experiencing complications due to CAH compared to the percentage of subjects experiencing complications treated with glucocorticoids (e.g., hydrocortisone, dexamethasone, prednisone, or prednisolone) monotherapy. For example, the percentage of subjects experiencing complications treated with the compounds of the present invention or pharma-ceutically acceptable salts thereof can be reduced by 10%, 25%, 40%, 50%, 60%, 70%, 80%, and 90% compared to subjects treated with glucocorticoids (e.g., hydrocortisone, dexamethasone, prednisone, or prednisolone).

[0209] In another embodiment, a method for antagonizing CRF1 in a cell is provided, comprising contacting the cell with a compound of the present invention, including the specific compounds described herein, or a pharma- ceutically acceptable salt thereof, under suitable conditions and for a sufficient time to allow interaction between the cell and the compound. In certain embodiments, the cell is a cell of a subject in need of treatment with a compound disclosed herein. Combination therapy

[0210] The compound of the present invention or its pharmaceutically acceptable salt can be used in combination treatment, in which the compound of the present invention or its pharmaceutically acceptable salt is administered together with other treatments, such as administration of one or more additional therapeutic agents. The additional therapeutic agent is typically a therapeutic agent that is normally used to treat the particular condition to be treated. The additional therapeutic agent may include glucocorticoids (e.g., hydrocortisone, dexamethasone, prednisone, or prednisolone) or mineralocorticoids (e.g., fludrocortisone). Examples of additional therapeutic agents include, but are not limited to, glucocorticoids (e.g., hydrocortisone, dexamethasone, prednisone, or prednisolone) and mineralocorticoids (e.g., fludrocortisone). Other treatments that can be administered together with the compound of the present invention or its pharmaceutically acceptable salt include, but are not limited to, surgical intervention.

[0211] The compounds of the present invention, or pharma- ceutically acceptable salts thereof, may be administered with one or more additional pharmaceutical agents together in a single pharmaceutical composition or as two or more separate pharmaceutical compositions.

[0212] The order of administration of the compound of the present invention, or a pharma- ceutically acceptable salt thereof, may be administered simultaneously with any / all of the additional agents, or sequentially in any order with any / all of the additional agents (e.g., the compound of the present invention, or a pharma- ceutically acceptable salt thereof, may be administered before or after any / all of the additional agents). Pharmaceutical Compositions, Formulations, and Dosage Forms

[0213] The present disclosure further provides compositions comprising any of the compounds disclosed and described herein (e.g., compounds of Formula (I), Formula (Ia), or Formula (III), including the specific compounds described herein) or pharma- ceutically acceptable salts thereof, and an excipient, e.g., a pharma- ceutically acceptable excipient for use in a method for treating CAH. A pharma- ceutically acceptable excipient is a physiologically and pharma- ceutically suitable, non-toxic, inert material or ingredient that does not interfere with the activity of a drug substance, and 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 arts and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like can be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents can also be used.

[0214] In some embodiments, the pharmaceutical composition comprises a compound of the invention or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula (III) or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a preparation of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a preparation of a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a preparation of a compound of formula (III) or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having the structure [ka] or a pharma- ceutically acceptable salt thereof.

[0215] For compositions formulated as liquid solutions, acceptable carriers and / or diluents include physiological saline and sterile water, and may include antioxidants, buffers, bacteriostatic agents and other common additives as necessary. The compositions may also be formulated as pills, capsules, granules, or tablets, which contain diluents, dispersants and surfactants, binders, and lubricants in addition to the CRF1 antagonist. Those skilled in the art will further understand how to formulate the CRF1 antagonist in a suitable manner, following practices such as those disclosed in Remington, supra. possible.

[0216] Methods of administration include systemic administration of the CRF1 antagonists described herein, preferably in the form of a pharmaceutical composition as discussed above. As used herein, systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets and capsules, as well as liquids, syrups, and the like. The compositions of the present invention include aqueous injection solutions, suspensions, and emulsions. These compositions may also contain flavorings, preservatives, suspending agents, thickening agents and emulsifying agents, and other pharma- ceutically acceptable additives. For parenteral administration, the compounds of the present invention can be prepared into aqueous injection solutions, which may contain, in addition to the CRF1 antagonist, buffers, antioxidants, bacteriostatic agents, and other additives that are generally used in such solutions.

[0217] As described herein, optimal doses are generally determined using experimental models and / or clinical trials. Optimal doses of CRF1 antagonists may depend on the subject's body mass, weight, blood volume, or other individual characteristics. For example, a medical practitioner may consider the subject's condition, i.e., stage of disease, severity of symptoms caused by the disease, overall health, as well as age, sex, and weight, and other factors apparent to a medical practitioner. Generally, the amount of the compound described herein is present in a dosage range of about 0.1 mg to about 2 mg per kg of subject's body weight. In certain embodiments, the daily dose is about 10 to 150 mg. Use of the minimum dose sufficient to provide effective treatment is usually preferred. Subjects may generally be monitored for therapeutic effectiveness by clinical evaluation, using assays appropriate for the condition being treated or prevented, methods of which are well known to those of skill in the art and described herein. The level of the compound administered to the subject may be monitored by determining the level of the compound in a body fluid, such as blood, blood fractions (e.g., plasma, serum), and / or urine, and / or other biological sample from the subject. Any method practiced in the art for detecting a compound can be used to measure the level of the compound during the course of a treatment regimen.

[0218] Pharmaceutical compositions containing CRF1 antagonists can be formulated for sustained release (also called 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 the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate-limiting membrane. The excipients for use in such formulations can be biocompatible and biodegradable, and preferably the formulation releases a relatively constant level of the active component. The amount of active compound contained in a sustained release formulation will vary depending on the implantation site, the release rate and expected duration, and the nature of the condition to be treated or prevented.

[0219] The pharmaceutical composition described herein, which comprises at least one of the CRF1 antagonist compounds described herein, can be administered to a subject in need by any one of several routes that effectively deliver an effective amount of the compound.Such administration routes include, for example, oral, parenteral (e.g., subcutaneous, intravenous, intramuscular, intrasternal, intracavity), enteral, rectal, intranasal, oral buccal, sublingual, intramuscular, and transdermal.

[0220] Pharmaceutical compositions for oral administration can be obtained by any suitable method, typically by uniformly mixing the compound with liquid or finely divided solid carriers or both in the required proportions, then optionally treating the mixture after adding suitable auxiliaries as desired, and forming the resulting mixture into the desired shape to obtain tablets or dragee cores.

[0221] Conventional excipients, such as binders, fillers, adjuvants, carriers, acceptable wetting agents, tableting lubricants and disintegrants, can be used in 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 that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives, such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavoring 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 sterilizing the solution by filtration, followed by freeze-drying, or simply filling and sealing suitable vials or ampoules.

[0222] As used herein, a "drug substance" defined in the context of a "pharmaceutical composition" refers to a component of a pharmaceutical composition that provides a primary pharmacological effect, e.g., a compound of the invention (e.g., a compound of Formula (I), Formula (Ia), or Formula (III)), including the specific compounds described herein, and pharma- ceutical acceptable salts thereof, as opposed to an "inactive ingredient," which may generally be recognized as not providing a therapeutic benefit.

[0223] As used herein, "excipient" refers to a substance added to a composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubricity, disintegration ability, and the like. "Diluent" refers to a type of excipient, an ingredient of a pharmaceutical composition that has no pharmacological activity, but may be pharmacologic necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug that has a mass that is too small to manufacture and / or administer. A diluent may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A pharmacologic acceptable excipient is a physiologically and pharmacologic suitable, non-toxic, inert material or ingredient that does not interfere with the activity of a drug substance. Pharmaceutically acceptable excipients are well known in the pharmaceutical arts and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. For compositions formulated as liquid solutions, acceptable carriers and / or diluents include physiological saline and sterile water, and may include antioxidants, buffers, bacteriostatic agents, and other common additives as necessary. In some embodiments, the diluent may be a buffered aqueous solution, such as, but not limited to, phosphate buffered saline. The compositions may also be formulated as capsules, granules, or tablets, which contain diluents, dispersing and surface active agents, binders, and lubricants in addition to the compounds disclosed and described herein. Those skilled in the art may further formulate the compounds disclosed and described herein in an appropriate manner and according to practices such as those disclosed in Remington, supra. .

[0224] In preparing pharmaceutical compositions containing the compounds of the present invention and their pharma-ceutically acceptable salts, drug substances are typically mixed with excipients, diluted by excipients, or enclosed in such carriers, for example in the form of capsules, sachets, paper or other containers.When excipients act as diluents, they can be solid, semi-solid, or liquid materials that act as vehicles, carriers, or media for active ingredients.Thus, the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing up to 10% by weight of active compounds, soft and hard gelatin capsules, suppositories, injectable sterile liquids, and sterile packaged powders.

[0225] For the preparation of solid form pharmaceutical compositions, such as powders, tablets, capsules, cachets, suppositories and dispersible granules, excipients may be one or more substances that can also act as diluents, flavorings, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Also included are solid form compositions that are intended to be converted immediately before use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These compositions may contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc. in addition to the drug substance.

[0226] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the drug substance is dispersed homogeneously therein, as by stirring, etc. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0227] 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.

[0228] Liquid form compositions include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid compositions can be formulated as solutions in aqueous polyethylene glycol solution. Injectable compositions, for example, injectable sterile aqueous or oily suspensions, can be formulated using suitable dispersing or wetting agents and suspending agents according to known techniques. Sterile injectable compositions can be injectable sterile solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0229] The pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents, such as suspending, stabilizing and / or dispersing agents. Alternatively, the pharmaceutical compositions may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0230] The pharmaceutical compositions may be formulated as aqueous solutions, aqueous-alcoholic solutions, solid suspensions, emulsions, liposomal suspensions, or lyophilized powders for reconstitution. Such pharmaceutical compositions may be administered directly or as a mixture for further dilution / reconstitution. Routes of administration include intravenous bolus, intravenous infusion, irrigation, and dropwise injection. Suitable solvents include water, alcohol, PEG, propylene glycol, and lipids, and pH adjustment using an acid, e.g., HCl or citric acid, may be used to increase solubility, and the resulting composition may be subjected to suitable sterilization procedures known in the art, e.g., 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.

[0231] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the drug substance in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.

[0232] Aqueous suspensions suitable for oral use can be made by dispersing finely divided drug substance in water with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0233] For topical administration to epithelium, the compound of the present invention and its pharma- ceutically acceptable salts can be formulated as gels, ointments, creams or lotions, or as transdermal patches.Also, formulations suitable for topical administration in the mouth include lozenges that contain the drug substance in a flavored base, usually sucrose and acacia or tragacanth; lozenges that contain the drug substance in an inert base, such as gelatin and glycerin or sucrose and acacia; and mouthwashes that contain the drug substance in a suitable liquid carrier.Ointments and creams can be formulated, for example, with an aqueous or oily base, with the addition of suitable thickening and / or gelling agents.Lotions can be formulated with an aqueous or oily base, and generally also contain one or more emulsifiers, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.In some embodiments, topical formulations can contain one or more conventional carriers. In some embodiments, the ointment may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. The composition of the carrier for the cream may be glycerol and one or more other components, for example, glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. The gel may be water-based in combination with isopropyl alcohol. Gels may be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, 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 invention or a pharma- ceutically acceptable salt thereof.

[0234] Solution or suspension can be directly applied to nasal cavity by conventional means, for example, by using dropper, pipette or spray.The preparation can be provided in single dose or multi-dose form.In the latter case of using dropper or pipette, this can be achieved by the patient administering a suitable predetermined volume of solution or suspension.In the case of spray, this can be achieved, for example, by using a metering atomizing spray pump.

[0235] Respiratory administration can also be achieved by using aerosol formulations in which the drug substance is provided in a pressurized pack with a suitable propellant. When the compounds of the present invention and pharma-ceutically acceptable salts thereof, or pharmaceutical compositions containing them, are administered as aerosols, for example as nasal aerosols or by inhalation, this can be done, for example, by using a spray, nebulizer, pump nebulizer, inhalation device, metered dose inhaler or dry powder inhaler. Pharmaceutical forms for administering the compounds of the present invention as aerosols can be prepared by processes well known to those skilled in the art. To prepare them, for example, solutions or dispersions of the compounds of the present invention in water, water / alcohol mixtures or suitable saline solutions can be used, using customary additives, for example benzyl alcohol or other suitable preservatives, absorption promoters for increasing bioavailability, solubilizers, dispersants, etc., and, where appropriate, customary propellants, including, for example, carbon dioxide, CFCs, for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane. Aerosols can also conveniently contain surfactants, for example lecithin. The dose of drug may be controlled by providing a metered valve.

[0236] Alternatively, the pharmaceutical composition can be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base, for example lactose, starch, starch derivatives, for example hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP).Advantageously, the powder carrier forms a gel in the nasal cavity.The powder composition can be presented in unit dose form, for example in gelatin capsules or cartridges, or in blister packs, from which the powder can be administered, for example by using an inhaler.

[0237] The compounds of the present invention and pharma- ceutically acceptable salts thereof may also be administered via a fast dissolving or slow release composition, where the composition comprises a biodegradable fast dissolving or slow release carrier (e.g., a polymeric carrier, etc.) and the compound of the present invention. Fast dissolving or slow release carriers are well known in the art and are used to entrap the drug substance and form a complex that decomposes / dissolves rapidly or slowly in an appropriate environment (e.g., aqueous, acidic, basic, etc.).

[0238] Pharmaceutical composition is preferably in unit dosage form.In such form, composition is divided into unit doses containing appropriate amount of drug substance.Unit dosage form can be a packaged composition, the package containing discrete amount of composition, for example, packaged tablets, capsules and powders in vials or ampoules.Also, unit dosage form can be a capsule, tablet, cachet or lozenge itself, or the appropriate number of any of these in packaged form.

[0239] Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.

[0240] The compositions can be formulated in unit dosage form, each dosage containing 1 to 1,000 mg (1 g), more usually 5 mg to 200 mg, or an equivalent mass of drug substance. The term "unit dosage form" refers to a physically discrete unit of a formulation suitable as a unitary dosage 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 suitable excipients as described herein.

[0241] The compositions described herein can be formulated to provide immediate and / or sustained release (also called extended, sustained, controlled, or slow release) of drug substance after administration to a subject by using procedures known in the art. For example, tablets containing the compounds of the present invention or pharma-ceutically acceptable salts thereof 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 an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass unchanged to the duodenum or to delay release. A variety of materials can be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0242] Pharmaceutical compositions containing drug substances can be formulated for sustained 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 the desired target site. Sustained release formulations can contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate-limiting membrane. The excipients for use in such formulations can be biocompatible and biodegradable, and preferably the formulation provides a relatively constant level of active component release. The amount of drug substance contained in a sustained release formulation will vary depending on the implantation site, the rate and expected duration of release, and the nature of the condition to be treated or prevented.

[0243] Liquid forms containing the drug substance which can be incorporated for oral administration or administration by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions containing edible oils, such as cottonseed oil, sesame oil, coconut oil or peanut oil, and similar excipients.

[0244] The pharmaceutical compositions described herein can be sterilized by conventional sterilization techniques or can be sterile filtered. Aqueous solutions can be packaged for use as is or lyophilized, and the lyophilized preparations are combined with a sterile aqueous carrier before administration. The pH of the composition is typically between 3 and 11, more preferably 5 and 9, and most preferably 7 and 8. It will be understood that the use of some of the above-mentioned excipients can result in the formation of pharma-ceutically acceptable salts.

[0245] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable excipients as described herein. In some embodiments, the compositions are administered by oral or nasal respiratory route for local or systemic effect. The compositions can be nebulized by using inert gas. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0246] The composition may be presented in a pack or dispenser device that may contain one or more unit dosage forms containing the drug substance as desired. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the agency of the drug form for human or veterinary administration. Such notice may be, for example, a labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. The composition may include the compound described herein, which is formulated with a compatible pharmaceutical carrier, and may also be prepared for the treatment of the indicated condition, placed in an appropriate container, and labeled.

[0247] As used herein, "dose" or "dosage" refers to a measured amount of a drug substance to be taken by a patient at one time. In certain embodiments where the drug substance is neither a free base nor a free acid, the amount is the molar equivalent to the corresponding amount of the free base or free acid.

[0248] To prepare solid compositions, such as tablets, the drug substance may be mixed with excipients to form a solid preformulation composition containing a homogeneous mixture of the components. When these preformulation compositions are referred to as homogeneous, the drug substance is typically uniformly dispersed throughout the composition, and thus the composition can be easily subdivided into equally effective unit dosage forms, such as tablets and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, 0.001 mg to 5000 mg of drug substance. In certain embodiments where the drug substance is not a free base or free acid of the compound of the invention, such as a salt or hydrate, the amount of the unit dosage form is 0.001 mg to 5000 mg of the molar equivalent to the corresponding amount of the free base or free acid of the compound of the invention. Representative amounts of 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 a range defined by any of the preceding amounts.In certain embodiments where the drug substance is neither a free base nor a free acid, the molar equivalent of the drug substance in a unit dosage form may include, 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 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 25 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 75 mg, 80 mg, 95 mg, 100 mg, 110 mg, 120 mg, 140 mg, 160 mg, 18 ...26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 35 mg 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 a range defined by any of the preceding amounts.

[0249] In particular, multiple doses may be administered daily, when a relatively large amount is deemed necessary, for example, two, three or four doses. Depending on the individual, it may be necessary to increase or decrease the doses described herein, as deemed appropriate by the patient's physician or caregiver.

[0250] The amount of drug substance required for use in treatment varies with the specific salt selected, as well as with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and is ultimately left to the discretion of the attending physician or clinician.Those skilled in the art generally understand how to extrapolate the in vivo data obtained in a model system, typically an animal model, to the data of another model, such as human.In some circumstances, these extrapolations can be made simply based on comparing the body weight of the animal model with the body weight of another model, such as a mammal, preferably a human, but more frequently, these extrapolations are not simply based on body weight, but rather incorporate a variety of factors.Typical factors include the type, age, body weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations, such as the activity, efficacy, pharmacokinetics, and toxicological profile of the particular compound used, whether a drug delivery system is utilized, whether acute or chronic conditions are treated or prophylaxis is performed, or whether, in addition to the compounds described herein, additional active compounds are administered as part of a drug combination. The dosage regimen for treating disease state using the compounds and / or compositions described herein is selected according to various factors mentioned above.Therefore, the actual dosage regimen used can vary widely and therefore may deviate from the preferred dosage regimen, and those skilled in the art will recognize that dosages and dosage regimens outside these typical ranges can be tested, and where appropriate, they can be used in the methods described herein.

[0251] As described herein, optimal doses are generally determined using experimental models and / or clinical trials. Optimal doses of the compounds disclosed and described herein may depend on the subject's body mass, weight, blood volume, or other individual characteristics. For example, a medical practitioner may consider the subject's condition, i.e., stage of disease, severity of symptoms caused by the disease, overall health, as well as age, sex, and weight, and other factors apparent to a medical practitioner. Generally, the amount of the compounds described herein is present in a dosage range of about 0.1 mg to about 2 mg per kg of subject's body weight. In certain embodiments, the daily dose is about 10 to 150 mg. Use of the minimum dose sufficient to provide effective treatment is usually preferred. Subjects may generally be monitored for therapeutic effectiveness by clinical evaluation, using assays appropriate for the condition being treated or prevented, methods of which are well known to those of skill in the art and described herein. The level of the compound administered to the subject may be monitored by determining the level of the compound in a body fluid, such as blood, blood fractions (e.g., plasma, serum), and / or urine, and / or other biological sample from the subject. Any method practiced in the art for detecting a compound can be used to measure the level of the compound during the course of a treatment regimen.

[0252] Usually, a kit is provided that contains one or more unit doses of the compound described herein, in oral or injectable doses.Such kit can include a container with unit doses, a package insert that contains information that describes the use and concomitant benefits of drug in treating the pathological condition of interest, and an appliance or device for delivering the composition as needed. Dosage Schedule / Amount

[0253] The compound of the present invention or its pharmaceutically acceptable salt can be effective over a wide dosage range and is generally administered in a therapeutically effective amount.However, it will be understood that the amount of compound actually administered will usually be determined by the physician according to the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound to be administered, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0254] The amount of compound or composition administered to a subject will also vary depending on what is being administered, the purpose of the administration, e.g., prophylaxis or treatment, the condition of the subject, the mode of administration, etc. In therapeutic applications, the composition can be administered to a subject 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 state being treated, as well as on factors such as the severity of the disease, the age, weight and general condition of the subject, and the judgment of the attending clinician.

[0255] Some typical dosage ranges are from 1 μg to 1 g of drug substance per kg of body weight per day, or the equivalent mass of drug substance if administered in the form of a salt, hydrate, etc. In some embodiments, the dose range is from about 0.01 mg to about 100 mg of drug substance per kg of body weight per day, or the equivalent mass of drug substance. Representative amounts for dosage of a drug substance 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 per kg of body weight per day, or an amount within a range defined by any of the preceding amounts. In certain embodiments where the drug substance is not a free base or free acid of a compound of the invention, such as a salt or hydrate, the corresponding molar equivalent of the drug substance of the free base or free acid of a compound of the invention in a 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 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg per kg of body weight per day, or an amount within a range defined by any of the preceding amounts.

[0256] Dosage can be a single dose or a series of two or more doses, given in the course of one or several days as required by the subject.In some embodiments, compound is administered for a continuous treatment period, for example, for one week or longer, or for several months or years.Effective dose can be estimated from dose-response curves derived from in vitro or animal model test systems, and human clinical trials.

[0257] Where a human dosage for a compound has been established for at least some condition, that dosage may be used, or a dosage between 0.1% and 500%, more preferably between about 25% and 250%, of the established human dosage may be used. Where a human dosage has not been established, such as in the case of a newly discovered pharmaceutical composition, an appropriate human dosage may be determined based on the ED, as verified by toxicity and efficacy studies in animals. 50 or other appropriate values ​​derived from in vitro or in vivo studies.

[0258] In the case of administration of pharmaceutically acceptable salt, dosage can be calculated as free form (e.g., free base or free acid). Often drugs are packaged in salt form, and the strength of the dosage form refers to the mass of this salt form, or the equivalent mass of the corresponding free base or free acid. As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even significantly exceed, the above-mentioned preferred dosage ranges, particularly to effectively and aggressively treat invasive disease or infection.

[0259] Dosage amount and interval may be adjusted individually to provide sufficient plasma levels of the active moiety to maintain the modulating effect, or the minimum effective concentration (MEC). The MEC varies from compound to compound, but can be estimated from in vitro data. The dosage required to achieve the MEC depends on individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably 30-90%, and most preferably 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0260] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicological properties of a particular compound, or a subset of compounds sharing a certain chemical moiety, can be established by determining in vitro toxicity on a cell line, for example a mammalian animal, preferably a human cell line. The results of such studies often predict toxicity in animals, for example mammals, or more specifically humans. Alternatively, the toxicity of a particular compound in an animal model, for example a mouse, rat, rabbit, or monkey, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model for determining efficacy, the skilled artisan can be guided by the state of the art to select the appropriate model, dose, route of administration, and / or regimen.

[0261] It will be clear to those skilled in the art that the dosage forms described herein may contain any of the compounds described herein or pharma- ceutically acceptable salts thereof as drug substances.In addition, various hydrates and solvates of the compounds described herein and their salts can be used as intermediates in the preparation of pharmaceutical compositions.Exemplary procedures for making and identifying suitable hydrates and solvates other than those mentioned herein are well known in the art.See, for example, KJ Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Britain, Vol. 95, See pages 202-209 of Marcel Dekker, Inc., New York, 1999. Accordingly, one aspect of the present invention relates to methods of administering hydrates and solvates of the compounds described herein and / or their pharma- ceutically acceptable salts, which can be isolated 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 Fischer titration, high resolution X-ray diffraction, and the like. Synthesis of compounds

[0262] Detailed synthetic methods for the compounds are described in the Examples herein. Those skilled in the chemical arts can make the compounds of the present disclosure, including the specific compounds described herein, by these methods or similar methods or other methods practiced by those skilled in the art.

[0263] In general, the compounds used in the reactions described herein can be made from commercially available chemicals and / or from compounds described in the chemical literature according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" include 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 The 5'-aminopropyl ether may be obtained from standard commercial sources including Sigma-Aldrich USA, Inc. (Richmond VA).

[0264] Methods known to those skilled in the art can be identified by various references and databases. Suitable references and treatises that detail the synthesis of reactants useful in preparing the compounds of the present disclosure or provide references to publications describing the preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York; 1983, HO House, "Modern Synthetic Reactions", 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972, TL Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992, and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley-Interscience, New York, 1992. Reactions useful for preparing the compounds of the present disclosure include: Additional suitable references and treatises detailing the synthesis of or providing references to literature describing the preparation 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" 2nd 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, LD et al. "A Guide to Organophosphorus Chemistry" (2000) Wiley-Interscience, ISBN: 0-471-31824-8, Solomons, TWG "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0, Stowell, JC, "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, 8 volumes, "Organic Reactions" (1942-2019) John Wiley & Sons, volumes 95 onwards, as well as "Chemistry of Functional Groups" John Wiley & Sons, hardcover (86) and electronic (26) editions.

[0265] Specific and similar reactants may also be identified through indexes of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, available in most public and university libraries, as well as through online databases (further details may be contacted at the American Chemical Society in Washington, DC). Chemicals that are known but not commercially available in catalogs may be prepared according to known methods by custom chemical synthesis companies, and many of the standard chemical supply companies (e.g., those listed above) offer custom synthesis services.

[0266] Abbreviation This specification contains a number of abbreviations, the definitions of which are listed in the table below. [Table 1] EXAMPLES

[0267] The following examples are included to demonstrate embodiments of the disclosure, however, one of ordinary skill in the art should appreciate in light of this disclosure that many changes can be made to the specific embodiments disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[0268] 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)

[0269] 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. [ka]

[0270] Step 1: Preparation of ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (compound 1-B) [ka]

[0271] A mixture of (4-bromo-2-fluorophenyl)methanol (20 g, 98 mmol) and imidazole (7.31 g, 107 mmol) in methylene chloride (100 mL) was treated with tert-butyldimethylsilyl chloride (16.17 g, 107 mmol) in methylene chloride (100 mL) at room temperature for 10 min. A white precipitate formed immediately and was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in heptane (100 mL). The organic phase was washed with water (2×40 mL), brine (2×40 mL), dried over NaSO4, and concentrated under reduced pressure. The residue was dissolved in c-hexane and passed through a silica pad (100 g), then the solvent was removed under reduced pressure to give compound 1-B as a yellowish oil (30.51 g, 98% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 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).

[0272] Step 2: Preparation of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)-2-cyclopropylethan-1-one (compound 3-B) [ka]

[0273] Magnesium turnings (2.34 g, 97 mmol, 1.38 equiv.) were suspended in anhydrous THF (39 mL). The mixture was maintained under stirring at 35° C. and treated with diisobutylaluminum hydride (1 M in heptane, 201 mL, 0.03 equiv.). The resulting mixture was treated with a small amount of ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (1-B, 3.01 g, 9.4 mmol, 0.1 wt. % overall) and the resulting suspension was stirred for 15 min. The remaining ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (1-B, 27.09 g, 84.6 mmol, 0.9 wt. % overall) was dissolved in THF (81 mL) and the resulting was added to the previously prepared suspension over 1 h. The resulting mixture was heated to 40° C. and stirred for 3 h. The Grignard suspension was then cooled to 15° C. and then treated with 2-cyclopropyl-N-methoxy-N-methylacetamide (2-B, 10 g, 70 mmol) in THF (60.2 mL) over 50 min. The resulting mixture was stirred at 20° C. for 2 h, then cooled to 5° C. and treated with 3N HCl (60.2 mL) over 30 min at a rate that maintained the internal temperature below 20° C. After the addition was complete, the mixture was stirred at 20° C. for 2 h. The mixture was left overnight to consume any residual magnesium. The mixture was combined with heptane (120 mL) and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, and filtered to remove solids. The solvent was removed under reduced pressure and the crude was passed through a pad of silica gel (100 g) eluted with c-hexane / 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 desbromo compound (3.7 g), which was used in the next step without separation. 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 desbromo compounds are present.

[0274] Step 3: Preparation of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)-2-cyclopropylethan-1-amine (compound 4-B) [ka]

[0275] A mixture of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)-2-cyclopropylethan-1-one (3-B, 10 g, 31 mmol, 1 equiv.) and ammonium acetate (11.95 g, 155 mmol, 5 equiv.) in methanol (50 mL) was stirred for 3 min and then treated with sodium cyanoborohydride (2.92 g, 47 mmol). The resulting mixture was stirred at room temperature for 30 min and then heated to 50° C. and stirred overnight. The solvent was removed under reduced pressure and the residue was combined with 2 M 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 as a waxy solid (10.4 g, estimated). 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) Residual desbromo compounds are present.

[0276] 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) [ka]

[0277] A suspension of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (5-B, 5.84 g, 22 mmol, 1 equiv.) in heptane (50 mL) was heated to 85° C. and then treated with compound 4-B in heptane (30 mL) over 35 min. The resulting mixture was stirred at 85° C. overnight and then cooled to room temperature. The solvent was removed under reduced pressure and the crude material was purified twice by flash chromatography (100 g, 100:0 to 96:4 c-hexane / AcOEt and 100:0 to 80:20 c-hexane / MTBE), the solvent was removed under reduced pressure to give compound 6-B as a yellowish oil after the second run (5.50 g, 44% yield). 1H NMR (400 MHz, CDCl3) δ ppm -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, Residual solution The solvent is present. LCMS: [M] + =575.

[0278] 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) [ka]

[0279] 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 min. The mixture was then cooled to -10°C and treated with aqueous KOH (64%, 1.8 mL) at a rate that maintained the temperature below 5°C (1 h) to give a mixture. The resulting mixture was treated with propargyl bromide in toluene (80%, 1.16 mL) at a rate that maintained the temperature below 5°C (30 min) to give a mixture. The resulting mixture was stirred at 5°C for 20 h and then combined with methyl tert-butyl ether (10 mL) and water (10 mL). After vigorous shaking, the layers were separated. 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.

[0280] 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) [ka]

[0281] Compound 7-B was dissolved in anhydrous THF (50 mL) and 1M TBAF in THF (10.4 mL) was added. The resulting mixture was stirred at room temperature for 3 h, then the solvent was removed under reduced pressure to give a residue. The residue was combined with water (10 mL) and the resulting aqueous mixture was extracted with methyl tert-butyl ether (2×25 mL). The combined organic layers were dried over Na2SO4, filtered to remove solids, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (50 g, 100:0 to 80:20 c-hexane / AcOEt) to give the first isolate as an orange foam (2 g, 46%). A second purification (50 g, 100:0 to 80:20 c-hexane / AcOEt) gave the final product as an orange foam (1.5 g). 1 H NMR (400 MHz, CDCl3) δ ppm 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 present. LCMS: [M] + =499.

[0282] 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)

[0283] 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. [ka]

[0284] Step 1: Preparation of 4-bromo-2-fluoro-1-((methoxymethoxy)methyl)benzene (compound 1-D) [ka]

[0285] A mixture of (4-bromo-2-fluorophenyl)methanol (20 g, 98 mmol) and DIPEA (25.5 mL, 107 mmol) in methylene chloride (100 mL) was treated with methoxymethyl chloride (8.17 mL, 107 mmol) in methylene chloride (20 mL) for 20 min at 4 °C. The resulting mixture was stirred for 48 h. The mixture was washed with 5% aqueous NaHCO3 (50 mL), dried over NaSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel 100 g, c-hexane / AcOEt 100:0 to 95:5) to give compound 1-D as a colorless oil (23.5 g, 88% yield). 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 present.

[0286] Step 2: Preparation of 2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethan-1-one (compound 3-D) [ka]

[0287] Magnesium turnings (2.34 g, 97 mmol, 1.2 equiv.) were suspended in anhydrous THF (40 mL). The mixture was treated with iodine (410 mg, 1.6 mmol, 0.02 equiv.). 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. % overall) and the resulting suspension was gently heated with a heat gun until discoloration occurred. The remaining 4-bromo-2-fluoro-1-((methoxymethoxy)methyl)benzene (18 g, 72 mmol, 0.9 wt. % overall) was dissolved in THF (120 mL) and the resulting solution was added to the previously prepared suspension over 1.5 h. The resulting mixture was stirred at room temperature for 1 h. The Grignard suspension was then cooled to 5° C. and then treated with 2-cyclopropyl-N-methoxy-N-methylacetamide (2-B, 17.25 g, 120 mmol) in THF (20 mL) over 20 min. 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 layers were washed with brine (170 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 100 g, 100:0 to 80:20 c-hexane / AcOEt) to give compound 3-D as a colorless oil (8.0 g, 39% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.15 (dd, J = 4.83, 1.32 Hz, 2H), 0.50 (d, J = 6.59 Hz, 2H), 0.92 - 1.14 (m, 1H), 2.95 (d, J = 6.59 Hz, 2H), 3.30 (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).

[0288] Step 3: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)-N-(1-phenylethyl)ethan-1-imine (compound 4-D) [ka]

[0289] A mixture of 2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethan-1-one (3-D, 1.8 g, 7 mmol, 1 equiv.), (S)-(-)-phenylethylamine (2.59 g, 21 mmol, 3.0 equiv.) and PTSA·HO (70 mg, 0.37 mmol, 0.05 equiv.) 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, estimated amount), which was used directly in the next step.

[0290] Step 4: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5-D) [ka]

[0291] Raney Nickel (50% wet, 2.38 g, 20 mmol) was washed with absolute ethanol (4 x 6 mL) and transferred to a HEL autoclave to provide a catalyst suspension. Compound 4-D (2.4 g, 6.8 mmol) was added to the catalyst suspension and ethanol was added to provide a final volume of 30 mL. The mixture was subjected to three vacuum / nitrogen cycles and two hydrogen purge cycles. The mixture was then stirred under hydrogen (initial pressure: 10 bar) at 25 °C for 6 h and at 60 °C for 24 h. The mixture was filtered and the solid was washed with ethanol (20 mL). The collected ethanol solution was concentrated and the residue was purified by column chromatography (25 g, 100:0 to 80:20 c-hexane / AcOEt) to give compound 5-D as a light oil (2 g, 83% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm -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) ) Residual solvent peak present. LCMS: [M+H] + =358.

[0292] Step 5: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethan-1-amine (compound 6-D) [ka]

[0293] A steel autoclave was charged with (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 min. The autoclave was then loaded onto a HEL hydrogenation system and the mixture was stirred under hydrogen (initial pressure: 8 bar) at 60° C. for 10 h, then cooled to 20° C. and stirred overnight. The mixture was filtered through a Celite® pad and the filtrate was concentrated to give crude compound 6-D (1.42 g, estimated amount), which was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ ppm -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 present. LCMS: [M+H] + =254.

[0294] 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) [ka]

[0295] A suspension of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (5-B, 1.51 g, 6 mmol, 1 equiv.) in heptane (15 mL) was heated to 90° C. and then treated with compound 6-D (1.42 g, 6 mmol, 1 equiv.) in heptane (7 mL) over 15 min. The resulting mixture was stirred at 85° C. for 3 h and then cooled to room temperature. The solvent was removed under reduced pressure to provide the crude product. The crude product was purified by flash chromatography (50 g, 100:0 to 90:10 c-hexane / AcOEt). The solvent was removed under reduced pressure to give compound 7-D as a yellow foam (4.46 g, 94% yield). MS: [M] + =505.

[0296] 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) [ka]

[0297] 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 aqueous KOH (64%, 4.5 mL) for 5 min at -10°C. The resulting mixture was treated with propargyl bromide in toluene (80%, 0.66 mL) for 5 min. The resulting mixture was stirred at 5°C for 5 h and then combined with methyl tert-butyl ether (10 mL) and water (10 mL). The layers were separated. 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 give compound 8-D as a residue, which was used directly in the next step without further purification.

[0298] 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) [ka]

[0299] Compound 8-D was dissolved in acetone (30 mL) and 37% aqueous HCl (1.7 g) was added. The resulting mixture was stirred at 55° C. for 45 min. The mixture was cooled to room temperature and combined with saturated Na2CO3 (5 mL) followed by water (10 mL). The volatiles were removed under reduced pressure and the aqueous mixture was combined with methyl tert-butyl ether (20 mL). The organic layer was collected and the aqueous phase was washed with methyl tert-butyl ether (2×10 mL). The combined organic layers were dried over Na2SO4, filtered to remove solids, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (50 g, 100:0 to 95:5 DCM / MTBE) to give the first isolate (1.4 g, 91% HPLC purity) as a yellowish foam. The purification was repeated on the first isolate under the same conditions to give a second isolate (1.1 g, 95% HPLC purity) as a yellowish foam. A third purification (50 g, 100:0 to 60:40 n-hexane / MTBE) gave compound 2 (1 g, 98% HPLC purity, 80% ee) as an off-white foam. MS: [M] + =499. 1 1 H NMR matches compound 1 of Example 1.

[0300] Example 2A Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-(1-phenylethyl)ethan-1-imine [ka]

[0301] The title compound can be prepared in a manner similar to the preparation of compound 4-D, using 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one in place of compound 3-D in step 3.

[0302] Example 2B Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine [ka]

[0303] The title compound can be prepared in a manner similar to that for preparing compound 5-D, using (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-(1-phenylethyl)ethan-1-imine in place of compound 4-D in step 4.

[0304] Example 3 (S)-(4-(1-((4-(2-chloro-4-(methoxy- 13 C-d3) Preparation of -5-methylphenyl)-5-methylthiazol-2-yl)(prop-2-yn-1-yl)amino)-2-cyclopropylethyl)-2-fluorophenyl)methanol (compound 3)

[0305] (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. [ka]

[0306] Step 1: 4-Chloro-2-(methoxy- 13 C-d3) Preparation of 1-methylbenzene (compound 1-F) [ka]

[0307] A mixture of 5-chloro-2-methylphenol (9 g, 63 mmol) and potassium carbonate (13.21 g, 69 mmol, 1.1 equiv.) 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 stirring mixture (a slight exotherm was observed, +1° C.) over 30 min. The mixture was stirred at room temperature for 24 h, then diluted with DMF (30 mL) and stirred at room temperature for an additional 15 h. Acetone was removed at atmospheric pressure (80° C.) until all acetone had distilled off. The remainder 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 as a yellow oil (10.6 g, estimated), 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) Residual solvent peaks present.

[0308] Step 2: 1-(2-chloro-4-(methoxy- 13 C-d3) Preparation of 5-methylphenyl)-2-thiocyanatopropan-1-one (compound 2-F) [ka]

[0309] Aluminum trichloride (9.55 g, 72 mmol, 1.15 equiv.) was charged to a 500 mL jacketed glass reactor, then DCM (40 mL) was added, and the resulting mixture was stirred at room temperature. Compound 1-F (10 g, 62 mmol, 1 equiv.) was added to the stirring mixture over 10 min at room temperature. The addition line was rinsed with DCM (10 mL) to ensure complete addition of compound 1-F. The dark suspension was heated at 30° C. and stirred for 10 min until nearly completely dissolved. The mixture was then cooled to 0° C. and treated with neat 2-bromopropanoyl chloride (12.27 g, 72 mmol, 1.15 equiv.) over 30 min, and the addition line was rinsed with DCM (10 mL) to ensure complete addition of 2-bromopropanoyl chloride. The resulting mixture was stirred at 0° C. for 20 h. The mixture was then cooled to -5°C and treated with water (50 mL) over 15 min. The resulting mixture was kept at 0°C and stirred for 30 min. The mixture was then combined with c-hexane (300 mL) and the resulting suspension was stirred overnight. The layers were then separated and the organic layer was washed with water (2 x 100 mL), a 1:1 mixture of 13% aqueous NaCl + 5% aqueous NaHCO3 (100 mL, pH 8 wash). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was suspended in c-hexane (100 mL) and filtered. The solution was concentrated (90 mL) and diluted with DCM (10 mL). In a round bottom flask, KSCN (9.68 g, 100 mmol, 1.6 equiv) and TBAB (0.30 g, 0.93 mmol, 0.015 equiv) were dissolved in water (10 mL). The aqueous mixture was heated to 55° C. and then treated with a previously prepared solution containing the bromo intermediate for 1 h. The resulting mixture was stirred for 3.5 h and then water (10 mL) was added. The resulting mixture was stirred for 10 min and the layers were separated at 50° C. The organic layer was concentrated under reduced pressure and the residue was combined with methanol (60 mL). A white solid was precipitated and the mixture was stirred at room temperature for 30 min and then at 0° C. for 1 h. The solid was collected by filtration and washed with cold methanol (10 mL) to give compound 2-F as a white powder (10.3 g, 60% yield). 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) Residual solvent peaks present.

[0310] Step 3: (S)-4-(2-chloro-4-(methoxy- 13 Preparation of C-d3)-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethyl)-5-methylthiazol-2-amine (Compound 3-F) [ka]

[0311] 1-(2-chloro-4-(methoxy- 13 A suspension of C-d3)-5-methylphenyl)-2-thiocyanatopropan-1-one (2-F, 2.16 g, 8 mmol, 1 equiv.) was heated to 90° C. and then treated with compound 6-D (2 g, 8 mmol, 1 equiv.) in heptane (10 mL) over 20 min. The resulting mixture was stirred at 85° C. for 5 h and then cooled to room temperature. The solvent was removed under reduced pressure to provide the crude product. The crude product was purified by flash chromatography (100 g, 95:5 to 60:40 n-hexane / methyl tert-butyl ether). The solvent was removed under reduced pressure to give compound 3-F as a yellow foam (3.5 g, 87% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm -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, 3H), 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) Residual solvent peaks LCMS:[M] + =575.

[0312] Step 4: (S)-(4-(1-((4-(2-chloro-4-(methoxy- 13 C-d3) Preparation of -5-methylphenyl)-5-methylthiazol-2-yl)(prop-2-yn-1-yl)amino)-2-cyclopropylethyl)-2-fluorophenyl)methanol (compound 3) [ka]

[0313] 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 min. The resulting mixture was kept at 0°C and treated with propargyl bromide in toluene (80%, 0.84 mL) for 10 min. The resulting mixture was stirred at 5°C overnight and then at room temperature for 1 h. The mixture was combined with methyl tert-butyl ether (10 mL) and water (10 mL). The layers were separated. 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 give 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 h. The mixture was cooled to room temperature and combined with saturated Na2CO3 (10 mL) followed by water (10 mL). Volatiles were removed under reduced pressure and the aqueous mixture was combined with methyl tert-butyl ether (20 mL). The organic layer was collected and the aqueous phase was extracted with methyl tert-butyl ether (2 x 20 mL). The combined organic layers were dried over Na2SO4, filtered to remove solids and concentrated under reduced pressure to give a first isolate. The first isolate was purified by column chromatography (100 g, 100:0 to 60:40 n-hexane / MTBE) to give a second isolate. A second purification (100 g, 100:0 to 95:5 DCM / MTBE) gave compound 3 (1.6 g, 99.5% HPLC purity, 93% ee) as an 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 = 5.6 Hz, 2H), 5.23 (t, J = 5.8 Hz, 1H), 5.27 (t, J = 7.6 Hz, 1H), 7.05 (s, 1H), 7.17 (s, 1H) 7.22 (d, J = 11.5 Hz, 1H) 7.26 (d, J = 7.9 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H). MS: 98.1% 13 CD3 purity.

[0314] Example 3A Preparation of enantiomerically enriched (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethan-1-amine (compound 6-D) used in Example 3, Step 3

[0315] Step 1A: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5-D) [ka]

[0316] Following the procedure described in Example 2, Step 3, compound 4-D (5.61 g, 15.8 mmol) was hydrogenated over Raney Nickel (3 equiv.) for 30 h. After isolation, the crude product was purified by three successive column chromatographic elutions (100 g, 100:0 to 90:10 hexane / AcOEt; 2×100 g, 100:0 to 95:5 c-hexane / IPA) to give a diastereomeric ratio of about 97:3 ( 1 Compound 5-D was obtained (3.1 g, 55% yield) with a diastereomeric ratio of about 85:15 d.r. (H-NMR, DMSO-d6, 94% de). Selected mixed chromatographic fractions were combined together to give compound 5-D (3.1 g, 55% yield) with a diastereomeric ratio of about 85:15 d.r. ( 1An additional sample of compound 5-D was obtained (1.43 g, 25% yield) with H-NMR, DMSO-d6, 70% de.

[0317] Step 2A: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-((methoxymethoxy)methyl)phenyl)ethan-1-amine (compound 6-D) [ka]

[0318] Following the procedure described in Example 2, Step 4, 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. The reaction was worked up as described in Example 2, Step 4 to give crude compound 6-D (2.2 g, estimated amount), which was used directly in Example 3, Step 3.

[0319] 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. [ka]

[0320] Step 1: Preparation of 4-chloro-2-(methoxy-d3)-1-methylbenzene (compound 1-G) [ka]

[0321] A mixture of 5-chloro-2-methylphenol and potassium is stirred in acetone at 20° C. for 15 min. A solution of iodomethane-d3 in acetone is added to the stirring mixture over 30 min. The mixture is stirred at room temperature for 24 h, then diluted with DMF and stirred at room temperature for an additional 15 h. Acetone is removed at atmospheric pressure (80° C.) until all acetone has distilled off. The remainder is combined with water and the resultant is extracted with pentane. The combined organic fractions are dried over Na2SO4, filtered to remove solids, and concentrated under reduced pressure to give compound 1-G.

[0322] Step 2: Preparation of 1-(2-chloro-4-(methoxy-d3)-5-methylphenyl)-2-thiocyanatopropan-1-one (compound 2-G) [ka]

[0323] Aluminum trichloride is charged to a 500 mL jacketed glass reactor, then DCM is added, and the resulting mixture is stirred at room temperature. Compound 1-G is added to the stirring mixture over 10 minutes at room temperature. The resulting mixture is heated at 30° C. and stirred for 10 minutes. The mixture is then cooled to 0° C. and treated with neat 2-bromopropanoyl chloride over 30 minutes. The resulting mixture is stirred at 0° C. for 20 hours. The mixture is then cooled to −5° C. and treated with water over 15 minutes. The resulting mixture is maintained at 0° C. and stirred for 30 minutes. The mixture is then combined with c-hexane and stirred overnight. The layers are then separated and the organic layer is washed with a 1:1 mixture of water and 13% aqueous NaCl+5% aqueous NaHCO3. The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the bromo intermediate. The bromo intermediate is suspended in c-hexane and filtered. The solution is concentrated and diluted with DCM. In a round-bottom flask, KSCN and TBAB are dissolved in water. The aqueous mixture is heated to 55° C. and then treated with a solution containing the bromo intermediate for 1 h. The resulting mixture is stirred for 3.5 h and then water is added. The resulting mixture is stirred for 10 min and the layers are separated at 50° C. The organic layer is concentrated under reduced pressure and the remainder is combined with methanol. The mixture is stirred at room temperature for 30 min and then at 0° C. for 1 h. The solid is collected by filtration and washed with cold methanol to give compound 2-G.

[0324] 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) [ka]

[0325] A mixture of compound 2-G in heptane is heated to 90° C. and then treated with compound 6-D in heptane for 20 min. The resulting mixture is stirred at 85° C. for 5 h and then cooled to room temperature. The solvent is removed under reduced pressure to provide the crude product. The crude product is purified by flash chromatography (100 g, 95:5 to 60:40 n-hexane / methyl tert-butyl ether). The solvent is removed under reduced pressure to provide compound 3-G.

[0326] 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) [ka]

[0327] A mixture of compound 3-G and TBAB in methyl tert-butyl ether (15 mL) is treated with aqueous KOH (64%) at -10°C for 15 min. The resulting mixture is kept at 0°C and treated with propargyl bromide (80%) in toluene for 10 min. The resulting mixture is stirred at 5°C overnight and then at room temperature for 1 h. The mixture is combined with methyl tert-butyl ether and water. The layers are separated and the aqueous layer is extracted with methyl tert-butyl ether. The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure to give the intermediate product. The intermediate product is dissolved in acetone and 37% aqueous HCl is added. The resulting mixture is stirred at 55°C for 1 h. The mixture is cooled to room temperature and combined with saturated Na2CO3 followed by water. The volatiles are removed under reduced pressure and the aqueous mixture is combined with methyl tert-butyl ether. The organic layer is collected and the aqueous phase is extracted with methyl tert-butyl ether. The combined organic layers are dried over Na2SO4, filtered to remove solids, and concentrated under reduced pressure to give a first isolate. The first isolate is purified by column chromatography (100:0 to 60:40 n-hexane / MTBE) to give a second isolate. The second isolate is purified by column chromatography (100:0 to 95:5 DCM / MTBE) to give compound 4.

[0328] 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. [ka]

[0329] A mixture of compound 3-G and TBAB in methyl tert-butyl ether (15 mL) is treated with aqueous KOH (64%) at -10°C for 15 min. The resulting mixture is kept at 0°C and treated with 3-bromoprop-1-yne-3,3-d2 for 10 min. The resulting mixture is stirred at 5°C overnight and then at room temperature for 1 h. The mixture is combined with methyl tert-butyl ether and water. The layers are separated and the aqueous layer is extracted with methyl tert-butyl ether. The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure to give the intermediate product. The intermediate product is dissolved in acetone and 37% aqueous HCl is added. The resulting mixture is stirred at 55°C for 1 h. The mixture is cooled to room temperature and combined with saturated Na2CO3 followed by water. The volatiles are removed under reduced pressure and the aqueous mixture is combined with methyl tert-butyl ether. The organic layers are collected and the aqueous phase is extracted with methyl tert-butyl ether. The combined organic layers are dried over Na2SO4, filtered to remove solids, and concentrated under reduced pressure to give a first isolate. The first isolate is purified by column chromatography (100:0 to 60:40 n-hexane / MTBE) to give a second isolate. The second isolate is purified by column chromatography (100:0 to 95:5 DCM / MTBE) to give compound 5.

[0330] LC-MS analysis was performed using the following method. Method:A Platform: Agilent 1260 UPLC with Thermo MSQ mass detector and Agilent DAD (220 and 254 nm); HPLC column: Waters BEH C18 XP, 2.5 μM, 50 × 3.0 mm; 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 over 1.5 minutes. Hold at 100% acetonitrile for 18 seconds. Return to 40% acetonitrile over 6 seconds, hold at 40% for 30 seconds. Method:B Platform: Agilent 1260 UPLC with Thermo MSQ mass detector and Agilent DAD (220 and 254 nm); HPLC column: Waters BEH C18 XP, 2.5 μM, 50 × 3.0 mm; 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 over 6.5 minutes. Increase to 99% acetonitrile over 6 seconds, then hold at 99% acetonitrile for 12 seconds. Return to 10% acetonitrile over 6 seconds, hold at 10% for 30 seconds.

[0331] 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. [ka]

[0332] A mixture of compound 2 (50 mg) and Boc-valine (26 mg) in MeCN (2 mL) was treated with DIC (19 mg, diisopropylcarbodiimide) followed by 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 eluting with EtOAc / Hex to give the Boc-protected intermediate as an oil. This material was dissolved in DCM (2 mL) and the resulting mixture was treated with 4M HCl in dioxane (2 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under vacuum and the resulting residue was triturated with MTBE. A solid precipitate was formed which was filtered off and dried by suction to give compound 6 (50 mg) as the HCl salt as a white powder. LCMS (Method: A) of the Boc-protected intermediate: m / z (M+H)=698.3; tR=1.99 min. LCMS of compound 6 (Method: B): m / z (M+H) = 598.2; tR = 4.48 min.

[0333] 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. [ka]

[0334] A mixture of compound 2 (50 mg) and glutaric anhydride (23 mg) in MeCN (2 mL) was 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 eluting with EtOAc / Hex to give the first isolate as an oil. The first isolate was dissolved in THF / water (1:1, 5 mL) and the resulting mixture was treated with sodium bicarbonate until pH 7 was reached (approximately 1 equivalent). The solvent was removed under vacuum and the resulting residue was placed under vacuum overnight to give compound 7 (31 mg) as the sodium salt as a white powder. LCMS of compound 7 (Method: B): m / z (M+H)=613.2; tR=5.05 min.

[0335] 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. [ka]

[0336] A mixture of compound 2 (50 mg) in MeCN (2 mL) was slowly treated with diphosphoryl chloride (50 mg, 2 equiv.) at room temperature and stirred for 30 min. The mixture was then added to excess aqueous K3PO4 (2 mL) with stirring. After stirring for 30 min, the solvent was removed under vacuum and 20% aqueous phosphoric acid (1 mL) was added to give a strongly acidic mixture. The mixture was extracted with DCM, and the DCM extract was dried over MgSO4 and concentrated under vacuum to give a first isolate. The first isolate was purified by HPLC (water / MeCN with 0.025% TFA) to give a second isolate as an oil. The second isolate was dissolved in water / MeCN (1 mL) and treated with 1M aqueous NaOH with stirring until the mixture reached pH 7 (approximately 2 equiv.). The solvent was then removed under vacuum to give compound 8 as the bis-sodium salt as an off-white powder (15 mg). LCMS (Method: B): m / z=579.0; tR=4.13 min.

[0337] Example 9 CRF1 receptor antagonist activity

[0338] Fleck et al. (J. Pharmacology and Experimental Therapeutics, 341(2):518-531, 2012) (hereinafter "Fleck et al.", the entire contents of which are incorporated herein by reference). As reported in

[2013] , the activity of CRF1 receptor antagonists is expressed as the binding (k1) and dissociation (k -1 ) rate constant, the kinetically derived affinity (K i ) K i =k -1 / k1

[0339] Compound 1 was evaluated according to these procedures and the kinetic K i was determined to be 1.14.

[0340] Example 10 Dissociation half-life (t 1 / 2)

[0341] The dissociation half-life (t 1 / 2 ) was also evaluated by the technique described in Fleck et al. As described herein, the dissociation rate constants of the labeled and unlabeled ligands were calculated using the formula k -1 is the half-life of drug dissociation from the receptor (t 1 / 2 ) is calculated by the following equation: -1 ) is calculated. t 1 / 2 =0.693 / k -1

[0342] Compound 1 was evaluated according to these procedures to determine its dissociation half-life (t 1 / 2 ) was determined to be 63 minutes.

[0343] These and other changes can be made to the embodiments in light of the above detailed description. In general, the terms used in the following claims should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Thus, the claims are not limited by this disclosure.

[0344] Incorporation by Reference Various references are cited herein, such as patents, patent applications, and publications, the disclosures of which are hereby incorporated by reference in their entireties. In an embodiment of the present invention, for example, the following items are provided: (Item 1) Compounds of formula (Ia) [ka] or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, Each R1a are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2R B [is]. (Item 2) R 7a C(R A )2R B and R C 2. The pharmaceutical composition according to item 1, wherein is hydrogen. (Item 3) R 7a 2. The pharmaceutical composition according to item 1, wherein is CHOH. (Item 4) The compound is a compound of formula (IIa) [ka] or a pharma- ceutically acceptable salt thereof. (Item 5) R 6a is CD3 or R 6a 5. The pharmaceutical composition according to any one of items 1 to 4, wherein is CH3. (Item 6) R 6a 5. The pharmaceutical composition according to any one of items 1 to 4, wherein is CD3. (Item 7) Each R 2a 7. The pharmaceutical composition according to any one of items 1 to 6, wherein is hydrogen. (Item 8) R 7a The pharmaceutical composition according to any one of items 4 to 7, wherein is CD2OH. (Item 9) The compound of formula (Ia) is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof. (Item 10) Compounds of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof, Each R 1a are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2a are independently hydrogen or deuterium; Each R3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2R B [is]. (Item 11) R 7a C(R A )2R B and R C The preparation according to item 10, wherein is hydrogen. (Item 12) R 7a The preparation of item 10, wherein is CHOH. (Item 13) The compound of formula (Ia) is a compound of formula (IIa) [ka] or a pharma- ceutically acceptable salt thereof. (Item 14) R 6a is CD3 or R 6a 14. The preparation according to any one of items 10 to 13, wherein is CH3. (Item 15) R 6a The preparation according to any one of items 10 to 13, wherein is CD3. (Item 16) Each R 2a16. The preparation according to any one of items 10 to 15, wherein is hydrogen. (Item 17) R 7a 17. The preparation according to any one of items 13 to 16, wherein is CD2OH. (Item 18) The compound of formula (Ia) is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof. (Item 19) 19. The preparation according to any one of items 10 to 18, comprising at least about 50% by weight of said compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. (Item 20) A method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof, Each R 1a are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2R B [is]. (Item 21) R 7a C(R A )2R B and R C The method according to item 20, wherein is hydrogen. (Item 22) R 7a The method of claim 20, wherein is CHOH. (Item 23) The compound of formula (Ia) is a compound of formula (IIa) [ka] or a pharma- ceutically acceptable salt thereof. (Item 24) R 6a is CD3 or R 6a 24. The method according to any one of items 20 to 23, wherein is CH3. (Item 25) R 6a 24. The method according to any one of items 20 to 23, wherein is CD3. (Item 26) Each R 2a 26. The method according to any one of items 20 to 25, wherein is hydrogen. (Item 27) R 7a 27. The method according to any one of items 23 to 26, wherein is CD2OH. (Item 28) The compound of formula (Ia) is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof. (Item 29) 29. The method according to any one of items 20 to 28, comprising administering said compound of formula (Ia) or a pharma- ceutically acceptable salt thereof in an amount sufficient to reduce a level of one or more biomarkers selected from (a) 17-hydroxyprogesterone (17-OHP), (b) testosterone, and (c) androstenedione in said subject. (Item 30) 30. The method of claim 29, wherein the reduction in the level of any of the biomarkers is determined by comparing the level of the biomarker measured during circadian release on the day before administration of the compound of formula (Ia) or a pharma- ceutically acceptable salt thereof with the level of the biomarker measured during circadian release on the day after administration of the compound of formula (Ia) or a pharma- ceutically acceptable salt thereof. (Item 31) 31. The method of claim 30, wherein the circadian release occurs between 2:00 am and 10:00 am. (Item 32) 32. The method according to any one of items 28 to 31, wherein the compound of formula (Ia) or a pharma- ceutically acceptable salt thereof is administered 3 to 8 hours prior to the circadian release of the biomarker. (Item 33) 1. A method for reducing the severity of one or more symptoms selected from hirsutism, precocious puberty, fertility problems, acne, and growth disorders in a subject with classical congenital adrenal hyperplasia, comprising: administering to the subject a therapeutically effective amount of a compound of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof in an amount sufficient to reduce androstenedione levels in said subject, Each R 1a are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2R B [is]. (Item 34) The compound of formula (Ia) is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof. (Item 35) 34. The method of claim 33, wherein the growth disorder is selected from one or more of accelerated height growth rate, accelerated weight growth rate, or accelerated bone age. (Item 36) 1. A method of reducing the level of one or more biomarkers in a subject with congenital adrenal hyperplasia, comprising: administering to the subject a therapeutically effective amount of a compound of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof, Each R 1a are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2RB [is]. (Item 37) The compound of formula (Ia) is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof. (Item 38) 38. The method of claim 37, wherein the one or more biomarkers are selected from: (a) 17-hydroxyprogesterone (17-OHP), (b) testosterone, and (c) androstenedione. (Item 39) 1. A method of reducing the dosage of a corticosteroid administered to a subject having congenital adrenal hyperplasia to control the congenital adrenal hyperplasia, comprising: administering to the subject a therapeutically effective amount of a compound of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof, Each R 1a are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2R B [is]. (Item 40) The compound of formula (Ia) is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof. (Item 41) 41. The method of claim 40, wherein the corticosteroid is a glucocorticoid. (Item 42) 1. A method of reducing severity of one or more side effects of glucocorticoid treatment in a subject with congenital adrenal hyperplasia, comprising: administering to the subject a therapeutically effective amount of a compound of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof, Each R 1a are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2aare independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3, R 7a is C(R A )3 or C(R A )2R B and Here, R 1a and R 7a At least one of C(R A )2R B is], The method of any one of claims 1 to 5, wherein the side effect is selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing's syndrome, Cushingoid features, growth inhibition, adrenal suppression, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, fatty liver, pancreatitis, hypertension, coronary heart disease, ischemic heart disease, heart failure, dermatoporosis, atrophoderma, ecchymosis, purpura, erosions, striae, delayed wound healing, purpura simplex, acne, hirsutism, hair loss, mood changes, depression, euphoria, emotional lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cellular immunity, predisposition to infection, reactivation of latent infection. (Item 43) The compound of formula (Ia) is a compound of the formula [ka] or a pharma- ceutically acceptable salt thereof. (Item 44) Compounds of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, Each R 1 are independently A )3 or C(R A )2R B and Each R A are independently hydrogen or deuterium; R B -OR C and R C is hydrogen or deuterium, Each R 2 are independently hydrogen or deuterium; Each R 3 are independently hydrogen or deuterium; R 4 teeth, [ka] and R 5 is hydrogen or deuterium, R 6 is C(R A )3, R 7 is C(R A )3 or C(R A )2R B and Here, R A , R 2 , R 3 and R 5 At least one of is deuterium, and R 1 and R 7 At least one of C(R A )2R B [is]. (Item 45) R 6 but 13 45. The compound according to item 44, which is CD3, or a pharma- ceutically acceptable salt thereof. (Item 46) R 6 is CD3 and R 7 45. The compound according to item 44, or a pharma- ceutically acceptable salt thereof, wherein is CH3. (Item 47) R 6 is CH3 and R 7 45. The compound according to item 44, or a pharma- ceutically acceptable salt thereof, wherein is CD3. (Item 48) R 6 is CD3 and R 7 45. The compound according to item 44, or a pharma- ceutically acceptable salt thereof, wherein is CD3. (Item 49) R 1 49. The compound according to any one of items 44 to 48, or a pharma- ceutically acceptable salt thereof, wherein is CD3. (Item 50) Each R A 50. The compound according to any one of items 44 to 49, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. (Item 51) Each R 2 51. The compound according to any one of items 44 to 50, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. (Item 52) Each R 3 52. The compound according to any one of items 44 to 51, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. (Item 53) A pharmaceutical composition comprising a compound according to any one of items 44 to 52 or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient. (Item 54) 53. A method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of items 44 to 52. (Item 55) 55. The method of claim 54, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered 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 subject. (Item 56) 55. The method according to item 54, wherein the reduction in the level of any of the biomarkers is determined by comparing the level of the biomarker measured during circadian release on the day before administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof with the level of the biomarker measured during circadian release on the day after administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. (Item 57) 57. The method of claim 56, wherein the circadian release occurs between 2:00 am and 10:00 am. (Item 58) 55. The method according to item 54, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered 3 to 8 hours prior to the circadian release of the biomarker. (Item 59) Compound of formula (III) [ka] or a pharma- ceutically acceptable salt thereof, R 11 teeth, a)-P(=O)(OR 33 )2 or -P(=O)(OR 33 )(N(R 33 )2) b) -C(=O)R 50 , c) -C(=O)N(R 33 )R 50 , d) -C(=O)OR 50 ,or e)R 50 and Each R 33are independently hydrogen, C1-C6 alkyl, haloC1-C6 alkyl or aryl, wherein the C1-C6 alkyl and aryl are each independently 10 where appropriate, 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 selected from one or more R 10 and / or R 20 where appropriate, Each R 10 are independently halo, haloC1-C6 alkyl, cyano, nitro, trimethylsilanyl, -O · (oxyl radical), -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 two R's as required 10 the groups taken together on a single atom form oxo, each t is independently 1 or 2; each p is independently 1, 2, or 3; Each R 20 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl, or heteroaryl, where each R 20 is R 10 and / or R 22 where appropriate, Each R 22 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocyclyl, or heteroaryl, where each R 22 is R 10 where appropriate, Each R 30 , R 31 and R 32 are independently hydrogen, haloC1-C6 alkyl, or C1-C6 alkyl; Each R 1a are independently A )3, Each R A are independently hydrogen or deuterium; Each R 2a are independently hydrogen or deuterium; Each R 3a are independently hydrogen or deuterium; R 4a teeth, [ka] and R 5a is hydrogen or deuterium, R 6a is C(R A )3]. (Item 60) Each R 33 are independently hydrogen, C1-C6 alkyl, haloC1-C6 alkyl or aryl; R 50is C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, or heterocyclyl; Each R 20 is 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; Each R 30 , R 31 and R 32 is independently hydrogen, haloC1-C6 alkyl, or C1-C6 alkyl; Item 59. The compound according to item 59. (Item 61) The compound is a compound of formula (IIIa) [ka] 61. The compound according to item 59 or 60, which is: (Item 62) The compound is a compound of formula (IIIaa) [ka] or a pharma- ceutically acceptable salt thereof. (Item 63) The compound is a compound of formula (IIIb) [ka] 61. The compound according to item 59 or 60, which is: (Item 64) The compound is a compound of formula (IIIbb) [ka] or a pharma- ceutically acceptable salt thereof. (Item 65) The compound is a compound of formula (IIIc) [ka] 61. The compound according to item 59 or 60, which is: (Item 66) The compound is a compound of formula (IIIcc) [ka] or a pharma- ceutically acceptable salt thereof. (Item 67) The compound is a compound of formula (IIId) [ka] 61. The compound according to item 59 or 60, which is: (Item 68) The compound is a compound of formula (IIIdd) [ka] or a pharma- ceutically acceptable salt thereof. (Item 69) The compound is a compound of formula (IIIe) [ka] 61. The compound according to item 59 or 60, which is: (Item 70) The compound is a compound of formula (IIIee) [ka] or a pharma- ceutically acceptable salt thereof. (Item 71) The compound is a compound of formula (IIIf) [ka] 61. The compound according to item 59 or 60, which is: (Item 72) The compound is a compound of formula (IIIff) [ka] or a pharma- ceutically acceptable salt thereof. (Item 73) R 11 But the following: [ka] [ka] [ka] [ka] [ka] [ka] Item 60. The compound according to item 59, selected from one of: (Item 74) The compound is a compound of the formula [ka] 61. The compound according to item 59 or 60, which is: (Item 75) The compound is a compound of the formula [ka] 61. The compound according to item 59 or 60, which is: (Item 76) The compound is a compound of the formula [ka] 61. The compound according to item 59 or 60, which is: (Item 77) A pharmaceutical composition comprising a compound according to any one of items 59 to 76 or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient. (Item 78) 77. A method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of items 59-76 or a pharma- ceutically acceptable salt thereof. (Item 79) Item 79. The method of item 78, wherein the compound of formula (III) or a pharma- ceutically acceptable salt thereof is administered 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 subject. (Item 80) Item 79. The method according to item 78, wherein the reduction in the level of any of the biomarkers is determined by comparing the level of the biomarker measured during circadian release on the day before administration of the compound of formula (III) or a pharma- ceutically acceptable salt thereof with the level of the biomarker measured during circadian release on the day after administration of the compound of formula (III) or a pharma- ceutically acceptable salt thereof. (Item 81) 81. The method of claim 80, wherein the circadian release occurs between 2:00 am and 10:00 am. (Item 82) 79. The method according to item 78, wherein the compound of formula (III) or a pharma- ceutically acceptable salt thereof is administered 3 to 8 hours prior to the circadian release of the biomarker. (Item 83) 1. A method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject 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). [ka] administering The method, wherein compound 2 is generated under physiological conditions or by solvolysis following administration of a prodrug of compound 2 or a pharma- ceutically acceptable salt thereof to the subject, and wherein said prodrug of compound 2 or said pharma- ceutically 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 pharmaceutical salt thereof. (Item 84) 1. A method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject 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). [ka] administering The method, wherein compound 2 is produced as a result of a metabolic chemical reaction following administration of a prodrug of compound 2, or a pharma- ceutically acceptable salt thereof, to the subject, and wherein said prodrug of compound 2, or said pharma- ceutically 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 pharmaceutical salt thereof. (Item 85) 1. A method of treating congenital adrenal hyperplasia in a subject in need thereof, comprising administering to the subject 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). [ka] or a pharma- ceutically acceptable salt thereof, The method, wherein said prodrug of compound 2 or said pharma- ceutically 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 pharmaceutical salt thereof. (Item 86) The method according to any one of items 83 to 85, wherein the prodrug or the pharma- ceutically acceptable salt thereof is a compound according to any one of items 59 to 76 or a pharma- ceutically acceptable salt thereof.

Claims

[Claim 1] The invention described in this specification.

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