Spirocyclic compounds as melanocortin 4 receptor antagonists and their uses

Abstract

Described herein are compounds of formula I and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , X 1 , Y 1 , Y 2 , Y 3 , Y 4 and Y 5 Defined herein; their use as MC4R antagonists; pharmaceutical compositions containing such compounds and salts; the use of such compounds and salts for treating, for example, cachexia, anorexia or anorexia nervosa; and intermediates and processes for preparing such compounds and salts.

Description

Technical Field

[0001] The present invention relates to novel pharmaceutical compounds, pharmaceutical compositions containing the compounds, and the use of the compounds as melanocortin receptor 4 (MC4R) antagonists. Background Art

[0002] Melanocortin is a peptide derived from promorphine melanocortin (pro-opiomelanocortin, POMC), which binds to and activates G protein-coupled receptors (GPCRs) of the melanocortin receptor family. Melanocortin regulates a variety of physiological processes, including sexual function and behavior, food intake and metabolism. To date, five melanocortin receptors (MCRs) have been identified in mammals: MC1R, MC2R, MC3R, MC4R and MC5R, which are expressed in various tissues. MC1R is specifically expressed in melanocytes and melanoma cells, MC2R is an ACTH receptor and is expressed in adrenal tissue, MC3R is mainly expressed in the brain and limbic system, MC4R is widely expressed in the brain and spinal cord, and MC5R is expressed in the brain and many peripheral tissues, including skin, adipose tissue, skeletal muscle and lymphoid tissue. See, for example, U.S. Patent No. 8,138,188 and Saleh et al., Front.Pharmacol., 2018, 9:560.

[0003] The MC4R is a G protein-coupled seven-transmembrane receptor expressed primarily in the hypothalamus, hippocampus, and thalamus (Gantz et al. 1993 J. Biol. Chem. 268:15174-15179). The receptor is involved in the central regulation of body weight: MC4R is activated by α-melanocyte-stimulating hormone (MSH), which is derived from promorpholinomelanocortin and is inactivated by agonist gene-related protein (AGRP). α-MSH induces weight loss, while ectopic expression of agonist protein causes obesity in agonist mice (Fan et al. 1993 Nature 385:165-168; Lu et al. 1994 Nature 371:799-802). Additional evidence for a role for the MC4R in body weight regulation comes from knockout models in mice (Huszar et al. 1997 Cell 88:131-141) and haploinsufficient mutations in humans (Vaisse et al. 1998 Nat. Genet. 20:113-114; Yeo et al. 1998 Nat. Genet. 20:111-112; Hinney et al. 1999 J. Clin. Endocrinol. Metab. 84:1483-1486). In MC4R knockout mice, weight gain can be discerned at 5 weeks of age. At 15 weeks of age, homozygous mutant females weigh, on average, twice as much as their wild-type littermates, while homozygous mutant males weigh approximately 50% more than wild-type controls. MC4R knockout heterozygous mice show weight gain that is intermediate between that seen in wild-type and homozygous mutant littermates, thus demonstrating a gene dosage effect of MC4R ablation on body weight regulation. Homozygous mutants have an approximately 50% increase in food intake compared to wild-type littermates (Huszar et al. 1997 Cell 88:131-141). [From Am. J. Hum. Genet., 65:1501-1507, 1999]. MC4R activation has been shown to induce penile erections in rodents, and MC4R inactivation has been shown to cause obesity (Hadley, 1999, Ann. NY Acad. Sci., 885:1-21; Wikberg et al. 2000, Pharmacol. Res., 42(5), 393-420; and reviewed in Saleh et al., Front. Pharmacol., 2018, 9:560).

[0004] In recent years, several types of small molecule MC4R antagonists have been reported in the literature and patent applications [see, for example, WO2010052256; WO2010081666; U.S. Patent 8,044,068; Chaki et al., Current Topics in Medicinal Chemistry, 2007, 7, 1145-1151; Foster et al., Current Topics in Medicinal Chemistry, 2007, 7, 1131-1136; Pontillo et al., Bioorganic & Medicinal Chemistry Letters 15 (2005) 2541-46; Vos et al., Bioorganic & Medicinal Chemistry Letters 16 (2006) 2302-2305; Tao, Endocrine Reviews, 2010, 31(4): 506-543; and Saleh et al., Front. Pharmacol., 2018, 9: 560]. Such MC4R antagonists can be used to treat and / or prevent MC4R-associated conditions, diseases or disorders, such as cachexia [including, for example, cachexia associated with chronic diseases, such as cachexia associated with cancer; cachexia associated with acquired immune deficiency syndrome (AIDS); cachexia associated with heart failure, such as cachexia associated with congestive heart failure (CHF); cachexia associated with chronic kidney disease (CKD); cachexia associated with chronic disease treatment, such as cachexia associated with cancer treatment or cachexia associated with heart failure (e.g., CHF) treatment]; cachexia associated with leukemia; cachexia associated with urticaria ... nausea; vomiting; weight loss (e.g., involuntary weight loss); growth retardation; sarcopenia; muscle atrophy; muscle weakness; frailty; osteoporosis; skeletal disorders (e.g., bone loss); pain; neuropathic pain; anxiety (e.g., post-traumatic stress disorder or PTSD); depression; hypertension; malnutrition; obesity (e.g., sarcopenia caused by chronic obesity); sexual dysfunction; and inflammatory diseases (e.g., inflammatory diseases associated with anorexia or cachexia or sarcopenia or muscle atrophy).

[0005] There is a continuing need for alternative MC4R antagonists, for example, for the development of novel and / or improved pharmaceutical products (e.g., more potent, more selective, less toxic, and / or with improved biopharmaceutical properties, such as physical stability; solubility; oral bioavailability; adequate metabolic stability; clearance; half-life) for treating or preventing MC4R-associated conditions, diseases, or disorders, such as those described herein. The present invention is directed to these and other important ends. Summary of the Invention

[0006] In one embodiment (Embodiment A1), the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in:

[0009] R 1 H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl or R 1a , wherein the C 3-6 Each of the cycloalkyl and 4- to 7-membered heterocycloalkyl groups is optionally substituted with 1, 2, 3, or 4 independently selected C 1-4 alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3 or 4 independently selected R B Substituted, wherein each R B Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl or R B1 ; or two adjacent R B Together with the two ring-forming atoms of the phenyl group to which it is attached, a fused 5- or 6-membered heteroaryl group is formed, each of which is optionally substituted by 1, 2 or 3 atoms each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy substituents;

[0010] R 1a is optionally 1, 2, 3 or 4 independently selected R A substituted 5- or 6-membered heteroaryl, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl, -N(C 1-4 Alkyl)2, R A1 or (C 3-4 Cycloalkyl)-C 1-4 Alkyl-, wherein the C 1-4 Alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4Each of the alkyl- is optionally substituted with 1, 2, 3, 4 or 5 each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy; or two adjacent R A Together with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which it is attached, a fused benzene ring or a fused 5- or 6-membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6-membered cycloalkyl is formed, each of which is optionally substituted by 1, 2 or 3 atoms each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy substituents;

[0011] R A1 is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl, each of which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy substituents;

[0012] R B1 is a 5- or 6-membered heteroaryl group, each of which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy substituents;

[0013] X 1 C(R X )2, where each R X are independently H or C 1-4 alkyl;

[0014] R 2 and R 3 Each of which is independently H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 Cycloalkyl or (C 3-4 Cycloalkyl)-C 1-4 Alkyl, where C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C1-4 Each of the alkyl- is optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from halogen, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy substituents;

[0015] or R 2 and R 3 Together with the carbon atom to which it is attached, it forms a carbon atom optionally substituted with 1, 2, 3, 4 or 5 carbon atoms each independently selected from halogen, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituent of haloalkoxy is substituted with C 3-6 Cycloalkyl;

[0016] Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Each of which is independently CR 4 or N, with the constraint Y 1 、Y 2 、Y 3 、Y 4 and Y 5 No more than 3 of them are N; and

[0017] Each R 4 are independently H, halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -N(C 1-2 Alkyl)2, C 3-4 Cycloalkyl or (C 3-4 Cycloalkyl)-C 1-4 Alkyl-, wherein the C 1-4 Alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is optionally substituted with 1, 2, 3, 4 or 5 each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted.

[0018] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier.

[0019] The present invention also provides a method for treating an MC4R-associated condition, disease or disorder in a mammal (eg, a human) in need of such treatment, comprising administering to the mammal (eg, a human) a compound of Formula I or a pharmaceutically acceptable salt of the compound.

[0020] The present invention also provides the compound of formula I or a pharmaceutically acceptable salt of the compound for use in treating MC4R-related conditions, diseases or disorders.

[0021] The MC4R-associated condition, disease or disorder includes one selected from the group consisting of cachexia [including, for example, cachexia associated with a chronic disease, such as cachexia associated with cancer; cachexia associated with acquired immune deficiency syndrome (AIDS); cachexia associated with heart failure, such as cachexia associated with congestive heart failure (CHF); cachexia associated with chronic kidney disease (CKD); cachexia associated with treatment of a chronic disease, such as cachexia associated with cancer treatment or cachexia associated with treatment of heart failure (e.g., CHF)]; anorexia or anorexia nervosa (e.g., anorexia nervosa); , anorexia associated with chemotherapy and / or radiation therapy); nausea; vomiting; weight loss (e.g., involuntary weight loss); failure to thrive; sarcopenia; muscle atrophy; muscle weakness [e.g., muscle weakness associated with chronic obstructive pulmonary disease (COPD)]; frailty; osteoporosis; skeletal disorders (e.g., bone loss); pain; neuropathic pain; anxiety (e.g., post-traumatic stress disorder or PTSD); depression; hypertension; malnutrition; obesity (e.g., sarcopenia caused by chronic obesity); sexual dysfunction; and inflammatory diseases (e.g., inflammatory diseases associated with anorexia or cachexia or sarcopenia or muscle atrophy).

[0022] The present invention also provides a method for treating a condition, disease or disorder in a mammal (e.g., a human) in need of such treatment, comprising administering to the mammal (e.g., a human) a compound of Formula I or a pharmaceutically acceptable salt of the compound, wherein the condition, disease or disorder is selected from the group consisting of cachexia [including, for example, cachexia associated with chronic diseases, such as cachexia associated with cancer; cachexia associated with acquired immune deficiency syndrome (AIDS); cachexia associated with heart failure, such as cachexia associated with congestive heart failure (CHF); cachexia associated with chronic kidney disease (CKD); cachexia associated with chronic disease treatment, such as cachexia associated with cancer; cachexia associated with AIDS; cachexia associated with heart failure, such as cachexia associated with congestive heart failure (CHF); cachexia associated with chronic kidney disease (CKD); cachexia associated with chronic disease treatment, such as cachexia associated with cancer; [cachexia associated with heart failure (e.g., CHF)]; anorexia or anorexia nervosa (e.g., anorexia nervosa in the elderly, anorexia associated with chemotherapy and / or radiation therapy); nausea; vomiting; weight loss (e.g., involuntary weight loss); growth retardation; sarcopenia; muscle atrophy; muscle weakness; frailty; osteoporosis; skeletal disorders (e.g., bone loss); pain; neuropathic pain; anxiety (e.g., post-traumatic stress disorder or PTSD); depression; hypertension; malnutrition; obesity (e.g., sarcopenia caused by chronic obesity); sexual dysfunction; and inflammatory diseases (e.g., inflammatory diseases associated with anorexia or cachexia or sarcopenia or muscle atrophy).

[0023] The present invention also provides a method for antagonizing melanocortin-4 receptor (MC4R), comprising contacting the MC4R with the compound of formula I or a pharmaceutically acceptable salt of the compound.

[0024] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0025] BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 An illustrative single crystal structure of Compound Example 14 is shown.

[0027] Figure 2 An illustrative single crystal structure of Compound Example 15 is shown.

[0028] Figure 3 Shown is a representative powder X-ray diffraction pattern observed for the crystalline form of P23.

[0029] Figure 4 Shown is a representative powder X-ray diffraction pattern observed for the crystalline form of C69.

[0030] Figure 5 Shown is a representative powder X-ray diffraction pattern observed for the crystalline form of P28.

[0031] Figure 6A representative powder X-ray diffraction pattern observed for the crystalline form of Example 14 is shown. DETAILED DESCRIPTION

[0032] The present invention may be understood more readily by reference to the following detailed description of illustrative embodiments of the invention and the Examples included therein.

[0033] It should be understood that the present invention is not limited to a particular synthetic manufacturing method, which may of course vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the present invention. In this specification and the claims that follow, reference will be made to various terms, which shall be defined as having the following meanings:

[0034] As used in this specification, "a" or "an" can mean one or more. As used in the claims herein, when used in conjunction with the word "comprising," the word "a" or "an" can mean one or more than one. As used herein, "another" can mean at least a second or more.

[0035] The term "about" is a relative term indicating an approximation of plus or minus 10%, in one embodiment plus or minus 5%, and in another embodiment plus or minus 2% of the nominal value to which it refers. This level of approximation is appropriate in the field of the present invention unless a closer range is specifically stated for the value.

[0036] As used herein, "compound" includes any pharmaceutically acceptable derivative or variant, including configurational isomers (e.g., cis-isomers and trans-isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. The term "prodrug" refers to a compound that is a drug precursor that, after administration, releases the drug in vivo via some chemical or physiological process (e.g., when the prodrug reaches physiological pH or is converted to the desired drug form via enzymatic action).

[0037] The term "alkyl" means a non-cyclic saturated aliphatic hydrocarbon group which may be straight or branched. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl. The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by a prefix that specifies the lower and upper number of carbon atoms in the moiety, i.e., the prefix C i-j A moiety indicating an integer "i" to an integer "j" number of carbon atoms (inclusive). Thus, for example, C 1-4 Alkyl refers to an alkyl group having one to four carbon atoms (inclusive).1-4 Representative examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. 1-4 Alkyl refers to an alkyl group of one to two carbon atoms (inclusive) (ie, methyl or ethyl). Alkyl groups, when so designated, may optionally be substituted with one or more (eg, one to five) suitable substituents.

[0038] At various places in this specification, substituents of compounds of the invention are disclosed in groups or ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "C 1-4 The term "alkyl" is specifically intended to include C1 alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, and C4 alkyl. For another example, the term "4- to 7-membered heterocycloalkyl" is specifically intended to include any 4-, 5-, 6-, or 7-membered heterocycloalkyl.

[0039] As used herein, the term "n-membered," where n is an integer, generally describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, pyridinyl is an example of a 6-membered heteroaryl ring and pyrazolyl is an example of a 5-membered heteroaryl.

[0040] As used herein, the term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. For example, the term "C 1-4 Alkoxy" or "C 1-4 "Alkyloxy" refers to -O-(C 1-4 alkyl); for another example, the term "C 1-2 Alkoxy" or "C 1-2 "Alkyloxy" refers to -O-(C 1-2 Alkyl). Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. When so specified, an alkoxy or alkyloxy group may be optionally substituted with one or more (e.g., one to five) suitable substituents.

[0041] As used herein, the term "halo" or "halogen" means -F, -Cl, -Br, or -I.

[0042] As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group has been replaced by a halogen atom). For example, the term "C 1-4 "Haloalkyl" refers to a C 1-4 Alkyl (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group has been replaced by a halogen atom); and the term "C 1-2 "Haloalkyl" refers to a C 1-2Alkyl (i.e., methyl or ethyl) (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group has been replaced by a halogen atom). Examples of haloalkyl groups include -CF3, -CHF2, -CH2F, -CH2CF3, -C2F5, -CH2Cl, and the like.

[0043] "Fluoroalkyl" means an alkyl group as defined herein substituted with one or more fluorine (-F) substituents (up to perfluoroalkyl, ie, each hydrogen atom of the alkyl group has been replaced by a fluorine atom). The term "C 1-2 "Fluoroalkyl" refers to a C 1-2 Alkyl (i.e., methyl or ethyl) (up to perfluoroalkyl, i.e., each hydrogen atom of the alkyl group has been replaced by a fluorine atom); and the term "C1 fluoroalkyl" refers to a methyl group having 1, 2, or 3 fluorine substituents. Examples of C1 fluoroalkyl groups include fluoromethyl, difluoromethyl, and trifluoromethyl; some examples of C2 fluoroalkyl groups include 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2-trifluoroethyl, and the like.

[0044] As used herein, the term "haloalkoxy" refers to an -O-haloalkyl group. For example, the term "C 1-4 "Haloalkoxy" refers to -O-(C 1-4 haloalkyl); and the term "C 1-2 "Haloalkoxy" refers to -O-(C 1-2 For example, the term "C1 haloalkoxy" refers to a methoxy group having one, two, or three halogen substituents. Examples of haloalkoxy groups are -OCF3 or -OCHF2.

[0045] As used herein, the term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl group having one or more (e.g., 1, 2, or 3) OH substituents. The term "C 1-4 Hydroxyalkyl" or "C 1-4 "Hydroxyalkyl" refers to a C 1-4 Alkyl; and the term "C 1-2 Hydroxyalkyl" or "C 1-2 "Hydroxyalkyl" refers to a C 1-2 Alkyl. Examples of hydroxyalkyl are -CH2OH or -CH2CH2OH.

[0046] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.). Cycloalkyl has 3 to 15 (e.g., 3 to 14, 3 to 10, 3 to 6, 3 to 4, or 4 to 6) carbon atoms. In some embodiments, cycloalkyl may optionally contain one, two or more non-cumulative non-aromatic double or triple bonds and / or one to three oxo groups. In some embodiments, bicycloalkyl has 6 to 14 carbon atoms. As used herein, the term "C 3-4 "Cycloalkyl" means a saturated cyclic hydrocarbon group containing 3 to 4 carbon atoms. 3-4 Examples of cycloalkyl groups include cyclopropyl and cyclobutyl. Also included in the definition of cycloalkyl are moieties having one or more aromatic rings (including aryl and heteroaryl) fused to a cycloalkyl ring, such as benzo or pyridyl derivatives of cyclopentane (5-membered cycloalkyl), cyclopentene, cyclohexane (6-membered cycloalkyl), and the like, such as 6,7-dihydro-5H-cyclopenta[b]pyridyl, 5,6,7,8-tetrahydroquinolinyl, or 1,5,6,7,8-tetrahydroisoquinolinyl, each of which includes a 5-membered or 6-membered cycloalkyl moiety fused to a heteroaryl ring (i.e., a pyridyl ring). When so specified, a cycloalkyl or C 3-4 A cycloalkyl group may be optionally substituted with one or more (eg, one to five) suitable substituents.

[0047] As used herein, the term "C 3-4 Cycloalkyl-C 1-4 "Alkyl-" means a C 3-4 Cycloalkyl, which is substituted by a C 3-4 The alkyl group is attached to the parent molecular moiety. 3-4 Cycloalkyl-C 1-4 Some examples of alkyl- include cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopropylpropyl, 3-cyclopropylpropyl, cyclobutylmethyl, 2-cyclobutylethyl, 2-cyclobutylpropyl, and 3-cyclobutylpropyl.

[0048] As used herein, the term "heterocycloalkyl" refers to a monocyclic or polycyclic ring [including two or more rings fused together, including spirocyclic, fused or bridged systems, such as bicyclic ring systems], a saturated or unsaturated, non-aromatic 4- to 15-membered ring system (such as a 4- to 14-membered ring system, a 4- to 12-membered ring system, a 5- to 10-membered ring system, a 4- to 7-membered ring system, a 4- to 6-membered ring system, or a 5- to 6-membered ring system) comprising 1 to 14 ring-forming carbon atoms and 1 to 10 ring-forming heteroatoms each independently selected from O, S and N (and, if present, optionally P or B). Heterocycloalkyl may also optionally contain one or more oxo groups (i.e., =O) or thioxo groups (i.e., =S). For example, the term "4- to 7-membered heterocycloalkyl" refers to a monocyclic or polycyclic ring, saturated or unsaturated, non-aromatic 4- to 7-membered ring system containing one or more ring heteroatoms each independently selected from O, S and N. For another example, the term "5- or 6-membered heterocycloalkyl" refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 5- or 6-membered ring system containing one or more ring-forming heteroatoms each independently selected from O, S and N. Heterocycloalkyl, when so designated, may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

[0049] Some examples of 4- to 7-membered heterocycloalkyl groups include azetidinyl, oxetanyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, tetrahydrodiazinyl, and tetrahydropyranyl (also known as oxanyl). Some other examples of 4 to 7 heterocycloalkyl groups include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyranyl (e.g., tetrahydro-2H-pyran-4-yl), imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, 1,3-oxazolidin-3-yl, 1,4-oxazepan-2 -yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl, oxazolidinone, 2-oxo-piperidinyl (e.g., 2-oxo-piperidin-1-yl), 2-oxoazepan-3-yl and the like.

[0050] As used herein, the term "heteroaryl" refers to a monocyclic or fused-ring polycyclic aromatic heterocyclic group having one or more heteroatom ring members (ring atoms) each independently selected from O, S, and N in at least one ring. Heteroaryl groups have 5 to 14 ring atoms, including 1 to 13 carbon atoms and 1 to 8 heteroatoms selected from O, S, and N. In some embodiments, heteroaryl groups have 5 to 10 ring atoms, including one to four heteroatoms. Heteroaryl groups may also contain one to three oxo or thioxo groups (i.e., =S). In some embodiments, heteroaryl groups have 5 to 8 ring atoms, including one, two, or three heteroatoms. For example, the term "5-membered heteroaryl" refers to a monocyclic heteroaryl group as defined above having 5 ring atoms in the monocyclic heteroaryl ring; the term "6-membered heteroaryl" refers to a monocyclic heteroaryl group as defined above having 6 ring atoms in the monocyclic heteroaryl ring; and the term "5- or 6-membered heteroaryl" refers to a monocyclic heteroaryl group as defined above having 5 or 6 ring atoms in the monocyclic heteroaryl ring. Heteroaryl groups, when so designated, may optionally be substituted with one or more (e.g., 1 to 5) suitable substituents. Examples of monocyclic heteroaryl groups include groups having 5 ring atoms (including one to three heteroatoms), or groups having 6 ring atoms (including one, two, or three nitrogen heteroatoms). Examples of fused bicyclic heteroaryl groups include two fused 5- and / or 6-membered monocyclic rings (including one to four heteroatoms).

[0051] Some examples of heteroaryl groups include pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrazinyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl), pyridazinyl (e.g., pyridazin-3-yl or pyridazin-4-yl), thienyl, furanyl, imidazolyl (e.g., 1H-imidazol-4-yl), pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl (e.g., pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl), 1,2,4-thiazolyl), 1H-imidazo[4,5-c]pyridinyl, 1H-imidazo[1,2-a]pyridinyl, ... H-pyrrolo[3,2-c]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-c][1,2,4]triazinyl, imidazo[1,5-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 1H-indazolyl, 9H-purinyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, isoxazolo[5,4-c]pyridazinyl, isoxazolo[3 ,4-c]pyridazinyl, pyrazolo[1,5-a]pyrimidinyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, pyridone, pyrimidone(), pyrazinone, pyrimidinone, 1H-imidazole-2(3H)-one, 1H-pyrrole-2,5-dione, 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridyl, 2,4(1H,3H)-dioxo-pyrimidinyl, 1H-2-oxo-pyrazinyl and similar groups.

[0052] As used herein, compounds of Formula I as described herein include optional substitutions and variables. It is understood that the normal valence of each of the designated (optionally substituted) atoms or moieties is not exceeded, and any of the optional substitutions results in a stable compound. It is also understood that combinations of optional substituents and / or variables are permissible only if such combinations result in stable compounds.

[0053] As used herein, unless otherwise specified, the point of attachment of a substituent may be from any suitable position of the substituent. For example, piperidinyl may be piperidin-1-yl (attached via the N atom of the piperidinyl), piperidin-2-yl (attached via a C atom at the piperidinyl 2 position), piperidin-3-yl (attached via a C atom at the piperidinyl 3 position), or piperidin-4-yl (attached via a C atom at the piperidinyl 4 position). For another example, pyridinyl (or pyridinyl) may be 2-pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl).

[0054] As used herein, a point of attachment of a substituent may be designated to indicate the position at which the substituent is attached to another moiety. For example, "(C 3-4 Cycloalkyl)-C 1-4 Alkyl-" means that the point of attachment occurs at "(C 3-4 Cycloalkyl)-C 1-4 Alkyl-"C 1-4 The alkyl" portion.

[0055] When a substituted or optionally substituted moiety is described without indicating the atom via which such moiety is bonded to the substituent, then the substituent may be bonded via any suitable atom in such moiety. For example, in a substituted "(C 3-4 Cycloalkyl)-C 1-4 In the "alkyl-", cycloalkylalkyl [i.e. (C 3-4 Cycloalkyl)-C 1-4 Substituents on the alkyl-] group may be bonded to any carbon atom on the alkyl portion or the cycloalkyl portion of the cycloalkylalkyl group. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0056] As used herein, the term "adjacent" to describe the relative position of two substituents on a ring structure means that the two substituents are respectively attached to two ring-forming atoms of the same ring, wherein the two ring-forming atoms are directly connected via a chemical bond. For example, in each of the following structures:

[0057]

[0058] Two R's 70 Any one of the groups is R 60 adjacent groups.

[0059] "Mammal" refers to warm-blooded vertebrates characterized by the secretion of milk by females for the nourishment of their young, such as guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, cows, goats, sheep, horses, monkeys, chimpanzees, and humans.

[0060] The term "pharmaceutically acceptable" means that a substance (eg, a compound of the invention) and any salt thereof, or a composition containing the substance or salt of the invention, is suitable for administration to a patient.

[0061] As used herein, the expressions "reaction inert solvent" and "inert solvent" refer to a solvent or mixtures thereof that do not interact with the starting materials, reagents, intermediates, or products in a manner that adversely affects the yield of the desired product.

[0062] As used herein, the term "selective" or "selective" refers to a compound having a greater effect in a first assay than the effect of the same compound in a second assay. For example, in a "gut-selective" compound, the first assay is for the half-life of the compound in the intestine, and the second assay is for the half-life of the compound in the liver.

[0063] "Therapeutically effective amount" means an amount of a compound of the invention that (i) treats or prevents a specific disease, condition, or disorder described herein; (ii) alleviates, ameliorates, or eliminates one or more symptoms of the specific disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of the specific disease, condition, or disorder.

[0064] As used herein, the terms "treating," "treat," or "treatment" encompass both preventative (i.e., prophylactic) and palliative treatment, including reversing, alleviating, mitigating, or slowing the progression of a disease (or disorder or condition) or any tissue damage associated with one or more symptoms of a disease (or disorder or condition).

[0065] As used herein, the term "contacting" refers to bringing the indicated moiety into an in vitro or in vivo system. For example, "contacting" MC4R with a compound of the invention includes administering a compound of the invention to a mammal (such as a human) having MC4R, as well as, for example, introducing a compound of the invention into a sample containing cells or purified preparations containing MC4R.

[0066] Embodiment A2 is another embodiment of Embodiment A1, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is a compound of Formula Ia:

[0067]

[0068] or a pharmaceutically acceptable salt thereof, and wherein the variable R 1 、R 2 、R 3 、X 1 、Y 1 、Y 2、Y 3 、Y 4 and Y 5 The same definitions as in Embodiment A1.

[0069] Embodiment A3 is another embodiment of Embodiment A1 or A2, wherein the compound or a pharmaceutically acceptable salt thereof is a compound of Formula II:

[0070]

[0071] or a pharmaceutically acceptable salt thereof, and wherein the variable R 1 、R 2 、R 3 、X 1 、Y 1 、Y 2 、Y 3 、Y 4 and Y 5 The same definitions as in Embodiment A1.

[0072] Embodiment A4 is another embodiment of any one of Embodiments A1 to A3, wherein the compound or a pharmaceutically acceptable salt thereof is a compound of Formula III:

[0073]

[0074] or a pharmaceutically acceptable salt thereof, and wherein the variable R 1 、R 2 、R 3 、Y 1 、Y 2 、Y 3 、Y 4 and Y 5 The same definitions as in Embodiment A1.

[0075] Embodiment A5 is a further embodiment of any one of Embodiments A1 to A4, wherein:

[0076] R 1 H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, optionally 1 to 4 C 1-4 alkyl-substituted 4- to 7-membered heterocycloalkyl, or R 1a ;

[0077] R 1a is optionally 1, 2, 3 or 4 independently selected R A substituted 5- or 6-membered heteroaryl, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl or (C 3-4 Cycloalkyl)-C 1-4 Alkyl-, wherein the C 1-4 Alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is optionally substituted with 1, 2, 3, 4 or 5 each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy; or two adjacent R A Together with the two ring atoms of the 5- or 6-membered heteroaryl to which they are attached, they form a fused benzene ring or a fused 5- or 6-membered heteroaryl, each of which is optionally substituted by 1, 2 or 3 atoms each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted.

[0078] Embodiment A6 is a further embodiment of any one of Embodiments A1 to A4, wherein R 1 is H, halogen or 4- to 7-membered heterocycloalkyl.

[0079] Embodiment A7 is a further embodiment of any one of Embodiments A1 to A4, wherein R 1 is H or halogen.

[0080] Embodiment A8 is a further embodiment of any one of Embodiments A1 to A4, wherein R 1 For H.

[0081] Embodiment A9 is a further embodiment of any one of Embodiments A1 to A4, wherein R 1 is a halogen (such as Cl).

[0082] Embodiment A10 is a further embodiment of any one of Embodiments A1 to A4, wherein R 1 is optionally 1 to 4 C 1-4 Alkyl-substituted 4- to 7-membered heterocycloalkyl (eg, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholino).

[0083] Embodiment A11 is a further embodiment of any one of Embodiments A1 to A4, wherein R 1 R1a .

[0084] Embodiment A12 is a further embodiment of any one of Embodiments A1 to A4, wherein:

[0085] R 1 R 1a ;and

[0086] R 1a is optionally 1, 2, 3 or 4 independently selected R A substituted 5-membered heteroaryl, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl or (C 3-4 Cycloalkyl)-C 1-4 Alkyl-, wherein the C 1-4 Alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is optionally substituted with 1, 2, 3, 4 or 5 each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy; or two adjacent R A Together with the two ring atoms of the 5-membered heteroaryl to which it is attached, a fused 5- or 6-membered heteroaryl is formed, each of which is optionally substituted by 1, 2 or 3 atoms each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted.

[0087] Embodiment A13 is another embodiment of Embodiment A11 or A12, wherein R 1a is optionally 1, 2, 3 or 4 independently selected R A substituted 5-membered heteroaryl, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl or (C 3-4 Cycloalkyl)-C 1-4 Alkyl-, wherein the C 1-4Alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is optionally substituted with 1, 2, 3, 4 or 5 each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted.

[0088] Embodiment A14 is another embodiment of Embodiment A11 or A12, wherein R 1a is optionally 1, 2, 3 or 4 independently selected R A substituted 5-membered heteroaryl, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl.

[0089] Embodiment A15 is a further embodiment of any one of Embodiments A12 to A14, wherein R 1a Each of the ring atoms of the 5-membered heteroaryl is a carbon or nitrogen atom.

[0090] Embodiment A16 is another embodiment of embodiment A11, wherein R 1a is pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2-thiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3-thiazolyl, imidazolyl, pyrazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl-, each of which is optionally substituted by 1, 2 or 3 groups each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 3-4 The cycloalkyl group is substituted with a substituent.

[0091] Embodiment A17 is another embodiment of embodiment A11, wherein R 1ais 1H-pyrazol-4-yl, 1H-1,2,4-triazol-3-yl, 2H-1,2,3-triazol-4-yl, 2H-tetrazol-5-yl, 1,2-thiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1H-imidazol-4-yl, pyrazolo[1,5-a]pyrimidin-3-yl or [1,2,4]triazolo[1,5-a]pyridin-2-yl, each of which is optionally substituted with 1, 2 or 3 each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 3-4 The cycloalkyl group is substituted with a substituent.

[0092] Embodiment A18 is a further embodiment of any one of Embodiments A1 to A4, wherein:

[0093] R 1 R 1a ;and

[0094] R 1a is 2, 3 or 4 independently selected R A substituted 5-membered heteroaryl, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl or (C 3-4 Cycloalkyl)-C 1-4 Alkyl-, wherein the C 1-4 Alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is optionally substituted with 1, 2, 3, 4 or 5 each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy; or two adjacent R A Together with the two ring atoms of the 5-membered heteroaryl to which it is attached, form a fused 5- or 6-membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl, each of which is optionally substituted by 1, 2 or 3 atoms each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted.

[0095] Embodiment A19 is another embodiment of embodiment A18, wherein two R A The two ring atoms of the 5-membered heteroaryl to which they are adjacent and which together with the 5-membered heteroaryl to which they are attached form a fused 5- or 6-membered heteroaryl, wherein the fused 5- or 6-membered heteroaryl is optionally fused with 1, 2 or 3 atoms each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted; and the remaining R A Each of (if present) is independently halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl or (C 3-4 Cycloalkyl)-C 1-4 Alkyl-, wherein the C 1-4 Alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is optionally substituted with 1, 2, 3, 4 or 5 each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted.

[0096] Embodiment A20 is another embodiment of embodiment A18, wherein two R A The two ring atoms of the 5-membered heteroaryl to which they are adjacent and which together form a fused 5- or 6-membered heterocycloalkyl, the fused 5- or 6-membered heterocycloalkyl being optionally substituted by 1, 2 or 3 atoms each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted; and the remaining R A Each of (if present) is independently halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl or (C 3-4 Cycloalkyl)-C1-4 Alkyl-, wherein the C 1-4 Alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is optionally substituted with 1, 2, 3, 4 or 5 each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted.

[0097] Embodiment A21 is a further embodiment of any one of Embodiments A1 to A4, wherein:

[0098] R 1 R 1a ;and

[0099] R 1a is optionally 1, 2, 3 or 4 independently selected R A Substituted 6-membered heteroaryl, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl or (C 3-4 Cycloalkyl)-C 1-4 Alkyl-, wherein the C 1-4 Alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is optionally substituted with 1, 2, 3, 4 or 5 each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy; or two adjacent R A Together with the two ring atoms of the 6-membered heteroaryl to which it is attached, form a fused benzene ring or a fused 5- or 6-membered heteroaryl, each of which is optionally substituted by 1, 2 or 3 atoms each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted.

[0100] Embodiment A22 is another embodiment of Embodiment A21, wherein R 1a is optionally 1, 2, 3 or 4 independently selected RA substituted 6-membered heteroaryl, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl or (C 3-4 Cycloalkyl)-C 1-4 Alkyl-, wherein the C 1-4 Alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is optionally substituted with 1, 2, 3, 4 or 5 each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted.

[0101] Embodiment A23 is another embodiment of Embodiment A21, wherein R 1a is optionally 1, 2, 3 or 4 independently selected R A substituted 6-membered heteroaryl, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl.

[0102] Embodiment A24 is a further embodiment of any one of Embodiments A21 to A23, wherein R 1a In another embodiment, each of the ring atoms of the 6-membered heteroaryl is a carbon or nitrogen atom. 1a In the 6-membered heteroaryl, 1, 2 or 3 of the ring atoms are nitrogen atoms (and the remaining ring atoms are carbon atoms).

[0103] Embodiment A25 is a further embodiment of any one of Embodiments A21 to A23, wherein R 1a is pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl, each of which is optionally substituted with 1, 2 or 3 independently selected R A Substituted, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl.

[0104] Embodiment A26 is a further embodiment of any one of Embodiments A21 to A23, wherein R 1a is pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl or pyrimidin-5-yl, each of which is optionally substituted with 1, 2 or 3 independently selected R A Substituted, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl.

[0105] Embodiment A27 is a further embodiment of any one of Embodiments A21 to A23, wherein R 1a is optionally 1, 2 or 3 independently selected R A Substituted pyrimidinyl, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl.

[0106] Embodiment A28 is a further embodiment of any one of Embodiments A21 to A23, wherein R 1a is optionally 1 or 2 independently selected R A Substituted pyrimidin-2-yl, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl.

[0107] Embodiment A29 is a further embodiment of any one of Embodiments A21 to A23, wherein R 1a It is pyrimidin-2-yl.

[0108] Embodiment A30 is a further embodiment of any one of Embodiments A1 to A4, wherein R 1 is phenyl, wherein the phenyl is substituted by 3 or 4 independently selected R B Substitution, where two adjacent R BTogether with the two ring-forming atoms of the phenyl group to which it is attached, a fused 5- or 6-membered heteroaryl group is formed, each of which is optionally substituted by 1, 2 or 3 atoms each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted; and the remaining R B Each of which is independently halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl;

[0109] Embodiment A31 is another embodiment of embodiment A30, wherein R 1 is 1,2-benzoxazolyl (e.g., 2-benzoxazolyl-6-yl) or 1,3-benzothiazolyl (e.g., 1,3-benzothiazol-5-yl), each of which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted.

[0110] Embodiment A32 is a further embodiment of any one of Embodiments A1 to A4, wherein R 1 is phenyl, wherein the phenyl is R B1 and optionally substituted with 1, 2 or 3 each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 3-4 The cycloalkyl group is substituted with a substituent.

[0111] Embodiment A33 is another embodiment of Embodiment A32, wherein R B1 is 1,3,4-oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), 1,2,4-oxadiazolyl (e.g., 1,2,4-oxadiazol-3-yl) or 1,3-oxazolyl (e.g., 1,3-oxazol-5-yl), each of which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 3-4 The cycloalkyl group is substituted with a substituent.

[0112] Embodiment A34 is a further embodiment of any one of Embodiments A1 to A3 and A5 to A33, wherein X 1 For CH2.

[0113] Embodiment A35 is a further embodiment of any one of Embodiments A1 to A3 and A5 to A33, wherein X 1 is CH(CH3).

[0114] Embodiment A36 is a further embodiment of any one of Embodiments A1 to A35, wherein R 2 and R 3 Each of which is independently H, F or C 1-4 alkyl.

[0115] Embodiment A37 is a further embodiment of any one of Embodiments A1 to A35, wherein R 2 and R 3 Each of which is independently H, F or C 1-2 alkyl.

[0116] Embodiment A38 is a further embodiment of any one of Embodiments A1 to A35, wherein R 2 and R 3 Each of 1-4 alkyl.

[0117] Embodiment A39 is a further embodiment of any one of Embodiments A1 to A35, wherein R 2 and R 3 Each of 1-2 alkyl.

[0118] Embodiment A40 is a further embodiment of any one of Embodiments A1 to A35, wherein R 2 and R 3 Each of is independently H or methyl.

[0119] Embodiment A41 is a further embodiment of any one of Embodiments A1 to A35, wherein R 2 C 1-4 Alkyl and R 3 For H.

[0120] Embodiment A42 is a further embodiment of any one of Embodiments A1 to A35, wherein R 2 C 1-2 Alkyl and R 3 For H.

[0121] Embodiment A43 is a further embodiment of any one of Embodiments A1 to A35, wherein R 2 is methyl and R 3 For H.

[0122] Embodiment A44 is a further embodiment of any one of Embodiments A1 to A43, wherein Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Each of which is independently CR 4 .

[0123] Embodiment A45 is a further embodiment of any one of Embodiments A1 to A43, wherein Y 1 、Y 2 、Y 3 、Y 4 and Y 5 One of them is N, and each of the others is independently CR 4 .

[0124] Embodiment A46 is a further embodiment of any one of Embodiments A1 to A43, wherein Y 3 is N, and Y 1 、Y 2 、Y 4 and Y 5 Each of which is independently CR 4 .

[0125] Embodiment A47 is a further embodiment of any one of Embodiments A1 to A43, wherein Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Two of them are N, and Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Each of the remaining CR 4 .

[0126] Embodiment A48 is a further embodiment of any one of Embodiments A1 to A43, wherein Y 1 N, Y 3 is N, and Y 2 、Y 4 and Y 5 Each of which is independently CR 4 .

[0127] Embodiment A49 is a further embodiment of any one of Embodiments A1 to A48, wherein each R 4 are independently H, halogen, C 1-2 Alkyl, C 1-2 Haloalkyl, -N(C 1-4 Alkyl)2, C 1-2 Alkoxy or C 1-2 Haloalkoxy.

[0128] Embodiment A50 is a further embodiment of any one of Embodiments A1 to A48, wherein each R 4 are independently H, F, Cl, -CH3, C1 fluoroalkyl, -OCH3 or C1 fluoroalkoxy.

[0129] Embodiment A51 is a further embodiment of any one of Embodiments A1 to A48, wherein each R 4 are independently H, halogen or C 1-2 Alkoxy.

[0130] Embodiment A52 is a further embodiment of any one of Embodiments A1 to A48, wherein each R 4 are independently H, F, Cl or -OCH3.

[0131] Embodiment A53 is a further embodiment of any one of Embodiments A1 to A48, wherein each R 4 are independently H, F or -OCH3.

[0132] Embodiment A54 is a further embodiment of any one of Embodiments A1 to A3, wherein:

[0133] R 1 R 1a ;

[0134] R 1a is pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2-thiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3-thiazolyl, imidazolyl, pyrazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl-, each of which is optionally substituted by 1, 2 or 3 groups each independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 3-4 Substitution of cycloalkyl groups;

[0135] X 1 is CH2 or CH(CH3);

[0136] R 2 C 1-2 Alkyl and R 3 is H;

[0137] Y 1 、Y 2 、Y 3 、Y 4 and Y 5 One of them is N, and Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Each of the remaining CR 4 ;and

[0138] Each R 4 are independently H, F, Cl, -CH3, C1 fluoroalkyl, -OCH3 or C1 fluoroalkoxy.

[0139] Embodiment A55 is a further embodiment of any one of Embodiments A1 to A3, wherein:

[0140] R 1 R 1a ;

[0141] R 1a is 1,2,4-triazolyl, 1,2,3-triazolyl or tetrazolyl (e.g., 2H-tetrazol-5-yl), each of which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 3-4 Substitution of cycloalkyl groups;

[0142] X 1 is CH2;

[0143] R 2 C 1-2 Alkyl and R 3 is H;

[0144] Y 3 N and Y 1 、Y 2 、Y 4 and Y 5 Each of which is independently CR 4 ;and

[0145] Each R 4are independently H, F, Cl, -CH3, C1 fluoroalkyl, -OCH3 or C1 fluoroalkoxy.

[0146] Embodiment A56 is a further embodiment of any one of Embodiments A1 to A3, wherein:

[0147] R 1 R 1a ;

[0148] R 1a is optionally 1, 2 or 3 independently selected R A Substituted tetrazolyl (e.g., 2H-tetrazol-5-yl), wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl (e.g. R 1a For C 1-4 alkyl, such as methyl-substituted 2H-tetrazol-5-yl);

[0149] X 1 is CH2;

[0150] R 2 is methyl and R 3 is H;

[0151] Y 3 is N, and Y 1 、Y 2 、Y 4 and Y 5 Each of which is independently CR 4 ;and

[0152] Each R 4 are independently H, F, Cl or -OCH3.

[0153] Embodiment A57 is a further embodiment of any one of Embodiments A1 to A3, wherein:

[0154] R 1 R 1a ;

[0155] R 1a is optionally 1, 2 or 3 independently selected R A Substituted pyrazolyl (e.g., 1H-pyrazol-4-yl), wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C1-4 Haloalkoxy or C 3-4 Cycloalkyl (e.g. R 1a For C 1-4 alkyl, such as methyl-substituted 1H-pyrazol-4-yl);

[0156] X 1 is CH2;

[0157] R 2 is methyl and R 3 is H;

[0158] Y 3 N and Y 1 、Y 2 、Y 4 and Y 5 Each of which is independently CR 4 ;and

[0159] Each R 4 are independently H, F, Cl or -OCH3 (e.g. each R 4 are independently H, F or -OCH3).

[0160] Embodiment A58 is a further embodiment of any one of Embodiments A1 to A3, wherein:

[0161] R 1 R 1a ;

[0162] R 1a is pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl, each of which is optionally substituted with 1, 2 or 3 independently selected R A Substituted, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl;

[0163] X 1 is CH2 or CH(CH3);

[0164] R 2 C 1-2 Alkyl and R 3 is H;

[0165] Y 1 、Y 2 、Y 3 、Y 4 and Y 5 One of them is N, and Y 1 、Y 2、Y 3 、Y 4 and Y 5 Each of the remaining CR 4 ;and

[0166] Each R 4 are independently H, F, Cl, -CHF2 or -OCH3.

[0167] Embodiment A59 is a further embodiment of any one of Embodiments A1 to A3, wherein:

[0168] R 1 R 1a ;

[0169] R 1a is pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl, each of which is optionally substituted with 1, 2 or 3 independently selected R A Substituted, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl;

[0170] X 1 is CH2;

[0171] R 2 C 1-2 Alkyl and R 3 is H;

[0172] Y 3 is N, and Y 1 、Y 2 、Y 4 and Y 5 Each of which is independently CR 4 ;and

[0173] Each R 4 are independently H, F or -OCH3.

[0174] Embodiment A60 is a further embodiment of any one of Embodiments A1 to A3, wherein:

[0175] R 1 R 1a ;

[0176] R 1a is optionally 1, 2 or 3 independently selected R A Substituted pyrimidinyl (eg, pyrimidin-2-yl), wherein each R A Halogen, -OH, -CN, C1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl (e.g. R 1a is unsubstituted pyrimidin-2-yl);

[0177] X 1 is CH2;

[0178] R 2 is methyl and R 3 is H;

[0179] Y 3 is N, and Y 1 、Y 2 、Y 4 and Y 5 Each of which is independently CR 4 ;and

[0180] Each R 4 are independently H, F, Cl or -OCH3 (e.g. each R 4 are independently H, F or -OCH3).

[0181] Embodiment A61 is a further embodiment of any one of Embodiments A1 to A3, wherein:

[0182] R 1 R 1a ;

[0183] R 1a is optionally 1, 2 or 3 independently selected R A Substituted [1,2,4] triazolo [1,5-a] pyridin-2-yl, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl (e.g. R 1a is unsubstituted [1,2,4]triazolo[1,5-a]pyridin-2-yl);

[0184] X 1 is CH2;

[0185] R 2 is methyl and R 3 is H;

[0186] Y 3 is N, and Y 1 、Y 2 、Y4 and Y 5 Each of which is independently CR 4 ;and

[0187] Each R 4 are independently H, F, Cl or -OCH3 (e.g. each R 4 are independently H, F or -OCH3).

[0188] Embodiment A62 is a further embodiment of any one of Embodiments A1 to A3, wherein:

[0189] R 1 R 1a ;

[0190] R 1a is pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl, each of which is optionally substituted with 1, 2 or 3 independently selected R A Substituted, wherein each R A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl;

[0191] X 1 is CH2 or CH(CH3);

[0192] R 2 C 1-2 Alkyl and R 3 is H;

[0193] Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Each of which is independently CR 4 ;and

[0194] Each R 4 are independently H, F, Cl, -CH3, -CF3, -CHF2 or -OCH3.

[0195] Embodiment A63 is a further embodiment of any one of Embodiments A1 to A3, wherein:

[0196] R 1 is H;

[0197] X 1 is CH2 or CH(CH3);

[0198] R 2 and R3 Each of 1-2 Alkyl (such as R 2 and R 3 Each of which is H);

[0199] Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Each of which is independently CR 4 ;and

[0200] Each R 4 are independently H, F, Cl, -CH3, -CF3, -CHF2 or -OCH3 (e.g. each R 4 are independently H or F, such as R 4 One of them is F and the rest is R 4 Each of them is H).

[0201] Embodiment A64 (another embodiment of Embodiment A1) provides a compound described herein selected from Examples 1 to 201 in the Examples section, or a pharmaceutically acceptable salt thereof (or, in the case where the exemplified compound is, for example, a salt, its parent compound).

[0202] Embodiment A65 (another embodiment of Embodiment A1) provides a compound selected from the group consisting of:

[0203] 2-(5-chloro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0204] 2-(6-methoxy-2-methylpyrimidin-4-yl)-1-[7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0205] 2-[6-(difluoromethoxy)pyridin-3-yl]-1-[7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0206] 1-[7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- pyridin-2,3'-pyrrolidin-1'-yl]-2-[4-(trifluoromethyl)phenyl]propan-1-one;

[0207] 1-(4,7-dimethyl-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin]-1'-yl)-2-(4-fluorophenyl)ethan-1-one;

[0208] 2-(5-Fluoro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0209] 2-(5-fluoro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0210] 2-(5-chloro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0211] 2-(5-Fluoro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidino]-1'-yl]propan-1-one; and

[0212] 2-(5-fluoro-2-methoxypyridin-4-yl)-1-{7-methyl-6-[(4,6- 2 H2)pyrimidin-2-yl]-3,4-dihydro-1H-spiro[1,8- pyridine-2,3'-pyrrolidino]-1'-yl}propan-1-one,

[0213] or a pharmaceutically acceptable salt thereof.

[0214] Embodiment A66 (another embodiment of Embodiment 1) provides a compound selected from the group consisting of:

[0215] (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0216] 2-(6-methoxy-2-methylpyrimidin-4-yl)-1-[(2S)-7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0217] 2-[6-(difluoromethoxy)pyridin-3-yl]-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0218] 1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- pyridin-2,3'-pyrrolidin-1'-yl]-2-[4-(trifluoromethyl)phenyl]propan-1-one;

[0219] 1-(4,7-dimethyl-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin]-1'-yl)-2-(4-fluorophenyl)ethan-1-one;

[0220] (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0221] (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0222] (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0223] (2R)-2-(5-Fluoro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidino]-1'-yl]propan-1-one; and

[0224] (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-{(2S)-7-methyl-6-[(4,6- 2 H2)pyrimidin-2-yl]-3,4-dihydro-1H-spiro[1,8- pyridine-2,3'-pyrrolidino]-1'-yl}propan-1-one,

[0225] or a pharmaceutically acceptable salt thereof.

[0226] Embodiment A67 (another embodiment of Embodiment A1) provides a compound selected from the group consisting of:

[0227] (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one, DIAST-1;

[0228] 2-(6-methoxy-2-methylpyrimidin-4-yl)-1-[(2S)-7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one, DIAST-1;

[0229] 2-[6-(difluoromethoxy)pyridin-3-yl]-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one, DIAST-2;

[0230] 1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidinyl]-1'-yl]-2-[4-(trifluoromethyl)phenyl]propan-1-one, DIAST-1;

[0231] 1-(4,7-dimethyl-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin]-1'-yl)-2-(4-fluorophenyl)ethan-1-one, DIAST-1;

[0232] (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0233] (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0234] (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one;

[0235] (2R)-2-(5-Fluoro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidino]-1'-yl]propan-1-one, DIAST-1; and

[0236] (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-{(2S)-7-methyl-6-[(4,6- 2 H2)pyrimidin-2-yl]-3,4-dihydro-1H-spiro[1,8- pyridine-2,3'-pyrrolidino]-1'-yl}propan-1-one,

[0237] or a pharmaceutically acceptable salt thereof.

[0238] Embodiment A68 (another embodiment of Embodiment A1) provides a compound which is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [pyridine-2,3'-pyrrolidin-1'-yl]propan-1-one, or a pharmaceutically acceptable salt thereof.

[0239] Embodiment A69, another embodiment of Embodiment A1, provides a compound which is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidino]-1'-yl]propan-1-one.

[0240] Embodiment A70 (another embodiment of Embodiment A69) provides (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- In another embodiment of embodiment A70, the crystalline form exhibits a powder X-ray diffraction pattern comprising at least one characteristic peak in 2θ selected from 8.7±0.2°, 11.1±0.2°, and 13.3±0.2°.

[0241] In another embodiment of Embodiment A70, the crystalline form is Form I described in Example 14 herein. In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least one characteristic peak at 8.7 ± 0.2° with respect to 2θ. In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least one characteristic peak at 11.1 ± 0.2° with respect to 2θ. In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least one characteristic peak at 13.3 ± 0.2° with respect to 2θ. In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least two characteristic peaks at 8.7 ± 0.2°, 11.1 ± 0.2°, and 13.3 ± 0.2° with respect to 2θ. In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising two characteristic peaks at 8.7 ± 0.2° and 11.1 ± 0.2° with respect to 2θ. In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least three characteristic peaks in 2Θ selected from 8.7±0.2°, 11.1±0.2°, and 13.3±0.2°.

[0242] In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least two characteristic peaks with respect to 2θ selected from 8.7±0.2°, 11.1±0.2°, and 26.0±0.2°. In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least two characteristic peaks with respect to 2θ selected from 8.7±0.2° and 26.0±0.2°. In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least two characteristic peaks with respect to 2θ selected from 11.1±0.2° and 26.0±0.2°. In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least three characteristic peaks with respect to 2θ selected from 8.7±0.2°, 11.1±0.2°, and 26.0±0.2°.

[0243] In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least two characteristic peaks with respect to 2θ as listed in Table XI. In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least three characteristic peaks with respect to 2θ as listed in Table XI. In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least four (e.g., 4, 5, 6, 7, 8, 9, or 10) characteristic peaks with respect to 2θ as listed in Table XI.

[0244] In some embodiments, Form I exhibits substantially Figure 1 The powder X-ray diffraction pattern shown in .

[0245] Each embodiment, example, or pharmaceutically acceptable salt thereof may be claimed individually or grouped together in any combination with any number of each embodiment described herein.

[0246] The spirocyclic compounds of formula I of the present invention (further including compounds of formula Ia, II or III) can be used in any of the pharmaceutical compositions, uses and methods of the present invention described herein.

[0247] The compounds of formula I of the present invention, or pharmaceutically acceptable salts thereof, are MC4R antagonists. Therefore, the present invention further provides a method for antagonizing MC4R (ex vivo or in vivo), comprising contacting (including culturing) the MC4R with a compound of formula I described herein, or a pharmaceutically acceptable salt thereof (such as one selected from Embodiments A1 to A70 or Examples 1 to 201 herein).

[0248] The amount of the compound of formula I or a pharmaceutically acceptable salt thereof used in any of the methods (or uses) of the present invention is effective to antagonize MC4R.

[0249] Another embodiment of the present invention includes the use of a compound of Formula I, or a pharmaceutically acceptable salt of said compound, such as one selected from Embodiments A1 to A70 or Examples 1 to 201 herein, as a medicament, particularly wherein said medicament is for use in treating an MC4R-associated condition, disease or disorder comprising administering a therapeutically effective amount to a mammal, such as a human, in need of such treatment.

[0250] Another embodiment of the present invention includes the use of a compound of Formula I, or a pharmaceutically acceptable salt of said compound, such as one selected from Embodiments A1 to A70 or Examples 1 to 201 herein, in the preparation of a medicament for treating an MC4R-associated condition, disease or disorder, comprising administering a therapeutically effective amount to a mammal, such as a human, in need of such treatment.

[0251] Another embodiment of the present invention includes the use of a compound of Formula I or a pharmaceutically acceptable salt of said compound (such as one selected from Embodiments A1 to A70 or Examples 1 to 201 herein) as a medicament, particularly wherein said medicament is used to treat a condition, disease or disorder selected from the group consisting of cachexia [including, for example, cachexia associated with chronic diseases, such as cachexia associated with cancer; cachexia associated with acquired immune deficiency syndrome (AIDS); cachexia associated with heart failure, such as cachexia associated with congestive heart failure (CHF); cachexia associated with chronic kidney disease (CKD); cachexia associated with chronic disease treatment, such as cachexia associated with cancer treatment or cachexia associated with heart failure (e.g., CHF) treatment]. cachexia associated with]; anorexia or anorexia nervosa (e.g., anorexia senile, anorexia associated with chemotherapy and / or radiation therapy); nausea; vomiting; weight loss (e.g., involuntary weight loss); growth retardation; sarcopenia; muscle atrophy; muscle weakness; frailty; osteoporosis; skeletal disorders (e.g., bone loss); pain; neuropathic pain; anxiety (e.g., post-traumatic stress disorder or PTSD); depression; hypertension; malnutrition; obesity (e.g., sarcopenia caused by chronic obesity); sexual dysfunction; and inflammatory diseases (e.g., inflammatory diseases associated with anorexia or cachexia or sarcopenia or muscle atrophy); comprising administering to a mammal (e.g., a human) in need of such treatment a therapeutically effective amount or a pharmaceutically acceptable salt of the compound.

[0252] Another embodiment of the present invention includes the use of a compound of Formula I or a pharmaceutically acceptable salt of said compound (such as one selected from Embodiments A1 to A70 or Examples 1 to 201 herein) in the preparation of a medicament for treating a condition, disease or disorder selected from: cachexia [including, for example, cachexia associated with a chronic disease, such as cachexia associated with cancer; cachexia associated with acquired immune deficiency syndrome (AIDS); cachexia associated with heart failure, such as cachexia associated with congestive heart failure (CHF); cachexia associated with chronic kidney disease (CKD); cachexia associated with chronic disease treatment, such as cachexia associated with cancer treatment or cachexia associated with heart failure (e.g., CHF) treatment ]; anorexia or anorexia nervosa (e.g., anorexia nervosa, anorexia associated with chemotherapy and / or radiation therapy); nausea; vomiting; weight loss (e.g., involuntary weight loss); stunting; sarcopenia; muscle atrophy; muscle weakness; frailty; osteoporosis; skeletal disorders (e.g., bone loss); pain; neuropathic pain; anxiety (e.g., post-traumatic stress disorder or PTSD); depression; hypertension; malnutrition; obesity (e.g., sarcopenia caused by chronic obesity); sexual dysfunction; and inflammatory diseases (e.g., inflammatory diseases associated with anorexia or cachexia or sarcopenia or muscle atrophy); comprising administering to a mammal (e.g., a human) in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound.

[0253] The compounds of this invention may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. Unless otherwise specified, it is intended that all stereoisomeric forms of the compounds of this invention and mixtures thereof (including racemic mixtures) form part of the present invention. In addition, all geometric and positional isomers are encompassed by the present invention. For example, if the compounds of this invention include double bonds or fused rings, cis-forms and trans-forms and mixtures are encompassed within the scope of the present invention.

[0254] The chiral compounds of the present invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography (typically high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC)) on a resin having an asymmetric stationary phase and a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing 0 to 50% isopropanol (typically 2% to 20%) and 0 to 5% alkylamine (typically 0.1% diethylamine (DEA) or isopropylamine). Concentration of the eluate yields an enriched mixture. When SFC is used, the mobile phase can consist of a supercritical fluid (typically carbon dioxide containing 2% to 50% of an alcohol such as methanol, ethanol, or isopropanol).

[0255] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by using chiral HPLC columns. Alternatively, specific stereoisomers can be synthesized using optically active starting materials, by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one stereoisomer into the other by asymmetric transformation.

[0256] In some embodiments, the compounds of the present invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of Formula I may be represented herein by solid lines (-), wavy lines ( ), solid wedge( ) or dashed wedge ( ). The use of a solid line to depict a bond to an asymmetric carbon atom is intended to include all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.). The use of a solid or dashed wedge to depict a bond to an asymmetric carbon atom is intended to include only the stereoisomer shown. The use of a wavy line to depict a bond to an asymmetric carbon atom is intended to include the stereochemistry is unknown (unless otherwise specified). The compounds of the present invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict a bond to an asymmetric carbon atom is intended to include all possible stereoisomers. For example, unless otherwise stated, it is intended that the compounds of the present invention can exist in enantiomeric and diastereomeric forms or in racemic form and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in the compounds of the present invention and the use of a solid or dashed wedge to depict bonds to other asymmetric carbon atoms in the same compound is intended to indicate that a mixture of diastereomers is present.

[0257] When a compound of the invention has two or more stereocenters and the absolute or relative stereochemistry is given in the name, the designations R and S refer to each stereocenter in ascending numerical order (1, 2, 3, etc.), respectively, according to the conventional IUPAC numbering scheme for each molecule. When a compound of the invention has one or more stereocenters and the stereochemistry is not given in the name or structure, it is understood that the name or structure is intended to encompass all forms of the compound, including racemic forms.

[0258] The compounds of the present invention may contain olefin-like double bonds. When such bonds are present, the compounds of the present invention exist in cis- and trans-configurations, and mixtures thereof. The term "cis" refers to the orientation of two substituents relative to each other and the plane of the ring (both "up" or both "down"). Similarly, the term "trans" refers to the orientation of two substituents relative to each other and the plane of the ring (the substituents are on opposite sides of the ring).

[0259] The intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations.

[0260] Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0261] Included within the scope of the claimed compounds of the present invention are all stereoisomers, geometric isomers, and tautomeric forms of the compounds of Formula I, including compounds exhibiting more than one isomeric type, and mixtures of one or more thereof. Also included are acid addition salts or base salts in which the counterion is optically active, such as D-lactate or L-lysine, or racemic, such as DL-tartrate or DL-arginine.

[0262] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of formula I wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0263] Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen such as 2 H and 3 H; isotopes of carbon, such as 11 C. 13 C and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I. 124 I and 125 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O. 17 O and 18 O; isotopes of phosphorus, such as 32 P; and isotopes of sulfur, such as 35 S.

[0264] Certain isotopically labeled compounds of Formula I (e.g., those containing a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) is particularly well-suited for this purpose due to its ease of incorporation and readily available means of detection.

[0265] By means of deuterium (i.e. 2 Substitution with heavier isotopes of H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0266] Positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 N) substitutions can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0267] Isotopically labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0268] The compounds of the present invention can be isolated and used per se or, where possible, in the form of their pharmaceutically acceptable salts. The term "salts" refers to inorganic and organic salts of the compounds of the present invention. Such salts can be prepared in situ during the final isolation and purification of the compounds, or by treating the compounds separately with a suitable organic or inorganic acid and isolating the salt thus formed.

[0269] Salts encompassed within the term "pharmaceutically acceptable salts" refer to compounds of the invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid to provide a salt of the compound of the invention suitable for administration to patients. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyphenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalene dicarboxylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, glucarate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinofoate. See, e.g., Berge, et al. J. Pharm. Sci. 66, 1-19 (1977); Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth (Wiley-VCH, 2002).

[0270] The compounds of Formula I and their pharmaceutically acceptable salts can exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used.

[0271] The currently accepted classification system for organic hydrates is one that defines isolated-site, channel, or metal-ion coordinated hydrates—see KR Morris, Polymorphism in Pharmaceutical Solids (HG Brittain, ed., Marcel Dekker, 1995). Isolated-site hydrates are hydrates in which water molecules are separated from one another by intervening organic molecules and are not in direct contact. In channel hydrates, water molecules are located in lattice channels adjacent to other water molecules. In metal-ion coordinated hydrates, water molecules are bound to the metal ion.

[0272] When the solvent or water is tightly bound, the complex can have a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content can depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0273] Also included within the scope of the present invention are multicomponent complexes (other than salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are generally defined as crystalline complexes of neutral molecular components bound together by non-covalent interactions, but may also be complexes of neutral molecules with salts. Co-crystals can be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together - see O. Almarsson and MJ Zaworotko, Chem. Commun., 17, 1889-1896 (2004). For a general review of multicomponent complexes, see Haleblian, J. Pharm. Sci., 64(8), 1269-1288 (1975).

[0274] The compounds of the present invention include compounds of formula I as defined above or pharmaceutically acceptable salts thereof, polymorphs and isomers thereof (including optical, geometric and tautomers) as defined below, and isotopically labeled compounds of formula I or pharmaceutically acceptable salts thereof.

[0275] The compounds of the present invention can be administered in the form of prodrugs. Thus, certain derivatives of a compound of Formula I or a pharmaceutically acceptable salt thereof, which may have little or no pharmacological activity themselves, can be converted, for example by hydrolytic cleavage, into a compound of Formula I or a pharmaceutically acceptable salt thereof having the desired activity when administered to or on the body. Such derivatives are referred to as "prodrugs." [Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association).]

[0276] Prodrugs can be produced, for example, by replacing appropriate functional groups present in a compound of formula I or a pharmaceutically acceptable salt thereof with certain moieties known to those skilled in the art as "pro-moieties", such as those described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

[0277] Some examples of such prodrugs include:

[0278] (i) where the compound of formula I or a pharmaceutically acceptable salt thereof contains an alcohol function (-OH), an ether thereof, for example, replacing the hydrogen with a (C1-C6)alkanoyloxymethyl group; or a phosphate ester (-O-PO3H2) or sulfate ester (-O-SO3H) or a pharmaceutically acceptable salt thereof; and

[0279] (ii) amides or carbamates of amino functional groups present in formula (I) or formula (II), wherein the hydrogen of the amino NH group is respectively (C1-C 10 )alkanoyl or (C1-C 10 ) alkoxycarbonyl replacement.

[0280] Active metabolites of the compounds of Formula I (including prodrugs) or pharmaceutically acceptable salts thereof, i.e., compounds formed in vivo following administration of the drug, typically by oxidation or dealkylation, are also included within the scope of the present invention. Some examples of metabolites according to the present invention include:

[0281] (i) in the case where the compound of formula I or its pharmaceutically acceptable salt contains a methyl group, its hydroxymethyl derivative (-CH3->-CH2OH); and

[0282] (ii) Where the compound of formula I or a pharmaceutically acceptable salt thereof contains an alkoxy group, a hydroxy derivative thereof (-OR->-OH).

[0283] Certain compounds of the invention may exist in more than one crystalline form (often referred to as "polymorphs"). Polymorphs can be prepared by crystallization under various conditions, such as using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; and / or various cooling patterns during crystallization, ranging from very fast to very slow cooling. Polymorphs can also be obtained by heating or melting a compound of the invention followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction, or such other techniques.

[0284] In general, the compounds of the present invention can be manufactured by methods including methods similar to those known in chemical technology, particularly according to the description contained herein. Certain methods for manufacturing the compounds of the present invention are provided as other features of the present invention and are illustrated by the following reaction schemes. Other methods can be described in the experimental section. Specific synthetic routes for preparing compounds of formula I or pharmaceutically acceptable salts thereof are summarized below. It should be noted that tetrazole is generally a high-energy functional group and should be treated with caution in the synthesis and operation of tetrazole-containing molecules.

[0285] The compounds of the present invention can be synthesized by synthetic routes including methods analogous to those well known in the chemical arts, particularly in light of the description contained herein. Starting materials are generally available from commercial sources such as MilliporeSigma (Milwaukee, WI), or are readily prepared using methods well known to those skilled in the art [e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, Vols. 1-19, Wiley, New York (1967-1999 editions) or Beilsteins Handbuch der Organischen Chemie, 4, Aufl. Edition, Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)]. Many of the compounds used herein are related to or derived from compounds of great scientific importance and commercial demand, and therefore many such compounds are commercially available or reported in the literature or are readily prepared from other commonly available substances by methods reported in the literature.

[0286] When preparing a compound of Formula I or a salt thereof, it should be noted that some of the preparation methods described herein may require protection of remote functional groups (e.g., primary amines, secondary amines, carboxyl groups in Formula I precursors). The need for such protection will vary depending on the properties of the remote functional groups and the conditions of the preparation method. Those skilled in the art can easily determine the need for such protection. The use of such protection / removal methods is also within the technical scope of this art. For a general description of protecting groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons, New York, 2014. For example, some compounds contain primary amine or carboxylic acid functional groups, which, if not protected, can interfere with reactions at other sites of the molecule. Therefore, such functional groups can be protected by appropriate protecting groups, which can be removed in subsequent steps. Suitable protecting groups for amine and carboxylic acid protection include those commonly used in peptide synthesis (such as N-tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethoxycarbonyl (Fmoc) for amines and lower alkyl groups, or benzyl esters of carboxylic acids), which are generally chemically unreactive under the described reaction conditions and can generally be removed without chemically altering other functional groups in the compound of Formula I.

[0287] The reaction can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), infrared spectroscopy, spectrophotometry (eg, UV-visible), mass spectrometry; or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0288] Can prepare formula I compound, its salt and intermediate according to following reaction scheme and accompanying discussion.The reaction scheme described below is intended to provide the general description of the method for preparing the compounds of this invention.Some compounds of this invention contain single chiral center with stereochemical mark (R or S), and other will contain two separate chiral centers with stereochemical mark (R or S).It will be apparent to those skilled in the art that no matter material is enantiomerically enriched or racemic, most synthetic transformations can be carried out in a similar manner.In addition, the resolution of required optically active material can be carried out at any required point in the sequence using well-known methods such as described herein and in the chemical literature.

[0289] Unless otherwise specified, in the following reaction schemes and discussions, R 1 、R 2 、R 3 、X 1 、Y 1、Y 2 、Y 3 、Y 4 、Y 5 and Structural Formula I (including, for example, Ia, II) as defined herein or as described herein. In general, the compounds of the present invention can be manufactured by methods including methods similar to those known in the chemical arts, particularly according to the description contained herein. Certain methods for making the compounds of the present invention and their intermediates are provided as other features of the present invention and are illustrated by the following reaction schemes. Other methods are described in the experimental section. The routes and examples provided herein (including corresponding descriptions) are for illustration only and are not intended to limit the scope of the present invention.

[0290] In the following reaction schemes, unless otherwise indicated, the variable X c 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 LG 1 LG 2 LG 3 LG 4 PG 1 PG 2 PG 3 PG 4 PG 5 PG 6 PG 7 and PG 8 As described herein or consistent with the claims of Formula I. For each of the variables, unless otherwise indicated later, its meaning remains the same as originally described.

[0291] Route 1 refers to the synthesis of compounds of Formula I, Ia, and II. Acids of Formula 1-1 can be reacted with amines of Formula 1-2 (or their salts) using standard amidation conditions with coupling reagents such as 1,1'-carbonyldiimidazole, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphaninyl trioxide (T3P), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), or others to provide compounds of Formula I. Alternatively, acids of Formula 1-1 can be reacted with amines of Formula 1-3 in a similar manner to form compounds of Formula Ia. Acids of Formula 1-1 can be purchased, synthesized as described in Org. Process Res. Dev. 1997, 1, 72, or as described herein. Amines of Formula 1-2 can be synthesized as described herein. Compounds of formula I containing mixtures of enantiomers or diastereomers can be separated into individual diastereomers or enantiomers as desired using supercritical fluid chromatography or reverse phase chromatography using chiral columns to produce compounds of formula Ia or II.

[0292] Route 1

[0293]

[0294] Scheme 2 describes an alternative synthesis of compounds of Formula II when a single enantiomer of an acid of Formula 2-1 (a subtype of an acid of Formula 1-1) is used. Some acids of Formula 2-1 may racemize or epimerize under some general amidation conditions as described in Scheme 1. Alternatively, high enantiomeric excess can be maintained throughout the reaction by using low temperatures, using solvents that aid in dissolving the reactants, using additives such as imidazolium or pyridinium salts, or other methods described in Org. Process Res. Dev. 2016, 20, 140; Org. Lett. 2012, 14, 1970; or Org. Process Res. Dev. 2009, 13, 106, or using the free base of an amine of Formula 1-3. Alternatively, if the general conditions are used, or if epimerization or racemization occurs, the resulting mixture of diastereomers can be separated using supercritical fluid or reverse phase chromatography using chiral columns, or they can be separated as diastereomeric salts using appropriate chiral acids under typical resolution conditions to form compounds of Formula II.

[0295] Route 2

[0296]

[0297] Scheme 3 describes a method for selectively synthesizing an acid of formula 2-1 as a single enantiomer. Acids of formula 3-1 can be purchased or synthesized using methods described in the literature or herein and are reacted with a well-known chiral auxiliary (X c), such as Evans-type (optically pure oxazolidinone), Myers-type (pseudoephedrine derivative) or others described in the literature to form an intermediate of formula 3-2. The compound of formula 3-2 is reacted with a strong base such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide or its analogue and an alkyl halide (when R 2 and / or R 3 is an alkyl group) or other electrophiles, such as N-fluorobenzenesulfonimide (when R 2 and / or R 3 When X is fluorine) treatment can form a compound of formula 3-3 with high diastereomeric excess. c The conditions for hydrolysis of the group depend on the individual properties, but generally, a reagent (inorganic base) such as pure potassium hydroxide, sodium hydroxide, lithium hydroxide, or an aqueous solution thereof with or without hydrogen peroxide and a protic solvent (such as methanol, ethanol, or others) or an aprotic solvent (such as tetrahydrofuran, or others) can be used to form the compound of formula 2-1.

[0298] Route 3

[0299]

[0300] Scheme 4 describes a method that can be used to synthesize an acid of Formula 4-9 (a subtype of the compound of Formula 1-1), Formula 4-7 (a subtype of the compound of Formula 2-1), or 4-8 (a subtype of the compound of Formula 2-1). 2 is a halide (e.g., F, Cl, Br, or I) or a leaving group such as -OTf] can be removed using S N Ar conditions, or by cross-coupling with a diprotected malonate of formula 4-2 (where PG 1 It can be methyl, ethyl, tert-butyl, benzyl, p-methoxybenzyl or other, and PG 2The reaction may be an orthogonal removal of the protecting group selected from the same option or may be the same protecting group) to obtain an intermediate of formula 4-3. The compound of formula 4-3 can be treated with an appropriate base, such as sodium hydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium carbonate, cesium carbonate or its analogues, and then alkylated with an alkylating agent such as iodomethane, ethyl iodide or other, a fluorinating agent such as N-fluorobenzenesulfonimide or other electrophilic agent to obtain a compound of formula 4-4. Alternatively, the compound of formula 4-1 can be reacted with a compound of formula 4-6 to directly form a compound of formula 4-4 (under conditions similar to the conversion of the compound of formula 4-1 to the compound of formula 4-3). The removal of the protecting group of the compound of formula 4-4 can be performed using standard methods (alkaline or acidic hydrolysis); or when PG 1 or PG 2 When the benzyl group is present, the intermediate of Formula 4-5 is formed by using a palladium catalyst with hydrogen or a reducing source, such as a formate, trialkylsilane, or other catalyst. Alternatively, the compound of Formula 4-4 can be directly formed into the acid of Formula 4-9 under conditions similar to those used to produce the compound of Formula 4-5, or conditions that may require elevated temperatures. The diacid of Formula 4-5 can also be monodecarboxylated using a base, an acid, copper (I) oxide, heating, or other suitable conditions to provide the racemic acid of Formula 4-9. Acids of formula 4-9 containing a mixture of enantiomers can be separated using supercritical fluid or reverse phase chromatography using a chiral column, or they can be separated and isolated as diastereomeric salts using appropriate chiral acids under classical resolution conditions such as described in Org. Process Res. Dev. 2011, 15, 53, or one enantiomer can be selectively converted to an ester and separated using biocatalysis as described in Adv. Synth. Catal., 2009, 351, 2333 (see also J. Org. Chem. 2003, 68, 7234) to form acids of formula 4-7 or 4-8 in high enantiomeric excess. Diacids of formula 4-5 can also be monodecarboxylated using biocatalysis such as aryl malonate decarboxylase (AMD enzyme) to provide single enantiomers of compounds of formula 4-7 or 4-8 in high enantiomeric excess. See, for example, (a) J. Am. Chem. Soc. 1990, 112, 4077; (b) Eur J. Biochem. 1992, 210, 475; (c) Appl. Environ. Microbiol. 2007, 73, 5676; (d) Appl. Microbiol. Biotechnol. 2016, 100, 8621.

[0301] Route 4

[0302]

[0303] Route 5 refers to the synthesis of the acid of formula 5-6 (a subtype of the compound of formula 1-1), formula 5-7 (a subtype of the compound of formula 2-1), and formula 5-8 (a subtype of the compound of formula 2-1), wherein R 2c It can be, for example, H, alkyl, C 3-4 Cycloalkyl, etc. (see R 2 or R 3 Definition of). Aryl or heteroaryl halide of formula 5-1 (wherein X 3 The aryl or heteroaryl halide of formula 5-1 can be reacted with a suitable reagent to perform a metal-halogen exchange, such as n-butyllithium, isopropylmagnesium chloride or a similar metal base or magnesium metal, and quenched with a dicarbonyl compound of formula 5-3 to obtain a compound of formula 5-4. Alternatively, the arene or heteroaromatic hydrocarbon of formula 5-2 can be directly deprotonated with a similar strong base or reagent, such as lithium diisopropylamide, 2,2,6,6-tetramethylpiperidinyl lithium, bis(2,2,6,6-tetramethylpiperidinyl)zinc or other variations of such substances, and reacted with a dicarbonyl compound of formula 5-3 to form a compound of formula 5-4. The compound of formula 5-4 can be treated with a strong acid, such as hydrochloric acid, sulfuric acid, boron trifluoride diethyl etherate or other Bronsted or Lewis acid to form a compound of formula 5-5. Compounds of formula 5-5 can be treated with a reducing agent such as silane or with hydrogen and a metal catalyst such as palladium in the presence of an acid to form compounds of formula 5-6. Alternatively, compounds of formula 5-4 can also be treated with a similar acid or with hydrogen and a metal catalyst such as palladium in the presence of a reducing agent such as silane to form acids of formula 5-6. Alternatively, compounds of formula 5-5 can be treated with hydrogen and a metal such as ruthenium or rhodium or other and a chiral ligand or many other methods such as those described in Org. Chem. Front. 2014, 1, 155 to selectively form acids of formula 5-7 or 5-8 in high enantiomeric excess. Alternatively, compounds of formula 5-5 can be converted with a biocatalyst such as ENE-reductase (such as described in ACS Catal. 2018, 8, 3532) or other methods to selectively form compounds of formula 5-7 or 5-8 in high enantiomeric excess. Alternatively, compounds of formula 5-6 containing mixtures of enantiomers can be separated using supercritical fluid or reverse phase chromatography with chiral columns, or they can be separated and separated as diastereomeric salts under typical resolution conditions using appropriate chiral acids to form compounds of formula 5-7 or 5-8.

[0304] Route 5

[0305]

[0306] Scheme 6 describes certain other methods for synthesizing acids of formula 1-1 and 2-1. Compounds of formula 6-1 can be deprotonated with a strong base and reacted with carbon dioxide or a carbonyl compound of formula 6-2 (where LG 1 is a leaving group such as chloride or alkoxide, and PG 1 The compound of formula 6-3 can be acylated with a strong base and treated with an alkylating agent to form a compound of formula 6-4 in a similar manner as described above for the conversion of the compound of formula 3-2 to the compound of formula 3-3. The compound of formula 6-4 can be treated under hydrolysis conditions to form a compound of formula 1-1 in a similar manner as described above for the conversion of the compound of formula 3-3 to the compound of formula 2-1, or when PG 1 When it is benzyl, a metal catalyst such as palladium / carbon and hydrogen is used, or when PG 1 It can be treated with acid to form a compound of formula 1-1 when the stable cationic form leaves or is removed. Alternatively, the steps can be reordered so that the compound of formula 6-3 is hydrolyzed to a compound of formula 6-5 and then alkylated using similarly described conditions to form a compound of formula 1-1. Alternatively, the compound of formula 6-4 can be treated with biocatalytic conditions, such as esterases, to form an acid of formula 2-1 in high enantiomeric excess. Alternatively, the compound of formula 6-6 can be treated with a strong acid such as hydrochloric acid or sulfuric acid in the presence of an alcohol such as methanol or ethanol to form a compound of formula 6-3. Alternatively, the compound of formula 6-6 can be alkylated to form a compound of formula 6-7 using a similar method as described for the conversion of the compound of formula 6-3 to the compound of formula 6-4. Alternatively, the compound of formula 6-7 can be directly hydrolyzed to an acid of formula 1-1 in the presence of water using a strong acid such as hydrochloric acid or sulfuric acid or a strong base such as sodium hydroxide, potassium hydroxide or lithium hydroxide. Alternatively, a compound of formula 6-8 (wherein LG 2 The compound of formula 6-8 can be purchased or prepared in various ways as described in the literature, or when LG 2 When R is, for example, Br or Cl, the compound of formula 6-1 is synthesized by reacting a halogenated electrophile such as N-bromosuccinimide, bromine or others, with a free radical initiating activator such as 2,2'-azobisisobutyronitrile, light or other reagents. 2(H) can be converted to all similar intermediates and compounds derived from 6-8 using similar methods. Compounds of formula 6-14 can be treated with a base and an alkylating agent as described for the conversion of 6-3 to 6-4 to form compounds of formula 1-1. Compounds of formula 6-11 can be purchased or synthesized using methods described in the literature. Compounds of formula 6-9 can be oxidized using an oxidizing agent such as potassium permanganate to also form compounds of formula 6-11. Compounds of formula 6-11 can be homologated using any number of methods reported in the literature, such as the Arndt-Eistert reaction (using an activating reagent such as thionyl chloride, ethyl chloroformate or others; followed by a diazomethane reagent; a silver salt such as silver benzoate, silver oxide or others; and a nucleophile such as water or an alcohol) or other methods described in the literature, such as the method described in J.Org.Chem.2001, 66, 5606, to form compounds of formula 6-10. Acids of Formula 1-1 containing a mixture of enantiomers can be separated using supercritical fluid or reverse phase chromatography with a chiral column, or they can be separated as diastereomeric salts using appropriate chiral acids under classical resolution conditions such as described in Org. Process Res. Dev. 2011, 15, 53, or the undesired enantiomer can be converted to an ester using biocatalysis as described in Adv. Synth. Catal., 2009, 351, 2333 (see also J. Org. Chem. 2003, 68, 7234) and separated to form acids of Formula 2-1 in high enantiomeric excess.

[0307] Route 6

[0308]

[0309] Scheme 7 describes compounds of formula 7-3, 7-4, 7-7, 7-8, 7-9 and 7-10 (wherein Q 1 The synthesis of the compound of formula 7-1 (wherein PG 1 Dealkylation conditions such as trimethylsilyl iodide, sodium methylthiolate or others, strong acids such as hydrobromic acid, boron tribromide, or when PG 1 When is benzyl, palladium or related metals and hydrogen can be used to form a compound of formula 7-2. The compound of formula 7-2 can be reacted with a difluoromethyl source, such as a difluorohaloacetate or (bromodifluoromethyl)trimethylsilane to form a compound of formula 7-3. The compound of formula 7-2 can also be reacted with a trifluoromethyl source, such as a difluorohaloacetate, in the presence of an electrophilic fluorine source, such as Selectfluor TM, trifluoromethyl halide is added to react, or via available and an electrophilic fluorine source, such as N-fluorobenzenesulfonimide or 1,3,5-trichloro-1,3,5-triazacyclohexane-2,4,6-trione (TCCA) (as described in J.Org.Chem.2019,84,15776) or other intermediate xanthate to be treated to form a compound of formula 7-4. Compound 7-5 (wherein LG 3 (may be Cl, Br, I, OTf or others) can be treated with a nucleophilic vinyl source, such as vinyl borate, vinyl stannane or others, using palladium-catalyzed cross-coupling conditions described in the literature to form a compound of formula 7-6. The compound of formula 7-6 can be oxidatively cleaved to an aldehyde using reagents such as ozone with triphenylphosphine or dimethyl sulfide, osmium tetroxide (or ruthenium trichloride) and sodium periodate or others to form a compound of formula 7-7. The compound of formula 7-7 can be treated with a nucleophilic difluoromethylation source, such as or And related reagents to form the compound of formula 7-8. The compound of formula 7-5 can be in S N Ar or cross-coupling conditions using palladium and a variety of ligands treated with alcohol to form compounds of formula 7-9 [wherein R 8 For example, C 1-4 Alkyl (such as methyl) or C 1-4 Haloalkyl (such as C1 fluoroalkyl)]. The compound of formula 7-5 can also be reacted with an amine under similar conditions to form a compound of formula 7-10 [wherein R 6 and R 7 Each of which is independently C 1-4 Alkyl (such as methyl), or R 6 and R 7 Together with the carbon atom to which it is attached, it forms a cyclopropyl group].

[0310] Route 7

[0311]

[0312] Scheme 8 describes the synthesis of compounds of formula 1-2 and 1-3. 4 It can be benzyl, p-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, benzoyl or other common nitrogen protecting groups; PG 5 Can be used with PG 4 The same or any of the similar protecting groups that can be orthogonally removed) can be halogenated by an electrophilic halogenating agent such as dibromohydantoin, N-bromosuccinimide, N-chlorosuccinimide, bromine, iodine or other halogenating agents to form a compound of formula 8-3 (wherein X 4The compound of formula 8-3 can be reacted with a diboron source [such as tetrahydroxydiboron, bis(neopentyldiol)diboron(5,5,5',5'-tetramethyl-2,2'-di-1,3,2-dioxaborolane) or bis(pinacolato)diboron(4,4,4',4',5,5,5',5'-octamethyl-2,2'-di-1,3,2-dioxaborolane)], a ditin source such as bis(tributyltin) or others, a strong metal-containing base such as isopropylmagnesium chloride, and then a zinc source such as zinc dichloride or others to form a compound of formula 8-2 (wherein M 1 The compound of formula 8-2 can be combined with the compound of formula 8-9 (wherein X 5 Cl, Br, I, OTf or others) under CC cross-coupling conditions (such as Suzuki (M 1 =boron), Stille (M 1 = tin), Negishi (M 1 = zinc halide), Kumada (M 1 = magnesium halide) type reaction or other) to form a compound of formula 8-4. Alternatively, compounds of formula 8-3 and 8-10 can be reacted in a cross-coupling reaction in a manner similar to 8-2 and 8-9, wherein the order of the nucleophile and electrophile is reversed, to form a compound of formula 8-4. Alternatively, in some cases, a compound of formula 8-1 can also be reacted with a compound of formula 8-9 under CH activation / direct arylation conditions to directly form a compound of formula 8-4. PG of compound of formula 8-4 4 and PG 5 The group can be removed using appropriate deprotection conditions, such as acid or hydrogenolysis or other removal, to form compounds of Formula 1-2. Note - If the compound of Formula 8-1, 8-2, 8-3, 8-4 or 1-2 contains a stereochemical mixture or is racemic, it can be separated into single enantiomers using supercritical fluid or reverse phase chromatography using a chiral column, or separated as diastereomeric salts using an appropriate chiral acid under classical resolution conditions and separated to form a high enantiomeric excess of the compound of Formula 8-5, 8-7, 8-6, 8-8 or 1-3, respectively. Alternatively, the compounds of Formula 8-5, 8-7, 8-6 and 8-8 can be reacted under the same conditions as their similar intermediates from this route without modifying the conditions that lead to the formation of the compound of Formula 1-3.

[0313] Route 8

[0314]

[0315] Route 9 refers to the synthesis of compounds of formula 9-13. 7 X 6 More reactive; for example, X 7 =Br, X 6 =Cl or X 7 =I, X 6 =Br or Cl, or other similar combinations) can be reacted with a compound of formula 9-2 under Sonogashira conditions using copper and palladium catalysts to form a compound of formula 9-3. The compound of formula 9-3 can be treated with various palladium, platinum or rhodium catalysts (on carbon or alumina or free) and hydrogen, trialkylsilane, formic acid to form a compound of formula 9-8. The compound of formula 9-8 can be treated with S under common CN cross-coupling conditions. N Ar type conditions or with palladium or copper and appropriate ligands to form compounds of formula 9-4. 5 In the case of a group such as a carbamate, and a stronger base such as sodium tert-butoxide or potassium tert-butoxide, the compound of formula 9-8 can be directly converted to the compound of formula 9-6. Alternatively, the compound of formula 9-9 (wherein R 11 It may be an aromatic hydrocarbon such as phenyl, an alkyl group such as ethyl or butyl, or an alcohol such as ethanol, or others; and (X 8 ) - Can be OMs - ,OTs - ,OTf - 、Cl - Br - , I -or its analogous groups) and a compound of formula 9-10 can be reacted together with a base such as potassium carbonate, sodium tert-butoxide, n-butyllithium or the like under Wittig conditions (such as described in Tetrahedron Lett. 2007, 48, 3359) or similar conditions to form a compound of formula 9-11. The compound of formula 9-11 can be converted to the compound of formula 9-8 using conditions similar to those described for the conversion of the compound of formula 9-3 to the compound of formula 9-8. Alternatively, the compound of formula 9-10 can be converted to the compound of formula 9-12 using an appropriate methylene Wittig salt in a manner similar to the conversion of 9-10 to 9-11. Alternatively, the compound of formula 9-11 can be reacted with a catalyst such as iridium or other catalysts with an appropriate ligand and blue LED light under photoredox isomerization conditions to form a compound of formula 9-7. Alternatively, the conversion of the compound of formula 9-11 can be carried out under the same photoredox conditions using a second catalyst, typically palladium, to form a compound of formula 9-5, the second catalyst being added to effect cyclization after isomerization. Alternatively, the compound of formula 9-3 can be treated with a poisoned catalyst such as Lindlar's catalyst (such as described in J. Org. Chem. 2001, 66, 3634) or palladium / barium sulfate and a hydrogen source, or by the method described in Tetrahedron Lett. 2008, 49, 2839, to form the compound of formula 9-7. Alternatively, the compound of formula 9-7 can be treated under hydrogenation conditions similar to those described for the conversion of the compound of formula 9-11 to 9-8 to form the compound of formula 9-8. Alternatively, the compounds of formula 9-10 and 9-2 can be converted to the compound of formula 9-2 by using alkyne-forming conditions, such as Corey Fuchs or other interconversions, or treated under oxidative cleavage conditions to form the compound of formula 9-10. Alternatively, the compound of formula 9-7 can be reacted under conditions similar to those described for the conversion of the compound of formula 9-8 to the compound of formula 9-6 to form the compound of formula 9-5. Depending on the choice of protecting group used, the compound of formula 9-5 can be reacted under conditions similar to those used to convert the compound of formula 9-11 to the compound of formula 9-8 to form the compound of formula 9-4, 9-13 or 9-6. Alternatively, the compound of formula 9-5 can be reacted under standard conditions to remove the PG 5 , thereby forming a compound of Formula 9-14. Depending on the choice of protecting group, the compound of Formula 9-14 can then be reacted under conditions similar to those used to convert the compound of Formula 9-5 to the compound of Formula 9-6 to form a compound of Formula 9-6 or 9-13. Alternatively, the compound of Formula 9-12 can be converted to the compound of Formula 9-11 by using Heck-type cross-coupling conditions with the compound of Formula 9-1. Alternatively, the compounds of Formula 9-12 and 9-1 can be converted to the compound of Formula 9-11 by using S N Ar or CN cross-coupling type conditions (where X 6 X 7More reactive, like X 7 =Cl, X 6 =Cl or Br or X 7 =Br, X 6 =Br or I, or other similar combinations) is converted to a compound of Formula 9-15. Compounds of Formula 9-15 can be reacted under conditions similar to those described for the conversion of compounds of Formula 9-12 to compounds of Formula 9-11 to form compounds of Formula 9-5.

[0316] Route 9

[0317]

[0318] Scheme 10 describes the synthesis of compounds of formula 10-11, which are stereochemically defined subtypes of compounds of formula 9-13. All transformations shown can be performed as described for analogous compounds and intermediates described in Scheme 9 and do not require modification or the use of different conditions.

[0319] Route 10

[0320]

[0321] Scheme 11 describes compounds of formula 11-6 and 11-7 (subtypes of compounds of formula 9-2 and 10-1, respectively, wherein PG 7 To allow the adjacent nitrogen to remain nucleophilic, a protecting group such as benzyl, p-methoxybenzyl or others, or possibly no protecting group) can be synthesized. The compound of formula 11-1 can be purchased or synthesized according to methods described in the literature and is combined with a compound of formula 11-2 (wherein PG is present) which has been deprotonated by a base such as potassium tert-butoxide, lithium diisopropylamide, sodium hydride, n-butyllithium, zinc or magnesium metal. 6 The compound of formula 11-3 is then reacted with a trimethylsilyl or other suitable alkyne protecting group to obtain a compound of formula 11-3. The terminal alkyne protecting group of the compound of formula 11-3 can then be removed using a reagent such as tetrabutylammonium fluoride, potassium carbonate, potassium hydroxide or other reagents to obtain a compound of formula 11-4. The hydroxyl group of the compound of formula 11-4 can be activated with acetyl chloride, benzoyl chloride, other acyl halides, other suitably activated acids or other activating groups such as haloformates, dialkyl halophosphates or others, and bases such as triethylamine, N,N-diisopropylethylamine, pyridine, 4-(dimethylamino)pyridine or the like to become a leaving group OR 9 (where R 9acetyl, benzoyl, tert-butyloxycarbonyl, dialkyl phosphate [P(O)(OAlk)2] or its analog} to form an activated compound of formula 11-5. The compound of formula 11-5 can be reacted with an amine protected with p-methoxybenzyl, benzyl or other protection in a reaction catalyzed by copper(I) chloride, copper(I) bromide (such as in J.Org.Chem. 2013, 78, 5647), a ruthenium catalyst (such as in New J.Chem. 2011, 35, 2427) and the like to form a compound of formula 11-6. If the compound of formula 11-6 contains a stereochemical mixture or is racemic, it can be separated into single enantiomers using supercritical fluid or reverse phase chromatography with a chiral column, or separated as diastereomeric salts under classical resolution conditions with an appropriate chiral acid and separated to form a compound of formula 11-7 in high enantiomeric excess.

[0322] Route 11

[0323]

[0324] Scheme 12 describes compounds of formula 9-1 and 9-9 (wherein R 11 The compound of formula 12-1 (which can be purchased or synthesized from 12-6 or synthesized by other methods described in the literature) can be treated with a reducing agent such as an aluminum hydride (lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum dihydride, diisobutylaluminum hydride, or others) or a borohydride-based substance (such as lithium borohydride, sodium borohydride, or others) to form a compound of formula 12-3. Alternatively, a compound of formula 12-2 (which can be purchased or formed from a compound of formula 12-1 using standard hydrolysis conditions or other methods described in the literature) can be converted using the same reagents and also by using a borane or borane-derived reagent to form a compound of formula 12-3. The OH group of the compound of formula 12-3 can be activated to a leaving group (LG) by using a suitable reagent such as methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, phosphorus oxychloride or thionyl chloride, phosphorus oxybromide or phosphorus tribromide, iodine and triphenylphosphine or imidazole, an acid such as hydrobromic acid or hydrochloric acid, or by using a combination of methods such as methanesulfonyl chloride followed by sodium iodide, sodium chloride, sodium bromide, potassium iodide, potassium chloride, potassium bromide or others. 4, which can be OMs, OTs, OTf, Cl, Br, I or other), to produce a compound of formula 12-4. Alternatively, a compound of formula 12-5 can be halogenated under free radical halogenation conditions such as those described for the conversion of compounds 6-1 to 6-8, to form a compound of formula 12-4. The compound of formula 12-4 can react with a compound of formula 12-9 (e.g., triphenylphosphine, triethylphosphine, triethyl phosphite or other phosphorus-containing nucleophiles) to produce a compound of formula 9-9. The compound of formula 12-6 can be nitrated under standard nitration conditions, such as fuming nitric acid, to produce a compound of formula 12-7. The nitro group of the compound of formula 12-7 can be reduced to an amine using a variety of conditions, such as palladium / carbon and hydrogen, zinc or iron and acetic acid or hydrochloric acid, tin (II) chloride or other, to produce a compound of formula 12-8. Compounds of formula 12-8 can be treated with sodium nitrite or isoamyl nitrite with hydrobromic acid, potassium bromide, potassium iodide, or other standard Sandmeyer-type conditions to produce compounds of formula 9-1. Compounds of formula 9-1 can be treated with carbonylation conditions such as palladium with an appropriate ligand such as 1,1'-bis(diphenylphosphino)ferrocene, a carbon monoxide source, and an alcohol such as ethanol or methanol, or can be treated with metal-halogen exchange conditions and quenched with an acyl source such as diethyl carbonate, carbon dioxide, ethyl chloroformate, or others to produce compounds of formula 12-1.

[0325] Route 12

[0326]

[0327] Scheme 13 describes a method for synthesizing compounds of formula 9-10. 8(Can be any C bonded alkyl or aryl, and can be purchased or synthesized using methods described in the literature) can be treated with conditions such as eliminating hydroxyl groups with methanesulfonyl chloride or p-toluenesulfonyl chloride, as described in Org.Lett.2016,18,1812, or other standard conditions to obtain compounds of formula 13-2. Compounds of formula 13-2 can react with commercially available compounds of formula 13-3 in 3+2 cycloadditions to form compounds of formula 13-4. Compounds of formula 13-4 can be directly reduced to compounds of formula 9-10 using conditions such as diisobutylaluminum hydride or other reducing agents that avoid excessive reduction. Alternatively, compounds of formula 13-4 can be reduced to compounds of formula 13-5 using conditions similar to those described for the conversion of compounds of formula 12-1 to 12-3. Compounds of formula 13-5 can then be oxidized using a variety of well-known reagents such as Collins chromium reagent, Dess-Martin periodinane reagent, Parikh-Doering reagent, other activated DMSO-based Swern type reagents, or many other reagents to provide compounds of formula 9-10. Alternatively, compounds of formula 13-8 can be treated with lithium diisopropylamide, lithium bis(trimethylsilyl)amide, n-butyllithium, or many other similar strong bases and a suitable acylating agent such as ethyl chloroformate, ethyl cyanoformate, or diethyl carbonate to form compounds of formula 13-9 (where PG 9 Can be used with PG 8 The compounds of formula 13-9 may be the same or may be different alkyl or aryl groups, such that they can be removed orthogonally under selective conditions). Compounds of formula 13-9 may be removed orthogonally under selective conditions using one equivalent of a base such as sodium hydroxide or lithium hydroxide or many other bases, or by employing a selective PG that can be removed by treatment with palladium on carbon and hydrogen. 9 , such as benzyl group is selectively hydrolyzed to form a compound of formula 13-10. Compounds of formula 13-10 can be converted to compounds of formula 13-4 using reactions such as Curtius rearrangement (such as described in Org. Biomol. Chem. 2018, 16, 2006), or other similar reactions that rearrange the acid or related acyl group to a dehomologated amine or protected amine, such as Hoffmann rearrangement, Lossen rearrangement, or Schmidt reaction.

[0328] Route 13

[0329]

[0330] Scheme 14 describes a method for synthesizing compounds of formula 10-8 (stereochemically defined isoforms of 9-10) and related intermediates. Racemic forms or mixtures of compounds of formula 13-4 can be separated into single enantiomers using supercritical fluid chromatography or reverse phase chromatography with a chiral column, or when PG4 or PG 5 When the protecting group does not eliminate the basicity of the nitrogen to which it is attached, it can also be separated using chiral acids under classical resolution conditions to provide compounds of formula 14-4. Alternatively, compounds of formula 13-9 can be exposed to various biocatalytic conditions, such as esterase ECS03 (AB 503574) from Enzymicals or using those described in Tetrahedron: Asymmetry 1998, 9, 2663, to form compounds of formula 14-1 (a subtype of compounds of formula 13-10). Compounds of formula 14-1 and 14-4 can be converted to their analogous compounds described in Scheme 13 using the described conditions without any modification or change in the reaction conditions.

[0331] Route 14

[0332]

[0333] Scheme 15 describes a subtype of 15-4 (a compound of formula 8-4, wherein X 1 =CH-CH3). The compound of formula 11-1 can be reacted with ammonia and an allyl boron reagent as described in Chem. Commun. 2005, 44, 5551 to form a compound of formula 15-1. The compound of formula 15-1 can be reacted with a similar method as described for the conversion of compounds of formula 9-12 to 9-15 to obtain a compound of formula 15-2. The compound of formula 15-2 can be reacted with a similar method as described for the conversion of compounds of formula 9-15 to 9-5 to obtain a compound of formula 15-3, with the rearrangement of the internal olefin as shown. A method similar to that described for the conversion of compounds of formula 9-5 to 9-4 can be used to convert the compound of formula 15-3 into a compound of formula 15-4. Alternatively, the compound of formula 15-2 can be reacted with ozonolysis conditions or other oxidative cleavage conditions in the presence of sodium borohydride to obtain a compound of formula 15-7. Compounds of formula 15-7 can be treated under conditions such as elimination of the hydroxyl group of the olefin using methanesulfonyl chloride or p-toluenesulfonyl chloride followed by a strong base, or by using Grieco elimination conditions using an aryl selenocyanate in the presence of a trialkylphosphine to give compounds of formula 15-8 (which are subtypes of compounds of formula 9-15, wherein PG 5 for H).

[0334] Route 15

[0335]

[0336] Scheme 16 describes formula 16-3 (wherein Y 7is N or CH), the synthesis of compounds 16-7, 16-11 and 16-14, which are all subtypes of 8-9 that are not commercially available. The compound of formula 16-1 can be reacted with an electrophilic halogen source in a manner similar to the conversion of compounds of formula 8-1 to 8-3 to form a compound of formula 16-2. The compound of formula 16-2 can be reacted with an electrophilic halogen source in a manner similar to the conversion of compounds of formula 7-2 to 7-3 (when R 12 is H) or the conversion of compounds of formula 7-2 to 7-4 (when R 12 is F) under similar conditions to produce a compound of formula 16-3. 9 Can be with X 5 The same halogen may be more reactive, so that when X 5 When X is Cl 9 For Br, or when X 5 When X is Br or Cl 9 I) can be reacted with cyclopropylboronic acid (when R 13 is cyclopropyl) and a copper source, such as copper (II) acetate, or other and a suitable ligand, such as 2,2'-bipyridine, and any number of bases, such as carbonates or amines, and a co-oxidant, such as oxygen that can be added or from air, to produce a compound of formula 16-5. Compounds of formula 16-5 (which can be purchased, such as when R 13 is methyl, or produced as described herein or in the literature) can be reacted under metal-halogen exchange conditions such as isopropylmagnesium chloride, n-butyllithium, magnesium or others and quenched with a carbonyl source such as N,N-dimethylformamide, morpholine-4-carboxaldehyde or others to produce a compound of Formula 16-6. The compound of Formula 16-6 can be reacted under conditions similar to those for the transformation of compounds of Formulas 7-7 to 7-8 to produce a compound of Formula 16-7. The compound of Formula 16-4 can be reacted with 4-halo-1-butene in the presence of a base such as potassium carbonate, sodium bicarbonate, sodium hydride, lithium diisopropylamide or others to produce a compound of Formula 16-8. The compound of Formula 16-8 can be reacted under Heck-like conditions as described for the transformation of compounds of Formulas 9-15 to 9-5 to produce a compound of Formula 16-9. Compounds of formula 16-9 can be reacted to form compounds of formula 16-10 and 16-11 via several steps in a manner similar to that described for the sequential conversion of compounds of formula 7-6 to 7-7 and then 7-8. 10(which may be Cl, Br or I, OTf or others) can be reacted with palladium / carbon or other common catalysts and deuterium gas (or other deuteride source, such as deuterated formate, under transfer hydrogenation conditions) to form compounds of Formula 16-13. Compounds of Formula 16-13 can be reacted under Sandmeyer-type conditions similar to those described for the conversion of compounds of Formulas 12-8 to 9-1 to produce compounds of Formula 16-14. Alternatively, compounds of Formula 16-15 can be reacted under Sandmeyer-type conditions similar to those described for the conversion of compounds of Formulas 12-8 to 9-1.

[0337] Route 16

[0338]

[0339] Scheme 17 describes a method for synthesizing a compound of formula 17-5 which is a subtype of a compound of formula 8-4, wherein R 1 For R 14 Substituted tetrazole, the R 14 It may be an optionally substituted alkyl or aryl group. The compound of formula 17-1 can be converted to compounds of formula 17-2 and 17-3 via similar transformations as described for the synthesis of compounds of formula 7-5 to 7-6 and 7-7. Alternatively, the compound of formula 17-1 can be directly converted to the compound of formula 17-3 in a manner similar to that used to convert the compound of formula 16-5 to the compound of formula 16-6. The compound of formula 17-3 can be reacted with a substituted hydrazine under standard condensation conditions using acid or base catalysis to form a compound of formula 17-4. The compound of formula 17-4 can be reacted with a diazo compound such as diethyl azodicarboxylate or di-tert-butyl azodicarboxylate in the presence of a hypervalent iodine source such as [bis(trifluoroacetoxy)iodo]benzene or others to produce a compound of formula 17-5.

[0340] Route 17

[0341]

[0342] Detailed descriptions of the individual reaction steps are provided in the Examples section below. Those skilled in the art will appreciate that other synthetic pathways can be used to synthesize compounds. Although specific starting materials and reagents are discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many compounds prepared by the methods described below can be further modified according to the present invention using conventional chemical methods well known to those skilled in the art.

[0343] Combination Potion

[0344] The compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents. "Administered in combination" or "combination therapy" means that the compounds of the present invention and one or more additional therapeutic agents are administered to the mammal being treated simultaneously. When administered in combination, the components may be administered simultaneously or sequentially in any order at different time points. Thus, the components may be administered separately but sufficiently close in time to provide the desired therapeutic effect. The phrases "administered concurrently," "co-administered," "administered simultaneously," and "administered simultaneously" mean that the compounds are administered in combination. Thus, the methods of prevention and treatment described herein encompass the use of combination agents.

[0345] The combination agent is administered to a mammal in a therapeutically effective amount. "Therapeutically effective amount" means an amount of a compound of the invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective in treating the desired disease / disorder / condition (e.g., cachexia, anorexia, anorexia nervosa, nausea; vomiting, growth failure, sarcopenia, muscle atrophy, weakness, osteoporosis, bone loss, pain, anxiety, depression, or hypertension).

[0346] In some embodiments, the compounds of the present invention may be co-administered with one or more other agents such as orlistat, TZDs and other insulin sensitizers, FGF21 analogs, metformin, omega-3-acid ethyl esters (e.g., Lovaza), fibrates, HMG CoA-reductase inhibitors, Ezetimibe, Probucol, ursodeoxycholic acid, TGR5 agonists, FXR agonists, vitamin E, betaine, pentoxifylline, CB 1 antagonists, carnitine, N-acetylcysteine, reduced glutathione, lorcaserin, a combination of naltrexone and bupropion, SGLT2 inhibitors (including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, ertugliflozin, ASP-1941, THR1474, TS-071, ISIS388626 and LX4211 and those in WO2010023594), phentermine, topiramate, GLP-1 receptor agonists, GIP receptor agonists, dual GLP-1 receptor / glucagon receptor agonists (e.g., OPK88003, MEDI 0382, JNJ-64565111, NN9277, BI456906), dual GLP-1 receptor / GIP receptor agonists [e.g., Tirzepatide (LY3298176), NN9423], angiotensin-receptor blockers, acetyl-CoA carboxylase (ACC) inhibitors, BCKDK inhibitors, hexokinese (KHK) inhibitors, ASK1 inhibitors, branched-chain α-ketoacid dehydrogenase kinase inhibitors (BCKDK inhibitors), CCR2 and / or CCR5 inhibitors, PNPLA3 inhibitors, DGAT1 inhibitors, DGAT2 inhibitors, FGF21 analogs, FGF19 analogs, PPAR agonists, FXR agonists, AMPK activators [e.g., ETC-1002 (bempedoic acid)], SCD1 inhibitors, or MPO inhibitors.

[0347] Exemplary GLP-1 receptor agonists include liraglutide, albiglutide, exenatide, albiglutide, lixisenatide, dulaglutide, semaglutide, HM15211, LY3298176, Medi-0382, NN-9924, TTP-054, TTP-273, efpeglenatide, those described in WO2018109607, those described in PCT / IB2019 / 054867, filed June 11, 2019, and those described in PCT / IB2019 / 054961, filed June 13, 2019, including the following:

[0348] 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0349] 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0350] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0351] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0352] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0353] 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0354] 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0355] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid;

[0356] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid;

[0357] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0358] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0359] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0360] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid;

[0361] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0362] 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0363] 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0364] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0365] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0366] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0367] 2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0368] 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0369] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid;

[0370] 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid;

[0371] 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0372] 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0373] 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0374] 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2;

[0375] 2-[(4-{2-[(4-chloro-2-fluorobenzyl)oxy]pyridin-3-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0376] 2-[(4-{2-[(4-chloro-2-fluorobenzyl)oxy]pyridin-3-yl}piperidin-1-yl)methyl]-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0377] 2-[(4-{2-[(4-cyano-2-fluorobenzyl)oxy]pyridin-3-yl}piperidin-1-yl)methyl]-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0378] 2-[(4-{2-[(4-cyano-2-fluorobenzyl)oxy]pyridin-3-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0379] 2-[(4-{3-[(4-chloro-2-fluorobenzyl)oxy]pyrazin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0380] 2-(6-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}-6-azaspiro[2.5]octan-1-yl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0381] 2-(6-{2-[(4-chloro-2-fluorobenzyl)oxy]-5-fluoropyrimidin-4-yl}-6-azaspiro[2.5]octan-1-yl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0382] 2-(6-{2-[(4-chloro-2-fluorobenzyl)oxy]-5-fluoropyrimidin-4-yl}-6-azaspiro[2.5]octan-1-yl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0383] 2-(6-{6-[(4-cyano-2-fluorobenzyl)oxy]-5-fluoropyridin-2-yl}-6-azaspiro[2.5]octan-1-yl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0384] 2-(6-{6-[(4-cyano-2-fluorobenzyl)oxy]-3-fluoropyridin-2-yl}-6-azaspiro[2.5]octan-1-yl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0385] 2-[(4-{2-[(4-chloro-2-fluorobenzyl)oxy]pyrimidin-4-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0386] 2-{[(2S)-4-{2-[(4-chloro-2-fluorobenzyl)oxy]-5-fluoropyrimidin-4-yl}-2-methylpiperazin-1-yl]methyl}-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0387] 2-{[(2S)-4-{2-[(4-chloro-2-fluorobenzyl)oxy]pyrimidin-4-yl}-2-methylpiperazin-1-yl]methyl}-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and

[0388] 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, and pharmaceutically acceptable salts thereof.

[0389] Exemplary ACC inhibitors include 4-(4-[(1-isopropyl-7-oxo-1,4,6,7-tetrahydro-1′H-spiro[indazole-5,4′-piperidinyl]-1′-yl)carbonyl]-6-methoxypyridin-2-yl)benzoic acid, gemcabene, and firsocostat (GS-0976), and pharmaceutically acceptable salts thereof.

[0390] Exemplary FXR agonists include tropifexor (2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid), cilofexor (GS-9674), obeticholic acid, LY2562175, Met409, TERN-101, and EDP-305, and pharmaceutically acceptable salts thereof.

[0391] Exemplary KHK inhibitors include [(1R,5R,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hexan-6-yl]acetic acid and pharmaceutically acceptable salts thereof.

[0392] Exemplary DGAT2 inhibitors include (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide [including its crystalline solid forms (Form 1 and Form 2)]. See U.S. Patent No. 10,071,992.

[0393] Exemplary BCKDK inhibitors include those described in U.S. Serial No. 62 / 868,057, filed June 28, 2019, and U.S. Serial No. 62 / 868,542, filed June 28, 2019, including the following:

[0394] 5-(5-chloro-4-fluoro-3-methylthiophen-2-yl)-1H-tetrazole;

[0395] 5-(5-chloro-3-difluoromethylthiophen-2-yl)-1H-tetrazole;

[0396] 5-(5-Fluoro-3-methylthien-2-yl)-1H-tetrazole;

[0397] 5-(5-chloro-3-methylthien-2-yl)-1H-tetrazole;

[0398] 5-(3,5-dichlorothiophen-2-yl)-1H-tetrazole;

[0399] 5-(4-bromo-3-methylthiophen-2-yl)-1H-tetrazole;

[0400] 5-(4-bromo-3-ethylthiophen-2-yl)-1H-tetrazole;

[0401] 5-(4-chloro-3-ethylthiophen-2-yl)-1H-tetrazole;

[0402] 3-Chloro-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0403] 3-Bromo-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0404] 3-(Difluoromethyl)-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0405] 5,6-Difluorothieno[3,2-b]thiophene-2-carboxylic acid; and

[0406] 3,5-difluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0407] or a pharmaceutically acceptable salt thereof.

[0408] In some embodiments, the compounds of the present invention may be co-administered with one or more antidiabetic agents. Suitable antidiabetic agents include: insulin; metformin; GLP-1 receptor agonists (described above); acetyl-CoA carboxylase (ACC) inhibitors (described above); SGLT2 inhibitors (described above); monoacylglycerol O-acyltransferase inhibitors; phosphodiesterase (PDE)-10 inhibitors; AMPK activators [e.g., ETC-1002 (bampedoic acid)]; sulfonylureas (e.g., acetohexamide; chlorpropamide; chlorpropamide; glibenclamide; glipizide; glyburide; glimepiride urea (glimepiride; gliclazide; glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide); meglitinides; α-amylase inhibitors (e.g., tendamistat; trestatin; and AL-3688); α-glucosidase hydrolase inhibitors (e.g., acarbose); α- Glucosidase inhibitors (e.g., adiposine; camiglibose; emiglitate; miglitol; voglibose; pradimicin-Q; and salbostatin); PPARγ agonists (e.g., balaglitazone; ciglitazone; darglitazone; englitazone); ne); isaglitazone; pioglitazone; and rosiglitazone); PPARα / γ agonists (e.g., CLX-0940; GW-1536; GW-1929; GW-2433; KRP-297; L-796449; LR-90; MK-0767; and SB-219994); protein tyrosine phosphatase-1B (PTP-1B) inhibitors [e.g., trodusquemine; hyrtiosal extract; and Zhang; S.et al., Drug Discovery Today, 12(9 / 10), 373-381 (2007)]; SIRT-1 activators (e.g., resveratrol; GSK2245840 or GSK184072); dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., those described in WO2005116014; sitagliptin; vildagliptin; alogliptin; dutogliptin; linagliptin; and saxagliptin); insulin secretagogues; fatty acid oxidases kinase inhibitors; A2 antagonists; c-jun N-terminal kinase (JNK) inhibitors; glucokinase activators (GKa), such as those described in WO2010103437; WO2010103438; WO2010013161; WO2007122482; TTP-399; TTP-355; TTP-547; AZD1656; ARRY403; MK-0599; TAK-329; AZD5658 or GKM-001; insulin; insulin mimetics; glycogen phosphorylase inhibitors (e.g., GSK1362885); VPAC2 receptor agonists; glucagon receptor modulators, such as those described in Demong, DE et al., Annual Reports in Medicinal Chemistry 2008, 43, 119-137; GPR119 modulators, especially agonists, such as WO2010140092; WO2010128425; WO2010128414; WO2010106457; Jones, RM et al., Annual Reports in Medicinal Chemistry 2009, 44, 149-170 (e.g., MBX-2982; GSK1292263; APD597; and PSN821); FGF21 derivatives or analogs, such as those described in Kharitonenkov, A. et al., Current Opinion in Investigational Drugs 2009, 10(4)359-364; TGR5 (also known as GPBAR1) receptor modulators, especially agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396, and INT777; GPR40 agonists, such as Medina, JC, Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, including but not limited to TAK-875; GPR120 modulators, especially agonists; high affinity nicotinic acid receptor (HM74A) activators; and SGLT1 inhibitors, such as GSK1614235. Another representative list of antidiabetic agents that can be combined with the compounds of the present invention can be found, for example, on page 28, line 35 to page 30, line 19 of WO2011005611.

[0409] Other antidiabetic agents may include inhibitors or modulators of carnitine palmitoyltransferase; inhibitors of fructose 1,6-bisphosphatase; inhibitors of aldose reductase; mineralocorticoid receptor inhibitors; inhibitors of TORC2; inhibitors of CCR2 and / or CCR5; inhibitors of PKC isoforms (e.g., PKCα, PKCβ, PKCγ); inhibitors of fatty acid synthase; inhibitors of serine palmitoyltransferase; modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, and SSTR5); inhibitors or modulators of PDHK2 or PDHK4; inhibitors of MAP4K4; modulators of the IL1 family, including IL1β; and modulators of RXRα. Additionally, suitable antidiabetic agents include those listed in Carpino, PA, Goodwin, B. Expert Opin. Ther. Pat., 2010, 20(12), 1627-51.

[0410] The compounds of the present invention may be co-administered with anti-heart failure agents such as ACE inhibitors (e.g., captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril), angiotensin II receptor blockers (e.g., candesartan, losartan, valsartan), angiotensin-receptor neprilysin inhibitors (sacubitril / valsartan), I fChannel blockers ivabradine, beta-adrenergic blockers (e.g., bisoprolol, metoprolol succinate, carvedilol), aldosterone antagonists (e.g., spironolactone, eplerenone), hydralazine, and isosorbide dinitrate, diuretics (e.g., furosemide, bumetanide, torsemide, chlorothiazide, amiloride, hydrochlorothiazide, indapamide, metolazone, triamterene), or digoxin.

[0411] The compounds of the present invention may also be co-administered with cholesterol or lipid lowering agents including the following exemplary agents: HMG-CoA reductase inhibitors (e.g., pravastatin, pitavastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (also known as itavastatin or nisvastatin or nisbastatin) and ZD-4522 (also known as rosuvastatin or atavastatin or visastatin); squalene synthase inhibitors; fibrates (e.g., gemfibrozil, pemafibrate, fenofibrate); nivolumab, nivolumab, nivolumab, nivolumab); bile acid sequestrants (e.g., questran, colestipol, colesevelam); ACAT inhibitors; MTP inhibitors; lipoxygenase inhibitors; cholesterol absorption inhibitors (e.g., ezetimibe); nicotinic acid agents (e.g., niacin, niacor, slo-niacin); omega-3 fatty acids (e.g., epanova, fish oil, eicosapentaenoic acid); cholesterol ester transfer protein inhibitors (e.g., obicetrapib); and PCSK9 modulators [e.g., alirocumab, evolocumab, bococizumab, ALN-PCS (inclisiran)].

[0412] The compounds of the present invention may also be used in combination with antihypertensive agents and such antihypertensive activity is readily determined by one skilled in the art according to standard assays (e.g., blood pressure measurements). Examples of suitable antihypertensive agents include: α-adrenergic blockers; β-adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine); vasodilators (e.g., hydralazine); diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, benzflumethiazide, methylchlorothiazide, trichlorothiazide, polythiazide, benzthiazide, ethacrynic acid tricurenafine); acidtricrynafen), chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone; renin inhibitors; ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrasentan, and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); dual ET / AII antagonists (e.g., WO 00 / 01389); neutral endopeptidase (NEP) inhibitors; vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates). An exemplary anti-anginal agent is ivabradine.

[0413] Examples of suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine, amlodipine and mibefradil.

[0414] Examples of suitable cardiac glycosides include digitalis and ouabain.

[0415] In one embodiment, the compounds of the invention may be co-administered with one or more diuretics. Examples of suitable diuretics include (a) loop diuretics such as furosemide (such as LASIX) TM ), torsemide (such as DEMADEX TM), bumetanide (such as BUMEX TM ) and ethacrynic acid (such as EDECRIN TM ); (b) thiazide-type diuretics, such as chlorothiazide (such as DIURIL TM , ESIDRIX TM or HYDRODIURIL TM ), hydrochlorothiazide (such as MICROZIDE TM ORETIC TM ), benzylthiazide, hydroflumethiazide (such as SALURON TM ), benzflumethiazide, methylchlorothiazide, polythiazide, trichloromethiazide, and indapamide (such as LOZOL TM ); (c) phthalimidine-type diuretics, such as chlorthalidone (such as HYGROTON TM ) and metolazone (such as ZAROXOLYN TM ); (d) quinazoline-type diuretics, such as quinethazolone; and (e) potassium-sparing diuretics, such as triamterene (such as DYRENIUM TM ) and amiloride (such as MIDAMOR TM or MODURETIC TM ).

[0416] In another embodiment, the compounds of the present invention may be co-administered with a loop diuretic. In yet another embodiment, the loop diuretic is selected from furosemide and torsemide. In yet another embodiment, one or more compounds of Formula I, or pharmaceutically acceptable salts thereof, may be co-administered with furosemide. In yet another embodiment, one or more compounds of Formula I, or pharmaceutically acceptable salts thereof, may be co-administered with torsemide, which may optionally be in a controlled-release or modified-release form.

[0417] In another embodiment, the compounds of the present invention may be co-administered with a thiazide diuretic. In yet another embodiment, the thiazide diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In yet another embodiment, one or more compounds of Formula I, or pharmaceutically acceptable salts thereof, may be co-administered with chlorothiazide. In yet another embodiment, one or more compounds of Formula I, or pharmaceutically acceptable salts thereof, may be co-administered with hydrochlorothiazide.

[0418] In another embodiment, one or more compounds of Formula I, or pharmaceutically acceptable salts thereof, may be co-administered with a phthalimidine-type diuretic. In yet another embodiment, the phthalimidine-type diuretic is chlorthalidone.

[0419] Examples of suitable mineralocorticoid receptor antagonists include spironolactone and eplerenone.

[0420] Examples of suitable phosphodiesterase inhibitors include: PDE III inhibitors (such as cilostazol); and PDE V inhibitors (such as sildenafil).

[0421] Those skilled in the art will recognize that the compounds of the present invention may also be used in combination with other cardiovascular or cerebrovascular treatments, including PCI, stenting, drug-eluting intravascular stents, stem cell therapy, and medical devices such as implanted pacemakers, defibrillators, or cardiac resynchronization therapy.

[0422] Especially when provided in a single dosage unit form, there may be chemical interactions between the active ingredients of the combination. For this reason, when the compounds of the present invention and the second therapeutic agent are combined in a single dosage unit, they are formulated so that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (i.e., reduced). For example, a kind of active ingredient can be coated with an enteric coating. By coating one of the active ingredients with an enteric coating, not only the contact between the active ingredients of the combination can be minimized, but also the release of one of these components in the gastrointestinal tract can be controlled so that one of these components is not released in the stomach, but released in the intestine. One of the active ingredients can also be coated with a material that realizes sustained release throughout the gastrointestinal tract and is also used to minimize the physical contact between the active ingredients of the combination. In addition, the sustained release component can be additionally coated with an enteric coating so that the release of this component occurs only in the intestine. Yet another approach would involve the formulation of a combination product in which one component is coated with a sustained and / or enteric release polymer and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other suitable materials known in the art to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

[0423] These and other means for minimizing contact between the components of the combination products of the invention, whether administered in a single dosage form or in separate forms but simultaneously by the same means, will be readily apparent to those skilled in the art, so long as they are consistent with this invention.

[0424] In combination therapy treatment, a compound of the invention and other drug therapies are administered to a mammal (e.g., a male or female human) by conventional methods. The compounds of Formula I or their salts are suitable for therapeutic use as agents that antagonize (including inhibit) MC4R in mammals, particularly humans, and are therefore useful in treating various conditions involving such effects (e.g., those described herein).

[0425] Diseases / disorders / conditions that can be treated according to the present invention include, but are not limited to, cachexia (e.g., cachexia associated with cancer, AIDS, CHF and / or CKD); anorexia / anorexia nervosa (e.g., anorexia nervosa in the elderly, anorexia associated with chemotherapy and / or radiation therapy); nausea; vomiting; weight loss (e.g., involuntary weight loss); stunting; sarcopenia; muscle atrophy; frailty; osteoporosis; skeletal disorders (e.g., bone loss); pain; neuropathic pain; anxiety; depression; hypertension; malnutrition; obesity; sexual dysfunction; and inflammatory diseases.

[0426] Administration of the compounds of the present invention can be carried out by any method of systemic and / or local delivery of the compounds of the present invention. Such methods include oral routes, parenteral routes, intraduodenal routes, buccal routes, intranasal routes, and the like. Generally, the compounds of the present invention are administered orally, but parenteral administration (e.g., intravenous, intramuscular, subcutaneous, or intramedullary) may be used, for example, when oral administration is not suitable for the intended purpose or the patient is unable to ingest the drug.

[0427] For administration to human patients, the oral daily dose of the compound herein can be, for example, within the range of 0.01 mg to 5000 mg, depending on the mode of administration and frequency, disease state, and age and condition of the patient. An oral daily dose within the range of 1 mg to 2000 mg (e.g., 3 mg to 2000 mg) can be used. Another oral daily dose is within the range of 5 mg to 1000 mg. For convenience, the compounds of the present invention can be administered in unit dosage form. If necessary, a unit dosage form of multiple doses per day can be used to increase the total daily dose. The unit dosage form can, for example, be a tablet or capsule containing about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 500, or 1000 mg of the compounds of the present invention. The total daily dose may be administered in single or divided doses and, at the physician's discretion, may exceed the typical range given herein.

[0428] For administration to human patients, the daily infusion dose of the compounds herein may be in the range of 1 mg to 2000 mg, depending, of course, on the mode and frequency of administration, the disease state, and the age and condition of the patient. Another daily infusion dose is in the range of 5 mg to 1000 mg. The total daily dose may be administered in a single or divided dose and may exceed the typical ranges given herein at the discretion of the physician.

[0429] According to the treatment methods of the present invention, a compound of the present invention or a combination of a compound of the present invention and at least one additional agent (referred to herein as a "combination") is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition. In the combination aspects of the present invention, the compound of the present invention and at least one other agent (e.g., another anti-cachexia or anti-anorexia agent) may be administered separately or in the form of a pharmaceutical composition comprising both. Such administration is generally preferably oral.

[0430] When a compound of the invention is administered in combination with at least one other pharmaceutical agent, such administration may be sequential or simultaneous in time. In some embodiments, simultaneous administration of the pharmaceutical combination is used. For separate or sequential administration, the compound of the invention and the additional pharmaceutical agent may be administered in any order, and each of them may be administered at an independent frequency or dosing regimen. In some embodiments, such administration is oral. In some embodiments, such administration may be oral and simultaneous. When a compound of the invention and the additional pharmaceutical agent are administered sequentially, each administration may be by the same or different methods.

[0431] According to the methods of the present invention, the compounds of the present invention or combination can be administered in the form of a pharmaceutical composition. Thus, the compounds of the present invention or combination can be administered separately or together to a patient in any conventional oral, rectal, transdermal, parenteral (e.g., intravenous, intramuscular or subcutaneous), intracisternal, intravaginal, intraperitoneal, topical (e.g., powder, ointment, cream, spray or emulsion), buccal or nasal dosage form (e.g., spray, drops or inhalant).

[0432] The compounds or combinations of the present invention may be administered alone or in admixture with one or more suitable pharmaceutical excipients, adjuvants, diluents, or carriers known in the art and selected with respect to the intended route of administration and standard pharmaceutical practice. The compounds or combinations of the present invention may be formulated to provide immediate release, delayed release, modified release, sustained release, pulsed release, or controlled release dosage forms, depending on the specificity of the route of administration and release profile commensurate with the therapeutic needs.

[0433] Pharmaceutical compositions contain a compound or combination of the invention in an amount generally ranging from about 1% to about 75%, 80%, 85%, 90% or even 95% (by weight) of the composition, typically ranging from about 1%, 2% or 3% to about 50%, 60% or 70%, more often ranging from about 1%, 2% or 3% to less than 50%, such as about 25%, 30% or 35%.

[0434] Methods for preparing various pharmaceutical compositions having specific amounts of active compounds are known to those skilled in the art. For example, see Remington, JP, The Science and Practice of Pharmacy, Lippincott Williams and Wilkins, Baltimore, Md. 20th edition, 2000.

[0435] Compositions suitable for parenteral injection generally include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers or diluents (including solvents and vehicles) include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like), suitable mixtures thereof, triglycerides (including vegetable oils such as olive oil), and injectable organic esters (such as ethyl oleate). Preferred carriers are Miglyol.RTM. brand caprylic / capric esters (e.g., Miglyol.RTM.812, Miglyol.RTM.829, Miglyol.RTM.840) with glycerol or propylene glycol, which are commercially available from Condea Vista, Cranford, NJ. Adequate fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using a surfactant.

[0436] Such compositions for parenteral injection may also contain excipients such as preservatives, wetting agents, emulsifiers, and dispersants. Microbial contamination of the compositions can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be achieved by using agents that delay absorption, such as aluminum monostearate and gelatin.

[0437] Solid dosage forms for oral administration include capsules, tablets, chewable tablets, buccal tablets, pills, powders, and multiparticulate formulations (granules). In such solid dosage forms, the compound or combination of the present invention is blended with at least one inert excipient, diluent, or carrier. Suitable excipients, diluents, or carriers include materials such as sodium citrate or dibasic calcium phosphate and / or (a) one or more fillers or extenders (e.g., microcrystalline cellulose (available as Avicel.TM. from FMC Corporation), starch, lactose, sucrose, mannitol, silicic acid, xylitol, sorbitol, dextrose, dibasic calcium phosphate, dextrin, α-cyclodextrin, β-cyclodextrin, polyethylene glycol, medium chain fatty acids, titanium oxide, magnesium oxide, aluminum oxide, and the like); (b) one or more binders (e.g., carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin, gum arabic, etc.); (e.g., arabic), ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, alginates, gelatin, polyvinyl pyrrolidone, sucrose, acacia, and the like); (c) one or more humectants (e.g., glycerin and the like); (d) one or more disintegrants (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, sodium lauryl sulfate, sodium starch glycolate (available as Explotab.™ from Edward Mendell), cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethylcellulose Type A (available as Ac-di-sol.™), potassium polyacrylate (ion exchange resin), and the like); (e) one or more dissolution retarding agents (e.g., solution (e.g., paraffin and the like); (f) one or more absorption accelerators (e.g., quaternary ammonium compounds and the like); (g) one or more wetting agents (e.g., cetyl alcohol, glyceryl monostearate and the like); (h) one or more adsorbents (e.g., kaolin, bentonite and the like); and / or one or more lubricants (e.g., talc, calcium stearate, magnesium stearate, stearic acid, polyethylene glycol stearate, cetyl alcohol, hydrogenated castor oil, sucrose esters of fatty acids, dimethyl polysiloxane, microcrystalline wax, yellow beeswax, white beeswax, solid polyethylene glycol, sodium lauryl sulfate and the like). In the case of capsules and tablets, the dosage form may also contain a buffer.

[0438] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (milk sugar) as well as high molecular weight polyethylene glycols and the like.

[0439] Solid dosage forms, such as tablets, dragees, capsules, and granules, can be prepared with coatings and shells, such as enteric coatings and other coatings known in the art. They may also contain opacifying agents and may also have such a composition that they release the compound of the invention and / or additional pharmaceutical agent in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The drug may also be in microencapsulated form, where appropriate with one or more of the above-mentioned excipients.

[0440] For tablets, the active agent will typically comprise less than 50% (by weight) of the formulation, e.g., less than about 10% by weight, such as 5% or 2.5% by weight. The bulk of the formulation comprises fillers, diluents, disintegrants, lubricants, and, optionally, flavoring agents. Combinations of such excipients are well known in the art. Often, the filler / diluent will comprise a mixture of two or more of the following components: microcrystalline cellulose, mannitol, lactose (all types), starch, and dicalcium phosphate. The filler / diluent mixture typically comprises less than 98% of the formulation, and preferably less than 95%, e.g., 93.5%. Preferred disintegrants include Ac-di-sol.™, Explotab.™, starch, and sodium lauryl sulfate. When present, the disintegrant will typically comprise less than 10% or less than 5%, e.g., about 3%, of the formulation. The preferred lubricant is magnesium stearate. When present, the lubricant will typically comprise less than 5% or less than 3%, e.g., about 1%, of the formulation.

[0441] Tablets can be made by standard tableting methods such as direct compression or wet, dry or melt granulation, congealing methods and extrusion. Tablet cores can be single-layer or multi-layer and can be coated with appropriate outer coatings known in the art.

[0442] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compounds or combinations of the present invention, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame seed oil, and the like), Miglyol.RTM. (available from CONDEA Vista, Cranford, NJ), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures thereof, and the like.

[0443] Besides such inert diluents, the composition may also include excipients, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0444] Oral liquid forms or combinations of the compounds of the invention include solutions in which the active compound is completely dissolved. Examples of solvents include all pharmaceutically precedent solvents suitable for oral administration, especially those in which the compounds of the invention exhibit good solubility, such as polyethylene glycol, polypropylene glycol, edible oils, and glyceryl and glyceride-based systems. Glyceryl and glyceride-based systems can include, for example, the following trademarked products (and corresponding generic products): Captex.TM.355EP (tricaprylin / caprin, from Abitec, Columbus Ohio); Crodamol.TM.GTC / C (medium-chain triglycerides, from Croda, Cowick Hall, UK); or Labrafac.TM.CC (medium-chain triglycerides, from Gattefosse); Captex.TM.500P (triacetin, also known as triacetin, from Abitec); Capmul.TM.MCM (medium-chain mono- and diglycerides, from Abitec); Migyol.TM.812 (caprylic / capric triglyceride, from Condea, Cranford, MD); NJ); Migyol.TM.829 (caprylic / capric / succinic triglycerides from Condea); Migyol.TM.840 (propylene glycol dicaprylate / dicaprate from Condea); Labrafil.TM.M1944CS (oleoyl macrogol-6 glycerides from Gattefosse); Peceol.TM. (monoolein from Gattefosse); and Maisine.TM.35-1 (monoolein from Gattefosse). Of particular interest are medium chain (about C8 to C 10 ) triglyceride oil. Such solvents often constitute the majority of the composition, i.e., greater than about 50%, typically greater than about 80%, for example, about 95% or 99%. Adjuvants and additives may also be included with the solvents, primarily as taste masking agents, palatability and flavoring agents, antioxidants, stabilizers, texture and viscosity modifiers, and solubilizing agents.

[0445] In addition to the compound or combination of the present invention, the suspension may further contain a carrier such as a suspending agent, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances and the like.

[0446] Compositions for rectal or vaginal administration preferably comprise suppositories, which can be prepared by mixing a compound or combination of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at normal room temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity, thereby releasing one or more active ingredients.

[0447] Dosage forms for topical administration of the compounds or combinations of this invention include ointments, creams, emulsions, powders and sprays. The drug is admixed with a pharmaceutically acceptable excipient, diluent or carrier and any preservatives, buffers or propellants that may be required.

[0448] Some compounds of the invention may be poorly soluble in water, for example, less than about 1 μg / mL. Therefore, liquid compositions in solubilizing non-aqueous solvents such as the medium chain triglyceride oils discussed above are preferred dosage forms for such compounds.

[0449] Solid amorphous dispersions, including dispersions formed by spray drying methods, are also preferred dosage forms for poorly soluble compounds of the invention. "Solid amorphous dispersion" means a solid material in which at least a portion of the poorly soluble compound is in amorphous form and dispersed in a water-soluble polymer. "Amorphous" means that the poorly soluble compound is not crystalline. "Crystalline" means that the compound exhibits long-range order in three dimensions, with at least 100 repeating units in each dimension. Thus, the term amorphous is intended to include not only substantially disordered materials, but also materials that may have some lesser degree of order, but have order in less than three dimensions and / or have order only over short distances. Amorphous materials can be characterized by techniques known in the art, such as powder X-ray diffraction (PXRD) crystallography, solid-state NMR, or thermal analysis techniques such as differential scanning calorimetry (DSC).

[0450] Preferably, at least a majority (i.e., at least about 60% by weight) of the poorly soluble compound in the solid amorphous dispersion is amorphous. The compound may exist in relatively pure amorphous domains or regions within the solid amorphous dispersion, as a solid solution of the compound uniformly distributed throughout the polymer, or any combination of these states or states intermediate thereto. Preferably, the solid amorphous dispersion is substantially homogeneous, such that the amorphous compound is dispersed as uniformly as possible throughout the polymer. As used herein, "substantially homogeneous" means that the portion of the compound present in the relatively pure amorphous domains or regions within the solid amorphous dispersion is relatively small, less than about 20% by weight of the total amount of the drug, and preferably less than 10% by weight.

[0451] Water-soluble polymers suitable for use in solid amorphous dispersions should be inert, meaning that they do not chemically react with poorly soluble compounds in an adverse manner, be pharmaceutically acceptable, and should have at least some solubility in aqueous solution at physiologically relevant pH (e.g., 1-8). The polymer can be neutral or ionizable and should have an aqueous solubility of at least 0.1 mg / mL in at least a portion of the pH range of 1-8.

[0452] The water-soluble polymers suitable for use in the present invention may be cellulosic or non-cellulosic. The polymers may be neutral or ionizable in aqueous solution. Of these, ionizable and cellulosic polymers are preferred, with ionizable cellulosic polymers being more preferred.

[0453] Exemplary water-soluble polymers include hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinylpyrrolidone (PVP), hydroxypropylcellulose (HPC), methylcellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO, also known as poloxamers), and mixtures thereof. Particularly preferred polymers include HPMCAS, HPMC, HPMCP, CMEC, CAP, CAT, PVP, poloxamers, and mixtures thereof. Most preferred is HPMCAS. See European Patent Application Publication No. 0901786A2, the disclosure of which is incorporated herein by reference.

[0454] The solid amorphous dispersion can be prepared according to any method for forming a solid amorphous dispersion in which at least a majority (at least 60%) of the poorly soluble compound is in an amorphous state. Such methods include mechanical, thermal, and solvent methods. Exemplary mechanical methods include milling and extrusion; melt methods include high-temperature fusion, solvent-modified fusion, and congealing methods; and solvent methods include non-solvent precipitation, spraying, and spray drying. See, for example, the following U.S. Patents, the relevant disclosures of which are incorporated herein by reference: U.S. Patents 5,456,923 and 5,939,099, which describe dispersions formed by extrusion methods; U.S. Patents 5,340,591 and 4,673,564, which describe dispersions formed by milling methods; and U.S. Patents 5,707,646 and 4,894,235, which describe dispersions formed by congealing methods. In a preferred method, the solid amorphous dispersion is formed by spray drying, as disclosed in European Patent Application Publication No. 0901786A2. In this method, the compound and the polymer are dissolved in a solvent such as acetone or methanol, and the solvent is then rapidly removed from the solution by spray drying to form a solid amorphous dispersion. The solid amorphous dispersion can be prepared to contain up to about 99% by weight of the compound, for example, 1%, 5%, 10%, 25%, 50%, 75%, 95%, or 98% by weight, as desired.

[0455] The solid dispersion can be used as a dosage form itself or it can serve as a manufacturing ready product (MUP) for preparing other dosage forms such as capsules, tablets, solutions, or suspensions. An example of an aqueous suspension is an aqueous suspension of a 1:1 (w / w) compound / HPMCAS-HF spray-dried dispersion containing 2.5 mg / mL of the compound in 2% polysorbate-80. Solid dispersions for tablets or capsules will generally be mixed with other excipients or adjuvants typically found in such dosage forms. For example, an exemplary filler for a capsule contains a 2:1 (w / w) compound / HPMCAS-MF spray-dried dispersion (60%), lactose (fast flow) (15%), microcrystalline cellulose (e.g., Avicel.sup. (RO-102) (15.8%), sodium starch glycolate (7%), sodium lauryl sulfate (2%), and magnesium stearate (1%).

[0456] HPMCAS polymers are available from Shin-Etsu Chemical Co., Ltd., Tokyo, Japan as low-, medium-, and high-grade Aqoa.sup.(R)-LF, Aqoat.sup.(R)-MF, and Aqoat.sup.(R)-HF, respectively. High-grade MF and HF are generally preferred.

[0457] Suitably, the compounds (or combinations) of the invention may be carried in drinking water so that therapeutic doses of the compounds are taken with the daily water supply. The compounds may be dosed directly into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble salt).

[0458] These compounds can also be administered to animals other than humans, for example, for the indications detailed above. The exact dosage of each active ingredient administered will vary depending on any number of factors, including but not limited to the type of animal and the type of disease state being treated, the age of the animal, and the route of administration or routes.

[0459] The dosage of the combination agent used in combination with the compound of Formula I or its salt is effective for the indication being treated. Such dosage can be determined by standard assays, such as those mentioned above and provided herein. The combination agents can be administered simultaneously or sequentially in any order.

[0460] These dosages are based on an average human subject weighing about 60 kg to 70 kg. A physician will readily be able to determine dosages for subjects weighing outside this range, such as infants and the elderly.

[0461] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, multiple doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Formulating parenteral compositions in unit dosage form is particularly advantageous for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as unit dosages for the mammalian subject to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the unit dosage forms of the present invention are dictated by and directly dependent on: (a) the unique characteristics of the chemotherapeutic agent and the specific therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such active compounds for treating individual sensitivity.

[0462] Therefore, it will be understood by those skilled in the art that, based on the disclosure provided herein, dosages and administration regimens can be adjusted according to methods well known in the art of treatment. That is, the maximum tolerable dose can be easily determined, and the effective amount that provides a detectable therapeutic benefit to the patient can also be determined, and the time required to administer each agent to provide a detectable therapeutic benefit to the patient can also be determined. Therefore, although certain dosages and administration regimens are exemplified herein, these examples are in no way limiting the dosages and administration regimens that can be provided to patients when practicing the present invention.

[0463] It should be noted that dosage values ​​may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular individual, a specific dosing regimen should be adjusted over time according to individual needs and the professional judgment of the personnel administering the composition or supervising the administration of the composition, and the dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition. For example, dosage may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects, such as toxic effects and / or experimental values. Therefore, the present invention encompasses intra-patient dose escalation as determined by those skilled in the art. Determining the appropriate dosage and regimen for administering a chemotherapeutic agent is well known in the art, and once the teachings disclosed herein are provided, those skilled in the art will understand that they are encompassed within this teaching.

[0464] The present invention further includes the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, as a medicament (such as a unit dose tablet or a unit dose capsule). In another embodiment, the present invention comprises the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament (such as a unit dose tablet or a unit dose capsule) to treat one or more of the conditions previously identified in the above section discussing treatment methods.

[0465] The pharmaceutical compositions of the present invention can be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a "unit dose" is an individual amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to an individual or a suitable fraction of such a dose, such as one-half or one-third of such a dose.

[0466] These agents and compounds of the present invention can be combined with pharmaceutically acceptable vehicles such as saline, Ringer's solution, dextrose solution, and the like. The specific dosing regimen, i.e., dosage, timing, and number of repetitions, will depend on the specific individual and the individual's medical history.

[0467] Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may include buffers such as phosphates, citrates, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexahydroxyquaternium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight ( less than about 10 residues); polypeptides; proteins such as serum albumin, gelatin, or Ig; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®. TM 、PLURONICS TM or polyethylene glycol (PEG).

[0468] Liposomes containing these agents and / or compounds of the invention are prepared by methods known in the art, such as those described in U.S. Patent Nos. 4,485,045 and 4,544,545. Liposomes with extended circulation times are disclosed in U.S. Patent No. 5,013,556. Particularly suitable liposomes can be produced by reverse phase evaporation using a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter with a defined pore size to produce liposomes with the desired diameter.

[0469] These agents and / or compounds of the invention may also be encapsulated in microcapsules prepared, for example, by coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions, respectively. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th ed., Mack Publishing (2000).

[0470] Sustained-release formulations can be used. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds of the invention, in the form of shaped articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels [e.g., poly(2-hydroxyethyl-methacrylate) or 'poly(vinyl alcohol)], polylactide (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate; degradable lactic acid-glycolic acid copolymers, such as those used in LUPRON DEPOT®. TM (Injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate); sucrose acetate isobutyrate and poly-D-(-)-3-hydroxybutyric acid.

[0471] Formulations for intravenous administration must be sterile. This is readily accomplished, for example, by filtration through sterile filtration membranes. The compound of the invention is typically placed in a container having a sterile access port, such as an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0472] Suitable emulsions include commercially available fat emulsions such as Intralipid TM , Liposyn TM Infonutrol TM 、Lipofundin TM and Lipiphysan TM Preparation. The active ingredient can be dissolved in a premixed emulsion composition, or it can be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and in the emulsion formed when mixed with a phospholipid (e.g., lecithin, soybean lecithin, or soy lecithin) and water. It will be appreciated that other ingredients, such as glycerol or glucose, can be added to adjust the emulsion tension. Suitable emulsions will typically contain up to 20% oil, for example, between 5% and 20%. The fat emulsion may comprise fat droplets between 0.1 and 1.0 μm, particularly between 0.1 and 0.5 μm, and have a pH in the range of 5.5 to 8.0.

[0473] The emulsion composition can be prepared by mixing the compound of the present invention with Intralipid TM or those emulsion compositions prepared from soybean oil, lecithin, glycerin and water or its components (soybean oil, lecithin, glycerin and water).

[0474] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered via the oral or nasal respiratory route to achieve local or systemic effects. Compositions in preferably sterile pharmaceutically acceptable solvents can be atomized using gases. Nebulized solutions can be inhaled directly from the atomizing device or the atomizing device can be attached to a mask, hood, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be preferably administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0475] The compounds herein may be formulated for oral, buccal, intranasal, parenteral (eg, intravenous, intramuscular, or subcutaneous), or rectal administration or in a form suitable for administration by inhalation. The compounds of the present invention may also be formulated for sustained delivery.

[0476] Methods for preparing various pharmaceutical compositions using a certain amount of active ingredient are known or will be apparent to those skilled in the art in light of the present invention. For examples of methods for preparing pharmaceutical compositions, see Remington, The Science and Practice of Pharmacy, 20th edition (Lippincott Williams & Wilkins, 2000).

[0477] The pharmaceutical compositions according to the present invention may contain from 0.1% to 95% of one or more compounds of the present invention, preferably from 1% to 70%. In any case, the composition to be administered will contain an amount of one or more compounds according to the present invention that is effective in treating the disease / condition of the individual being treated.

[0478] Because one aspect of the present invention is about treating the diseases / conditions described herein with a combination of active ingredients that can be applied separately, the present invention is also about combining individual pharmaceutical compositions in the form of a kit. The kit comprises two individual pharmaceutical compositions: a compound of Formula I or a pharmaceutically acceptable salt thereof or a prodrug thereof or a salt of such a compound or prodrug and a second compound as described above. The kit comprises components for accommodating individual compositions, such as containers, separating bottles, or separating foil packages. The kit typically includes instructions for administering the individual components. The kit form is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosing intervals, or when the prescribing physician needs to titrate the individual components of the combination.

[0479] An example of such a medicine box is a so-called blister package. Blister packages are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, and similar dosage forms). Blister packages generally consist of a thin sheet of relatively rigid material covered with a preferably transparent plastic material foil. During the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the groove and, relative to the plastic foil, the thin sheet of relatively rigid material is sealed on one side of the foil opposite to the direction in which the groove is formed. Thus, the tablet or capsule is sealed in the groove between the plastic foil and the thin sheet. Preferably, the strength of the thin sheet makes it possible to remove the tablet or capsule from the blister package by manually applying pressure on the groove, thereby forming an opening in the thin sheet at the position of the groove. Subsequently, the tablet or capsule can be removed via this opening.

[0480] It may be necessary to provide a memory aid on the kit, for example in the form of numbers next to the tablets or capsules, where the numbers correspond to the days specified in the protocol for the tablets or capsules to be taken. Another example of such a memory aid is a calendar printed on a card, for example, as follows "Monday, Tuesday of week 1, etc. ... Monday, Tuesday of week 2, ... " etc. Other variations of the memory aid will be apparent. A "daily dose" may be a single tablet or capsule or several pills or capsules to be taken on a specified date. In addition, a daily dose of a compound of the invention may consist of one tablet or capsule, while a daily dose of a second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0481] In another specific embodiment of the present invention, a dispenser is provided that is designed to dispense daily doses one at a time in the order in which they are intended to be used. Preferably, the dispenser is equipped with a memory aid to further facilitate compliance with the regimen. One example of such a memory aid is a mechanical counter that indicates the target number of daily doses dispensed. Another example of such a memory aid is a battery-powered microchip memory coupled to a liquid crystal reader or an audio reminder signal that, for example, reads out the date the last daily dose was taken and / or reminds when the next dose should be taken.

[0482] Furthermore, since one aspect of the present invention pertains to treating the diseases / conditions described herein with combinations of active ingredients that can be administered in conjunction, the present invention also pertains to combining separate pharmaceutical compositions in a single dosage form, such as, but not limited to, a single tablet or capsule, a double or multi-layer tablet or capsule, or through the use of separate components or compartments within a tablet or capsule.

[0483] The active ingredient can be delivered as a solution in an aqueous or non-aqueous vehicle, with or without additional solvents, co-solvents, excipients, or compounding agents selected from pharmaceutically acceptable diluents, excipients, vehicles, or carriers.

[0484] The active ingredient can be formulated together with pharmaceutically acceptable excipients as a solid dispersion or a self-emulsifying drug delivery system (SEDDS).

[0485] The active ingredient can be formulated as an immediate release or controlled (e.g., suspended, delayed, or extended) release tablet or capsule. Alternatively, the active ingredient can be delivered as the active ingredient alone within the capsule shell without additional excipients.

[0486] Example

[0487] The following describes the synthesis of various compounds of the present invention. Other compounds within the scope of the present invention can be prepared using the methods described in these examples, alone or in combination with techniques generally known in the art. All starting materials in these preparations and examples are commercially available or can be prepared by methods known in the art or as described herein.

[0488] Reactions were carried out in air or, when oxygen-sensitive or moisture-sensitive reagents or intermediates were used, under an inert atmosphere (nitrogen or argon). When appropriate, reaction equipment was dried using a heat gun under dynamic vacuum and anhydrous solvents (Sure-Seal from Aldrich Chemical Company, Milwaukee, Wisconsin) were used. TM product or DriSolv from EMD Chemicals, Gibbstown, NJ TM product). In some cases, commercial solvents were passed through The column was filtered through a molecular sieve until the following water QC standards were achieved: a) <100 ppm for dichloromethane, toluene, N,N-dimethylformamide, and tetrahydrofuran; b) <180 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. For extremely sensitive reactions, the solvent was further treated with sodium metal, calcium hydride, or molecular sieves and distilled immediately before use. Other commercially available solvents and reagents were used without further purification. With respect to the synthetic reference procedures in other examples or methods, the reaction conditions (reaction time and temperature) may vary. The product was generally dried under vacuum before proceeding to further reactions or submitting for biological testing.

[0489] When indicated, the reactants were heated by microwave irradiation using a Biotage Initiator or Personal Chemistry EmrysOptimizer microwave. Reaction progress was monitored using thin layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS), high performance liquid chromatography (HPLC), and / or gas chromatography-mass spectrometry (GCMS) analysis. TLC was performed on pre-coated silica gel disks with a fluorescent indicator (254 nm excitation wavelength) and visualized under UV light and / or staining with iodine, potassium permanganate, cobalt (II) chloride, phosphomolybdic acid, and / or cerium ammonium molybdate. LCMS data were obtained on an Agilent 1100 series instrument with a Leap Technologies autosampler, a Gemini C18 column, an acetonitrile / water gradient, and trifluoroacetic acid, formic acid, or ammonium hydroxide modifiers. Column eluents were analyzed using a Waters ZQ mass spectrometer scanning in positive and negative ion modes from 100 to 1200 Da. Other similar instruments were also used. HPLC data were generally acquired on an Agilent 1100 series instrument using the specified column, an acetonitrile / water gradient, and trifluoroacetic acid or ammonium hydroxide modifier. GCMS data were acquired using a Hewlett Packard 6890 oven with an HP 6890 syringe, an HP-1 column (12 m × 0.2 mm × 0.33 μm), and helium carrier gas. Samples were analyzed on an HP 5973 mass selective detector using electron ionization scanning from 50 to 550 Da. Purification was performed by medium performance liquid chromatography (MPLC) using an Isco CombiFlash Companion, AnaLogix IntelliFlash 280, Biotage SP 1, or Biotage Isolera One instrument and prepacked Isco RediSep or Biotage Snap silica cartridges. Chiral purification is typically performed by chiral supercritical fluid chromatography (SFC) using Berger or Thaler instruments; columns such as ChiralPAK-AD, ChiralPAK-AS, ChiralPAK-IC, Chiralcel-OD, or Chiralcel-OJ; and mixtures of CO2 with methanol, ethanol, 2-propanol, or acetonitrile (alone or modified with trifluoroacetic acid or propane-2-amine). UV detection is used to trigger fraction collection. For synthetic reference procedures in other Examples or Methods, purification may vary: In general, the solvents and solvent ratios used for the eluent / gradient are selected to provide the appropriate R f or retention time.

[0490] Mass spectrometric data were reported from LCMS analysis. Mass spectrometric analysis (MS) was performed using atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (EI), or electron scattering (ES) ionization sources. Proton nuclear magnetic spectroscopy (NMR) was performed using low-field parts per million (ppm) protons from tetramethylsilane. 1 H NMR chemical shifts were recorded on 300, 400, 500, or 600 MHz Varian, Bruker, or Jeol spectrometers. Chemical shifts are expressed in parts per million (ppm, δ) referenced to the residual peaks of the deuterated solvent (chloroform, 7.26 ppm; CD2HOD, 3.31 ppm; acetonitrile-d2, 1.94 ppm; dimethylsulfoxide-d5, 2.50 ppm; DHO, 4.79 ppm). Peak shapes are described as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br s, broad singlet; app, apparent. Analytical SFC data were generally acquired on a Berger analytical instrument as described above. Optical rotation data were acquired on a PerkinElmer Model 343 polarimeter using a 1 dm unit. Microanalysis was performed by Quantitative Technologies and was within 0.4% of the calculated value.

[0491] Unless otherwise noted, chemical reactions were performed at room temperature (approximately 23 degrees Celsius).

[0492] Unless otherwise noted, all reactants were either obtained commercially and used without further purification, or were prepared using methods known in the literature.

[0493] The terms "concentrate," "evaporate," and "concentrate in vacuo" refer to the removal of solvent under reduced pressure on a rotary evaporator at a bath temperature below 60°C. The abbreviations "min" and "h" stand for "minutes" and "hours," respectively. The term "TLC" means thin layer chromatography, "room temperature" means a temperature between 18 and 25°C, "GCMS" means gas chromatography-mass spectrometry, "LCMS" means liquid chromatography-mass spectrometry, "UPLC" means ultra-performance liquid chromatography, "HPLC" means high-performance liquid chromatography, and "SFC" means supercritical fluid chromatography.

[0494] Hydrogenations can be performed in a Parr shaker under pressurized hydrogen at the specified temperature, or in an all-hydrogen Thales-nano H-Cube flow hydrogenation apparatus at a flow rate between 1-2 mL / min.

[0495] HPLC, UPLC, LCMS, GCMS, and SFC retention times were measured using the methods specified in the procedures.

[0496] In some embodiments, chiral separations are performed to separate the enantiomers or diastereomers of certain compounds of the invention (in some embodiments, the separated enantiomers are designated as ENT-1 and ENT-2 based on their order of elution; similarly, the separated diastereomers are designated as DIAST-1 and DIAST-2 based on their order of elution). In some embodiments, the brightness of the enantiomers is measured using a polarimeter. Based on their observed rotation data (or their specific rotation data), the enantiomer that rotates clockwise is referred to as the (+)-enantiomer and the enantiomer that rotates counterclockwise is referred to as the (-)-enantiomer. Racemic compounds are indicated by the absence of a drawn or depicted stereochemistry or by the presence of a (+ / -) adjacent to the structure; in the latter case, the indicated stereochemistry represents only one of the two enantiomers that constitute the racemic mixture.

[0497] The compounds and intermediates described below are named using the naming guidelines provided by ACD / ChemSketch 2017.2.1, file version C40H41, build version 99535 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The naming guidelines provided by ACD / ChemSketch 2017.2.1 are well known to those skilled in the art and are believed to generally conform to the International Union for Pure and Applied Chemistry (IUPAC) recommendations for organic nomenclature and CAS indexing rules.

[0498] Many compounds in this paper 1 The H NMR spectrum indicated a mixture of rotamers due to the presence of amide and / or carbamate functionality and has been tabulated to reflect the presence of more than one rotamer.

[0499] preparation

[0500] Preparations P1-P33 describe the preparation of some of the starting materials or intermediates used to prepare certain compounds of the present invention.

[0501] Preparation P1

[0502] 2-(5-Chloro-2-methoxypyridin-4-yl)propanoic acid (P1)

[0503]

[0504] Step 1. Synthesis of methyl (5-chloro-2-methoxypyridin-4-yl)acetate (C1).

[0505] A solution of lithium diisopropylamine in tetrahydrofuran (2M; 1.9 L, 3.8 mol) was added dropwise to a -30°C solution of 5-chloro-2-methoxy-4-methylpyridine (197 g, 1.25 mol) in tetrahydrofuran (1.4 L). After stirring the reaction mixture at -30°C for 1 hour, dimethyl carbonate (338 g, 3.75 mol) was added dropwise; at the end of the addition, the reaction mixture was warmed to 25°C and stirred for 1 hour. It was then poured into hydrochloric acid (0.5 M, 7 L, 3.5 mol) and extracted with ethyl acetate (2 x 1.5 L); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (gradient: 0% to 20% ethyl acetate / petroleum ether) gave C1 as a yellow oil. Yield: 203 g, 0.941 mol, 75%. LCMS m / z 216.1 (chlorine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.10 (s, 1H), 6.82 (s, 1H), 3.90 (s, 3H), 3.79 (s, 2H), 3.71 (s, 3H).

[0506] Step 2. Synthesis of methyl 2-(5-chloro-2-methoxypyridin-4-yl)propanoate (C2).

[0507] To a -78°C solution of C1 (175 g, 0.812 mol) in tetrahydrofuran (1.2 L) was added a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2 M; 455 mL, 0.910 mol) dropwise. The reaction mixture was stirred at -78°C for 1 hour, followed by the dropwise addition of a solution of iodomethane (172.6 g, 1.216 mol) in tetrahydrofuran (100 mL) at -78°C, and stirring was continued at this temperature for 2 hours. The reaction mixture was then poured into saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate (2 x 100 mL); the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo to afford C2 as a brown oil. This material was contaminated with some dimethylated byproduct, methyl 2-(5-chloro-2-methoxypyridin-4-yl)-2-methylpropanoate, by NMR and LCMS analysis. Yield: 136 g, ≤0.592 mol, ≤73%. LCMS m / z 230.1 (chlorine isotope pattern observed) [M+H] + . 1H NMR (400 MHz, methanol-d4), product peak only: δ 8.10 (s, 1H), 6.76 (s, 1H), 4.10 (q, J = 7.2 Hz, 1H), 3.89 (s, 3H), 3.69 (s, 3H), 1.48 (d, J = 7.2 Hz, 3H).

[0508] Step 3. Synthesis of 2-(5-chloro-2-methoxypyridin-4-yl)propanoic acid (P1).

[0509] To a 25 ° C solution of C2 (168 g, 0.732 mol) in tetrahydrofuran (1 L) at 25 ° C, a solution of lithium hydroxide monohydrate (61.4 g, 0.146 mol) in water (300 mL) was added dropwise. The mixture was stirred for 2 hours and then concentrated in vacuo. The aqueous residue was poured into water (500 mL) and washed with tert-butyl methyl ether (2×500 mL). The aqueous layer was then adjusted to pH 4 by adding 3M hydrochloric acid and extracted with ethyl acetate (2×500 mL); the combined ethyl acetate layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give P1 as a white solid. Yield: 122 g, 0.566 mol, 77%. LCMS m / z 216.1 (chlorine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.10 (s, 1H), 6.79 (s, 1H), 4.06 (q, J = 7.1 Hz, 1H), 3.89 (s, 3H), 1.48 (d, J = 7.2 Hz, 3H).

[0510] Preparations P2 and P3

[0511] (2R)-2-(5-chloro-2-methoxypyridin-4-yl)propanoic acid (P2) and (2S)-2-(5-chloro-2-methoxypyridin-4-yl)propanoic acid (P3)

[0512]

[0513] P1 (5.00 g, 23.2 mmol) was separated into its component enantiomers via supercritical fluid chromatography (column: Chiral Technologies Chiralpak IG, 30×250 mm, 5 μm; mobile phase: 95:5 carbon dioxide / methanol; flow rate: 80 mL / min; back pressure: 120 bar). The first-eluting enantiomer (an oil that solidified upon standing) was designated P2, and the second-eluting enantiomer was designated P3.

[0514] The absolute stereochemistry indicated was assigned via X-ray crystallographic structure determination of 15 synthesized using this batch P2 (see below, Example 15, Alternative Step 3).

[0515] P2—yield: 2.4 g, 11.1 mmol, 48%. 1 H NMR (400 MHz, chloroform-d) δ 8.13 (s, 1H), 6.75 (s, 1H), 4.12 (q, J = 7.2 Hz, 1H), 3.91 (s, 3H), 1.53 (d, J = 7.2 Hz, 3H). Retention time: 3.98 min (Analytical conditions: Column: Chiral Technologies Chiralpak IG, 4.6×250 mm, 5 μm; Mobile phase A: carbon dioxide; Mobile phase B: methanol; Gradient: 5% B for 1.00 min, then 5% to 60% B over 8 min; Flow rate: 3.0 mL / min; Back pressure: 120 bar).

[0516] P3 - Yield: 2.4 g, 11.1 mmol, 48%. Retention time: 4.22 minutes (same analytical conditions as for P2).

[0517] Preparation P4

[0518] Lithium 2-(6-methoxy-2-methylpyrimidin-4-yl)propionate (P4)

[0519]

[0520] Step 1. Synthesis of dimethyl (6-methoxy-2-methylpyrimidin-4-yl)(methyl)malonate (C3) and methyl 2-(6-methoxy-2-methylpyrimidin-4-yl)propionate (C4).

[0521] Sodium hydride (60% in mineral oil; 1.14 g, 28.5 mmol) was added to a solution of dimethyl methylmalonate (5.53 g, 37.8 mmol) in N,N-dimethylformamide (25 mL). After 30 minutes, 4-chloro-6-methoxy-2-methylpyrimidine (3.00 g, 18.9 mmol) was added, and the reaction mixture was heated at 100 ° C for 16 hours. It was then diluted with water (150 mL) and extracted with ethyl acetate (3×50 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (gradient: 0% to 10% ethyl acetate / petroleum ether) to give the product as a yellow oil (2.60 g). Based on NMR and LCMS analysis, this was judged to be an impure mixture of C3 and C4, which was used directly in the following step. LCMS m / z 211.1 and 269.2 [M+H] + .1 H NMR (400 MHz, methanol-d4), characteristic peaks: δ 6.68 (s), 6.60 (s), 3.96 (s), 3.94 (s), 3.81 (q, J = 7.2 Hz), 3.75 (s), 3.68 (s), 2.54 (s), 2.52 (s), 1.79 (s), 1.47 (d, J = 7.3 Hz).

[0522] Step 2. Synthesis of lithium 2-(6-methoxy-2-methylpyrimidin-4-yl)propionate (P4).

[0523] A solution of C3 and C4 (from the previous step; 2.60 g, ≤18.9 mmol) and lithium hydroxide monohydrate (1.22 g, 29.1 mmol) in a mixture of tetrahydrofuran (45 mL) and water (15 mL) was stirred at 45° C. for 3 hours. After the reaction mixture had been concentrated in vacuo, the residue was lyophilized to give P4 as a white solid. Yield: 2.3 g, 11 mmol, 58% over 2 steps. LCMS m / z 197.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 6.66 (s, 1H), 3.94 (s, 3H), 3.61 (q, J = 7.3 Hz, 1H), 2.53 (s, 3H), 1.44 (d, J = 7.2 Hz, 3H).

[0524] Preparation P5

[0525] 2-[6-(Difluoromethoxy)pyridin-3-yl]propanoic acid (P5)

[0526]

[0527] Step 1. Synthesis of 2-(difluoromethoxy)-5-iodopyridine (C5).

[0528] Sodium chloro(difluoro)acetate (4.62 g, 30.3 mmol) and potassium carbonate (5.58 g, 40.4 mmol) were added to a 25° C. solution of 5-iodopyridin-2-ol (4.46 g, 20.2 mmol) in N,N-dimethylformamide (100 mL), and the reaction mixture was stirred at 50° C. for 16 hours. It was then diluted with water (500 mL) and extracted with ethyl acetate (3×100 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 8% ethyl acetate / petroleum ether) provided C5 as an oil. Yield: 2.10 g, 7.75 mmol, 38%. 1H NMR (400 MHz, chloroform-d) δ 8.39 (br d, J = 2.2 Hz, 1H), 7.97 (dd, J = 8.6, 2.3 Hz, 1H), 7.40 (t, J HF =72.6Hz,1H),6.74(br d,J=8.6Hz,1H).

[0529] Step 2. Synthesis of diethyl [6-(difluoromethoxy)pyridin-3-yl]malonate (C6).

[0530] A mixture of C5 (1.9 g, 7.0 mmol), diethyl malonate (1.68 g, 10.5 mmol), copper (I) iodide (133 mg, 0.698 mmol), pyridine-2-carboxylic acid (172 mg, 1.40 mmol) and cesium carbonate (7.42 g, 22.8 mmol) in tetrahydrofuran (50 mL) was stirred at 80 ° C for 16 hours, then the reaction mixture was diluted with ethyl acetate (100 mL) and washed with aqueous ammonium chloride solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification using silica gel chromatography (gradient: 0% to 15% ethyl acetate / petroleum ether) gave C6 (2.4 g) as a colorless oil. By 1 H NMR analysis showed that this material contained residual diethyl malonate; a portion of this sample was used directly in the next step. LCMS m / z 304.0 [M+H] + . 1 H NMR (400 MHz, chloroform-d), product peak only: δ 8.14 (br s, 1H), 7.90 (br d, J = 8.4 Hz, 1H), 7.45 (t, J HF =72.9 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.59 (s, 1H), 4.26-4.17 (m, 4H, assumed value; partially obscured by residual diethyl malonate), 1.31-1.24 (m, 6H, assumed value; partially obscured by residual diethyl malonate).

[0531] Step 3. Synthesis of diethyl [6-(difluoromethoxy)pyridin-3-yl](methyl)malonate (C7).

[0532] To a solution of C6 (from the previous step; 750 mg, ≤2.2 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.03 g, 7.45 mmol). Iodomethane (527 mg, 3.71 mmol) was added dropwise, and the reaction mixture was stirred at 25 ° C for 4 hours. It was then combined with a similar reaction performed using C6 (250 mg, ≤0.73 mmol), poured into water (200 mL), and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo; silica gel chromatography (gradient: 0% to 15% ethyl acetate / petroleum ether) gave C7 as an oil. Combined yield: 738 mg, 2.33 mmol, 80% in 2 steps. LCMS m / z 318.2 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.20 (br s, 1H), 7.81 (br d, J = 8.7 Hz, 1H), 7.45 (t, J HF =72.9Hz, 1H), 6.90 (d, J = 8.7Hz, 1H), 4.30-4.18 (m, 4H), 1.87 (s, 3H), 1.27 (t, J = 7.1Hz, 6H).

[0533] Step 4. Synthesis of 2-[6-(difluoromethoxy)pyridin-3-yl]propanoic acid (P5).

[0534] To a 25° C. solution of C7 (738 mg, 2.33 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide (279 mg, 11.6 mmol) in water (3 mL). The reaction mixture was stirred at 25° C. for 16 hours, then diluted with water (100 mL) and washed with dichloromethane (3×50 mL). The organic layers were discarded. After the aqueous layer had been adjusted to pH 5 by the addition of 5M hydrochloric acid, it was extracted with dichloromethane (3×50 mL); the combined organic layers were concentrated in vacuo to give P5 as a solid. Yield: 337 mg, 1.55 mmol, 67%. LCMS m / z 218.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.15 (d, J = 2.5 Hz, 1H), 7.83 (dd, J = 8.5, 2.5 Hz, 1H), 7.51 (t, J HF =73.2Hz, 1H), 6.94 (d, J = 8.5Hz, 1H), 3.78 (q, J = 7.2Hz, 1H), 1.49 (d, J = 7.2Hz, 3H).

[0535] Preparation P6

[0536] 2-(5-Fluoro-2-methoxypyridin-4-yl)propanoic acid (P6)

[0537]

[0538] Step 1. Synthesis of diphenylmethyl (5-fluoro-2-methoxypyridin-4-yl)malonate (C8).

[0539] This reaction was carried out in three parallel batches. To a 25°C solution of diphenylmethyl malonate (607 g, 2.13 mol) in tetrahydrofuran (1.5 L) was added pyridine-2-carboxylic acid (35.0 g, 284 mmol), followed by copper (I) iodide (27.1 g, 142 mmol), and then freshly ground cesium carbonate (1.39 kg, 4.27 mol). After the reaction mixture was heated to 70°C, it was treated dropwise with a solution of 5-fluoro-4-iodo-2-methoxypyridine (360 g, 1.42 mol) in tetrahydrofuran (800 mL), and stirring was continued at 70°C for 16 hours.

[0540] The three reaction mixtures were then combined, cooled to 25°C, and filtered through celite. The filter pad was rinsed with ethyl acetate (3 x 500 mL), and the combined filtrates were concentrated in vacuo while maintaining the internal temperature below 40°C. The residue was dissolved in ethyl acetate (2 L), washed sequentially with saturated aqueous ammonium chloride solution (500 mL) and saturated aqueous sodium chloride solution (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure at 40°C. Silica gel chromatography (Gradient: 1% to 8% ethyl acetate / petroleum ether) provided C8 (1.87 kg) as a yellow oil. By 1 H NMR analysis showed this material to be contaminated with diphenylmethyl malonate; a portion was used in the next step. LCMS m / z 410.1 [M+H] + . 1 H NMR (400 MHz, chloroform-d), product peak only: δ 8.01 (d, J = 1.3 Hz, 1H), 7.40-7.25 (m, 10H, assumed value; partially obscured by residual diphenylmethyl malonate), 6.83 (d, J = 4.8 Hz, 1H), 5.20 (AB quartet, J AB =12.2Hz,Δν AB =11.9Hz,4H),5.00(s,1H),3.89(s,3H).

[0541] Step 2. Synthesis of diphenylmethyl (5-fluoro-2-methoxypyridin-4-yl)(methyl)malonate (C9).

[0542] This reaction is carried out in two parallel batches. A solution of C8 (from the previous step; 575g, ≤1.31mol) in acetonitrile (1.5L) was stirred in an ice-water bath for 20 minutes, followed by the addition of potassium carbonate (582g, 4.21mol). Stirring was continued for another 10 minutes. Subsequently, iodomethane (302g, 2.13mol) was added to the reaction mixture at 0°C, and the reaction was allowed to proceed until LCMS analysis indicated conversion to C9. After merging the two reaction mixtures, it was filtered through diatomaceous earth, and the filter cake was washed with acetonitrile (2×1L). The combined filtrate was concentrated at 40°C and the residue was distributed between ethyl acetate (2L) and water (500mL). The water layer was extracted with ethyl acetate (2×1L), and the combined organic layer was washed with saturated sodium chloride aqueous solution (1L), dried over sodium sulfate, filtered and concentrated under reduced pressure at 40°C. The obtained crude product was dissolved in petroleum ether (1.5L) and stirred at 0°C for 2 hours; solids were collected via filtration. The filtrate was concentrated in vacuo, and the residue was dissolved in petroleum ether (500 mL) and then cooled to 0 ° C to give additional solid, which was separated by filtration. The two solids were combined, suspended in petroleum ether (800 mL), and stirred at 20 ° C for 16 hours. It was then collected by filtration to give C9 as a yellow solid. Yield: 670 g, 1.58 mol, 60% in 2 steps. LCMS m / z 423.8 [M + H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (d, J = 2.6 Hz, 1H), 7.36-7.20 (m, 10H), 6.54 (d, J = 5.1 Hz, 1H), 5.18 (s, 4H), 3.87 (s, 3H), 1.85 (s, 3H).

[0543] Step 3. Synthesis of 2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (P6).

[0544] This reaction was carried out in four parallel batches. To a 25 ° C solution of C9 (200 g, 472 mmol) in ethyl acetate (1 L) was added 10% palladium on carbon (wet; 40 g). The mixture was degassed under vacuum and then purged with nitrogen; this evacuation-purge cycle was performed a total of three times. The mixture was degassed again under vacuum and then purged with hydrogen; this evacuation-purge cycle was also performed a total of three times. The mixture was hydrogenated (30 psi) at 50 ° C for 16 hours. The four reaction mixtures were combined and filtered through a pad of celite, and the filtrate was concentrated in vacuo at 45 ° C. Silica gel chromatography (gradient: 10% to 20% ethyl acetate / petroleum ether) gave P6 as a white solid. Combined yield: 270 g, 1.36 mmol, 72%. LCMS m / z 199.7 [M + H] + . 1HNMR (400 MHz, CHLOROFORM-d) δ 7.98 (d, J = 1.7 Hz, 1H), 6.70 (d, J = 4.9 Hz, 1H), 3.97 (q, J = 7.3 Hz, 1H), 3.89 (s, 3H), 1.53 (d, J = 7.3 Hz, 3H).

[0545] Preparations P7 and P8

[0546] (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (P7) and (2S)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (P8)

[0547]

[0548] P6 (700 g, 3.51 mol) was separated into its component enantiomers by supercritical fluid chromatography (column: Chiral Technologies Chiralpak AD-H, 50×250 mm, 5 μm; mobile phase: 9:1 carbon dioxide / 2-propanol; flow rate: 250 mL / min; back pressure: 120 bar). The first-eluting enantiomer was designated P7, and the second-eluting enantiomer was designated P8; both were isolated as solids.

[0549] P7 - Yield: 260 g, 1.30 mol, 37%. Retention time: 3.17 minutes (Analytical conditions: Column: Chiral Technologies Chiralpak AD-H, 4.6×250 mm, 5 μm; Mobile phase A: carbon dioxide; Mobile phase B: 2-propanol; Gradient: 5% B for 1.00 minute, then 5% to 60% B over 8 minutes; Flow rate: 3.0 mL / min; Back pressure: 120 bar).

[0550] P8 - Yield: 400 g, 2.01 mol, 57%. Retention time: 3.36 minutes (same analytical conditions as for P7).

[0551] The indicated absolute stereochemistry of P7 and P8 was assigned based on comparison with a sample of P7 synthesized in an alternative preparation of P7 (#1); the configuration of the material was confirmed via X-ray crystallography studies of derivative compound 14 (see below).

[0552] Retention time of P7 from preparations P7 and P8: 2.86 min.

[0553] Retention time of P7 from an alternative preparation of P7 (#1): 2.86 minutes.

[0554] Retention times of the racemic mixtures of P7 and P8 were 2.87 and 3.16 minutes.

[0555] These three analyses were performed using the same analytical method: [column: Chiral Technologies Chiralpak IG, 4.6×250 mm, 5 μm; mobile phase A: carbon dioxide; mobile phase B: methanol; gradient: 5% B for 1 minute, then 5% to 60% B over 7 minutes; flow rate: 3 mL / min; back pressure: 120 bar].

[0556] Alternative preparation of P7 (#1)

[0557] (2R)-2-(5-Fluoro-2-methoxypyridin-4-yl)propanoic acid (P7)

[0558]

[0559] Step 1. Synthesis of disodium (5-fluoro-2-methoxypyridin-4-yl)(methyl)malonate (C10).

[0560] A 1.0 M pH 8.0 buffer solution was prepared as follows: a solution of 2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris; 121 g, 1.00 mol) in water (900 mL) was adjusted to pH 8.0 by adding hydrochloric acid (37.5 wt %, approximately 40 mL) and then brought to a volume of 1 L by adding water.

[0561] The hydrogenation reactor was charged with palladium hydroxide on carbon (10%; 5.00 g). To this was added a solution of C9 (50.0 g, 118 mmol) in toluene (50 mL, 1 volume); the flask was rinsed with additional toluene (50 mL), which was also added to the reaction mixture. A mixture of aqueous sodium hydroxide (2.0 M, 118 mL, 236 mmol), the aforementioned pH 8.0 buffer solution (1.0 M; 250 mL, 250 mmol), and water (132 mL) was added, and the resulting mixture was purged with nitrogen (3.5 bar) followed by hydrogen (3.5 bar); this purging process was performed three times in total. After the mixture had reached 20° C., it was stirred at 100 rpm, pressurized with hydrogen to 3.45 bar, and then the stirring rate was increased to 750 rpm. After hydrogenation was carried out at 20° C. for 4 hours, the stirring rate was reduced to 250 rpm and the reaction was purged with nitrogen (3.5 bar) three times. The catalyst was removed by filtration and the reactor was rinsed with water (100 mL), which was then used to wash the filter cake. The aqueous phase containing the combined filtrates (590 mL, pH 8.2) of C10 was used directly in the following step. LCMS m / z 244.2 [M+H] + .

[0562] Step 2. Synthesis of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (P7).

[0563] A 2 L jacketed vessel with an overhead stirrer (set to a jacket temperature of 20°C) was charged with C10 (the aqueous solution from the previous step; ≤ 118 mmol) and the stirring rate was set to 200 rpm. Bordetella bronchiseptica AMD enzyme lyophilized cell-free extract powder (1.75 gm) [This aryl malonate decarboxylase (AMD enzyme) from Bordetella bronchiseptica is a wild-type enzyme described in the literature with accession number Q05115, which was recombinantly expressed in E. coli and fed as a lyophilized cell-free extract powder. References: SK Gaβmeyer et al., ChemCatChem, 2016, 8, 916-921; K. Okrasa et al., Angew. Chem. Int. Ed. 2009, 48, 7691-7694] A solution of [acid] in water (17.5 mL) was then fed to the reactor, and the enzyme container (5 mL) was rinsed with water. After 15 hours, the stirring speed was reduced to 100 rpm, and the pH of the reaction mixture was adjusted to pH 6.0 by sequentially adding hydrochloric acid (4.0 M, 5 mL portions, 38 mL). At this point, the mixture was stirred for 1.5 hours to allow off-gassing to subside, and then acidified to pH ≤ 2.0 by further addition of hydrochloric acid (4.0 M, 85 mL total). Tert-butyl methyl ether (300 mL) was added and stirring was continued at 200 rpm for 15 minutes. The mixture was then filtered through diatomaceous earth (25 g) using a Büchner funnel and filter paper; the reactor was rinsed with tert-butyl methyl ether (100 mL), which was then used to wash the filter cake. The aqueous layer of the combined filtrate was extracted with tert-butyl methyl ether (300 mL) in the same manner. The combined organic layer was dried over sodium sulfate (50 g) and filtered; the filter cake was washed with tert-butyl methyl ether (25 mL). The combined filtrate was concentrated in vacuo at 30 ° C to give an oil, which solidified overnight under vacuum drying to give P7 as an off-white solid. Yield: 18.88 g, 94.8 mmol, 80% in 2 steps. 1 H NMR (400 MHz, CHLOROFORM-d) δ 11.4-10.3 (br s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 6.70 (d, J = 4.9 Hz, 1H), 3.97 (q, J = 7.2 Hz, 1H), 3.89 (s, 3H), 1.53 (d, J = 7.2 Hz, 3H).

[0564] A combination of P7 from the previous step (18.6 g, 93.4 mmol) and P7 from a similar reaction of C10 with AMD enzyme (24.9 g, 125 mmol) gave a slightly pink solid with 98.5% enantiomeric excess. 1 H NMR (400 MHz, methanol-d4) δ 7.94 (d, J = 1.9 Hz, 1H), 6.74 (d, J = 5.0 Hz, 1H), 3.93 (q, J = 7.3 Hz, 1H), 3.87 (s, 3H), 1.48 (d, J = 7.3 Hz, 3H). Retention time: 2.86 min [column: Chiral Technologies Chiralpak IG, 4.6 × 250 mm, 5 μm; mobile phase A: carbon dioxide; mobile phase B: methanol; gradient: 5% B for 1 minute, then 5% to 60% B over 7 minutes; flow rate: 3 mL / min; back pressure: 120 bar].

[0565] The indicated absolute stereochemistry of P7 was assigned based on the conversion of this batch of P7 to Example 14; the absolute stereochemistry of 14 was determined via single crystal X-ray analysis (see below).

[0566] Alternative preparation of P7 (#2)

[0567] (2R)-2-(5-Fluoro-2-methoxypyridin-4-yl)propanoic acid (P7)

[0568]

[0569] Step 1. Synthesis of diphenylmethyl (5-fluoro-2-methoxypyridin-4-yl)malonate (C8).

[0570] A mixture of pyridine-2-carboxylic acid (24.6 g, 0.200 mol), copper (I) iodide (19.1 g, 0.100 mol) and cesium carbonate (977 g, 3.00 mol) in tetrahydrofuran (1.26 L; 5 volumes) was heated to an internal temperature of 60-70° C., followed by the addition of a solution of 5-fluoro-4-iodo-2-methoxypyridine (253 g, 1.00 mol) and diphenylmethyl malonate (426 g, 1.50 mol) in tetrahydrofuran (250 mL, 1 volume). After the reaction mixture had been heated at 60-70° C. for approximately 3-6 hours, it was allowed to cool to 15-30° C. and filtered through celite (250 g). The filter cake was washed with tetrahydrofuran (500 mL, 2 volumes), and the combined filtrates containing C8 were used directly in the following step. Representative 1H NMR (500 MHz, chloroform-d) δ 8.00 (d, J = 1.3 Hz, 1H), 7.40-7.24 (m, 10H, assumed value; partially obscured by residual diphenylmethyl malonate), 6.82 (d, J = 4.8 Hz, 1H), 5.20 (AB quartet, J AB =12.3Hz,Δν AB =14.9Hz,4H),4.99(s,1H),3.88(s,3H).

[0571] Step 2. Synthesis of diphenylmethyl (5-fluoro-2-methoxypyridin-4-yl)(methyl)malonate (C9).

[0572] Iodomethane (284 g, 2.00 mol) was slowly added to a 10°C to 20°C mixture of cesium carbonate (977 g, 3.00 mol) and a solution of C8 (from the previous step, in tetrahydrofuran; ≤ 1.00 mol). After the reaction mixture had been stirred at 10°C to 20°C for approximately 10 to 12 hours, it was filtered through celite (250 g). The filter cake was washed with tetrahydrofuran (500 mL, 1.2 volumes), and the combined filtrates were concentrated to 1 to 2 volumes. The resulting mixture was diluted with propan-2-yl acetate (1.25 L, 3.1 volumes), washed sequentially with water (750 mL, 1.8 volumes), aqueous ammonium chloride (20%; 750 mL), and aqueous sodium chloride (20%; 750 mL), and concentrated in vacuo. The remaining solvent was exchanged with heptane, and precipitation was allowed to occur from heptane (2 to 3 volumes) at 15°C to 25°C. The resulting solid was collected by filtration and triturated with a mixture of heptane (450 mL) and propan-2-yl acetate (50 mL) to provide C9 as a solid. Three batches of the chemistry in steps 1 and 2 were performed, and the final batch of C9 was combined. Yield: 675 g, 1.59 mol, approximately 53% over 2 steps. Representative 1 HNMR (500MHz, DMSO-d6) δ8.15 (d, J = 2.0 Hz, 1H), 7.39-7.21 (m, 10H), 6.75 (d, J = 5.0 Hz, 1H), 5.21 (s, 4H), 3.81 (s, 3H), 1.81 (s, 3H).

[0573] Step 3. Synthesis of disodium (5-fluoro-2-methoxypyridin-4-yl)(methyl)malonate (C10).

[0574] A buffer solution [pH 8.0; 2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris; 121 g, 1.00 mol) and concentrated hydrochloric acid (46 mL, 0.23 vol) in water (1 L, 5 vol)] and palladium hydroxide on carbon (10%, 20 g) were added to a mixture of C9 (200 g, 0.472 mol) in toluene (400 mL, 2 vol) at 15° C. to 25° C. A solution of sodium hydroxide (38.8 g, 0.970 mol) in water (1 L, 5 vol) was added, and the mixture was stirred for approximately 10 to 20 minutes. After the reactor was purged with nitrogen and then with hydrogen, the reaction mixture was stirred under a bag of hydrogen (approximately 10 L) at 15° C. to 30° C. until HPLC analysis indicated the presence of ≤0.5% C9 (approximately 22 hours) (retention time: 11.44 minutes. HPLC conditions. Column: Agilent Technologies ZORBAX Eclipse Plus C18, 4.6×100 mm, 3.5 μm; mobile phase A: 0.1% phosphoric acid / water; mobile phase B: acetonitrile; gradient: 5% B for 3 minutes, then 5% to 100% B over 9 minutes, then 100% B for 3 minutes; flow rate: 1.5 mL / min). The reaction mixture was filtered, and the filter cake was washed with water (2.6 volumes); the aqueous layer of the filtrate containing C10 was used directly in the following step.

[0575] Step 4. Synthesis of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (P7).

[0576] A mixture of AMD enzyme (7 g) in water (70 mL, 0.35 vol) and C10 (from the previous step, in aqueous solution, ≤0.472 mol) was stirred at 15°C to 30°C until HPLC analysis indicated the presence of ≤0.5% C10 (approximately 16 hours). [Retention time: 5.80 minutes. HPLC conditions were the same as described in Step 3 for the synthesis of disodium (5-fluoro-2-methoxypyridin-4-yl)(methyl)malonate (C10). Hydrochloric acid (4.0 M) was then slowly added until the pH of the reaction mixture reached 6.0, and stirring was continued for 1.5 hours. The pH was then adjusted to ≤2.0 (range, 1.5 to 2.0) by further addition of hydrochloric acid (4.0 M). After the addition of tert-butyl methyl ether (1.2 L, 6 vol), the mixture was filtered through celite (100 g), and the aqueous phase of the filtrate was extracted with tert-butyl methyl ether (800 mL, 4 vol). The combined organic layers were washed with aqueous sodium chloride solution (15%; 600 mL, 3 volumes) and concentrated to 2 to 2.5 volumes at a temperature of ≤45°C and a pressure of ≤-0.08 MPa. n-Heptane (600 mL, 3 volumes) was added and the mixture was concentrated to 3 to 5 volumes at a temperature of ≤45°C and a pressure of ≤-0.08 MPa; this heptane dilution / concentration was performed a total of 3 times. After the resulting mixture had been stirred at 0°C to 10°C for approximately 1 to 2 hours, the precipitate was collected by filtration to give P7 as an off-white solid with an enantiomeric excess of 99.8%. Yield: 80.0 g, 0.402 mol, 85% in 2 steps. Representative 1 H NMR (500 MHz, CHLOROFORM-d) δ 11.68 (v br s, 1H), 7.99 (br s, 1H), 6.70 (d, J = 4.9 Hz, 1H), 3.97 (q, J = 7.2 Hz, 1H), 3.88 (s, 3H), 1.52 (d, J = 7.3 Hz, 3H).

[0577] Preparation P9

[0578] 2-[5-(Difluoromethyl)-2-methoxypyridin-4-yl]propanoic acid (P9)

[0579]

[0580] Step 1. Synthesis of methyl 2-(5-bromo-2-methoxypyridin-4-yl)propanoate (C11).

[0581] A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2M; 1 mL, 2 mmol) was added dropwise to a -78 ° C solution of methyl (5-bromo-2-methoxypyridin-4-yl)acetate (415 mg, 1.60 mmol) in tetrahydrofuran (50 mL). After the reaction mixture was stirred at -78 ° C for 1 hour, iodomethane solution (0.5 mL, 8 mmol) was added dropwise. Upon completion of the addition, the reaction mixture was warmed to -30 ° C and allowed to stir at this temperature for 3 hours, then diluted with aqueous ammonium chloride solution and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo while keeping the temperature below 45 ° C. Purification via silica gel chromatography (eluent: 1:3 ethyl acetate / petroleum ether) gave C11 as a colorless oil. Yield: 376 mg, 1.37 mmol, 86%. LCMS m / z 276.0 (bromine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.23 ​​(s, 1H), 6.76 (s, 1H), 4.10 (q, J = 7.1 Hz, 1H), 3.89 (s, 3H), 3.69 (s, 3H), 1.48 (d, J = 7.2 Hz, 3H).

[0582] Step 2. Synthesis of methyl 2-(5-vinyl-2-methoxypyridin-4-yl)propanoate (C12).

[0583] A mixture of C11 (376 mg, 1.37 mmol), potassium vinyl trifluoroborate (460 mg, 3.43 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (201 mg, 0.275 mmol) and potassium phosphate (872 mg, 4.11 mmol) in N,N-dimethylformamide (20 mL) was stirred at 100 ° C for 16 hours. The reaction mixture was then filtered; the filtrate was poured into water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (gradient: 0% to 30% ethyl acetate / petroleum ether) to give C12 as a colorless oil. Yield: 188 mg, 0.850 mmol, 62%. LCMS m / z 222.1 [M+H] + . 1H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1H), 6.81 (dd, J = 17.3, 10.9 Hz, 1H), 6.63 (s, 1H), 5.56 (br d, J = 17.3 Hz, 1H), 5.32 (br d, J = 10.8 Hz, 1H), 3.95-3.87 (m, 1H), 3.93 (s, 3H), 3.67 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H).

[0584] Step 3. Synthesis of methyl 2-(5-formyl-2-methoxypyridin-4-yl)propanoate (C13).

[0585] A solution of C12 (195 mg, 0.881 mmol) in dichloromethane (10 mL) was cooled to -78 ° C and subsequently treated with an ozone-rich oxygen stream until the blue color remained. After 5 minutes, a stream of dry nitrogen was bubbled through the reaction mixture until the blue color disappeared, followed by the addition of triphenylphosphine (439 mg, 1.67 mmol). The resulting mixture was warmed to 25 ° C and stirred for 2 hours, at which point it was combined with a similar reaction using C12 (63 mg, 0.28 mmol) and concentrated in vacuo. The residue was purified using silica gel chromatography (gradient: 0% to 30% ethyl acetate / petroleum ether) to obtain C13 as a colorless oil. Combined yield: 124 mg, 0.555 mmol, 48%. LCMS m / z 224.0 [M+H] + .

[0586] Step 4. Synthesis of methyl 2-[5-(difluoromethyl)-2-methoxypyridin-4-yl]propanoate (C14).

[0587] To a solution of C13 (124 mg, 0.555 mmol) in dichloromethane (5 mL) was added trifluorinated [bis(2-methoxyethyl)amino]sulfur (614 mg, 2.78 mmol). After the reaction mixture was stirred at 25 ° C for 16 hours, it was poured into a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane (50 mL). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 20% ethyl acetate / petroleum ether) gave C14 as a colorless oil. Yield: 110 mg, 0.449 mmol, 81%. LCMS m / z 246.1 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.28 (s, 1H), 6.87 (s, 1H), 6.76 (t, J HF=54.5Hz, 1H), 4.11 (q, J = 6.9Hz, 1H), 4.03 (s, 3H), 3.69 (s, 3H), 1.52 (d, J = 7.0Hz, 3H).

[0588] Step 5. Synthesis of 2-[5-(difluoromethyl)-2-methoxypyridin-4-yl]propanoic acid (P9).

[0589] To a solution of C14 (145 mg, 0.591 mmol) in methanol (10 mL) was added a solution of lithium hydroxide (43 mg, 1.8 mmol) in water (4 mL), and the reaction mixture was stirred at 20 ° C for 4 hours, then it was concentrated in vacuo and washed with tert-butyl methyl ether (2×5 mL). The aqueous layer was adjusted to pH 5 by adding 2M hydrochloric acid and then extracted with ethyl acetate (3×10 mL). The combined ethyl acetate layers were washed with water (3×10 mL) and with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give P9 as a yellow oil. Yield: 132 mg, 0.571 mmol, 97%. LCMS m / z 232.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.26 (s, 1H), 6.96 (t, J HF =54.4Hz, 1H), 6.84 (s, 1H), 4.12 (q, J = 7.2Hz, 1H), 3.94 (s, 3H), 1.48 (d, J = 7.2Hz, 3H).

[0590] Preparation P10

[0591] 2-Fluoro-2-(2-methoxypyridin-4-yl)propanoic acid (P10)

[0592]

[0593] Step 1. Synthesis of dimethyl (2-methoxypyridin-4-yl)malonate (C15).

[0594] To a -10 ° C solution of 2-methoxy-4-methylpyridine (5.00 g, 40.6 mmol) in tetrahydrofuran (30 mL) was added lithium diisopropylamide (2M solution in tetrahydrofuran; 81.2 mL, 162 mmol). After the reaction mixture had been stirred at -10 ° C for 1.5 hours, dimethyl carbonate (14.6 g, 162 mmol) was added and stirring was continued at -10 ° C for 1.5 hours. The reaction mixture was then warmed to 25 ° C and allowed to stir for 16 hours, then quenched by adding aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (3×30 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0% to 20% ethyl acetate / petroleum ether) gave C15 as a yellow oil. Yield: 4.92 g, 20.6 mmol, 51%. LCMS m / z 240.1 [M + H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.17 (d, J = 5.0 Hz, 1H), 6.95 (d, J = 4.8 Hz, 1H), 6.80 (s, 1H), 4.59 (s, 1H), 3.96 (s, 3H), 3.77 (s, 6H).

[0595] Chromatographic purification also yielded the monoacylated product, methyl (2-methoxypyridin-4-yl)acetate. Yield: 1.29 g, 7.12 mmol, 18%. LCMS m / z 182.1 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.11 (br d, J = 5.3 Hz, 1H), 6.81 (dd, J = 5.4, 1.5 Hz, 1H), 6.68-6.66 (m, 1H), 3.93 (s, 3H), 3.71 (s, 3H), 3.57 (s, 2H).

[0596] Step 2. Synthesis of dimethyl (2-methoxypyridin-4-yl)(methyl)malonate (C16).

[0597] Sodium bis(trimethylsilyl)amide (2M solution in tetrahydrofuran; 14.0 mL, 28.0 mmol) was added to a -78 ° C solution of C15 (4.47 g, 18.7 mmol) in tetrahydrofuran (30 mL). After the reaction mixture was stirred at -78 ° C for 1 hour, iodomethane (1.40 mL, 22.5 mmol) was added. The reaction mixture was then warmed to -40 ° C, stirred for 2 hours, warmed to 25 ° C and stirred for another 16 hours, then quenched with aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (2×30 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 10% ethyl acetate / petroleum ether) gave C16 as a yellow oil. Yield: 3.29 g, 13.0 mmol, 70%. LCMS m / z 254.1 [M + H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (d, J = 5.5 Hz, 1H), 6.88 (br d, J = 5.5 Hz, 1H), 6.74 (br s, 1H), 3.95 (s, 3H), 3.78 (s, 6H), 1.83 (s, 3H).

[0598] Step 3. Synthesis of 2-(2-methoxypyridin-4-yl)propanoic acid (C17).

[0599] A solution of C16 (3.28 g, 13.0 mmol) and lithium hydroxide (1.24 g, 51.8 mmol) in a mixture of tetrahydrofuran (20 mL) and water (10 mL) was stirred at 45° C. for 5 hours. LCMS analysis indicated conversion to C17: LCMS m / z 182.1 [M+H] + , and the reaction mixture was concentrated in vacuo to provide C17 (2.40 g) as a white solid. This material was used directly in the next step.

[0600] Step 4. Synthesis of methyl 2-(2-methoxypyridin-4-yl)propanoate (C18).

[0601] A mixture of C17 (from the previous step; 2.40 g, ≤13.0 mmol) and sulfuric acid (2.5 mL) in methanol (25 mL) was stirred at 60 °C for 16 hours. The reaction mixture was then concentrated in vacuo, washed with aqueous sodium bicarbonate solution, and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give C18 as a colorless oil. Yield: 1.56 g, 7.99 mmol, 61% over 2 steps. LCMS m / z 196.2 [M+H] + . 1H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (d, J = 5.4 Hz, 1H), 6.81 (dd, J = 5.4, 1.5 Hz, 1H), 6.67 (br s, 1H), 3.93 (s, 3H), 3.67 (s, 3H), 3.66 (q, J = 7.1 Hz, 1H), 1.47 (d, J = 7.2 Hz, 3H).

[0602] Step 5. Synthesis of methyl 2-fluoro-2-(2-methoxypyridin-4-yl)propanoate (C19).

[0603] To a -78 ° C solution of C18 (500 mg, 2.56 mmol) in tetrahydrofuran (13 mL) was added lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 3.33 mL, 3.33 mmol). After the reaction mixture had been stirred at -78 ° C for 30 minutes, a solution of N-(phenylsulfonyl)-N-fluorobenzenesulfonamide (969 mg, 3.07 mmol) in tetrahydrofuran (2 mL) was added. The reaction mixture was stirred at -10 ° C for 3 hours, then quenched with aqueous ammonium chloride and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo; silica gel chromatography (gradient: 0% to 10% ethyl acetate / petroleum ether) gave C19 as a yellow oil. Yield: 400 mg, 1.88 mmol, 73%. LCMS m / z 214.1 [M+H] + . 1 HNMR (400 MHz, chloroform-d) δ 8.18 (d, J = 5.4 Hz, 1H), 7.00 (dd, J = 5.5, 1.6 Hz, 1H), 6.88 (br d, J = 1.5 Hz, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 1.89 (d, J HF =22.3Hz,3H).

[0604] Step 6. Synthesis of 2-fluoro-2-(2-methoxypyridin-4-yl)propanoic acid (P10).

[0605] A solution of C19 (400 mg, 1.88 mmol) and lithium hydroxide (89.9 mg, 3.75 mmol) in a mixture of tetrahydrofuran (10 mL) and water (2 mL) was stirred at 45 ° C for 4 hours. The reaction mixture was then concentrated in vacuo, diluted with water (12 mL), and adjusted to pH 6 by adding 3M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (2×20 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give P10 as a yellow oil. Yield: 300 mg, 1.51 mmol, 80%. LCMS m / z 200.1 [M+H]+ . 1 H NMR (400 MHz, chloroform-d) δ 9.9-9.4 (br s, 1H), 8.21 (d, J = 5.6 Hz, 1H), 7.08 (dd, J = 5.6, 1.6 Hz, 1H), 6.95 (br s, 1H), 3.95 (s, 3H), 1.92 (d, J HF =22.2Hz,3H).

[0606] Preparation P11

[0607] 2-[3-(Difluoromethoxy)-5-methoxyphenyl]propanoic acid (P11)

[0608]

[0609] Step 1. Synthesis of 1-(difluoromethoxy)-3-methoxy-5-methylbenzene (C20).

[0610] Aqueous potassium hydroxide (20% solution; 60.9 g, 217 mmol) and [bromo(difluoro)methyl](trimethyl)silane (11.3 mL, 72.7 mmol) were added sequentially to a 0°C solution of 3-methoxy-5-methylphenol (5.00 g, 36.2 mmol) in dichloromethane (50 mL). After the reaction mixture had been stirred at 0°C for 4.5 hours, it was diluted with water (50 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated in vacuo, and purified via silica gel chromatography (Gradient: 0% to 5% ethyl acetate / petroleum ether) to provide C20 as a colorless oil. Yield: 6.27 g, 33.3 mmol, 92%. 1 H NMR (400 MHz, methanol-d4) δ 6.76 (t, J HF =74.4Hz,1H),6.60(br s,1H),6.53(br s,1H),6.49-6.46(m,1H),3.76(s,3H),2.30(s,3H).

[0611] Step 2. Synthesis of 1-(bromomethyl)-3-(difluoromethoxy)-5-methoxybenzene (C21).

[0612] A mixture of C20 (3.00 g, 15.9 mmol), 2,2'-azobisisobutyronitrile (262 mg, 1.60 mmol), and N-bromosuccinimide (2.84 g, 15.9 mmol) in tetrachloromethane (90 mL) was stirred at 80° C. for 8 hours. The mixture was concentrated in vacuo to afford C21 as a yellow oil. Yield: 4.0 g, 15 mmol, 94%.1 H NMR (400 MHz, methanol-d4), product peak only, characteristic peaks: δ 6.84 (s, 1H), 6.77 (s, 1H), 6.63-6.60 (m, 1H), 4.50 (s, 2H), 3.81 (s, 3H).

[0613] Step 3. Synthesis of [3-(difluoromethoxy)-5-methoxyphenyl]acetonitrile (C22).

[0614] To a solution of C21 (4.0 g, 15 mmol) in acetonitrile (150 mL) were added potassium carbonate (3.11 g, 22.5 mmol) and trimethylsilyl cyanide (2.2 g, 22 mmol) sequentially. The resulting mixture was stirred at 80 °C for 16 hours, at which time LCMS analysis indicated the presence of C22: LCMS m / z 214.1 [M+H] + The reaction mixture was concentrated under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated in vacuo, and purified using silica gel chromatography (gradient: 0% to 30% ethyl acetate / petroleum ether) to afford C22 as a yellow oil. Yield: 1.20 g, 5.63 mmol, 38%. 1 H NMR (400 MHz, methanol-d4) δ 6.84 (t, J HF =73.9Hz,1H),6.81(br s,1H),6.73(br s,1H),6.68-6.66(m,1H),3.89(s,2H),3.82(s,3H).

[0615] Step 4. Synthesis of 2-[3-(difluoromethoxy)-5-methoxyphenyl]propionitrile (C23).

[0616] The conversion of C22 (3.00 g, 14.1 mmol) to C23 was carried out using the procedure described for the synthesis of C16 from C15 in Preparation P10. Silica gel chromatography (gradient: 0% to 5% ethyl acetate / petroleum ether) provided C23 as a yellow oil. Yield: 1.00 g, 4.40 mmol, 31%. LCMS m / z 228.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 6.85 (t, J HF =73.9Hz,1H),6.84-6.82(m,1H),6.77-6.74(m,1H),6.69-6.66(m,1H),4.11(q,J=7.2Hz,1H),3.82(s,3H),1.60(d,J=7.3Hz,3H).

[0617] Step 5. Synthesis of ethyl 2-[3-(difluoromethoxy)-5-methoxyphenyl]propanoate (C24).

[0618] Thionyl chloride (5.3 mL, 73 mmol) was added dropwise to a 0 ° C solution of C23 (900 mg, 3.96 mmol) in ethanol (40 mL). The reaction mixture was stirred at 85 ° C for 16 hours, then diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 6% ethyl acetate / petroleum ether) gave C24 (700 mg, 2.55 mmol, 64%) as a yellow oil. Yield: 700 mg, 2.55 mmol, 64%. LCMS m / z 275.1 [M + H] + . 1 H NMR (400 MHz, methanol-d4) δ 6.80 (t, J HF =74.2Hz,1H),6.74-6.71(m,1H),6.65(br s,1H),6.59(dd,J=2.2,2.2Hz,1H),4.19-4.05(m,2H),3.79(s,3H),3.72(q,J=7.2Hz,1H),1.44(d,J=7.2Hz,3H),1.20(t,J=7.1Hz,3H).

[0619] Step 6. Synthesis of 2-[3-(difluoromethoxy)-5-methoxyphenyl]propanoic acid (P11).

[0620] To a solution of C24 (700 mg, 2.55 mmol) in tetrahydrofuran (30 mL) was added a solution of lithium hydroxide monohydrate (535 mg, 12.8 mmol) in water (10 mL). After the reaction mixture had been stirred at 25 ° C. for 16 hours, it was concentrated in vacuo, diluted with water (20 mL), and washed with dichloromethane (3×25 mL). These organic layers were discarded. The aqueous layer was adjusted to approximately pH 2 using 2M hydrochloric acid; it was then extracted with dichloromethane (3×25 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give P11 as a yellow oil. Yield: 628 mg, 2.55 mmol, quantitative. LCMS m / z 247.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 6.79 (t, J HF=74.2Hz,1H),6.77-6.73(m,1H),6.69-6.66(m,1H),6.59(dd,J=2.2,2.2Hz,1H),3.79(s,3H),3.69(q,J=7.2Hz,1H),1.44(d,J=7.2Hz,3H).

[0621] Preparation P12

[0622] 2-[5-Fluoro-2-(trifluoromethoxy)pyridin-4-yl]propanoic acid (P12)

[0623]

[0624] Step 1. Synthesis of diethyl (5-fluoro-2-methoxypyridin-4-yl)malonate (C25).

[0625] The reaction of 5-fluoro-4-iodo-2-methoxypyridine (3.45 g, 13.6 mmol) and diethyl malonate (3.28 g, 20.5 mmol) was carried out using the method described for the synthesis of C6 from C5 in Preparation P5. Purification by silica gel chromatography (gradient: 0% to 15% ethyl acetate / petroleum ether) gave C25 as a colorless oil. Yield: 2.80 g, 9.82 mmol, 72%. LCMS m / z 286.1 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (br s, 1H), 6.84 (br d, J = 4.8 Hz, 1H), 4.87 (s, 1H), 4.30-4.21 (m, 4H), 3.90 (s, 3H), 1.28 (t, J = 7.1 Hz, 6H).

[0626] Step 2. Synthesis of diethyl (5-fluoro-2-methoxypyridin-4-yl)(methyl)malonate (C26).

[0627] To a solution of C25 (2.80 g, 9.82 mmol) in acetonitrile (100 mL) was added potassium carbonate (4.07 g, 29.4 mmol), followed by dropwise addition of iodomethane (2.09 g, 14.7 mmol). The reaction mixture was stirred at 25 °C for 2 days, after which LCMS analysis indicated conversion to C26: LCMS m / z 300.1 [M+H] + The reaction mixture was poured into water (1 L) and extracted with ethyl acetate (2×100 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford C26 as a yellow oil. Yield: 2.25 g, 7.52 mmol, 77%. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.95 (d, J = 2.7 Hz, 1H), 6.58 (d, J = 5.2 Hz, 1H), 4.30-4.22 (m, 4H), 3.90 (s, 3H), 1.81 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H).

[0628] Step 3. Synthesis of diethyl (5-fluoro-2-hydroxypyridin-4-yl)(methyl)malonate (C27).

[0629] Trimethylsilyl iodide (7.52 g, 37.6 mmol) was added dropwise to a solution of C26 (2.25 g, 7.52 mmol) in acetonitrile (100 mL), and the reaction mixture was stirred at 100 °C for 4 h, at which time LCMS analysis indicated conversion to C27: LCMS m / z 286.1 [M+H] + The reaction mixture was poured into aqueous sodium bicarbonate (100 mL), and the resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with aqueous sodium dithionite (200 mL), filtered, concentrated in vacuo, and purified by silica gel chromatography (Gradient: 0% to 15% methanol / dichloromethane) to afford C27 as a white solid. Yield: 685 mg, 2.40 mmol, 32%. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.29-7.26 (m, 1H, assumed value; partially obscured by solvent peak), 6.43 (d, J = 6.4 Hz, 1H), 4.35-4.19 (m, 4H), 1.80 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H).

[0630] Step 4. Synthesis of diethyl [5-fluoro-2-(trifluoromethoxy)pyridin-4-yl](methyl)malonate (C28).

[0631] A solution of 1-trifluoromethyl-1,2-benzoiodooxolan-3-(1H)-one (759 mg, 2.40 mmol) and C27 (685 mg, 2.40 mmol) in nitromethane (20 mL) was stirred at 100 ° C for 16 hours. After removing the solvent in vacuo, the residue was purified by silica gel chromatography (gradient: 0% to 20% ethyl acetate / petroleum ether) to give C28 as a colorless oil. Yield: 283 mg, 0.801 mmol, 33%. LCMS m / z 354.0 [M+H] + . 1H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 5.0 Hz, 1H), 4.34-4.22 (m, 4H), 1.85 (s, 3H), 1.28 (t, J = 7.1 Hz, 6H).

[0632] Step 5. Synthesis of 2-[5-fluoro-2-(trifluoromethoxy)pyridin-4-yl]propanoic acid (P12).

[0633] To a solution of C28 (300 mg, 0.849 mmol) in tetrahydrofuran (10 mL) at 25 ° C. was added a solution of lithium hydroxide (102 mg, 4.26 mmol) in water (3 mL). After the reaction mixture was stirred at 25 ° C. for 16 hours, it was combined with a similar reaction using C28 (50 mg, 0.14 mmol), diluted with water (100 mL), and washed with dichloromethane (3×50 mL). These organic layers were discarded. The aqueous layer was adjusted to pH 5 by adding 5M hydrochloric acid and extracted with dichloromethane (3×50 mL); the combined dichloromethane layers were concentrated in vacuo to give P12 as a white solid. Combined yield: 230 mg, 0.909 mmol, 92%. LCMS m / z 254.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.17 (d, J = 1.5 Hz, 1H), 7.20 (d, J = 4.8 Hz, 1H), 4.05 (q, J = 7.3 Hz, 1H), 1.53 (d, J = 7.3 Hz, 3H).

[0634] Preparation P13

[0635] 2-[2-(Difluoromethoxy)-5-fluoropyridin-4-yl]propanoic acid (P13)

[0636]

[0637] Step 1. Synthesis of methyl 2-(5-fluoro-2-methoxypyridin-4-yl)propanoate (C29).

[0638] Sulfuric acid (0.2 mL) was added to a solution of P6 (1.80 g, 9.04 mmol) in methanol (20 mL), and the reaction mixture was stirred at 70 ° C for 12 hours, then it was concentrated under reduced pressure. The residue was treated with saturated aqueous sodium bicarbonate solution (30 mL) until the pH reached 8, and it was then extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to give C29 as a colorless oil. Yield: 1.85 g, 8.68 mmol, 96%. LCMS m / z 214.1 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (br s, 1H), 6.65 (d, J = 5.0 Hz, 1H), 3.93 (q, J = 7.3 Hz, 1H), 3.89 (s, 3H), 3.69 (s, 3H), 1.49 (d, J = 7.3 Hz, 3H).

[0639] Step 2. Synthesis of methyl 2-(5-fluoro-2-hydroxypyridin-4-yl)propanoate (C30).

[0640] A solution of C29 (700 mg, 3.28 mmol) and trimethylsilyl iodide (1.97 g, 9.85 mmol) in acetonitrile (10 mL) was stirred at 80° C. for 4 hours. The reaction mixture was concentrated in vacuo, and the residue was purified using silica gel chromatography (gradient: 0% to 10% methanol / dichloromethane) to provide C30 as a light brown oil. Yield: 550 mg, 2.76 mmol, 84%. LCMS m / z 200.1 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.99 (d, J = 3.5 Hz, 1H), 6.93 (d, J = 5.8 Hz, 1H), 3.99 (q, J = 7.2 Hz, 1H), 3.75 (s, 3H), 1.58 (d, J = 7.2 Hz, 3H).

[0641] Step 3. Synthesis of methyl 2-[2-(difluoromethoxy)-5-fluoropyridin-4-yl]propanoate (C31).

[0642] A mixture of C30 (580 mg, 2.91 mmol) and sodium chloro(difluoro)acetate (888 mg, 5.82 mmol) in acetonitrile (10.0 mL) was stirred at 100° C. for 12 hours. The reaction mixture was then concentrated in vacuo and subjected to silica gel chromatography (gradient: 0% to 30% ethyl acetate / petroleum ether) to afford C31 as a colorless oil. Yield: 550 mg, 2.21 mmol, 76%. LCMS m / z 250.1 [M+H]+ . 1 H NMR (400 MHz, chloroform-d) δ 7.99 (d, J = 1.3 Hz, 1H), 7.36 (t, J HF =72.9Hz, 1H), 6.86 (d, J = 4.8Hz, 1H), 3.99 (q, J = 7.3Hz, 1H), 3.72 (s, 3H), 1.53 (d, J = 7.3Hz, 3H).

[0643] Step 4. Synthesis of 2-[2-(difluoromethoxy)-5-fluoropyridin-4-yl]propanoic acid (P13).

[0644] A solution of lithium hydroxide monohydrate (455 mg, 10.8 mmol) in water (5 mL) was added to a solution of C31 (1.00 g, 4.01 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at 25 ° C for 10 hours, then it was concentrated under reduced pressure, and the aqueous residue was washed with dichloromethane (3×10 mL). The aqueous layer was then adjusted to pH 7 by adding 1M hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined ethyl acetate layers were concentrated in vacuo to give P13 as a colorless oil. Yield: 830 mg, 3.53 mmol, 88%. LCMS m / z 236.1 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.99 (br s, 1H), 7.35 (t, J HF =72.8Hz, 1H), 6.86 (d, J = 4.8Hz, 1H), 3.98 (q, J = 7.2Hz, 1H), 1.52 (d, J = 7.3Hz, 3H).

[0645] Preparation P14

[0646] 2-[2-(Dimethylamino)-5-fluoropyridin-4-yl]propanoic acid (P14)

[0647]

[0648] Step 1. Synthesis of tert-butyl (2-chloro-5-fluoropyridin-4-yl)acetate (C32).

[0649] Lithium diisopropylamide (2M solution in tetrahydrofuran; 50.5 mL, 101 mmol) was added to a -78 ° C solution of 2-chloro-5-fluoro-4-methylpyridine (4.90 g, 33.7 mmol) in tetrahydrofuran (200 mL). After the reaction mixture had been stirred at -50 ° C for 1 hour, it was cooled to -78 ° C, and a solution of di-tert-butyl dicarbonate (8.51 mL, 37.0 mmol) in tetrahydrofuran (30 mL) was added. The reaction mixture was then warmed to -30 ° C, stirred for 2 hours, and diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 10% ethyl acetate / petroleum ether) gave C32 as an oil. Yield: 4.90 g, 19.9 mmol, 59%. LCMS m / z 246.1 (chlorine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (br s, 1H), 7.29 (d, J=5.2 Hz, 1H), 3.59 (s, 2H), 1.46 (s, 9H).

[0650] Step 2. Synthesis of tert-butyl 2-(2-chloro-5-fluoropyridin-4-yl)propanoate (C33).

[0651] The conversion of C32 (4.60 g, 18.7 mmol) to C33 was carried out using the method described for the synthesis of C16 from C15 in Preparation P10. Silica gel chromatography (gradient 0% to 20% ethyl acetate / petroleum ether) provided C33 as an oil. Yield: 4.40 g, 16.9 mmol, 90%. LCMS m / z 262.1 (chlorine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.19 (br s, 1H), 7.28 (d, J = 5.1 Hz, 1H), 3.87 (q, J = 7.3 Hz, 1H), 1.48 (d, J = 7.2 Hz, 3H), 1.42 (s, 9H).

[0652] Step 3. Synthesis of 2-[2-(dimethylamino)-5-fluoropyridin-4-yl]propanoic acid (P14).

[0653] A mixture of C33 (3.00 g, 11.6 mmol), dimethylamine (2 M solution in tetrahydrofuran; 8.66 mL, 17.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.06 g, 1.16 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos; 1.08 g, 2.31 mmol), and sodium tert-butoxide (3.33 g, 34.7 mmol) in toluene (100 mL) was stirred at 100° C. for 16 hours. After the reaction mixture had been concentrated in vacuo, it was diluted with water and washed with dichloromethane (3×30 mL). The aqueous layer was then adjusted to pH 5 by the addition of 5 M hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 10% methanol / dichloromethane) provided P14 as a gray solid. Yield: 700 mg, 3.30 mmol, 28%. LCMS m / z 213.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.87 (d, J = 2.1 Hz, 1H), 6.57 (d, J = 4.9 Hz, 1H), 3.90 (q, J = 7.2 Hz, 1H), 3.04 (s, 6H), 1.48 (d, J = 7.2 Hz, 3H).

[0654] Preparation P15

[0655] Lithium 2-(5-chloro-2-methoxypyrimidin-4-yl)propionate (P15)

[0656]

[0657] Step 1. Synthesis of dimethyl (2,5-dichloropyrimidin-4-yl)(methyl)malonate (C34).

[0658] Sodium hydride (60% dispersion in mineral oil; 1.31 g, 33 mmol) was slowly added to a 0°C solution of dimethyl methylmalonate (4.78 g, 32.7 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at 0°C for 30 minutes, followed by the dropwise addition of a solution of 2,4,5-trichloropyrimidine (5.00 g, 27.3 mmol) in tetrahydrofuran (10 mL) at 0°C. Stirring was continued at 0°C for 30 minutes, at which point the reaction mixture was slowly warmed to 25°C and stirred at this temperature for 30 minutes. After the addition of saturated aqueous ammonium chloride (100 mL), the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed sequentially with water and saturated aqueous sodium chloride, then combined with the organic layer from a similar reaction performed using 2,4,5-trichloropyrimidine (500 mg, 2.73 mmol), dried over sodium sulfate, filtered, and concentrated in vacuo while maintaining the temperature below 40°C. Silica gel chromatography (gradient: 10% to 13% ethyl acetate / petroleum ether) provided C34 as a colorless oil. Combined yield: 6.82 g, 23.3 mmol, 78%. LCMS m / z 293.0 (dichloroisotope pattern observed) [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.74 (s, 1H), 3.79 (s, 6H), 1.90 (s, 3H).

[0659] Step 2. Synthesis of dimethyl (5-chloro-2-methoxypyrimidin-4-yl)(methyl)malonate (C35).

[0660] A solution of sodium methoxide in methanol (30% solution; 4.66 g, 26 mmol) was added dropwise to a solution of C34 (6.32 g, 21.6 mmol) in methanol (120 mL). After the reaction mixture had been stirred at 25 ° C for 2 hours, it was concentrated in vacuo while keeping the temperature below 40 ° C, diluted with water (50 mL), and extracted with ethyl acetate (2×100 mL). The organic layer was combined with the organic layer from a similar reaction using C34 (500 mg, 1.71 mmol), washed sequentially with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 11% to 15% ethyl acetate / petroleum ether) gave C35 as a colorless oil. Combined yield: 4.00 g, 13.9 mmol, 60%. LCMS m / z 289.0 (chlorine isotope pattern observed) [M + H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 3.95 (s, 3H), 3.79 (s, 6H), 1.88 (s, 3H).

[0661] Step 3. Synthesis of lithium 2-(5-chloro-2-methoxypyrimidin-4-yl)propionate (P15).

[0662] A solution of lithium hydroxide monohydrate (1.65 g, 39.3 mmol) in water (20 mL) was added dropwise to a solution of C35 (3.78 g, 13.1 mmol) in tetrahydrofuran (60 mL). The reaction mixture was stirred at 35 ° C for 3 hours, then concentrated in vacuo. The resulting aqueous mixture was washed with dichloromethane and then purified by reverse phase chromatography (column: C 18; gradient: 0% to 10% acetonitrile / water) to give P15 as a white solid. Yield: 1.87 g, 8.40 mmol, 64%. LCMS m / z 217.1 [M + H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.37 (s, 1H), 4.05 (q, J = 7.2 Hz, 1H), 4.00 (s, 3H), 1.55 (d, J = 7.2 Hz, 3H).

[0663] Preparation P16

[0664] 2-[2-(Difluoromethoxy)-6-methoxypyridin-4-yl]propanoic acid (P16)

[0665]

[0666] Step 1. Synthesis of methyl 2-(difluoromethoxy)-6-methoxypicolinate (C36).

[0667] Methyl 2-hydroxy-6-methoxypicolinate (900 mg, 4.91 mmol) was converted to C36 using the method described for the synthesis of C5 from 5-iodopyridin-2-ol in Preparation P5. Silica gel chromatography (gradient: 0% to 8% ethyl acetate / petroleum ether) provided C36 as a colorless oil. Yield: 720 mg, 3.09 mmol, 63%. LCMS m / z 234.1 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.39 (t, J HF =73.0Hz,1H),7.10(br s,1H),7.00(br s,1H),3.94(s,3H),3.93(s,3H).

[0668] Step 2. Synthesis of 2-(difluoromethoxy)-6-methoxypicolinic acid (C37).

[0669] Using the method described for the synthesis of P11 from C24 in Preparation P11, C36 (1.10 g, 4.72 mmol) was hydrolyzed to afford C37 as a white solid. Yield: 980 mg, 4.47 mmol, 95%. LCMS m / z 220.1 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.41 (t, J HF =72.8Hz, 1H), 7.15 (d, J = 1.1Hz, 1H), 7.05 (d, J = 1.0Hz, 1H), 3.95 (s, 3H).

[0670] Step 3. Synthesis of methyl [2-(difluoromethoxy)-6-methoxypyridin-4-yl]acetate (C38).

[0671] A solution of C37 (980 mg, 4.47 mmol) in thionyl chloride (6.49 mL, 89.0 mmol) was stirred at 70°C for 2.5 hours, then concentrated under reduced pressure. After the resulting acid chloride was dissolved in a mixture of tetrahydrofuran (8 mL) and acetonitrile (8 mL), it was cooled to 0°C and treated with freshly distilled triethylamine (0.87 mL, 6.2 mmol) followed by (diazomethyl)(trimethyl)silane (2 M solution in diethyl ether; 3.35 mL, 6.70 mmol). The reaction mixture was stirred at 0°C for 8 hours, then diluted with diethyl ether (25 mL) and washed sequentially with 10% aqueous citric acid (5 mL), saturated aqueous sodium bicarbonate (15 mL), and saturated aqueous sodium chloride (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude diazoketone. This material was suspended in methanol (10 mL) in an ultrasonic bath; a solution of silver benzoate (512 mg, 2.24 mmol) in triethylamine (1.86 mL, 13.3 mmol) was gradually added at room temperature while sonicating the reaction mixture. After 30 minutes, the volatiles were removed in vacuo, and the residue was purified using silica gel chromatography (gradient: 0% to 10% ethyl acetate / petroleum ether) to afford C38 as a colorless oil. Yield: 340 mg, 1.38 mmol, 31%. LCMS m / z 248.0 [M+H] + . 1 HNMR (400 MHz, chloroform-d) δ 7.40 (t, J HF =73.4Hz,1H),6.45(br s,1H),6.40(br s,1H),3.88(s,3H),3.71(s,3H),3.57(s,2H).

[0672] Step 4. Synthesis of methyl 2-[2-(difluoromethoxy)-6-methoxypyridin-4-yl]propanoate (C39).

[0673] To a -78 ° C solution of C38 (230 mg, 0.930 mmol) in tetrahydrofuran (20 mL) was added sodium bis(trimethylsilyl)amide (2M solution in tetrahydrofuran; 0.56 mL, 1.1 mmol), and the reaction mixture was stirred at -78 ° C for 1 hour. Iodomethane (57.9 μL, 0.93 mmol) was then added and stirring was continued at -78 ° C for 2 hours. After adding saturated aqueous ammonium chloride solution (10 mL), the mixture was combined with a similar reaction using C38 (100 mg, 0.405 mmol) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo; silica gel chromatography (gradient: 0% to 4% ethyl acetate / petroleum ether) gave C39 as a colorless oil. Combined yield: 150 mg, 0.574 mmol, 43%. LCMS m / z 262.1[M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 7.51 (t, J HF =73.3Hz,1H),6.50(br d,J=1Hz,1H),6.43(br d,J=1Hz,1H),3.88(s,3H),3.78(q,J=7.2Hz,1H),3.68(s,3H),1.44(d,J=7.2Hz,3H).

[0674] Step 5. Synthesis of 2-[2-(difluoromethoxy)-6-methoxypyridin-4-yl]propanoic acid (P16).

[0675] C39 (130 mg, 0.498 mmol) was hydrolyzed using the method described for the synthesis of P12 from C28 in Preparation P12 to provide P16 as a colorless oil. Yield: 101 mg, 0.409 mmol, 82%. LCMS m / z 248.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.51 (t, J HF =73.3Hz,1H),6.53(br d,J=1.1Hz,1H),6.46(br d,J=1.1Hz,1H),3.88(s,3H),3.72(q,J=7.1Hz,1H),1.44(d,J=7.2Hz,3H).

[0676] Preparations P17 and P18

[0677] 7-methyl-3,4-dihydro-1H-spiro[1,8- tert-Butyl 2,3'-pyrrolidine]-1'-carboxylate (P17) and 7-methyl-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidine]-1,1'-dicarboxylic acid di-tert-butyl ester (P18)

[0678]

[0679] Step 1. Synthesis of 2-chloro-3-iodo-6-methylpyridine (C40).

[0680] To a 0° C. mixture of 2-chloro-6-methylpyridin-3-amine (400 g, 2.80 mol) in water (5.0 L) and hydrochloric acid (5.0 M; 3.3 L, 16.5 mol) was added a solution of sodium nitrite (290 g, 4.20 mol) in water (800 mL) dropwise at a rate that maintained the internal reaction temperature below 5° C. The reaction mixture was stirred under ice cooling for 30 minutes, then cooled to −5° C., followed by the addition of tert-butyl methyl ether (3.0 L), followed by the dropwise addition of a solution of potassium iodide (929 g, 5.60 mol) in water (800 mL), while maintaining the internal reaction temperature below 10° C. The reaction mixture was then slowly warmed to 25° C. and stirring was continued at 25° C. for 16 hours. After adjusting the pH to 9 by adding 2M aqueous sodium hydroxide solution, the mixture was extracted with ethyl acetate (3×2.0 L); the combined organic layers were washed twice with aqueous sodium sulfite solution and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0% to 5% ethyl acetate / petroleum ether) gave C40 as a white solid. Yield: 610 g, 2.41 mol, 86%. LCMS m / z 253.9 (chlorine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.13 (d, J = 7.9 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 2.44 (s, 3H).

[0681] Step 2. Synthesis of 1-benzyl-3-[(trimethylsilyl)ethynyl]pyrrolidin-3-ol (C41).

[0682] A solution of n-butyllithium in tetrahydrofuran (2.5 M; 3.75 L, 9.4 mol) was added dropwise to a -78°C solution of ethynyl(trimethyl)silane (1.01 kg, 10.3 mol) in tetrahydrofuran (4.0 L). The reaction mixture was stirred at -78°C for 1 hour, followed by the dropwise addition of a solution of 1-benzylpyrrolidin-3-one (1.50 kg, 8.56 mol) in tetrahydrofuran (1.5 L). After the addition was complete, the reaction mixture was warmed to 20°C, stirred at 20°C for 16 hours, and then poured into an aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (2 x 2.0 L), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford C41 as a yellow oil. Yield: 2.25 kg, 8.23 ​​mol, 96%. LCMS m / z 274.2[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.37-7.28 (m, 4H), 7.28-7.22 (m, 1H), 3.66 (AB quartet, J AB =12.7Hz,Δν AB =12.2Hz,2H),2.89-2.77(m,3H),2.65(ddd,J=9.4,7.9,5.5Hz,1H),2.30-2.21(m,1H),2.12-2.03(m,1H),0.14(s,9H).

[0683] Step 3. Synthesis of 1-benzyl-3-ethynylpyrrolidin-3-ol (C42).

[0684] A mixture of C41 (2.77 kg, 10.1 mol) and potassium carbonate (2.80 kg, 20.3 mol) in methanol (10 L) was stirred at 25 °C for 3 hours, then the reaction mixture was filtered and the filtrate was concentrated in vacuo. After the residue was diluted with ethyl acetate (10 L), it was filtered. The filtrate was concentrated under reduced pressure to give C42 (2.30 kg) as a black oil. This material was used directly in the next step. LCMS m / z 202.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4), characteristic peaks: δ 7.37-7.28 (m, 4H), 7.28-7.22 (m, 1H), 3.66 (AB quartet, J AB =12.7Hz,Δν AB=12.7Hz,2H),2.89-2.78(m,3H),2.65(ddd,J=9.4,7.9,5.7Hz,1H),2.27(ddd,J=13.3,7.9,6.8Hz,1H),2.14-2.04(m,1H).

[0685] Step 4. Synthesis of 1-benzyl-3-ethynylpyrrolidin-3-yl acetate (C43).

[0686] To a 0°C solution of C42 (from the previous step; 2.30 kg, ≤10.1 mol) and triethylamine (3.17 L, 22.7 mol) in dichloromethane (10 L) was added acetyl chloride (1.35 kg, 17.2 mol) in a dropwise manner. The reaction mixture was then stirred at 25°C for 30 minutes before the addition of water (10 L). The resulting mixture was extracted with dichloromethane (2 x 3.0 L), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford C43 (2.82 kg) as a brown oil. A portion of this material was used in the following step. LCMS m / z 244.2 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 7.38-7.23 (m, 5H), 3.65 (s, 2H), 3.05 (s, 2H), 3.03 (s, 1H), 2.77 (ddd, J = 9.5, 7.4, 6.1 Hz, 1H), 2.66 (ddd, J = 9.5, 7.4, 6.5 Hz, 1H), 2.46 (ddd, J = 13.6, 7.4, 6.1 Hz, 1H), 2.40-2.31 (m, 1H), 2.02 (s, 3H).

[0687] Step 5. Synthesis of 1-benzyl-3-ethynyl-N-[(4-methoxyphenyl)methyl]pyrrolidin-3-amine (C44).

[0688] A mixture of C43 (from the previous step; 1.20 kg, ≤4.30 mol), 1-(4-methoxyphenyl)methanamine (1.35 kg, 9.84 mmol) and copper(I) chloride (48.8 g, 0.493 mol) in tetrahydrofuran (6.0 L) was degassed under vacuum and then purged with nitrogen; this evacuation-purging cycle was performed a total of three times. The reaction mixture was then stirred at reflux for 45 minutes before it was concentrated in vacuo. This material was combined with three similar reactions performed using C43 (from the previous step; 900 g of C43, ≤3.2 mol, was used in three reactions) and purified by silica gel chromatography (gradient: 0% to 50% ethyl acetate / petroleum ether) to give C44 as a brown oil. Combined yield: 620 g, 1.93 mol, 26% over 3 steps. LCMS m / z 321.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.36-7.21 (m, 7H), 6.85 (br d, J = 8.7 Hz, 2H), 3.81-3.69 (m, 2H), 3.77 (s, 3H), 3.65 (AB quartet, J AB =12.7Hz,Δν AB =9.9 Hz, 2H), 2.88 (s, 1H), 2.82-2.67 (m, 2H), 2.79 (AB quartet, J AB =9.8Hz,Δν AB =37.8Hz,2H),2.27(ddd,J=13.4,7.7,6.0Hz,1H),2.09-2.01(m,1H).

[0689] Step 6. Synthesis of 1-benzyl-3-[(2-chloro-6-methylpyridin-3-yl)ethynyl]-N-[(4-methoxyphenyl)methyl]pyrrolidin-3-amine (C45).

[0690] A mixture of C44 (426 g, 1.33 mol), C40 (303 g, 1.20 mmol), dichlorobis(triphenylphosphine)palladium(II) (46.6 g, 66.4 mmol) and copper(I) iodide (12.6 g, 66.2 mmol) in triethylamine (2.0 L) was degassed under vacuum and then purged with nitrogen; this evacuation-purging cycle was performed a total of three times. The reaction mixture was stirred at reflux for 16 hours, then filtered; the filtrate was concentrated in vacuo and combined with material from two similar reactions performed using C40 (12.17 g, 48.0 mmol; 146 g, 0.576 mol). The resulting mixture was purified via silica gel chromatography (gradient: 20% to 50% ethyl acetate / petroleum ether) to give C45 as a black oil. Combined yield: 420 g, 0.942 mol, 52%. LCMS m / z 446.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.80 (d, J = 7.8 Hz, 1H), 7.39-7.20 (m, 8H), 6.86 (d, J = 8.6 Hz, 2H), 3.87 (AB quartet, J AB =12.0Hz,Δν AB =29.6 Hz, 2H), 3.76 (s, 3H), 3.70 (AB quartet, J AB =13.0Hz,Δν AB =9.3 Hz, 2H), 3.00 (d, component of AB quartet, J =9.9 Hz, 1H), 2.87-2.77 (m, 3H), 2.51 (s, 3H), 2.44-2.33 (m, 1H), 2.21-2.10 (m, 1H).

[0691] Step 7. Synthesis of 1-benzyl-3-[2-(2-chloro-6-methylpyridin-3-yl)ethyl]-N-[(4-methoxyphenyl)methyl]pyrrolidin-3-amine (C46).

[0692] A mixture of C45 (40.0 g, 89.7 mmol) and platinum (IV) oxide (4.09 g, 18.0 mmol) in methanol (400 mL) was hydrogenated (60 psi) for 3 hours at 25°C. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo to afford C46 as a black oil. Yield: 40.5 g, assumed quantitative. LCMS m / z 450.3 [M+H] + . 1H NMR (400 MHz, methanol-d4), characteristic peaks: δ 7.61 (d, J = 7.7 Hz, 1H), 7.38-7.23 (m, 7H), 7.17 (d, J = 7.7 Hz, 1H), 6.88 (br d, J = 8.7 Hz, 2H), 3.78 (s, 3H), 3.64 (AB quartet, J AB =12.0Hz,Δν AB =21.6Hz,2H),3.64(s,2H),2.46(s,3H).

[0693] Step 8. Synthesis of 1'-benzyl-1-[(4-methoxyphenyl)methyl]-7-methyl-3,4-dihydro-1H-spiro[1,8- pyridine-2,3'-pyrrolidine](C47).

[0694] A mixture of C46 (400 g, 0.89 mol), palladium (II) acetate (9.97 g, 44.4 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos; 41.5 g, 88.9 mmol) and sodium tert-butoxide (170 g, 1.77 mol) in 1,4-dioxane (4.0 L) was stirred at 90 ° C for 10 hours, then the reaction mixture was filtered and the filtrate was concentrated in vacuo. After the residue was partitioned between ethyl acetate (2 L) and water (2 L), the aqueous layer was extracted with ethyl acetate (1 L). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated in vacuo, and subjected to silica gel chromatography (gradient: 0% to 10% ethyl acetate / petroleum ether) to give C47 as a white solid. Yield: 195 g, 0.472 mol, 53%. LCMS m / z 414.3 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.38-7.21 (m, 5H, assumed value; partially obscured by solvent peak), 7.17 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 2H), 6.32 (d, J = 7.3 Hz, 1H), 5.07-4.92 (m, 2H), 3.77 (s, 3H), 3.54 (br AB quartet, J AB =13Hz,Δν AB=40Hz,2H),2.95(d,J=10.2Hz,1H),2.92-2.83(m,1H),2.83-2.73(m,1H),2.73-2 .63(m,1H),2.43-2.31(m,1H),2.29-2.08(m,2H),2.23(s,3H),2.03-1.73(m,3H).

[0695] Step 9. Synthesis of 1'-benzyl-7-methyl-3,4-dihydro-1H-spiro[1,8- pyridine-2,3'-pyrrolidine](C48).

[0696] To a 0°C solution of C47 (190 g, 0.459 mol) in dichloromethane (1.5 L) was added trifluoroacetic acid (523 g, 4.59 mol), and the reaction mixture was stirred at 25°C for 3 hours. It was then concentrated in vacuo; the residue was diluted with ethyl acetate (1.5 L) and washed with saturated aqueous sodium carbonate solution (1.0 L), and this aqueous layer was extracted with ethyl acetate (2 x 300 mL). The combined organic layers were concentrated in vacuo and purified via silica gel chromatography (gradient: 0% to 10% methanol / dichloromethane) to give C48 (179 g) as a brown oil. This material was directly subjected to the following step. LCMS m / z 294.3 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 9.1-8.3 (br s, 1H), 7.41-7.35 (m, 2H), 7.35-7.28 (m, 2H), 7.28-7.22 (m, 2H, assumed value; partially obscured by solvent peak), 6.35 (d, J = 7.3 Hz, 1H), 3.72 (s, 2H), 2.96-2.85 (m, 1H), 2.80-2.62 (m, 5H), 2.42 (s, 3H), 2.05 (ddd, J = 13.1, 8.1, 5.0 Hz, 1H), 1.98-1.81 (m, 3H).

[0697] Step 10. Synthesis of 7-methyl-3,4-dihydro-1H-spiro[1,8- tert-Butyl 2,3'-pyrrolidine]-1'-carboxylate (P17) and 7-methyl-3,4-dihydro-1H-spiro[1,8- [P18] di-tert-butyl 2,3'-pyrrolidine-1,1'-dicarboxylate.

[0698] A mixture of C48 (from the previous step; 179 g, ≤0.459 mol), di-tert-butyl dicarbonate (199.7 g, 915 mmol) and palladium hydroxide (17.9 g, 127 mmol) in methanol (2.0 L) and ethyl acetate (2.0 L) was hydrogenated at 55 psi and 25 ° C for 18 hours. The reaction mixture was then filtered through a pad of celite and the filtrate was concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 50% dichloromethane / ethyl acetate) provided P17 and P18 as white solids.

[0699] P17 - Yield: 101 g, 0.333 mol, 73% in 2 steps. LCMS m / z 304.3 [M+H] + . 1 HNMR (400 MHz, methanol-d4) δ 7.20 (d, J = 7.3 Hz, 1H), 6.44 (d, J = 7.4 Hz, 1H), 3.62-3.44 (m, 2H), 3.37-3.3 (m, 2H, assumed value; partially obscured by solvent peak), 2.84-2.66 (m, 2H), 2.27 (s, 3H), 2.05-1.92 (m, 2H), 1.92-1.76 (m, 2H), [1.48 (s) and 1.46 (s, total 9H].

[0700] P18 - Yield: 21.3 g, 52.8 mmol, 12% in 2 steps. LCMS m / z 404.3 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ 7.49 (d, J = 7.7 Hz, 1H), 7.02 (br d, J = 7.7 Hz, 1H), [3.85 (d, J = 11.3 Hz) and 3.75 (d, J = 11.2 Hz), total 1H], 3.62-3.47 (m, 2H), 3.40-3.24 (m, 1H, assumed value; partially obscured by solvent peak), 2.89-2.73 (m, 2H), 2.54-2.27 (m, 1H), 2.44 (s, 3H), 2.13-1.82 (m, 3H), 1.46 (s, 9H), [1.43 (s) and 1.43 (s), total 9H].

[0701] Preparations P19 and P20

[0702] (2S)-7-methyl-3,4-dihydro-1H-spiro[1,8- tert-Butyl pyrrolidine-2,3'-pyrrolidine-1'-carboxylate (P19) and (2R)-7-methyl-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidine]-1'-carboxylic acid tert-butyl ester (P20)

[0703]

[0704] To a solution of C48 (4.45 g, 15.2 mmol) in a mixture of methanol (20 mL) and ethyl acetate (25 mL) was added di-tert-butyl dicarbonate (3.97 g, 18.2 mmol). After the addition of palladium hydroxide on carbon (900 mg), the reaction mixture was hydrogenated at 80 psi for 18 hours, at which time LCMS analysis indicated complete conversion to P19 / P20: LCMS m / z 304.2 [M+H] + . The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the residue was dissolved in ethyl acetate, washed sequentially with saturated sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Separation of the component enantiomers was carried out via supercritical fluid chromatography {column: Chiral Technologies Chiralpak IB, 30×250 mm, 5 μm; mobile phase 9:1 carbon dioxide / [ethanol containing 0.2% (7 M ammonia / methanol)]; flow rate: 80 mL / min; back pressure: 100 bar}. The first eluting enantiomer was designated P19 and the second eluting enantiomer was designated P20. Both were isolated in solid form.

[0705] P19 - Yield: 1.60 g, 5.27 mmol, 35%. Retention time: 3.75 min [Analytical conditions: Column: Chiral Technologies Chiralpak IB, 4.6 × 250 mm, 5 μm; Mobile phase A: carbon dioxide; Mobile phase B: ethanol containing 0.2% (7 M ammonia / methanol); Gradient: 5% B for 1 minute, then 5% to 60% B over 8 minutes; Flow rate: 3.0 mL / min; Back pressure: 120 bar].

[0706] P20 - Yield: 1.50 g, 4.94 mmol, 32%. Retention time: 3.96 minutes (same analytical conditions as for P19).

[0707] The absolute stereochemistry indicated is assigned based on the conversion of this batch of P19 to P23 in the following alternative preparation of P23 (#1). The absolute configuration of P23 was determined via its use in the synthesis of 14, which was analyzed via single crystal X-ray crystallography (see below).

[0708] Preparation P21

[0709] 6-Bromo-7-methyl-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidine]-1,1'-dicarboxylic acid di-tert-butyl ester (P21)

[0710]

[0711] To a 0°C solution of P18 (20 g, 50 mmol) in dichloromethane (200 mL) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (7.09 g, 24.8 mmol) in six portions over 30 minutes. The reaction mixture was stirred at 0°C for 1 hour, then treated with saturated aqueous sodium sulfite solution (200 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 40% ethyl acetate / petroleum ether) gave P21 as a white solid. Yield: 22.8 g, 47.2 mmol, 94%. LCMS m / z 384.1 (bromine isotope pattern observed) {[M-(2-methylprop-1-ene, and CO2)]+H} + . 1 HNMR (400 MHz, CHLOROFORM-d) δ 7.51 (br s, 1H), [3.89 (d, J = 11.0 Hz) and 3.73 (d, J = 11.0 Hz), total 1H], 3.65-3.51 (m, 1H), 3.46 (d, J = 11.0 Hz, 1H), 3.38-3.26 (m, 1H), [2.87-2.56 (m) and 2.15-1.70 (m), total 6H], 2.57 (s, 3H), [1.46 (s) and 1.45 (s), total 18H].

[0712] Preparation P22

[0713] 6-Bromo-7-methyl-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidine]-1'-carboxylic acid tert-butyl ester (P22)

[0714]

[0715] 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (2.47 g, 8.64 mmol) was added portionwise to a 0° C. solution of P17 (5.25 g, 17.3 mmol) in dichloromethane (69 mL) over 20 minutes. After the reaction mixture had been stirred at 0° C. for 45 minutes, LCMS analysis indicated conversion to P22: LCMS m / z 384.3 (bromine isotope pattern observed) [M+H] +After 1 hour at 0°C, the reaction mixture was treated with saturated aqueous sodium sulfite (100 mL), and the mixture was extracted with dichloromethane. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide P22 as a solid. Yield: 6.60 g, 17.3 mmol, quantitative. 1 H NMR (400 MHz, Methanol-d4) δ 7.40 (br s, 1H), 3.61-3.43 (m, 2H), 3.37-3.3 (m, 2H, assumed value; mostly obscured by water peak), 2.85-2.67 (m, 2H), 2.37 (s, 3H), 2.06-1.92 (m, 2H), 1.92-1.75 (m, 2H), [1.47 (s) and 1.46 (s, total 9H].

[0716] Preparations P23 and P24

[0717] (2S)-6-Bromo-7-methyl-3,4-dihydro-1H-spiro[1,8- tert-Butyl]-2,3'-pyrrolidine-1'-carboxylate (P23) and (2R)-6-bromo-7-methyl-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidine]-1'-carboxylic acid tert-butyl ester (P24)

[0718]

[0719] 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (5.65 g, 19.8 mmol) was added portionwise to a 0 °C solution of P17 (10.0 g, 32.9 mmol) in dichloromethane (150 mL), and the reaction mixture was stirred at 0-5 °C for 1 hour, at which time LCMS analysis indicated that bromination had occurred: LCMS m / z 382.3 [M+H] +Saturated aqueous sodium sulfite (20 mL) followed by water (50 mL) were added; the resulting aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo; silica gel chromatography (gradient: 0% to 100% ethyl acetate / heptane) afforded a racemic mixture of P23 and P24 as a light yellow foam (11.8 g). This was combined with the product of a similar reaction performed using P17 (7.40 g, 24.4 mmol) to afford a light yellow foam (20.9 g, 54.6 mmol, 95% combined yield) and separated into its component enantiomers via supercritical fluid chromatography [column: Chiral Technologies Chiralcel OJ, 50×250 mm, 5 μm; mobile phase 4:1 carbon dioxide / (1:1 methanol / acetonitrile); flow rate: 250 mL / min; back pressure: 120 bar]. The first eluting enantiomer was designated P23, and the second eluting enantiomer was designated P24.

[0720] The absolute stereochemistry indicated is assigned based on the conversion of this batch of P23 to P28 (see Preparation P28), and subsequently to Example 14; the absolute stereochemistry of 14 was determined via single crystal X-ray analysis (see below).

[0721] P23, isolated as a yellow oil which solidified upon standing - combined yield: 9.37 g, 24.5 mmol, 43%. 1 HNMR (400 MHz, DMSO-d6) δ 7.37 (s, 1H), 7.02-6.96 (m, 1H), [3.55-3.40 (m), 3.36-3.26 (m, assumed value; partially obscured by water peak), and 3.24-3.13 (m), total 4H], 2.75-2.55 (m, 2H), 2.31 (s, 3H), 1.95-1.78 (m, 2H), 1.76-1.60 (m, 2H), [1.40 (s) and 1.38 (s), total 9H]. Retention time: 4.01 min [Analytical conditions. Column: Chiral Technologies Chiralcel OJ-H, 4.6×250 mm, 5 μm; mobile phase A: carbon dioxide; mobile phase B: methanol containing 0.2% (7 M ammonia / methanol); gradient: 5% B for 1 minute, then 5% to 60% B over 8 minutes; flow rate: 3.0 mL / min; back pressure: 120 bar].

[0722] P24-combined yield: 11.8 g, which contained ethanol; corrected estimate: 28.4 mmol, 50%. 1H NMR (400 MHz, DMSO-d6), characteristic peaks: δ 7.37 (s, 1H), 7.01-6.96 (m, 1H), 2.75-2.55 (m, 2H), 2.31 (s, 3H), 1.95-1.78 (m, 2H), 1.76-1.60 (m, 2H), [1.40 (s) and 1.38 (s, total 9H]. Retention time: 4.32 minutes (same analytical conditions as for P23).

[0723] Alternative preparation of P23 (#1)

[0724] (2S)-6-Bromo-7-methyl-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidine]-1'-carboxylic acid tert-butyl ester (P23)

[0725]

[0726] 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (625 mg, 2.19 mmol) was added portionwise to a 0°C solution of P19 (material from Preparations P19 and P20; 1.10 g, 3.63 mmol) in dichloromethane (20 mL). After the reaction mixture was stirred at room temperature for 1 hour, LCMS analysis indicated conversion to P23: LCMS m / z 384.2 (bromine isotope pattern observed) [M+H] + Saturated aqueous sodium sulfite solution was then added, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, concentrated in vacuo, and purified using silica gel chromatography (Gradient: 10% to 40% ethyl acetate / heptane) to provide P23 as a white solid. Yield: 1.25 g, 3.27 mmol, 90%. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.33 (s, 1H), 5.15-5.01 (br s, 1H), 3.59-3.45 (m, 2H), 3.43-3.25 (m, 2H), 2.81-2.66 (m, 2H), 2.43 (s, 3H), 2.01-1.74 (m, 4H), 1.48-1.43 (br s, 9H).

[0727] The absolute stereochemistry of this sample of P23 was assigned as indicated by comparison with samples from preparations P23 and P24:

[0728] Retention time of P23 from an alternative preparation of P23 (#1): 4.08 min

[0729] Retention times of the racemic mixtures of P23 and P24 were 4.07 and 4.36 minutes.

[0730] Retention time of P23 from preparations P23 and P24: 4.01 min

[0731] Retention time of P24 from preparations P23 and P24: 4.32 minutes

[0732] These four analyses were performed using the same analytical method: [column: Chiral Technologies ChiralcelOJ-H, 4.6×100 mm, 5 μm; mobile phase A: carbon dioxide; mobile phase B: methanol containing 0.2% (7 M ammonia / methanol); gradient: 5% B for 1 minute, then 5% to 60% B over 8 minutes; flow rate: 3.0 mL / min].

[0733] Alternative preparation of P23 (#2)

[0734] (2S)-6-Bromo-7-methyl-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidine]-1'-carboxylic acid tert-butyl ester (P23)

[0735]

[0736]

[0737] Step 1. Synthesis of (2-chloro-6-methylpyridin-3-yl)methanol (C49).

[0738] Sodium bis(2-methoxyethoxy)aluminum hydride solution (70%; 1.05 kg, 2.5 equivalents) was added to a solution of 2-chloro-6-methylpyridine-3-carboxylic acid (250 g, 1.46 mol) in toluene (2.5 L) at -5°C to 5°C. After the reaction mixture had been stirred at -5°C to 5°C for 19 hours, it was treated with a solution of sodium hydroxide (145.7 g, 3.642 mol, 2.50 equivalents) in water (1.25 L), while maintaining the internal temperature below 0°C to 10°C. The resulting mixture was then allowed to warm to 25°C; after 15 minutes, the aqueous layer was extracted with propan-2-yl acetate (2 x 1.25 L). These two extracts were combined with toluene and filtered through silica gel (125 g). The filter cake was rinsed with propan-2-yl acetate (125 mL), and the combined filtrates were concentrated to 8 volumes at 40-45° C. to afford C49 (1.602 kg, 11.2 wt% C49) as a toluene solution; most of this solution was used in the following step. Estimated yield: 179.4 g, 1.138 mol, 78%. 1H NMR (400MHz, DMSO-d6) δ7.81 (d, J = 7.8Hz, 1H), 7.29 (d, J = 7.7Hz, 1H), 5.48 (t, J = 5.6Hz, 1H), 4.50 (d, J = 5.6Hz, 2H), 2.43 (s, 3H).

[0739] Step 2. Synthesis of (2-chloro-6-methylpyridin-3-yl)methyl methanesulfonate (C50).

[0740] Triethylamine (134.2 g, 1.326 mol) was added to a solution of C49 in toluene (from the previous step; 1.537 kg, containing 11.2% C49, 172.1 g, 1.09 mol). The solution was cooled to -5°C to 5°C and then treated with methanesulfonyl chloride (128.5 g, 1.122 mol) in a dropwise manner while maintaining the internal temperature at -5°C to 5°C. After the reaction mixture was stirred at this temperature for 2 hours, triethylamine (22.7 g, 0.224 mol) was added again, followed by the dropwise addition of methanesulfonyl chloride (25.7 g, 0.224 mol). Stirring was continued at -5°C to 5°C for 1 hour, then the reaction mixture was treated with water (805 mL) while maintaining the internal temperature below 25°C and then stirred at 25°C for 15 minutes. The organic layer was washed with water (805 mL) and concentrated to give C50 (861 g) as a toluene solution. This solution was used directly in the following step. 1 H NMR (400MHz, DMSO-d6) δ7.92 (d, J = 7.7Hz, 1H), 7.36 (d, J = 7.7Hz, 1H), 5.30 (s, 2H), 3.29 (s, 3H), 2.48 (s, 3H).

[0741] Step 3. Synthesis of 2-chloro-3-(iodomethyl)-6-methylpyridine (C51).

[0742] Sodium iodide (230 g, 1.53 mol) was dissolved in acetone (1.13 kg) at 25 ° C; to this solution was added a solution of C50 in toluene (from the previous step; 861 g, ≤ 1.09 mol of C50). After the reaction mixture was stirred at 25 ° C for 1 hour, a solution of sodium metabisulfite (57.86 g, 0.3044 mol) in water (1.45 L) was added and stirring was continued for 30 minutes. The organic layer was separated, diluted with toluene (417 mL), and concentrated to 5 volumes to provide C51 (1.110 kg, 22.93 wt% C51) as a toluene solution. This solution was used directly in the following step. Estimated yield: 254.5 g, 0.9514 mol, 87% over 2 steps. 1H NMR (400MHz, DMSO-d6) δ7.90 (d, J = 7.7 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 4.55 (s, 2H), 2.41 (s, 3H).

[0743] Step 4. Synthesis of [(2-chloro-6-methylpyridin-3-yl)methyl](triphenyl)phosphonium iodide (C52).

[0744] A solution of C51 in toluene (from the previous step; 1.110 kg, 22.93 wt% C51, 254.5 g, 0.9514 mol) was diluted with acetonitrile (1.29 L) and treated with triphenylphosphine (262 g, 0.999 mol). After stirring the reaction mixture at 25°C for 4 hours, it was cooled to 10°C, stirred at this temperature for 16 hours, and filtered. The filter cake was washed with toluene (255 mL) and dried at 45°C for 4 hours to provide C52 as a solid. Yield: 412.6 g, 0.7788 mol, 56% over 4 steps. Purity: 99.7% by HPLC. 1 H NMR (400MHz, DMSO-d6) δ7.97-7.90(m,3H),7.80-7.71(m,8H),7.71-7.66(m,4H),7.44(dd,J=7.8,2.4Hz,1H),7.20(d,J=7.8Hz,1H),5.15(d,J HP =15.0Hz, 2H), 2.40 (d, J = 2.4Hz, 3H).

[0745] Step 5. Synthesis of diethyl 1-benzylpyrrolidine-3,3-dicarboxylate (C53).

[0746] A solution of ethyl 1-benzylpyrrolidine-3-carboxylate (700 g, 3.00 mol) in tetrahydrofuran (4.20 L) was added dropwise over 5 hours to a solution of lithium diisopropylamide (2.0 M, 2.40 L, 4.80 mol) at -80°C to -70°C. Stirring was continued at -80°C to -70°C for 2 hours, followed by the addition of ethyl chloroformate (423.5 g, 3.90 mol) over 3 hours while maintaining the reaction temperature at -80°C to -70°C. After the reaction mixture was stirred at -80°C to -70°C for 2 hours, the temperature was adjusted to -50°C to -40°C, and the reaction was quenched by the addition of a solution of acetic acid (288 g, 4.80 mol) in tetrahydrofuran (1.40 L) while maintaining the temperature at -50°C to -40°C. The resulting mixture was warmed to 15°C to 25°C and partitioned between water (3.50 L) and 2-methyltetrahydrofuran (7.0 L). After this mixture had been stirred at 15°C to 25°C for 30 minutes, the aqueous layer was extracted with 2-methyltetrahydrofuran (7.0 L), and the combined organic layers were washed with a solution of acetic acid (288 g, 4.80 mol) in water (4.2 L) and then with an aqueous sodium sulfate solution (10%; 2 x 3.50 kg). The organic layer was concentrated to 2-3 volumes in vacuo while maintaining the temperature below 50°C. Ethanol (4.90 L, 7 volumes) was added, and the solution was again concentrated to 2-3 volumes in vacuo while maintaining the temperature below 50°C. This ethanol addition / concentration was performed three times in total, with a final round using 2.80 L of ethanol, followed by concentration to 4-5 volumes. This provided C53 (3.148 kg, 24.23 wt% C53) as an ethanol solution. A portion of this solution was used in the following step. Estimated yield: 762.8 g, 2.498 mol, 83%. 1 H NMR (400MHz, DMSO-d6) δ7.35-7.20 (m, 5H), 4.12 (q, J = 7.1Hz, 4H), 3.57 (s, 2H), 2 .90(s,2H),2.55(t,J=6.9Hz,2H),2.29(t,J=6.8Hz,2H),1.14(t,J=7.1Hz,6H).

[0747] Step 6. Synthesis of diethyl pyrrolidine-3,3-dicarboxylate, L-tartrate (C54).

[0748] Ethanol (720 mL, 6 volumes) was added to a solution of C53 (120 g, 0.393 mol) in ethanol (from the previous step; approximately 500 mL). After adding wet palladium on carbon (10%; 12 g), the reaction vessel was evacuated and charged with argon three times, and then evacuated and charged with hydrogen three times. Hydrogenation was then carried out at 40 to 50 psi and 40 to 50 ° C for 24 hours. The resulting mixture was filtered through celite (50 g); the filter cake was washed with ethanol (240 mL, 2 volumes), and the combined filtrates were concentrated in vacuo to 2.5 to 3.5 volumes while maintaining the temperature at or below 45 ° C. This solution was added to a 40 to 50 ° C solution of L-tartaric acid (76.7 g, 0.511 mol) in water (85 mL, 0.7 volumes) and ethanol (465 mL) over 2 hours. After the mixture was stirred at 40°C to 50°C for 1 hour, C54 seeds (0.4 g; see below) were added at 45°C. The mixture was cooled to 10°C over 6 hours and then stirred at 10°C for 4 hours; filtration provided a filter cake, which was washed with ethanol (2 volumes) and dried at 40°C for 20 hours to provide C54 as a solid. Yield: 127.4 g, 0.3487 mol, 89%. HPLC purity: 99.1%. 1 H NMR (400MHz, DMSO-d6) δ4.16 (q, J = 7.1 Hz, 4H), 4.03 (s, 2H), 3.49 (s, 2H), 3.08 (t, J = 7.1 Hz, 2H), 2.32 (t, J = 7.1 Hz, 2H), 1.18 (t, J = 7.1 Hz, 6H).

[0749] The seed material used above was obtained from another round of the same C54 synthesis, in which solid C54 was formed directly upon cooling.

[0750] Step 7. Synthesis of 1-tert-butyl 3,3-diethyl pyrrolidine-1,3,3-tricarboxylate (C55).

[0751] Di-tert-butyl dicarbonate (19.7 g, 90.3 mmol) was added dropwise to a 20-30°C mixture of C54 (88.12 g, 0.2412 mol) and triethylamine (73.33 g, 0.7247 mol) in dichloromethane (881 mL, 10 volumes). Additional di-tert-butyl dicarbonate (19.2 g, 88.0 mmol and 19.3 g, 88.4 mmol) was added dropwise after periodic HPLC analysis. After the reaction mixture had been stirred at 20-30°C for 18 hours, the pH was adjusted to 7 by the addition of hydrochloric acid (1 M; 309 g), and stirring was continued for 15 minutes. The organic layer was stirred with aqueous sodium sulfate (10%; 485.30 g) at 20-30°C for 15 minutes, and then the organic layer was concentrated in vacuo to 1-2 volumes while maintaining the temperature below 40°C. Dimethyl sulfoxide (71.7 g) was added to afford C55 (154.2 g, 48.9 wt% C55) as a dimethyl sulfoxide solution. Most of this material was carried on to the following step. Estimated yield: 75.4 g, 0.239 mol, 99%. 1 H NMR (400MHz, DMSO-d6) δ4.16 (q, J = 7.1Hz, 4H), 3.67 (br s, 2H), 3.34-3.26 (m, 2H), 2.37-2.28 (m, 2H), 1.39 (s, 9H), 1.17 (br t, J = 7.1Hz, 6H).

[0752] Step 8. Synthesis of (3R)-1-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)pyrrolidine-3-carboxylic acid (C56).

[0753] ECS-esterase 03 enzyme [Bacillus stearothermophilus, recombinant from Escherichia coli (EC 3.1.1.1); 0.540 g] was added to phosphate buffer (0.1 M; pH = 6.92, 580 mL, 8.2 volumes) at 20°C to 30°C. A solution of C55 (72.2 g, 0.229 mol) in dimethyl sulfoxide (from the previous step; approximately 148 g) was added; additional dimethyl sulfoxide (9 mL) was used to rinse the initial container and also added to the reaction mixture. The initial reaction pH was 7.08; after stirring at 20°C to 30°C for 1 hour, the pH dropped to 6.58. The pH was maintained at 7.5 over 24 hours using a pH autotitrator by adding aqueous sodium hydroxide solution (2 M; 121 mL, 0.242 mol). Hydrochloric acid (6 M; 52 mL, 0.312 mol) was added to bring the pH to 2.39; ethyl acetate (435 mL, 6.0 vol) was then added, and the mixture was stirred at 20-30° C. for 30 minutes. Filtering through celite (18.0 g) gave a filter cake, which was rinsed with ethyl acetate (2×75 mL). The combined filtrate was stirred at 20-30° C. for 30 minutes, and the aqueous layer was then stirred with ethyl acetate (217 mL, 3.0 vol) for 30 minutes. The combined organic layers were washed twice with water (360 mL, 5.0 vol) by stirring for 30 minutes. The resulting solution was concentrated in vacuo to 1-2 vol while maintaining the temperature below 40° C., and then diluted with toluene (360 mL); this concentration / dilution procedure was performed a total of three times, providing C56 (418.3 g, 15.67 wt% C56) as a toluene solution. Estimated yield: 65.6 g, 0.228 mol, quantitative. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.99 (v br s, 1H), 4.22 (q, J = 7.1 Hz, 2H), [3.88 (br s) and 3.83 (br s), total 2H], 3.51-3.38 (m, 2H), 2.41 (t, J = 7.1 Hz, 2H), 1.44 (s, 9H), 1.26 (br t, J = 7 Hz, 3H).

[0754] Step 9. Synthesis of 1-tert-butyl 3-ethyl (3S)-3-{[(benzyloxy)carbonyl]amino}pyrrolidine-1,3-dicarboxylate (C57)...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in: R 1 is H, halogen, 4- to 7-membered heterocycloalkyl, phenyl or R 1a wherein the phenyl group is optionally substituted with 1 or 2 independently selected R B1 replace; or R 1 is the sum of two adjacent R B Substituted phenyl, wherein the two adjacent R B Together with the two ring-forming atoms of the phenyl group to which it is attached, it forms a fused 5- or 6-membered heteroaryl group, each of which is optionally substituted by 1 or 2 C 1-4 Alkyl substituent substitution; R 1a is optionally 1 or 2 independently selected R A substituted 5- or 6-membered heteroaryl, wherein each R A For halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl, -N(C 1-4 Alkyl)2, or R A1 ; or two adjacent R A Together with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which it is attached, it forms a fused 5- or 6-membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl, each of which is optionally substituted by 1 or 2 atoms each independently selected from halogen or C 1-4 Substitution of alkyl groups; R A1 is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl group, which is optionally substituted by C 1-4 Alkyl substitution; R B1 is a 5- or 6-membered heteroaryl group, which is optionally C 1-4 Alkyl substitution; X 1 C(R X )2, where each R X independently H or C 1-4 alkyl; R 2 and R 3 Each of which is independently H, halogen, or C 1-4 alkyl; Y 1 , Y 2 , Y 3 , Y 4 and Y 5 Each of which is independently CR 4 or N, with the restriction Y 1 , Y 2 , Y 3 , Y 4 and Y 5 No more than 3 of them are N; and Each R 4 are independently H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 Haloalkoxy.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ia: or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula II: or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula III: or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: R 1 For R 1a ;and R 1a is optionally 1 or 2 independently selected R A Substituted 6-membered heteroaryl, wherein each R A For halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, or C 3-4 Cycloalkyl; or two adjacent R A Together with the two ring atoms of the 6-membered heteroaryl to which it is attached, a fused 5- or 6-membered heteroaryl is formed, which is optionally substituted by 1 or 2 atoms each independently selected from halogen or C 1-4 The alkyl group is substituted with a substituent.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1a is optionally 1 or 2 independently selected R A Substituted pyrimidinyl, wherein each R A For halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-4 Cycloalkyl.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 1a It is pyrimidin-2-yl.

8. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein X 1 For CH2.

9. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each of which is independently H, F or C 1-4 alkyl.

10. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl and R 3 For H.

11. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein Y 3 is N, and Y 1 , Y 2 , Y 4 and Y 5 Each of which is independently CR 4 .

12. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein each R 4 are independently H, halogen or C 1-2 Alkoxy.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(2-methyl-2H-tetrazolyl-5-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one, DIAST-1; 2-(6-methoxy-2-methylpyrimidin-4-yl)-1-[(2S)-7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidin-1'-yl]propan-1-one, DIAST-1; 2-[6-(Difluoromethoxy)pyridin-3-yl]-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidino]-1'-yl]propan-1-one, DIAST-2; 1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [pyridin-2,3'-pyrrolidinyl]-1'-yl]-2-[4-(trifluoromethyl)phenyl]propan-1-one, DIAST-1; 1-(4,7-dimethyl-3,4-dihydro-1H-spiro[1,8- pyridin-2,3'-pyrrolidin]-1'-yl)-2-(4-fluorophenyl)ethan-1-one, DIAST-1; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(2-methyl-2H-tetrazolyl-5-yl)-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidino]-1'-yl]propan-1-one; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidino]-1'-yl]propan-1-one; (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidino]-1'-yl]propan-1-one; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidino]-1'-yl]propan-1-one, DIAST-1; and (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-{(2S)-7-methyl-6-[(4,6- 2 H2)pyrimidin-2-yl]-3,4-dihydro-1H-spiro[1,8- pyrrolidine-2,3'-pyrrolidino]-1'-yl}propan-1-one.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidino]-1'-yl]propan-1-one.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, which is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- [2,3'-pyrrolidino]-1'-yl]propan-1-one.

16. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, which is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- A pharmaceutically acceptable salt of pyridine-2,3'-pyrrolidin-1'-yl]propan-1-one.

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8- A crystalline form of [2,3'-pyrrolidino]-1'-yl]propan-1-one.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

19. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for antagonizing melanocortin-4 receptor (MC4R).

20. A method of antagonizing melanocortin-4 receptor (MC4R) in an ex vivo system, comprising contacting the MC4R with a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

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