Triazole-pyridyl-substituted azacyclohexyl acetic acid compounds as LPA receptor antagonists

Abstract

The present application relates to novel substituted azacyclohexyl acetic acid compounds, the preparation of the novel substituted azacyclohexyl acetic acid compounds, pharmaceutical compositions comprising the novel substituted azacyclohexyl acetic acid compounds, and the use of the novel substituted azacyclohexyl acetic acid compounds as medicaments for treating diseases associated with lysophosphatidic acid receptor (LPA) disorders.

Description

Technical Field

[0001] The present application relates to novel substituted azacyclohexyl acetic acid compounds and analogs, the manufacture of said novel substituted azacyclohexyl acetic acid compounds and analogs, pharmaceutical compositions comprising said novel substituted azacyclohexyl acetic acid compounds and analogs, and the use of said novel substituted azacyclohexyl acetic acid compounds and analogs as medicaments for the treatment of diseases associated with dysregulation of lysophosphatidic acid receptors (LPARs). Background Art

[0002] Lysophosphatidic acid (LPA) is a small glycerophospholipid (1- or 2-acyl-sn-glycerol 3-phosphate) with a molecular weight of 430-480 daltons, consisting of a glycerol backbone esterified with a phosphate group and fatty acids with variable chain lengths and degrees of saturation (Yang and Chen, World J Gastroenterol 24:4132-4151, 2018). LPA can be formed from precursor molecules in plasma, serum, or tissue (membrane phospholipids) by several pathways: (1) by hydrolytic removal of the choline group of lysophosphatidylcholine by lysophospholipase D (lysoPLD or autotoxin); (2) by hydrolysis of the fatty acyl chain from phosphatidic acid by phospholipase A1 or A2 to produce 2-acyl or 1-acyl LPA; and (3) by resynthesis from glycerol 3-phosphate by acyltransferase (Kihara et al., Experimental Cell Res 333:171-177, 2015). In tissues or cells, LPA represents a mixture of 1- or 2-acyl-sn-glycerol 3-phosphates.

[0003] Lysophosphatidic acid (LPA) acts as a signaling molecule and exerts its effects by binding to G protein-coupled receptors called LPA receptors (LPARs). To date, six identified LPA receptors (LPAR1-6) are known to be expressed in various tissues and / or cells. LPA plays important roles in pathophysiological processes such as autoimmune diseases, fibrotic diseases, cancer, inflammation, neuropathic pain, etc. by binding to its receptors (Budd and Qian, Future Med Chem 5:1935-52, 2013; Valdés-Rives and González-Arenas, Mediators Inflamm 2017:9173090, 2017; Lopane et al., Biochim Biophys Acta Rev Cancer 1868:277-282, 2017; Ueda H., Pain 158 Suppl 1:S55-S65, 2017).

[0004] Fibrosis is a repair (or "healing") process characterized by the excessive accumulation of the extracellular matrix (ECM). When tissue damage (caused by infection, autoimmune reaction, mechanical injury, etc.) is chronic, the continuous production of profibrotic mediators leads to an uncontrolled healing process and the replacement of damaged cells by connective tissue associated with excessive ECM production (Weiskirchen et al., Molecular Aspects Med. 65:2-15, 2019). Because it alters the architecture and function of organs, fibrosis is closely associated with morbidity and mortality and is often the cause of morbidity and mortality. It is estimated that 45% of all deaths in developed countries are attributed to some type of chronic fibrosis such as idiopathic pulmonary fibrosis, systemic sclerosis, cirrhosis, chronic cardiovascular disease, progressive kidney disease (renal fibrosis), or diabetes (Wynn T.A., Nat. Rev. Immunol. 4:583-594, 2004).

[0005] The profibrotic effects of LPA through binding to its receptor LPAR1 have been established in the lung, liver, and other organs or tissues and have two main characteristics: 1) There is a positive correlation between the appearance of fibrosis markers and the increased production of LPA associated with increased LPAR1 expression; 2) Fibrosis is attenuated in LPAR1− / − mice or by treatment with LPAR antagonists (Rancoule et al., Expert Opin. Investig. Drugs 20:657–667, 2011). For example, in the bleomycin model of pulmonary fibrosis, LPA levels in bronchoalveolar lavage fluid are significantly elevated after lung injury, and mice lacking the LPAR1 gene (LPAR1− / − mice) significantly prevent fibrosis and mortality (Tager et al., Nat. Med. 14:45–54, 2008). Treatment with a small molecule LPAR1 antagonist can reduce pulmonary fibrosis in the bleomycin mouse model (Swanet et al., Br. J. Pharmacol. 160:1699–1713, 2010). Recently, in a chemically induced cirrhosis and HCC rat model, the expression of Lapr1 was significantly increased in hepatic stellate cells, while lysoPLD (autotoxin) was higher in hepatocytes (Nakagawa et al., Cancer Cell 30:879–890, 2016). Transcriptome analysis of human and rat liver tissues indicates that the LPA pathway through activation of LPAR1 is a functional driver of cirrhosis and HCC. Thus, inhibition of LPAR1 and lysoPLD by chemical inhibitors attenuates the fibrotic process and reduces HCC nodules in a cirrhosis-driven HCC rat model (Id.). SUMMARY OF THE INVENTION

[0006] On the one hand, the present invention relates to a compound of formula (I)

[0007]

[0008] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

[0009] wherein:

[0010] L 1 is a covalent bond or CH2 optionally substituted with 1 or 2 methyl groups;

[0011] L 2 is a covalent bond or (CR 7 R 7 ) p ;

[0012] L 3is a covalent bond, O or NR 7 , provided that L 2 and L 3 at least one of which is not a covalent bond;

[0013] Q is C(=O)NR 9 R 10 , C(=O)OR 10 or a ring selected from 5 - or 6 - membered heteroaryl or 5 - or 6 - membered heterocyclic group, wherein said ring comprises at least one carbon atom, at least one nitrogen atom and optionally 1 to 4 additional heteroatoms selected from nitrogen, oxygen and sulfur, wherein oxygen can be a ring member and / or an oxo group attached to a ring member, and wherein said ring is substituted by (R 3 ) n and an R 4 ;

[0014] X 1 is N, O or CR 6a ;

[0015] X 2 is N or NR 6 ;

[0016] X 3 is N, NR 6 or CR 6 , wherein the dashed circle represents a bond forming a five - membered aromatic ring;

[0017] Y 1 , Y 2 , Y 3 and Y 4 are each independently N or CR 5 , provided that at least one but not more than two of Y 1 , Y 2 , Y 3 and Y 4 are N;

[0018] Z is CH2 or O;

[0019] R 1 is independently, each time it appears, hydrogen, halogen, C 1-6 alkyl, halo - C 1-6 alkyl, OH, C 1-6 alkyl - OH, C 1-6 alkoxy, halo - C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b , C 1-6 alkyl - NR a R b or a 4 - to 6 - membered heterocyclic group, or two R1 The group together with the carbon atom to which it is attached forms C=O;

[0020] R 2 is (CR 7 R 7 ) q -R 8 ;

[0021] R 3 is independently, at each occurrence, hydrogen, halogen, CN, C 1-6 alkyl or C 3-7 cycloalkyl;

[0022] R 4 is independently hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, a (CH2) 11 substituted by 1 to 4 R q -5- to 6-membered heteroaryl ring, a (CH2) 11 substituted by 1 to 4 R q -5- to 7-membered heterocyclic ring, where each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0023] R 5 is independently, at each occurrence, hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy, halo-C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a Rb or C 1-6 alkyl-NR a R b ;

[0024] R 6a and R 6 are each independently hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl upon each occurrence;

[0025] R 7 is independently hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or two R 7 groups together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring;

[0026] R 8 is C(=O)OR 7 、C(=O)NR a R b 、CN、C(=O)NHC(=O)R 7 、C(=O)NHS(=O)2R 7 、C(=O)NHS(=O)R 7 、S(=O)2R 7 、P(=O)(OH)2 or

[0027] R 9 and R 10 are each independently hydrogen, C 11 alkyl substituted with 1 to 4 R 1-6 、(CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkynyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 3-7 cycloalkyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -phenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q-A 5- to 6-membered heteroaryl ring, substituted by 1 to 4 Rs 11 (CR 12 R 12 ) q -A 5- to 7-membered heterocyclic ring; or R 9 and R 10 together with the nitrogen atom to which they are attached form a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted by 1 to 4 Rs 11 , said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

[0028] R 11 is independently, in each occurrence, hydrogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, wherein each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0029] R 12 is independently, in each occurrence, hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, or two R 12 groups together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl ring;

[0030] R a and R b are independently, in each occurrence, hydrogen or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing three to seven ring atoms, said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted by one to three groups, which may be the same or different, selected from C1-4 The group consisting of alkyl, phenyl and benzyl;

[0031] m is 1 or 2;

[0032] n is 0, 1 or 2;

[0033] p is independently 1, 2, 3 or 4 each time it appears; and

[0034] q is independently 0, 1, 2, 3 or 4 each time it appears.

[0035] The present invention also relates to pharmaceutical compositions comprising the compound of formula (I), their manufacture and their use as a medicament for the treatment of diseases associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1). Thus, the compound of formula (I) can be used for the treatment of pathological fibrosis (e.g., pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, skin fibrosis, ocular fibrosis or pancreatic fibrosis), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy or systemic sclerosis. Detailed Description

[0036] On the one hand, the technology of the present invention provides compounds and pharmaceutically acceptable forms of said compounds, including but not limited to their salts, hydrates, solvates, isomers, stereoisomers, enantiomers, prodrugs and isotopically labeled derivatives.

[0037] On the other hand, the technology of the present invention provides methods for treating and / or controlling various diseases and disorders, said methods comprising administering to a patient a therapeutically effective amount of a compound or a pharmaceutically acceptable form thereof (e.g., salts, hydrates, solvates, isomers, stereoisomers, enantiomers, prodrugs and isotopically labeled derivatives) provided herein. Non-limiting examples of diseases and disorders are described herein.

[0038] On the other hand, the technology of the present invention provides methods for preventing various diseases and disorders, said methods comprising administering to a patient in need of such prevention a prophylactically effective amount of a compound or a pharmaceutically acceptable form thereof (e.g., salts, hydrates, solvates, isomers, stereoisomers, enantiomers, prodrugs and isotopically labeled derivatives) provided herein. Non-limiting examples of diseases and disorders are described herein.

[0039] On the other hand, the technology of the present invention, a compound or a pharmaceutically acceptable form thereof (e.g., salts, hydrates, solvates, isomers, stereoisomers, enantiomers, prodrugs and isotopically labeled derivatives) provided herein can be administered in combination with another medicament (“second active agent”) or treatment. The second active agent includes small molecules and macromolecules (e.g., proteins and antibodies).

[0040] The present disclosure also provides pharmaceutical compositions (e.g., single unit dosage forms) that can be used in the methods provided herein. In one embodiment, the pharmaceutical composition comprises a compound provided herein or a pharmaceutically acceptable form thereof (e.g., salts, hydrates, solvates, isomers, stereoisomers, prodrugs, and isotopically labeled derivatives), and optionally one or more second active agents.

[0041] Although specific embodiments have been discussed, the specification is illustrative only and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art after reading this specification.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this specification belongs.

[0043] Definition

[0044] As used in the specification and claims, the singular forms "a / an" and "the" include plural referents unless the context clearly dictates otherwise.

[0045] As used herein, "agent", "additional agent", "therapeutic agent", or "second active agent" refers to a biological, pharmaceutical, or chemical compound or another moiety. Non-limiting examples include simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamins, vitamin derivatives, carbohydrates, toxins, or chemotherapeutic compounds and their metabolites. A variety of compounds can be synthesized, such as small molecules and oligomers (e.g., oligopeptides and oligonucleotides) and synthetic organic compounds based on various core structures. Additionally, various natural sources can provide active compounds, such as plant or animal extracts, etc. One of ordinary skill in the art can readily recognize that there is no limitation on the structural nature of the agents of the present disclosure.

[0046] "Administration" of the disclosed compounds encompasses delivering a compound described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, to a subject using any suitable formulation or route of administration discussed herein.

[0047] As used herein, the terms "co-administer", "combine administration", and grammatical equivalents thereof encompass administering two or more agents to a subject such that the two agents and / or their metabolites are present in the subject simultaneously. Co-administration includes simultaneous administration in separate compositions, administration at separate times in separate compositions, or administration in a composition in which both agents are present.

[0048] The term "effective amount" or "therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition described herein sufficient to effect the intended application, including but not limited to the treatment of a disease, as described below. In some embodiments, the amount is an amount effective for detectable inhibition of LPA1, which amount can be determined, for example, in an LPA1 functional antagonist assay. The therapeutically effective amount can vary depending on the intended application (in vitro or in vivo) or the subject being treated and the condition (e.g., the weight and age of the subject, the severity of the condition, the mode of administration, etc.) that can be readily determined by one of ordinary skill in the art. The term also applies to a dose that will induce a response in a target cell, e.g., a reduction in cell migration. The specific dose will vary depending on, for example, the compound selected, the species of the subject, and its age / underlying health or risk of health condition, the dosing regimen followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue being administered to, and the physical delivery system being carried.

[0049] Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order.

[0050] As used herein, the terms "treatment", "treating", "alleviating", "controlling", and "ameliorating" are used interchangeably herein. These terms refer to a method of obtaining a beneficial or desired result, including but not limited to a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" refers to eradicating or ameliorating the underlying condition being treated. Additionally, a therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the underlying condition such that an improvement is observed in the patient, even though the patient may still be suffering from the underlying condition. For a prophylactic benefit, a pharmaceutical compound and / or composition can be administered to a patient at risk of developing a disease or reporting one or more physiological symptoms of a disease, even though a diagnosis of such disease has not yet been made.

[0051] As used herein, the terms "preventing" and "prophylaxis" refer to administering a pharmaceutical compound or drug or a composition comprising a pharmaceutical compound or drug to a subject prior to a disease, disorder, or condition fully manifesting itself to prevent the occurrence and / or mitigate the severity of one or more symptoms of the disease, disorder, or condition. One of ordinary skill in the art recognizes that the term "preventing" is not an absolute term. In the medical field, "preventing" should be understood to mean prophylactically administering a drug to significantly reduce the likelihood or severity of a disease, disorder, or condition or its symptoms, and this is the meaning in which such terms are used in the present disclosure.

[0052] As used herein, the term "therapeutic effect" encompasses the therapeutic and / or prophylactic benefits as described above. Prophylactic effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting or reversing the progression of a disease or condition, or any combination thereof.

[0053] A "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., males or females of any age group such as, for example, pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged or elderly)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including rodents (e.g., mice, rats), cattle, pigs, horses, sheep, goats, cats and / or dogs; and / or avians, including avians such as chickens, ducks, geese, quails and / or turkeys.

[0054] The term "in vivo" refers to events occurring within a subject. In vivo also includes events occurring in rodents such as rats, mice, guinea pigs, etc.

[0055] The term "in vitro" refers to events occurring outside of a subject. For example, in vitro assays encompass any assay conducted outside of a subject. In vitro assays encompass cell-based assays in which live or dead cells are employed. In vitro assays also encompass cell-free assays in which intact cells are not employed.

[0056] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. (incorporated herein by reference) describe pharmaceutically acceptable salts in detail in the Journal of Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include those salts derived from suitable inorganic acids and organic acids, as well as inorganic bases and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by the reaction of an amino group with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by using other methods employed in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, besylates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, glucuronates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, tosylates, undecanoates, valerates, etc. In some embodiments, the organic acids from which the salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0057] The salts can be prepared in situ during the isolation and purification of the disclosed compounds or separately, such as by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 alkyl) 4Salts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Additionally, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates when appropriate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts can be selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0058] As used herein, the term "solvate" refers to a compound that further contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate can be the disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are, for example, complexes that can contain from 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It should be understood that the term "compound" as used herein encompasses compounds and solvates of compounds and mixtures thereof.

[0059] In some embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable form of the compound. The prodrug can be inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in the blood). In certain cases, the prodrug has improved physical and / or delivery properties compared to the parent compound. The prodrug can increase the bioavailability of the compound when administered to a subject (e.g., by allowing enhanced absorption into the blood after oral administration) or enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of the disclosed compounds that have enhanced water solubility or active transport across intestinal membranes relative to the parent compound.

[0060] Prodrug compounds generally offer the advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14 and “Bioreversible Carriers in Drug Design,” ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987 provide discussions of prodrugs, both of which are incorporated herein by reference in their entirety. Exemplary advantages of prodrugs can include, but are not limited to, their physical properties such as enhanced water solubility upon parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance the stability of the drug upon long-term storage.

[0061] The term “prodrug” also is intended to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to an animal subject. Prodrugs of the active compounds described herein can be prepared by modifying the functional groups present in the active compounds in such a way that the modifying moiety cleaves in vivo or upon conventional manipulation to the parent active compound. Prodrugs include compounds in which a hydroxyl, amino, or mercapto group is bonded to any group that cleaves to form a free hydroxyl, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols or acetamides in the active compound, formamide and benzamide derivatives of the amine functional group, etc. Other examples of prodrugs include compounds that include -NO, -NO2, -ONO, or -ONO2 moieties. Prodrugs generally can be prepared using well-known methods such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995) and Design of Prodrugs (H. Bundgaard ed., Elsevier, New York, 1985).

[0062] For example, if the disclosed compound or a pharmaceutically acceptable form of the compound contains a carboxylic acid functional group, the prodrug may include a pharmaceutically acceptable ester formed by replacing the hydrogen atom of the acid group with a group such as: (C 1-8 )alkyl, (C 1-12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 10 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-4-yl, di-N,N-(C 1-2 )alkylamino(C 2-3 )alkyl (such as [3-dimethylaminoethyl), carbamoyl-(C 1-2 )alkyl, N,N-di(C 1-2 )alkylaminocarbonyl-(C 1-2 )alkyl and piperidino-, pyrrolidino- or morpholino(C 2-3 )alkyl.

[0063] Similarly, if the disclosed compound contains an alcohol functional group, the prodrug may be formed by replacing the hydrogen atom of the alcohol group with a group such as: (C 1-6 )alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 )alkoxycarbonylaminomethyl, succinyl, (C 1-6 )alkanoyl, α-amino(C 1-4 )alkanoyl, aroyl and α-aminoacyl or α-aminoacyl-α-aminoacyl, where each α-aminoacyl is independently selected from the naturally occurring L-amino acids, -P(O)(OH)2, -P(O)(O(C 1-6 )alkyl)2 or a glycosyl radical (a radical formed by removing the hydroxy group of a hemiacetal form of a carbohydrate).

[0064] If the disclosed compound incorporates an amine functional group, the prodrug may be formed by replacing the hydrogen atom in the amine group with a group such as: R-carbonyl, RO-carbonyl, NRR'-carbonyl, where R and R' are each independently selected from (C 1–10 )alkyl, (C3-7 ) cycloalkyl, benzyl, natural α - aminoacyl or natural α - aminoacyl - natural - α - aminoacyl, -C(OH)C(O)OY 1 , wherein Y 1 is H, (C 1-6 )alkyl or benzyl, -C(OY 2 )Y 3 , wherein Y 2 is (C 1-4 )alkyl, and Y 3 is (C 1-6 )alkyl, carboxy(C 1-6 )alkyl, amino(C 1-4 )alkyl or mono - N - or di - N,N - (C 1-6 )alkylaminoalkyl; and -C(Y 4 )Y 5 , wherein Y 4 is H or methyl, and Y 5 is mono - N - or di - N - (C16)alkylamino, morpholino, piperidin - 1 - yl or pyrrolidin - 1 - yl.

[0065] In some embodiments, the disclosed compounds may encompass isomers. "Isomers" are different compounds having the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. As used herein, the term "isomers" encompasses any and all geometric isomers and stereoisomers. For example, "isomers" encompasses geometric cis - and trans - isomers of double bonds, also known as E - and Z - isomers; R - and S - enantiomers; diastereomers, (d) - isomers and (l) - isomers, their racemic mixtures; and other mixtures thereof, such as those falling within the scope of the present disclosure.

[0066] Geometric isomers can be represented by the symbol ----- which represents a bond that can be a single bond, double bond or triple bond as described herein. Various geometric isomers and their mixtures resulting from the arrangement of substituents around a carbon - carbon double bond or around a carbon ring are provided herein. Substituents around a carbon - carbon double bond are designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both "E" and "Z" isomers.

[0067] Substituents around a carbon-carbon double bond can alternatively be referred to as "cis" or "trans", where "cis" indicates substituents on the same side of the double bond and "trans" indicates substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be designated as "cis" or "trans". The term "cis" indicates substituents on the same side of the plane of the ring and "trans" indicates substituents on opposite sides of the plane of the ring. A mixture of compounds in which the substituents are arranged on the same side and opposite sides of the plane of the ring is designated as "cis / trans".

[0068] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is assigned according to the Cahn-Ingold-Prelog R-S system. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be assigned as R or S. A resolved compound of unknown absolute configuration can be designated as (+) or (-), depending on the direction (right-handed or left-handed) in which it rotates plane-polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms defined as (R)- or (S)- according to the absolute stereochemistry at each asymmetric atom. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to encompass all such possible isomers, including racemic mixtures, substantially optically pure forms, and mixtures of intermediates. Optically active (R)- and (S)-isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0069] A mixture of a pair of enantiomers in any proportion can be referred to as a "racemic" mixture. The term "(±)" is used to indicate a racemic mixture where appropriate. In some embodiments, the compounds of the techniques of the present invention are racemic mixtures of (S)- and (R)-isomers. In some embodiments, the racemic mixture has equal amounts of the two enantiomers.

[0070] In some embodiments, the enantiomers provided are partially or substantially free of the corresponding enantiomer and can be referred to as "optically enriched", "enantiomerically enriched", "enantiomerically pure", and "non-racemic", which are used interchangeably herein. The "enantiomeric excess" or "% enantiomeric excess" of such compounds can be calculated using the equation shown below. In the example shown below, the composition contains one enantiomer, for example 90% of the S enantiomer, and another enantiomer, for example 10% of the R enantiomer.

[0071] ee = (90 - 10) / 100 = 80%.

[0072] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. In some embodiments, the compositions described herein have an enantiomeric excess of the S enantiomer of: at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5%, or a range between any two of the foregoing values and including any two of the foregoing values (e.g., 50 - 99.5% ee). In other words, the composition has an enantiomeric excess of the S enantiomer relative to the R enantiomer. In other embodiments, some of the compositions described herein have an enantiomeric excess of the R enantiomer of: at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5%, or a range between any two of the foregoing values (e.g., 50 - 99.5% ee). In other words, the composition has an enantiomeric excess of the R enantiomer relative to the S enantiomer. In cases where the enrichment amount of one enantiomer is much greater than about 80% by weight, the composition is referred to as a "substantially enantiomerically enriched", "substantially enantiomerically pure", or "substantially non-racemic" formulation.

[0073] Enantiomers can be separated from a racemic mixture or prepared by asymmetric synthesis by any method known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), formation and crystallization of chiral salts. See, for example, Enantiomers, Racemates and Resolutions (edited by Jacques, Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Stereochemistry of Carbon Compounds (edited by E.L. Eliel, McGraw-Hill, NY, 1962); and Tables of Resolving Agents and Optical Resolutions, page 268 (edited by E.L. Eliel, Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

[0074] Optical isomers can be obtained by resolution of a racemic mixture according to conventional methods, such as by formation of diastereomeric salts, by treatment with an optically active acid or base. Examples of suitable acids include, but are not limited to, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, xyloyl tartaric acid, and camphorsulfonic acid. The diastereomeric mixture is separated by crystallization and the isomers are then separated by release of the optically active base from these salts. Another method involves the synthesis of covalently linked diastereomeric molecules by reaction of the disclosed compounds with an activated form of an optically pure acid or an optically pure isocyanate. The synthesized diastereomers can be separated by conventional methods such as chromatography, distillation, crystallization, or sublimation and then hydrolyzed to provide an enantiomerically enriched compound. Optically active compounds can also be obtained by using optically active starting materials. In some embodiments, these isomers can be in the form of free acids, free bases, esters, or salts.

[0075] In any embodiment, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" is a type of isomer that includes two or more interconvertible compounds, which are generated by at least one formal hydrogen atom migration and at least one valence change (e.g., single bond to double bond, triple bond to single bond, and vice versa). "Tautomerization" includes prototropic or prototropic tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "prototropic tautomerization" involves proton migration accompanied by a change in bond order. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. In cases where tautomerization can occur (e.g., in solution), a chemical equilibrium of tautomers can be reached. Tautomerization (i.e., the reaction that provides tautomeric pairs) can be catalyzed by an acid or a base, or can occur without the action or presence of an external agent. Exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactam; enamine-imine and enamine-(different) enamine tautomerizations. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0076] Unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention with the replacement of hydrogen by deuterium or tritium or the replacement of carbon by 13 C or 14 C-enriched carbon are within the scope of this disclosure.

[0077] This disclosure also includes pharmaceutically acceptable forms as "isotopically labeled derivatives", which are the same compounds as those described herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H, 3 H, 13 C 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36Cl. Certain disclosed compounds that are isotopically labeled (e.g., those compounds labeled with 3 H and 14 C) can be used for compound and / or substrate tissue distribution assays. Tritiated isotopes (i.e., 3 H) and carbon-14 isotopes (i.e., 14 C) can be readily prepared and detected. Further, substitution with heavier isotopes (such as deuterium, i.e., 2 H) can provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dose requirements) due to greater metabolic stability. Isotopically labeled disclosed compounds can generally be prepared by substituting non-isotopically labeled reagents with isotopically labeled reagents. In some embodiments, compounds are provided herein that may also contain non-natural proportions of atomic isotopes at one or more atoms that make up such compounds. All isotopic variations (whether radioactive or non-radioactive) of the compounds disclosed herein are encompassed within the scope of this disclosure. In some embodiments, radiolabeled compounds can be used to study the metabolism and / or tissue distribution of a compound or to alter the rate or pathway of metabolism or other aspects of biological function.

[0078] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like. A pharmaceutically acceptable carrier or excipient does not destroy the pharmacological activity of the disclosed compound and is non-toxic when administered in a dose sufficient to deliver a therapeutically effective amount of the compound. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions disclosed herein is contemplated. Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, glucose, and sucrose; starches such as corn starch, potato starch; celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; glycols such as polyethylene glycol and propylene glycol; esters such as ethyl oleate, ethyl laurate; agar; buffering agents such as magnesium hydroxide, aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; release agents; coating agents; sweetening agents, flavoring agents, and fragrances; preservatives; antioxidants; ion exchange agents; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopheryl polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms such as Tween or other similar polymeric delivery matrices; serum proteins such as human serum albumin; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based materials; polyacrylates; waxes; and polyethylene-polypropylene-block polymers. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrins or chemically modified derivatives such as hydroxyalkyl cyclodextrins (including 2- and 3-hydroxypropyl-cyclodextrin) or other solubilizing derivatives may also be used to enhance the delivery of the compounds described herein.

[0079] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry as well as specific functional moieties and reactivity are described in the following references: Organic Chemistry, Thomas Sorrell, University Science Books, Sansalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0080] Unless otherwise indicated herein, the recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value and sub-range falling within the stated range, and each separate value and sub-range is incorporated into this specification as if it were individually recited herein. For example, "C 1-6 alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0081] "Alkyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, the straight-chain or branched-chain hydrocarbon chain group having no unsaturation and having from one to ten carbon atoms (e.g., C 1-10 alkyl). When it appears herein, a numerical range such as "1 to 10" refers to each integer within the given range; for example, "1 to 10 carbon atoms" means that the alkyl group can consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, but the definition of the present invention also encompasses the occurrence of the term "alkyl" without a specified numerical range. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl; while saturated branched-chain alkyl groups include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl group is connected to the parent molecule by a single bond. Unless otherwise stated in the specification, the alkyl group can optionally be substituted with one or more substituents disclosed herein. In non-limiting embodiments, the substituted alkyl group can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0082] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., C 2-10 alkenyl). Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer within the given range; for example, "2 to 10 carbon atoms" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In any embodiment, the alkenyl group includes from two to eight carbon atoms. In other embodiments, the alkenyl group includes from two to six carbon atoms (e.g., C 2-6 alkenyl). The alkenyl group is connected to the parent molecular structure by a single bond. For example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. One or more carbon-carbon double bonds can be located internally (such as in 2-butene) or terminally (such as in 1-butene). Examples of C 2-4 alkenyl include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), 2-methylprop-2-enyl (C4), butadienyl (C4), and the like. C 2-6Examples of alkenyl include the aforementioned C 2-4 alkenyl and pentenyl (C5), pentadienyl (C5), hexenyl (C6), 2,3-dimethyl-2-butenyl (C6), etc. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatriene (C8), etc. Unless otherwise specified in the specification, alkenyl may optionally be substituted with one or more substituents disclosed herein.

[0083] "Alkynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one triple bond, and having two to ten carbon atoms (i.e., C 2-10 alkynyl). Whenever a numerical range such as "2 to 10" appears herein, it refers to each integer within the given range. For example, "2 to 10 carbon atoms" means that the alkynyl may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In any embodiment, the alkynyl includes two to eight carbon atoms. In other embodiments, the alkynyl has two to six carbon atoms (e.g., C 2-6 alkynyl). The alkynyl is connected to the parent molecular structure by a single bond. For example, ethynyl, propynyl, butynyl, pentynyl, 3-methyl-4-pentenyl, hexynyl, etc. Unless otherwise specified in the specification, the alkynyl may optionally be substituted with one or more substituents disclosed herein.

[0084] "Alkoxy" refers to the group -O-alkyl, which includes 1 to 10 straight-chain, branched-chain, saturated cyclic configuration carbon atoms and combinations thereof connected to the parent molecular structure through oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, cyclopropoxy, cyclohexyloxy, etc. "Lower alkoxy" refers to an alkoxy containing one to six carbons. In some embodiments, C 1-4 alkoxy is an alkoxy containing both straight-chain and branched-chain alkyls having 1 to 4 carbon atoms. Unless otherwise specified in the specification, the alkoxy may optionally be substituted with one or more substituents disclosed herein. The terms "alkenyloxy" and "alkynyloxy" are very similar to the above description of "alkoxy", where the prefix "alk" is replaced by "alken" or "alkyn", respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein.

[0085] "Aromatic" or "aryl" refers to a group having 6 to 14 ring atoms (e.g., C 6-14 aromatic or C 6-14 aryl), said group having at least one ring having a carbocyclic conjugated π-electron system (e.g., phenyl, fluorenyl, and naphthyl). In some embodiments, the aryl is C 6-10Aryl. For example, a divalent group formed from a substituted benzene derivative and having a free valence at a ring atom is named a substituted phenylene. In other embodiments, a divalent group derived from a monovalent polycyclic hydrocarbon group whose name ends with "-yl" by removing a hydrogen atom from a carbon atom having a free valence is named by adding "-idene" to the name of the corresponding monovalent group. For example, a naphthyl group having two attachment points is called naphthylidene. Whenever it appears herein, a numerical range such as "6 to 14 aryl" refers to each integer within the given range. For example, "6 to 14 ring atoms" means that the aryl can be composed of 6 ring atoms, 7 ring atoms, etc., up to and including 14 ring atoms. The term encompasses monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In a polycyclic group, only one ring needs to be aromatic, so groups such as indanyl are encompassed within the definition of aryl. Non-limiting examples of aryl include phenyl, benzonaphthyl, naphthyl, tetrahydronaphthyl, phenanthryl, anthryl, fluorenyl, indolyl, indanyl, etc. Unless otherwise specified in the specification, aryl may optionally be substituted by one or more substituents disclosed herein.

[0086] "Cycloalkyl" and "carbocyclic group" each refer to a monocyclic or polycyclic radical containing only carbon and hydrogen, and may be saturated or partially unsaturated. If the carbocyclic ring contains at least one double bond, the partially unsaturated cycloalkyl may be referred to as "cycloalkenyl", or if the carbocyclic ring contains at least one triple bond, the partially unsaturated cycloalkyl may be referred to as "cycloalkynyl". Cycloalkyl includes groups having 3 to 13 ring atoms (i.e., C 3-13 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer within the given range. For example, "3 to 13 carbon atoms" means that the cycloalkyl can be composed of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused cyclic structures that do not contain heteroatoms. The term also encompasses monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" may be C 3-8 cycloalkyl. In some embodiments, "cycloalkyl" may be C 3-5 cycloalkyl. Illustrative examples of cycloalkyl include, but are not limited to, the following moieties: C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. C 3-7 Examples of carbocyclic groups include norbornyl (C7). C 3-8 Examples of carbocyclic groups include the aforementioned C 3-7Carbocyclic groups and cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, etc. C 3-13 Examples of carbocyclic groups include the above C 3-8 Carbocyclic groups and octahydro-1H-indenyl, decahydronaphthyl, spiro[4.5]decyl, etc. Unless otherwise specified in the specification, cycloalkyl groups can be optionally substituted by one or more substituents disclosed herein. The terms "cycloalkenyl" and "cycloalkynyl" are very similar to the above description of "cycloalkyl", where the prefix "alkane" is replaced by "alkene" or "alkyne" respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

[0087] "Halogen group", "halide" or alternatively "halogen" means fluorine, chlorine, bromine or iodine. The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures substituted by one or more halogen groups or combinations thereof, preferably substituted by one, two or three halogen groups. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy respectively, where the halogen group is fluorine, such as but not limited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, -O-CHF2, etc. Each of alkyl, alkenyl, alkynyl and alkoxy is as defined herein and can be optionally further substituted as defined herein.

[0088] "Heteroaryl" or alternatively "heteroaromatic" refers to a 5- to 18-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms provided in the aromatic ring system (e.g., having 6, 10 or 14 π electrons shared in the ring array), where each heteroatom is independently selected from nitrogen, oxygen, phosphorus and sulfur ("5- to 18-membered heteroaryl"). The heteroaryl polycyclic system can contain one or more heteroatoms in one or two rings. Whenever a numerical range such as "5 to 18" appears herein, it refers to each integer within the given range. For example, "5 to 18 ring atoms" means that a heteroaryl group can be composed of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. In some instances, a heteroaryl group can have 5 to 14 ring atoms. In some embodiments, a heteroaryl group has a divalent group derived, for example, by removing a hydrogen atom from an atom having a free valence from a monovalent heteroaryl group whose name ends with "-yl", and the divalent group is named by adding "-ene" to the name of the corresponding monovalent group. For example, a pyridyl group having two attachment points is pyridylene.

[0089] For example, an N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms in the ring skeleton is a nitrogen atom. One or more of the heteroatoms in the heteroaryl may optionally be oxidized. One or more nitrogen atoms (if present) may also optionally be quaternized. The heteroaryl also includes a ring system substituted with one or more N-oxide (-O-) substituents, such as pyridyl N-oxide. The heteroaryl is attached to the parent molecular structure through any atom of the ring.

[0090] "Heteroaryl" also includes a ring system in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment to the parent molecular structure is on the aryl group or on the heteroaryl ring, or a ring system in which a heteroaryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment to the parent molecular structure is on the heteroaryl ring. For polycyclic heteroaryls, where one of the rings does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment to the parent molecular structure can be on either ring, i.e., the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms provided in an aromatic ring system and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, the heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms provided in an aromatic ring system and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, the heteroaryl is a 5- to 6-membered aromatic ring system having ring carbon atoms provided in an aromatic ring system and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0091] Examples of heteroaryl include, but are not limited to, azacyclic group, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzodioxepinyl, benzoxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, dibenzodioxinyl, benzoxazolyl, chromenyl, chromenone, benzofuranyl, chromenone, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzimidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazoline, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothienyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinone, oxadiazolyl, 2-oxoazacyclic group, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl and phenylthio group (i.e., thienyl). Unless otherwise specified in the specification, the heteroaryl may optionally be substituted by one or more substituents disclosed herein.

[0092] "Heterocyclic group", "heterocycloalkyl group" or "heterocyclic carbocyclic group" each refers to any 3- to 18-membered non-aromatic group, monocyclic or polycyclic moiety, including at least one carbon atom and at least one heteroatom selected from nitrogen, oxygen, phosphorus and sulfur. The heterocyclic group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, where the polycyclic ring system can be a fused ring, bridged ring or spiro ring system. The heterocyclic group polycyclic system can contain one or more heteroatoms in one or two rings. The heterocyclic group can be saturated or partially unsaturated. If the heterocyclic group contains at least one double bond, the partially unsaturated heterocycloalkyl group can be referred to as "heterocyclenyl", or if the heterocyclic group contains at least one triple bond, the partially unsaturated heterocycloalkyl group can be referred to as "heterocyclynyl". Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer within the given range. For example, "5 to 18 ring atoms" means that the heterocyclic group can be composed of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. For example, a divalent group derived from a monovalent heterocyclic group whose name ends with "-yl" by removing a hydrogen atom from the atom with a free valence is named by adding "-ene" to the name of the corresponding monovalent group. For example, a piperidinyl group with two attachment points is piperidinylene.

[0093] The N-containing heterocyclic group moiety refers to a non-aromatic group in which at least one ring atom is a nitrogen atom. The heteroatoms in the heterocyclic group can be optionally oxidized. One or more nitrogen atoms (if present) can be optionally quaternized. The heterocyclic group also includes a ring system substituted by one or more nitroxy (-O-) substituents, such as piperidinyl N-oxide. The heterocyclic group is attached to the parent molecular structure through any atom of any ring in the ring.

[0094] "Heterocyclic group" also includes ring systems in which a heterocyclic group ring as defined above is fused to one or more carbocyclic groups, where the point of attachment is on the carbocyclic group or the heterocyclic group ring or ring system, in which a heterocyclic group ring as defined above is fused to one or more aryl or heteroaryl groups, and where the point of attachment to the parent molecular structure is on the heterocyclic group ring. In some embodiments, the heterocyclic group is a 5- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 14-membered heterocyclic group"). In some embodiments, the heterocyclic group is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("3- to 10-membered heterocyclic group"). In some embodiments, the heterocyclic group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 8-membered heterocyclic group"). In some embodiments, the heterocyclic group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 6-membered heterocyclic group"). In some embodiments, the 5- to 6-membered heterocyclic group has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5- to 6-membered heterocyclic group has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5- to 6-membered heterocyclic group has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0095] "Heterocyclic group" may include one or more keto groups (-C(=O)-) as part of the ring. Examples of keto-containing heterocycles include, but are not limited to, pyridin-2(1H)-one, pyrazin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, pyridin-4(1H)-one, imidazolidin-2-one, 1,3-dihydro-2H-imidazol-2-one, 2,4-dihydro-3H-1,2,4-triazol-3-one, oxazol-2(3H)-one, and oxazolidin-2-one. The keto-containing heterocyclic group can be obtained by removing a hydrogen atom from its corresponding keto-containing heterocycle at any available N-H or C-H position.

[0096] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, tetrahydrothiazolyl, and dithiolanyl. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, diazolonyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thiohexanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, thiomorpholinyl, dithialkyl, dioxolanyl, and triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclic groups include, but are not limited to, indolyl, isoindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, benzoxolanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, benzothianyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, 3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, phenanthridinyl, indolyl, phthalimido, naphthalimido, dihydrobenzopyranyl, benzothiophenyl, 1H-benzo[e][1,4]diazinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, hydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0097] Unless otherwise specified in the specification, the heterocyclic group may optionally be substituted with one or more substituents disclosed herein.

[0098] When substituents are specified by their conventional chemical formulas (written from left to right), they equally encompass the chemically identical substituents that result when the structure is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0099] A "leaving group or atom" is any group or atom that will cleave from the starting material under the reaction conditions to facilitate the reaction at a specific site. Suitable non-limiting examples of such groups include halogen atoms, methanesulfonyloxy, p-nitrobenzenesulfonyloxy, trifluoromethoxy, and toluenesulfonyloxy, unless otherwise specified.

[0100] "Protecting group" has the meaning customarily associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a polyfunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site and such that the group can be readily removed after the selective reaction is complete. Non-limiting examples of functional groups that can be masked with protecting groups include amines, hydroxyls, thiols, carboxylic acids, and aldehydes. For example, a hydroxy protecting form is the protection of at least one hydroxy present in a compound with a hydroxy protecting group. A variety of protecting groups are disclosed, e.g., Greene's Protective Groups in Organic Synthesis, 5th Edition, Wiley (2014), which is incorporated herein by reference in its entirety. For additional background information on protecting group methodologies (materials, methods, and strategies for protection and deprotection) and other synthetic chemical transformations that can be used to produce the compounds described herein, see R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); Greene's Protective Groups in Organic Synthesis, 5th Edition, Wiley (2014); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley & Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons (1995). These references are incorporated herein by reference in their entirety.

[0101] The term "substituted" or "substitution" means that at least one hydrogen present on a group atom (e.g., a carbon or nitrogen atom) is replaced by an acceptable substituent, e.g., a substituent that produces a stable compound when replacing a hydrogen, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reactions. Unless otherwise specified, a "substituted" group can have substituents at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. Substituents include one or more groups that are individually and independently selected from the following: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, acylamino, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo (i.e., F, Cl, Br, I), haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphite, silyl, sulfinyl, sulfonyl, sulfonamido, hyposulfurous, sulfonate, urea, -Si(R a )3, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ) or -O-P(=O)(OR a )2, where each R aIndependently is hydrogen, alkyl, haloalkyl, carbocyclic group, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkyl alkyl, heteroaryl or heteroaryl alkyl, and each of these moieties (except hydrogen) can optionally be substituted by one or more substituents (up to six, valence permitting) selected from the following: OH, NH2, oxo, halogen, nitro, COOH, C(O)NH2 or cyano. For example, a cycloalkyl substituent can have a halide, etc. substituted at one or more ring carbons. Protecting groups that can form protective derivatives of the above substituents are known to those skilled in the art and can be found in references such as Greene and Wuts mentioned above.

[0102] Suitable substituents include but are not limited to haloalkyl and trihaloalkyl, alkoxyalkyl, halophenyl, -M-heteroaryl, -M-heterocycle, -M-aryl, -M-OR a , -M-SR a , -M-N(R a )2, -M-OC(O)N(R a )2, -M-C(=NR a )N(R a )2, -M-C(=NR a )OR a , -M-P(O)(R a )2, Si(R a )3, -M-NR a C(O)R a , -M-NR a C(O)OR a , -M-C(O)R a , -M-C(=S)R a , -M-C(=S)NR a R a , -M-C(O)N(R a )2, -M-C(O)NR a -M-N(R a )2, -M-NR a C(NR a )N(R a )2, -M-NR a C(S)N(R a )2, -M-S(O)2R a , -M C(O)R a , -M-OC(O)R a , -MC(O)SR a , -M-S(O)2N(R a )2, -C(O)-M-C(O)R a , -MCO2R a, -MC(=O)N(R a )2, -M-C(=NH)N(R a )2 and -M-OC(=NH)N(R a )2 (wherein M is C 1-6 alkyl).

[0103] When a ring system (e.g., cycloalkyl, heterocyclic, aryl or heteroaryl) is substituted by several substituents that vary within a well - defined range, it is understood that the total number of substituents does not exceed the normal available valences under existing conditions. Thus, for example, a phenyl ring substituted by "p" substituents (where "p" ranges from 0 to 5) can have from 0 to 5 substituents, while it is understood that a pyridyl ring substituted by "p" substituents has a number of substituents in the range from 0 to 4. The maximum number of substituents that a group in the disclosed compounds can have can be readily determined. Substituted groups only encompass combinations of substituents and variables that result in stable or chemically viable compounds. A stable compound or a chemically viable compound is a compound that has, among other things, sufficient stability to allow its preparation and detection. In some embodiments, the disclosed compounds are stable enough that when maintained at a temperature of 40 °C or lower, in the absence of moisture (e.g., less than about 10%, less than about 5%, less than about 2%, less than about 1% or less than about 0.5%) or other chemical reaction conditions, for a period of, for example, at least about 3 days, at least about one week, at least about 2 weeks, at least about 4 weeks or at least about 6 weeks, the compound does not undergo substantial change.

[0104] The term "combine, combining, to combine, combination" refers to the act of adding at least one chemical substance to another chemical substance either sequentially or simultaneously. In some embodiments, bringing these chemical substances together may result in the initial chemical substances being transformed into one or more different chemical substances. This transformation can occur through one or more chemical reactions, such as cases of covalent bond formation, cleavage, rearrangement, etc. A non - limiting example can include the hydrolysis of an ester into an alcohol and a carboxylic acid, which can be produced by the combination of the ester with a suitable base. In another non - limiting example, an aryl fluoride can be combined with an amine to provide an arylamine through a substitution process. These terms also encompass changes in the association of charged chemical substances and the generation of charged chemical substances, such as but not limited to N - oxide formation, acid addition salt formation, base addition salt formation, etc. These terms encompass the generation and / or transformation of free radical chemical substances and isotopically labeled chemical substances.

[0105] The term "convert, converting, to convert, conversion" refers to a subset of "combine" and its grammatical equivalents, where the action of one or more reagents converts one or more functional groups on a chemical substance into another functional group. For example, conversion includes, but is not limited to, converting a nitro functional group on a chemical substance to an amine using a reducing agent. Conversion also includes changes to charged chemical substances, radical chemical substances, and isotopically labeled chemical substances. However, the term "conversion" does not include changes to conserved bonds in the disclosed genus and compounds.

[0106] Compound

[0107] On the one hand, the present invention relates to a compound of formula (I)

[0108]

[0109] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

[0110] wherein:

[0111] Z is CH2 or O;

[0112] Y 1 、Y 2 、Y 3 and Y 4 are each independently N or CR 5 , provided that at least one but no more than two of Y 1 、Y 2 、Y 3 and Y 4 are N;

[0113] X 1 is N, O, or CR 6a ;

[0114] X 2 is N or NR 6 ;

[0115] X 3 is N, NR 6 or CR 6 , where the dashed circle represents a bond forming a five-membered aromatic ring;

[0116] L 1 is a covalent bond or CH2 optionally substituted by 1 or 2 methyl groups;

[0117] L 2 is a covalent bond or (CR 7 R 7 ) p ;

[0118] L 3 is a covalent bond, O, or NR 7 provided that L 2 and L 3 at least one of which is not a covalent bond;

[0119] Q is C(=O)NR 9 R 10 、C(=O)OR 10 or a ring selected from 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclic group, wherein said ring comprises at least one carbon atom, at least one nitrogen atom and optionally 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein oxygen can be a ring member and / or an oxo group attached to a ring member, and wherein said ring is substituted by (R 3 ) n and one R 4 ;

[0120] R 1 is independently, each occurrence, hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, halo-C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b 、C 1-6 alkyl-NR a R b or a 4- to 6-membered heterocyclic group, or two R 1 groups together with the carbon atom to which they are attached form C=O;

[0121] R 2 is (CR 7 R 7 ) q -R 8 ;

[0122] R 3 is independently, each occurrence, hydrogen, halogen, CN, C 1-6 alkyl or C 3-7 cycloalkyl;

[0123] R 4 is independently hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2)p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, substituted by 1 to 4 R 11 substituted (CH2) q -5- to 6-membered heteroaryl ring, substituted by 1 to 4 R 11 substituted (CH2) q -5- to 7-membered heterocyclic ring, wherein each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0124] R 5 is, independently at each occurrence, hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy, halo C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b or C 1-6 alkyl-NR a R b ;

[0125] R 6a and R 6 are, independently at each occurrence, hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl;

[0126] R 7 is, independently at each occurrence, hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or two R 7 groups together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring;

[0127] R 8 is C(=O)OR 7 、C(=O)NR a R b 、CN、C(=O)NHC(=O)R 7, C(=O)NHS(=O)₂R 7 , C(=O)NHS(=O)R 7 , S(=O)₂R 7 , P(=O)(OH)₂ or

[0128] R 9 and R 10 is independently, each time it appears, hydrogen, C 11 alkyl substituted with 1 to 4 R 1-6 alkyl, C 11 alkenyl substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkynyl substituted with 1 to 4 R 11 alkenyl, C 12 R 12 ) q -C 2-6 cycloalkyl substituted with 1 to 4 R 11 alkynyl, C 12 R 12 ) q -C 3-7 phenyl substituted with 1 to 4 R 11 alkyl, C 12 R 12 ) q -a 5- to 6-membered heteroaryl ring substituted with 1 to 4 R 11 alkyl, C 12 R 12 ) q -a 5- to 7-membered heterocyclic ring; or R 11 and R 12 together with the nitrogen atom to which it is attached form a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted with 1 to 4 R 12 ) q wherein the ring can optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; 9 and R 10 is independently, each time it appears, hydrogen, C 11 alkyl, halo C

[0129] R 11 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH₂) p -C 1-6 alkoxy, phenyl, (CH₂) p-phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, where each phenyl is independently optionally substituted with 1 to 3 substituents selected from halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0130] R 12 is independently hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl each time it appears, or two R 12 groups together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl ring;

[0131] R a and R b are independently hydrogen or C 1-6 alkyl each time they appear, or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocycle containing three to seven ring atoms, said ring being optionally capable of containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and being optionally substituted with one to three groups which may be the same or different and are selected from the group consisting of C 1-4 alkyl, phenyl and benzyl;

[0132] m is 1 or 2;

[0133] n is 0, 1 or 2;

[0134] p is independently 1, 2, 3 or 4 each time it appears; and

[0135] q is independently 0, 1, 2, 3 or 4 each time it appears.

[0136] In some embodiments, the compound of formula (I) comprises a compound of formula (II):

[0137]

[0138] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0139] wherein:

[0140] L 1is a covalent bond or CH2 optionally substituted by 1 or 2 methyl groups;

[0141] L 2 is a covalent bond or (CR 7 R 7 ) p ;

[0142] L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;

[0143] Q is a ring selected from the group consisting of: 5 - membered heteroaryl, 5 - membered heterocyclic, 6 - membered heteroaryl and 6 - membered heterocyclic, wherein said ring comprises at least one carbon atom, at least one nitrogen atom and optionally 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein oxygen can be a ring member and / or an oxo(=O) attached to a ring member, and wherein said ring is substituted by (R 3 ) n and one R 4 ;

[0144] X 1 is N or CR 6a ;

[0145] Z is CH2 or O;

[0146] R 1 is independently, in each occurrence, hydrogen, halogen, C 1-6 alkyl, halo - C 1-6 alkyl, OH, C 1-6 alkyl - OH, C 1-6 alkoxy, halo - C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b , C 1-6 alkyl - NR a R b or a 4 - to 6 - membered heterocyclic group, or two R 1 groups together with the carbon atom to which they are attached form C = O;

[0147] R 3 is independently, in each occurrence, hydrogen, halogen, CN, C 1-6 alkyl or C 3-7 cycloalkyl;

[0148] R 4 is independently hydrogen, halogen, C 1-6 alkyl, halo - C 1-6 alkyl, C 2-6 alkenyl, C2-6 Alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, substituted by 1 to 4 R 11 substituted (CH2) q -5- to 6-membered heteroaryl ring, substituted by 1 to 4 R 11 substituted (CH2) q -5- to 7-membered heterocyclic ring, wherein each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0149] R 5 is, independently at each occurrence, hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy, halo-C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b or C 1-6 alkyl-NR a R b ;

[0150] R 6a is hydrogen or methyl;

[0151] R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl;

[0152] R 7 is, independently at each occurrence, hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or R 7 and R 7 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring;

[0153] R 11 is, independently at each occurrence, hydrogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl, O(CH2) p -C 3-7 cycloalkyl, where each phenyl is independently optionally substituted with one to three substituents selected from halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0154] R 13 is, independently at each occurrence, hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl;

[0155] R a and R b are, independently at each occurrence, hydrogen or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocycle containing three to seven ring atoms, said ring being optionally capable of containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and being optionally substituted with one to three groups which may be the same or different, said groups being selected from the group consisting of C 1-4 alkyl, phenyl and benzyl;

[0156] n is 0, 1 or 2;

[0157] p is, independently at each occurrence, 1, 2, 3 or 4;

[0158] t is 0, 1, 2 or 3; and

[0159] w is 0 or 1, provided that when L 1 is a covalent bond, w is 1, and further provided that when L 1 is CH2 optionally substituted with 1 or 2 methyl groups, w is 0.

[0160] In some embodiments, the compound of formula I comprises a compound of formula (IIa) or (IIaa):

[0161]

[0162] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0163] wherein:

[0164] L 2 is a covalent bond or (CR 7 R 7 ) p ;

[0165] L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;

[0166] Q is a ring selected from the group consisting of: 5 - membered heteroaryl, 5 - membered heterocyclic, 6 - membered heteroaryl and 6 - membered heterocyclic, wherein said ring comprises at least one carbon atom, at least one nitrogen atom and optionally 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein oxygen can be a ring member and / or an oxo attached to a ring member, and wherein said ring is substituted by (R 3 ) n and an R 4 ;

[0167] X 1 is N or CR 6a ;

[0168] R 1 is independently, in each occurrence, hydrogen, halogen, C 1-6 alkyl, halo - C 1-6 alkyl, OH, C 1-6 alkyl - OH, C 1-6 alkoxy, halo - C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b , C 1-6 alkyl - NR a R b or a 4 - to 6 - membered heterocyclic, or two R 1 groups together with the carbon atom to which they are attached form C═O;

[0169] R 3 is independently, in each occurrence, hydrogen, halogen, CN, C 1-6 alkyl or C 3-7 cycloalkyl;

[0170] R 4 is independently hydrogen, a halogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, substituted by 1 to 4 Rs 11 substituted (CH2) q -a 5- to 6-membered heteroaryl ring, substituted by 1 to 4 Rs 11 substituted (CH2) q -a 5- to 7-membered heterocyclic ring, wherein each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0171] R 5 is independently, at each occurrence, hydrogen, a halogen, C 1-6 alkyl, halo-C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy, halo-C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b or C 1-6 alkyl-NR a R b ;

[0172] R 6a is hydrogen or methyl;

[0173] R 6 is hydrogen, a halogen, CN, methyl, ethyl, propyl or cyclopropyl;

[0174] R 7 is independently, at each occurrence, hydrogen, C 1-4 alkyl, C3-5 a cycloalkyl group, or R 7 and R 7 together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl ring;

[0175] R 11 is, independently at each occurrence, hydrogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, wherein each phenyl is independently optionally substituted by one to three substituents selected from the group consisting of halogen, C 1-6 alkyl, or C 1-6 alkoxy;

[0176] R 13 is, independently at each occurrence, hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl;

[0177] R a and R b are, independently at each occurrence, hydrogen or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which it is attached form a saturated or unsaturated heterocyclic ring containing three to seven ring atoms, said ring being optionally capable of containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and being optionally substituted by one to three groups which may be the same or different and are selected from the group consisting of C 1-4 alkyl, phenyl and benzyl;

[0178] n is 0, 1 or 2;

[0179] p is, independently at each occurrence, 1, 2, 3 or 4; and

[0180] t is 0, 1, 2 or 3.

[0181] In some embodiments, the compound of formula I comprises a compound of formula (IIb) or (IIbb):

[0182]

[0183] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0184] wherein:

[0185] L 2 is a covalent bond or (CR 7 R 7 ) p ;

[0186] L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;

[0187] Q is a ring selected from the group consisting of: 5 - membered heteroaryl, 5 - membered heterocyclic, 6 - membered heteroaryl and 6 - membered heterocyclic, wherein said ring comprises at least one carbon atom, at least one nitrogen atom and optionally 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein said ring is substituted by (R 3 ) n and an R 4 ;

[0188] X 1 is N or CR 6a ;

[0189] R 3 is independently, in each occurrence, hydrogen, halogen, CN, C 1-6 alkyl or C 3-7 cycloalkyl;

[0190] R 4 is independently hydrogen, halogen, C 1-6 alkyl, halo - C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl - C 3-7 cycloalkyl, C 2-6Alkynyl-C 3-7 Cycloalkyl, O(CH2) p -C 3-7 Cycloalkyl, substituted by 1 to 4 R 11 Substituted (CH2) q -5- to 6-membered heteroaryl ring, substituted by 1 to 4 R 11 Substituted (CH2) q -5- to 7-membered heterocyclic ring, where each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0191] R 5 Is independently, in each occurrence, hydrogen, halogen, C 1-6 Alkyl, halo C 1-6 Alkyl, OH, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, halo C 1-6 Alkoxy, CN, C 3-7 Cycloalkyl, NR a R b Or C 1-6 Alkyl-NR a R b ;

[0192] R 6a Is hydrogen or methyl;

[0193] R 6 Is hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl;

[0194] R 7 Is independently, in each occurrence, hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, or R 7 And R 7 Together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl ring;

[0195] R 11 Is independently, in each occurrence, hydrogen, C 1-6 Alkyl, halo C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, (CH2) p -C 1-6 Alkoxy, phenyl, (CH2) p -Phenyl, O(CH2) p -Phenyl, CN, C 3-7Cycloalkyl, (CH2) p -C 3-7 Cycloalkyl, C 2-6 Alkenyl-C 3-7 Cycloalkyl, C 2-6 Alkynyl-C 3-7 Cycloalkyl, O(CH2) p -C 3-7 Cycloalkyl, wherein each phenyl is independently optionally substituted with one to three substituents selected from halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0196] R 13 is independently, each time it appears, hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl;

[0197] R a and R b are independently, each time they appear, hydrogen or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocycle containing three to seven ring atoms, said ring being optionally capable of containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and being optionally substituted with one to three groups which may be the same or different, said groups being selected from the group consisting of C 1-4 alkyl, phenyl and benzyl;

[0198] n is 0, 1 or 2;

[0199] p is independently, each time it appears, 1, 2, 3 or 4; and

[0200] t is 0, 1, 2 or 3.

[0201] In some embodiments, the compound of formula I comprises a compound of formula (IIc) or (IIcc):

[0202]

[0203] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0204] wherein:

[0205] L 2 is a covalent bond or (CR 7 R 7 ) p ;

[0206] L 3 is a covalent bond, O or NR 7 , provided that L 2 and L3 At least one of them is not a covalent bond;

[0207] Q is a ring selected from the group consisting of: 5-membered heteroaryl, 5-membered heterocyclic group, 6-membered heteroaryl and 6-membered heterocyclic group, wherein said ring contains at least one carbon atom, at least one nitrogen atom and optionally contains 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein said ring is substituted by (R 3 ) n and one R 4 substituted;

[0208] X 1 is N or CR 6a ;

[0209] R 3 is independently, each time it appears, hydrogen, halogen, CN, C 1-6 alkyl or C 3-7 cycloalkyl;

[0210] R 4 is hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl, O(CH2) p -C 3-7 cycloalkyl, substituted by 1 to 4 R 11 of (CH2) q -5- to 6-membered heteroaryl ring, or substituted by 1 to 4 R 11 of (CH2) q -5- to 7-membered heterocyclic ring, wherein each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0211] R 5 is independently, each time it appears, hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, OH, C 1-6 alkyl-OH, C1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy, halo-C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b or C 1-6 alkyl-NR a R b ;

[0212] R 6a is hydrogen or methyl;

[0213] R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl;

[0214] R 7 is independently, at each occurrence, hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or R 7 and R 7 together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl ring;

[0215] R 11 is independently, at each occurrence, hydrogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl, O(CH2) p -C 3-7 cycloalkyl, where each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0216] R 13 is independently, at each occurrence, hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl;

[0217] R a and R bis independently hydrogen or C at each occurrence 1-6 alkyl, or R a and R b together with the nitrogen atom to which it is attached form a saturated or unsaturated heterocycle containing three to seven ring atoms, said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted by one to three groups which may be the same or different, said groups selected from the group consisting of C 1-4 alkyl, phenyl and benzyl;

[0218] n is 0, 1 or 2;

[0219] p is independently 1, 2, 3 or 4 at each occurrence; and

[0220] t is 0, 1, 2 or 3.

[0221] In some embodiments, the compound of formula I comprises a compound of formula (IId) or (IIdd):

[0222]

[0223] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0224] wherein:

[0225] * in formula (IIdd) represents a chiral center having an R or S configuration;

[0226] L 2 is a covalent bond or (CR 7 R 7 ) p ;

[0227] L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;

[0228] Q is a ring selected from the group consisting of: 5-membered heteroaryl, 5-membered heterocyclic, 6-membered heteroaryl and 6-membered heterocyclic, wherein said ring comprises at least one carbon atom, at least one nitrogen atom and optionally 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein oxygen may be a ring member and / or an oxo (=O) attached to a ring member, and wherein said ring is substituted by (R 3 ) n and an R 4 ;

[0229] X 1 is N or CR 6a ;

[0230] R 1 is, independently at each occurrence, hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, halo-C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b , C 1-6 alkyl-NR a R b or a 4- to 6-membered heterocyclic group, or two R 1 groups together with the carbon atom to which they are attached form C=O;

[0231] R 3 is, independently at each occurrence, hydrogen, halogen, CN, C 1-6 alkyl or C 3-7 cycloalkyl;

[0232] R 4 is independently hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl, O(CH2) p -C 3-7 cycloalkyl, (CH2) 11 substituted by 1 to 4 R q -a 5- to 6-membered heteroaryl ring, (CH2) 11 substituted by 1 to 4 R q -a 5- to 7-membered heterocyclic ring, wherein each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0233] R 5 is, independently at each occurrence, hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, OH, C1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy, halo-C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b or C 1-6 alkyl-NR a R b ;

[0234] R 6a is hydrogen or methyl;

[0235] R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl;

[0236] R 7 is independently at each occurrence hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or two R 7 groups together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring;

[0237] R 11 is independently at each occurrence hydrogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, where each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0238] R a and R b are independently at each occurrence hydrogen or C 1-6 alkyl, or R a and R bTogether with the nitrogen atom to which it is attached, form a saturated or unsaturated heterocycle containing three to seven ring atoms, said ring being optionally capable of containing one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and being optionally substituted by one to three groups which may be the same or different and are selected from the group consisting of C 1-4 alkyl, phenyl and benzyl;

[0239] n is 0, 1 or 2;

[0240] p is independently 1, 2, 3 or 4 at each occurrence; and

[0241] t is 0, 1, 2 or 3.

[0242] In some embodiments, the compound of formula I comprises a compound of formula (III):

[0243]

[0244] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0245] wherein:

[0246] X 1 is N or CR 6a ;

[0247] Z is CH2 or O;

[0248] L 1 is a covalent bond or CH2 optionally substituted by 1 or 2 methyl groups;

[0249] L 2 is a covalent bond or (CR 7 R 7 ) p ;

[0250] L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;

[0251] R 1 is independently at each occurrence hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, halo-C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b 、C 1-6 alkyl-NR a Rb or a 4- to 6-membered heterocyclic group, or two R 1 groups together with the carbon atom to which they are attached form C═O;

[0252] R 5 is independently, each time it appears, hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy, halo C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b or C 1-6 alkyl-NR a R b ;

[0253] R 6a is hydrogen or methyl;

[0254] R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl;

[0255] R 7 is independently, each time it appears, hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or two R 7 groups together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring;

[0256] R 9 and R 10 are independently, each time they appear, hydrogen, C 11 alkyl substituted with 1 to 4 R 1-6 groups, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkynyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 3-7 cycloalkyl, (CR 11 substituted with 1 to 4 R 12 R 12 )q - phenyl, substituted by 1 to 4 Rs 11 - a 5- to 6-membered heteroaryl ring, substituted by 1 to 4 Rs 12 R 12 ) q - a 5- to 6-membered heteroaryl ring, substituted by 1 to 4 Rs 11 - a 5- to 7-membered heterocyclic ring; or R 12 R 12 ) q - a 5- to 7-membered heterocyclic ring; or R 9 and R 10 together with the nitrogen atom to which they are attached form a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted by 1 to 4 Rs, said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; 11

[0257] R 11 is independently, in each occurrence, hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p - C 1-6 alkoxy, phenyl, (CH2) p - phenyl, O(CH2) p - phenyl, CN, C 3-7 cycloalkyl, (CH2) p - C 3-7 cycloalkyl, C 2-6 alkenyl - C 3-7 cycloalkyl, C 2-6 alkynyl - C 3-7 cycloalkyl, O(CH2) p - C 3-7 cycloalkyl, where each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl, or C 1-6 alkoxy;

[0258] R 12 is independently, in each occurrence, hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, or two R 12 groups together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl ring;

[0259] R 13 is independently, in each occurrence, C 1-4 alkyl or C 3-5 cycloalkyl;

[0260] R a and R​b is independently hydrogen or C 1-6 alkyl at each occurrence, or R a and R b together with the nitrogen atom to which it is attached form a saturated or unsaturated heterocycle containing three to seven ring atoms, said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally being substituted by one to three groups which may be the same or different, said groups being selected from the group consisting of C 1-4 alkyl, phenyl and benzyl;

[0261] p is independently 1, 2, 3 or 4 at each occurrence;

[0262] q is independently 0, 1, 2, 3 or 4 at each occurrence;

[0263] t is 0, 1, 2 or 3; and

[0264] w is 0 or 1, provided that when L 1 is a covalent bond, w is 1, and further provided that when L 1 is CH2 optionally substituted by 1 to 2 methyl groups, w is 0.

[0265] In some embodiments, the compound of formula I comprises a compound of formula (IIIa) or (IIIaa):

[0266]

[0267] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0268] wherein:

[0269] L 2 is a covalent bond or (CR 7 R 7 ) p ;

[0270] L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;

[0271] X 1 is N or CR 6a ;

[0272] R 1 is independently hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6alkoxy, halo-C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b , C 1-6 alkyl-NR a R b or a 4- to 6-membered heterocyclic group, or two R 1 groups together with the carbon atom to which they are attached form C=O;

[0273] R 5 is independently, each time it appears, hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy, halo-C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b or C 1-6 alkyl-NR a R b ;

[0274] R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl;

[0275] R 7 is independently, each time it appears, hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or two R 7 groups together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring;

[0276] R 9 and R 10 are independently, each time they appear, hydrogen, C 11 alkyl substituted with 1 to 4 R 1-6 alkyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkynyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 3-7Cycloalkyl, substituted by 1 to 4 R 11 (CR 12 R 12 ) q -phenyl, substituted by 1 to 4 R 11 (CR 12 R 12 ) q -a 5- to 6-membered heteroaryl ring, substituted by 1 to 4 R 11 (CR 12 R 12 ) q -a 5- to 7-membered heterocyclic ring; or R 9 and R 10 together with the nitrogen atom to which they are attached form a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted by 1 to 4 R 11 which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

[0277] R 11 is independently, in each occurrence, hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, where each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0278] R 12 is independently, in each occurrence, hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, or R 12 and R 12 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl ring;

[0279] R 13 is independently, in each occurrence, hydrogen, C 1-4alkyl or C 3-5 cycloalkyl;

[0280] R a and R b is, independently at each occurrence, hydrogen or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which it is attached form a saturated or unsaturated heterocycle having three to seven ring atoms, said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally being substituted by one to three groups, which may be the same or different, selected from the group consisting of C 1-4 alkyl, phenyl and benzyl;

[0281] t is 0, 1, 2 or 3;

[0282] p is, independently at each occurrence, 1, 2, 3 or 4; and

[0283] q is, independently at each occurrence, 0, 1, 2, 3 or 4.

[0284] In some embodiments, the compound of formula I comprises a compound of formula (IIIb) or (IIbb):

[0285]

[0286] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0287] wherein:

[0288] L 2 is a covalent bond or (CR 7 R 7 ) p ;

[0289] L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;

[0290] X 1 is N or CR 6a ;

[0291] R 5 is, independently at each occurrence, hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy, halo C1-6 Alkoxy, CN, C 3-7 Cycloalkyl, NR a R b or C 1-6 Alkyl - NR a R b ;

[0292] R 6a is hydrogen or methyl;

[0293] R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl;

[0294] R 7 is independently, at each occurrence, hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or R 7 and R 7 together with the carbon atom to which it is attached form a 3 - to 5 - membered cycloalkyl ring;

[0295] R 9 and R 10 are independently, at each occurrence, hydrogen, C 11 alkyl substituted by 1 to 4 R 1-6 alkyl, C 11 alkyl substituted by 1 to 4 R 12 R 12 )(CR q -C 2-6 alkenyl, C 11 alkenyl substituted by 1 to 4 R 12 R 12 )(CR q -C 2-6 alkynyl, C 11 alkynyl substituted by 1 to 4 R 12 R 12 )(CR q -C 3-7 cycloalkyl, C 11 cycloalkyl substituted by 1 to 4 R 12 R 12 )(CR q -phenyl, C 11 phenyl substituted by 1 to 4 R 12 R 12 )(CR q -a 5 - to 6 - membered heteroaryl ring, C 11 heteroaryl ring substituted by 1 to 4 R 12 R 12 )(CR q -a 5 - to 7 - membered heterocyclic ring; or R 9 and R 10 together with the nitrogen atom to which they are attached form a ring substituted by 1 to 4 R11 A substituted saturated or unsaturated 3- to 7-membered heterocycle, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

[0296] R 11 which is, independently at each occurrence, hydrogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl, O(CH2) p -C 3-7 cycloalkyl, where each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0297] R 12 which is, independently at each occurrence, hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, or R 12 and R 12 together with the carbon atom to which it is attached form a 3- to 6-membered cycloalkyl ring;

[0298] R 13 which is, independently at each occurrence, hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl;

[0299] R a and R b which are, independently at each occurrence, hydrogen or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which it is attached form a saturated or unsaturated heterocycle containing three to seven ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may optionally be substituted by one to three groups, which groups are selected from the group consisting of C 1-4 alkyl, phenyl and benzyl;

[0300] t is 0, 1, 2 or 3;

[0301] p is independently 1, 2, 3 or 4 each time it appears; and

[0302] q is independently 0, 1, 2, 3 or 4 each time it appears.

[0303] In some embodiments, the compound of formula I comprises a compound of formula (IIIc) or (IIIcc):

[0304]

[0305] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0306] wherein:

[0307] L 2 is a covalent bond or (CR 7 R 7 ) p ;

[0308] L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;

[0309] X 1 is N or CR 6a ;

[0310] R 5 is independently hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy, halo C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b or C 1-6 alkyl-NR a R b ;

[0311] R 6a is hydrogen or methyl;

[0312] R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl;

[0313] R 7 is independently hydrogen, C 1-4 alkyl, C 3-5cycloalkyl, or R 7 and R 7 together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl ring;

[0314] R 9 and R 10 each occurrence is independently hydrogen, C 11 alkyl substituted with 1 to 4 R 1-6 alkyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkynyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 3-7 cycloalkyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -phenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -5- to 6-membered heteroaryl ring, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -5- to 7-membered heterocyclic ring; or R 9 and R 10 together with the nitrogen atom to which it is attached form a saturated or unsaturated 3- to 7-membered heterocycle substituted with 1 to 4 R 11 wherein the ring can optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;

[0315] R 11 each occurrence is independently hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7Cycloalkyl, (CH2) p -C 3-7 Cycloalkyl, C 2-6 Alkenyl-C 3-7 Cycloalkyl, C 2-6 Alkynyl-C 3-7 Cycloalkyl, O(CH2) p -C 3-7 Cycloalkyl, wherein each phenyl is independently optionally substituted by one to three substituents selected from halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0316] R 12 is independently, in each occurrence, hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, or R 12 and R 12 together with the carbon atom to which it is attached form a 3- to 6-membered cycloalkyl ring;

[0317] R 13 is independently, in each occurrence, hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl;

[0318] R a and R b are independently, in each occurrence, hydrogen or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which it is attached form a saturated or unsaturated heterocycle containing three to seven ring atoms, which ring can optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and can optionally be substituted by one to three groups, which groups are selected from the group consisting of C 1-4 alkyl, phenyl and benzyl;

[0319] t is 0, 1, 2 or 3;

[0320] p is independently, in each occurrence, 1, 2, 3 or 4; and

[0321] q is independently, in each occurrence, 0, 1, 2, 3 or 4.

[0322] In some embodiments, the compound of formula I comprises a compound of formula (IIId) or (IIIdd):

[0323]

[0324] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0325] wherein:

[0326] * in formula (IIIdd) represents a chiral center having an R or S configuration;

[0327] L 2 is a covalent bond or (CR 7 R 7 ) p ;

[0328] L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;

[0329] X 1 is N or CR 6a ;

[0330] R 1 is independently, each time it appears, hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, halo C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b , C 1-6 alkyl-NR a R b or a 4- to 6-membered heterocyclic group, or two R 1 groups together with the carbon atom to which they are attached form C=O;

[0331] R 5 is independently, each time it appears, hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy, halo C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b or C 1-6 alkyl-NR a R b ;

[0332] R 6a is hydrogen or methyl;

[0333] R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl;

[0334] R 7 is independently, at each occurrence, hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or R 7 and R 7 together with the carbon atom to which it is attached form a 3- to 5-membered cycloalkyl ring;

[0335] R 9 and R 10 are independently, at each occurrence, hydrogen, C 11 alkyl substituted with 1 to 4 R 1-6 groups, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkynyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 3-7 cycloalkyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -phenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -a 5- to 6-membered heteroaryl ring, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -a 5- to 7-membered heterocyclic ring; or R 9 and R 10 together with the nitrogen atom to which they are attached form a saturated or unsaturated 3- to 7-membered heterocycle substituted with 1 to 4 R 11 groups, said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;

[0336] R 11 is independently, at each occurrence, hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 Cycloalkyl, (CH2) p -C 3-7 Cycloalkyl, C 2-6 Alkenyl-C 3-7 Cycloalkyl, C 2-6 Alkynyl, O(CH2) p -C 3-7 Cycloalkyl, wherein each phenyl is independently optionally substituted by one to three of halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0337] R 12 is independently hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl each time it appears, or R 12 and R 12 together with the carbon atom to which it is attached form a 3- to 6-membered cycloalkyl ring;

[0338] R a and R b are independently hydrogen or C 1-6 alkyl each time they appear, or R a and R b together with the nitrogen atom to which it is attached form a saturated or unsaturated heterocycle containing three to seven ring atoms, the ring being optionally capable of containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and being optionally substituted by one to three groups which may be the same or different and are selected from the group consisting of C 1-4 alkyl, phenyl and benzyl;

[0339] t is 0, 1, 2 or 3;

[0340] p is independently 1, 2, 3 or 4 each time it appears; and

[0341] q is independently 0, 1, 2, 3 or 4 each time it appears.

[0342] In any embodiment, Z is CH2. In some other embodiments, Z is O.

[0343] In any embodiment, L 1 is a covalent bond. In some other embodiments, L 1 is CH2 optionally substituted by 1 to 2 methyl groups. In still other embodiments, L 1 is CH2.

[0344] In any embodiment, L 1is a covalent bond and w is 1. In some other embodiments, L 1 is CH2 optionally substituted with 1 to 2 methyl groups and w is 0.

[0345] In any embodiment, R 1 is independently hydrogen at each occurrence. In some other embodiments, R 1 is independently halogen at each occurrence. In still other embodiments, m is 2, one R 1 is hydrogen and the other R 1 is halogen. In still other embodiments, m is 2, one R 1 is hydrogen and the other R 1 is F. In still other embodiments, R 1 is independently F at each occurrence.

[0346] In any embodiment, Y 2 is N and each of Y 1 , Y 3 and Y 4 is independently CR 5 . In some other embodiments, Y 1 is CR 5 , Y 2 is N and each of Y 3 and Y 4 is independently CH. In still other embodiments, Y 1 is CR 5 , Y 2 is N, Y 3 is N and Y 4 is CH.

[0347] In any embodiment, the moiety in formula (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd) and (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId) and (IIIdd) is

[0348] In any embodiment, R 5 is methyl or ethyl. In some other embodiments, R 5 is CHF2 or CF3. In still other embodiments, R 5 is hydrogen or CN.

[0349] In any embodiment, t is 0. In some other embodiments, t is 1. In still other embodiments, t is 2. In still other embodiments, t is 3.

[0350] In any embodiment, X 1 is N, X 2 is N, and X 3 is NR 6 . In some other embodiments, X 1 is CH, X 2 is N, and X 3 is NR 6 . In still other embodiments, X 1 is O, X 2 is N, and X 3 is CR 6 .

[0351] In any embodiment, R 6 is hydrogen. In some other embodiments, R 6 is methyl. In still other embodiments, R 6 is ethyl. In still other embodiments, R 6 is cyclopropyl.

[0352] In any embodiment, R 6a is hydrogen. In some other embodiments, R 6a is methyl. In still other embodiments, R 6a is ethyl. In still other embodiments, R 6a is cyclopropyl.

[0353] In any embodiment, L 2 is a covalent bond. In some other embodiments, L 2 is (CR 7 R 7 ) p . In still other embodiments, L 2 is CH2.

[0354] In any embodiment, L 3 is a covalent bond. In some other embodiments, L 3 is O. In still other embodiments, L 3 is NR 7 .

[0355] In any embodiment, R 7 is independently hydrogen each time it appears. In some other embodiments, R 7 is independently C 1-4 alkyl each time it appears. In still other embodiments, R 7 is independently C 3-5 cycloalkyl each time it appears. In still other embodiments, R 7 is independently hydrogen or methyl each time it appears.

[0356] In any embodiment, q is 0. In some other embodiments, q is 1. In still other embodiments, q is 2.

[0357] In any embodiment, R 8 is COOH.

[0358] In any embodiment, R 9 is C 1-4 alkyl. In some other embodiments, R 9 is methyl. In still other embodiments, R 9 is ethyl.

[0359] In any embodiment, R 10 is C 11 alkyl substituted with 1 to 4 R 1-6 groups, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkynyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 3-7 cycloalkyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -phenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -a 5- to 6-membered heteroaryl ring, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -a 5- to 7-membered heterocyclic ring. In some other embodiments, R 10 is C 1-6 alkyl. R 10 is (CH2) p -C 3-7 cycloalkyl. In still other embodiments, R 9 and R 10 together with the nitrogen atom to which they are attached form a group substituted with 1 to 4 R 11A substituted saturated or unsaturated 3- to 7-membered heterocycle, which ring can optionally contain an additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0360] In any embodiment, Q is C(=O)NR 9 R 10 . In certain other embodiments, Q is a ring (also referred to herein as a "Q ring") selected from the group consisting of: a 5-membered heteroaryl, a 5-membered heterocyclic group, a 6-membered heteroaryl, and a 6-membered heterocyclic group, wherein said ring comprises at least carbon atoms, at least one nitrogen atom, and optionally 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein oxygen can be a ring member and / or an oxo attached to a ring member, and wherein said ring is substituted by (R 3 ) n and R 4 .

[0361] In any embodiment, Q is and each of which is substituted at any available carbon or nitrogen position by (R 3 ) n and an R 4 .

[0362] In any embodiment, Q is substituted at any available carbon position by (R 3 ) n and an R 4 .

[0363] In any embodiment, Q is and each of which is substituted at any available carbon or nitrogen position by (R 3 ) n and an R 4 .

[0364] In any embodiment, R 3 is, independently at each occurrence, hydrogen, halogen, or C 1-4 alkyl. In certain other embodiments, R 3 is, independently at each occurrence, C 1-4 alkyl. In still other embodiments, R 3 is, independently at each occurrence, methyl.

[0365] In any embodiment, n is 0. In certain other embodiments, n is 1. In still other embodiments, n is 2.

[0366] In any embodiment, R 4 is independently hydrogen, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, (CH2) p -C 1-6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 Cycloalkyl, (CH2) p -C 3-7 Cycloalkyl, C 2-6 Alkenyl-C 3-7 Cycloalkyl, C 2-6 Alkynyl-C 3-7 Cycloalkyl, O(CH2) p -C 3-7 Cycloalkyl, wherein each phenyl is independently optionally substituted with 1 to 3 substituents selected from halogen, C 1-6 alkyl or C 1-6 alkoxy. In certain other embodiments, R 4 is independently a (CH2) 11 -5- to 6-membered heteroaryl ring substituted with 1 to 4 R q or a (CH2) 11 -5- to 7-membered heterocyclic ring substituted with 1 to 4 R q In still other embodiments, R 4 is independently C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl or C 2-6 alkenyl-C 3-7 cycloalkyl.

[0367] In any embodiment, R 11 is independently hydrogen at each occurrence. In certain other embodiments, R 11 is independently C 1-6 alkyl at each occurrence. In still other embodiments, R 11 is independently C 1-6 alkoxy at each occurrence. In still other embodiments, R 11 is independently (CH2) p -C 1-6 alkoxy at each occurrence. In still other embodiments, R 11 is independently phenyl at each occurrence. In still other embodiments, R 11Independently at each occurrence is (CH2) p -phenyl. In still other embodiments, R 11 Independently at each occurrence is C 3-7 Cycloalkyl. In still other embodiments, R 11 Independently at each occurrence is (CH2) p -C 3-7 Cycloalkyl. In still other embodiments, R 11 Independently at each occurrence is C 2-6 Alkynyl-C 3-7 Cycloalkyl. In still other embodiments, R 11 Independently at each occurrence is O(CH2) p -C 3-7 Cycloalkyl. In any embodiment, each phenyl is independently optionally substituted with one to three of halogen, C 1-6 Alkyl or C 1-6 Alkoxy.

[0368] In any embodiment, R 12 Independently at each occurrence is hydrogen. In certain other embodiments, R 12 Independently at each occurrence is C 1-4 Alkyl. In still other embodiments, R 12 Independently at each occurrence is C 3-7 Cycloalkyl. In still other embodiments, R 12 And R 12 Together with the carbon atom to which it is attached form a 3- to 6-membered cycloalkyl ring.

[0369] In any embodiment, R a And R b Independently at each occurrence is hydrogen. In certain other embodiments, R a And R b Independently at each occurrence is C 1-6 Alkyl. In still other embodiments, R 12 Independently at each occurrence is C 3-7 Cycloalkyl. In still other embodiments, R a And R b Together with the nitrogen atom to which it is attached form a saturated or unsaturated heterocycle containing three to seven ring atoms, said ring being optionally capable of containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and being optionally substituted with one to three groups, which may be the same or different, selected from the group consisting of C 1-4 Alkyl, phenyl and benzyl.

[0370] In any embodiment, the Moiety in formulas (II) and (III) is In certain other embodiments, in Formulas (II) and (III), the moiety is and w is 1.

[0371] In any embodiment, R 13 is hydrogen. In certain other embodiments, R 13 is methyl. In still other embodiments, R 13 is cyclopropyl.

[0372] In any embodiment, the compound is selected from:

[0373]

[0374] In any embodiment, the compound is selected from:

[0375]

[0376]

[0377] In any embodiment, the compound is selected from:

[0378]

[0379] In any embodiment, the compound is selected from:

[0380]

[0381]

[0382] On the other hand, the present invention relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier.

[0383] In still another aspect, the present invention relates to a method for treating a disease associated with a dysregulation of lysophosphatidic acid receptor 1 (LPA1) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein. In some embodiments, the disease is pathological fibrosis (e.g., pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, skin fibrosis, ocular fibrosis, or pancreatic fibrosis), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, or systemic sclerosis.

[0384] In yet another aspect, the present invention relates to a method for preparing compounds of formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId) and (IIIdd), said method comprising each of the exemplified compounds and intermediates described herein.

[0385] In any embodiment, the present invention relates to an intermediate selected from:

[0386]

[0387] General synthetic method

[0388] The compounds of the present invention can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as understood by those skilled in the art. Preferred methods include but are not limited to the exemplary schemes and working examples described below. Unless otherwise specified, all substituents are defined as above. Reactions are carried out in solvents or solvent mixtures suitable for the reagents and materials used and suitable for the proposed transformations. This will sometimes require judgment to modify the order of synthetic steps or to select a particular method scheme rather than another to obtain the desired compounds of the present invention.

[0389] It will be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of protecting groups for protecting the reactive functional groups present in the compounds described in the present invention. An authoritative description of many alternatives for the trained practitioner is Greene et al., Protective Groups in Organic Synthesis, 5th Edition, Wiley (2014). It will also be recognized that the compound names mentioned in the description of Schemes 1 - 12 are for convenience only and do not necessarily reflect the actual chemical names of those compounds.

[0390] Scheme 1

[0391]

[0392] Scheme 1 describes the synthesis of carbonyl azine oxazole N - heteroaryl - azacyclohexyl acetic acid 8. PG1 and PG2 each represent a protecting group, and L 2 is (CR 7 R 7 ) p(e.g., CH2). The haloazine derivative 1 reacts with piperidine acetate 2 under Buchwald conditions, via a suitable catalyst (e.g., Pd(OAc)2 / BINAP) or nucleophilic aromatic substitution reaction or Ullmann reaction, to obtain the corresponding carbonylazine N - heteroarylpiperidine acetate formate 3. The protected hydroxymethylazole 3 is deprotected to obtain hydroxymethylazole 4, which is then reacted with MsCl (or PBr3) to obtain the mesylate (or Br) 5. The mesylate (or Br) 5 is treated with 2 - hydroxyazine 6 in the presence of a suitable base (e.g., K2CO3, nucleophilic substitution reaction) to obtain the corresponding carbonylazine N - heteroarylpiperidine acetate formate 7, followed by deprotection of the ester to obtain the desired carbonylazine L 2 -azole N - heteroaryl - azacyclohexylacetic acid 8.

[0393] Scheme 2

[0394]

[0395] Scheme 2 describes an alternative synthetic route for carbonylazine N - heteroaryl - azacyclohexylacetic acid 8. PG1 and PG2 each represent a protecting group, and L 2 is (CR 7 R 7 ) p (e.g., CH2). The protected hydroxymethylazole derivative 1 is deprotected to obtain hydroxymethylazole 9, which is then reacted with MsCl (or PBr3) to obtain the mesylate (or Br) 10. The mesylate (or Br) 10 is treated with 2 - hydroxyazine in the presence of a suitable base (e.g., K2CO3, nucleophilic substitution reaction) to obtain the corresponding N - substituted carbonylazine 11. The haloazine derivative 11 reacts with piperidine acetate formate under Buchwald conditions, via a suitable catalyst (e.g., Pd(OAc)2 / BINAP) or nucleophilic aromatic substitution reaction or Ullmann reaction, to obtain the corresponding piperidine acetate formate 7, followed by deprotection of the ester to obtain the desired carbonylazine L 2 -azole N - heteroaryl - azacyclohexylacetic acid 8.

[0396] Scheme 3

[0397]

[0398] Scheme 3 describes the synthesis of N-substituted azaheterocyclopentyl ketone N-heteroaryl-azacyclohexyl acetic acid 13. Treatment of mesylate (or Br) 5 with azaheterocyclopentyl ketone 6a in the presence of a suitable base (e.g., t-BuOK, nucleophilic substitution reaction) gives the corresponding N-substituted azacyclopentyl ketone 12, followed by ester deprotection to give the desired N-substituted azacyclopentyl ketone-N-heteroaryl-azacyclohexyl acetic acid 13.

[0399] Scheme 4

[0400]

[0401] Scheme 4 describes the synthesis of oxo-Q-ring N-heteroaryl-azacyclohexyl acetic acid 16, where Q represents a 5-membered heteroaryl or heterocyclic group or a 6-membered heteroaryl or heterocyclic group. Base-mediated S N Ar reaction of hydroxymethylazole 4 with a suitable halo- or methylsulfonyl-substituted Q-ring 14 (X is halo or methylsulfonyl) gives oxo-Q-ring N-heteroaryl piperidine acetate 15, followed by ester deprotection to give the desired oxo-Q-ring N-heteroaryl-azacyclohexyl acetic acid 16.

[0402] Scheme 5

[0403]

[0404] Scheme 5 describes an alternative synthesis of oxo-Q-ring N-heteroaryl-azacyclohexyl acetic acid 16, where Q represents a 5-membered heteroaryl or heterocyclic group or a 6-membered heteroaryl or heterocyclic group. Base-mediated S N Ar reaction of hydroxymethylazole 9 with a suitable halo- or methylsulfonyl-substituted Q-ring 14 (X is halo or methylsulfonyl) gives oxo-Q-ring 17, which reacts with a piperidine ethyl ester derivative under Buchwald conditions, via a suitable catalyst (e.g., Pd(OAc)2 / BINAP) or nucleophilic aromatic substitution reaction or Ullmann reaction, to give the corresponding oxo-Q-ring N-heteroaryl piperidine acetate 15, followed by ester deprotection to give the desired oxo-Q-ring N-heteroaryl-azacyclohexyl acetic acid 16.

[0405] Scheme 6

[0406]

[0407] Scheme 6 describes the synthesis of amino-Q-ring N-heteroaryl-azacyclohexylacetic acid 21. Hydroxymethylazole 4 is reacted with MsCl and a suitable base (e.g., TEA) to obtain the corresponding mesylate 17. The mesylate 17 is displaced with NaN3 (or other azide reagent) to give azide 18, which is then reduced (e.g., Staudinger reduction with PPh3 / water) to obtain amine 19. Then amine 19 is reacted with a halo- or methylsulfonyl-substituted Q-ring 14 (X is halo or methylsulfonyl) in the presence of a suitable base or by Pd-catalyzed amination to obtain amino-azinepiperidine acetate 20, which is then deprotected to give the desired amino-Q-ring N-heteroaryl-azacyclohexylacetic acid 21.

[0408] Scheme 7

[0409]

[0410] Scheme 7 describes the synthesis of oxy-azole N-heteroaryl-azacyclohexylacetic acid 24. Hydroxymethylazole 4 is reacted with a suitable haloazole or methylsulfonylazole 22 (which is a 5-membered heteroaryl ring containing at least one nitrogen and may contain an additional 1 to 3 heteroatoms selected from N, O, and S) in the presence of a suitable base (nucleophilic aromatic substitution reaction) to obtain oxy-azole N-heteroarylpiperidine acetate 23, which is then deprotected to give the desired oxy-azole N-heteroaryl-azacyclohexylacetic acid 24.

[0411] Scheme 8

[0412]

[0413] Scheme 8 describes the synthesis of amino-azole N-heteroaryl-azacyclohexylacetic acid 28. Hydroxymethylazole 4a is oxidized to the corresponding aldehyde 25 (e.g., using Dess-Martin periodinane or Swern Oxidation). Then aldehyde 25 can be reductively aminated with a suitable amino-azole 26 (which is a 5-membered heteroaryl ring containing at least one nitrogen and may contain an additional 1 to 3 heteroatoms selected from N, O, and S) to obtain amino-azole N-heteroarylpiperidine acetate 27. Subsequently, 27 is deprotected to give amino-azole N-heteroaryl-azacyclohexylacetic acid 28.

[0414] Scheme 9

[0415]

[0416] Scheme 9 describes the synthesis of alkylated triazole N-heteroaryl-azacyclohexyl acetic acid 32. In the presence of a suitable base, treatment of mesylate or Br-substituted compound 10 with triazole 29 gives alkylated triazole 30. Then the haloazine 30 is reacted with piperidine acetate 2 under Buchwald conditions with a suitable catalyst (e.g., Pd(OAc)2 / BINAP) to give the corresponding alkylated triazole N-heteroaryl piperidine acetate 31, followed by ester deprotection to give the desired alkylated triazole N-heteroaryl-azacyclohexyl acetic acid 32.

[0417] Scheme 10

[0418]

[0419] Scheme 10 describes the synthesis of alkylated tetrazole N-heteroaryl-azacyclohexyl acetic acids 36 and 37. Hydroxymethylazole 4 is reacted with tetrazole 33 under Mitsunobu conditions to give regioisomeric tetrazoles 34 and 35. Deprotection of piperidine acetates 34 and 35 gives regioisomeric alkylated tetrazole N-heteroaryl-azacyclohexyl acetic acids 36 and 37.

[0420] Scheme 11

[0421]

[0422] Scheme 11 describes the synthesis of carbamoyloxymethylazole N-heteroaryl-azacyclohexyl acetic acid 41. Hydroxymethylazole 4 is reacted with 4-nitrophenyl chloroformate in the presence of a suitable base to give the corresponding 4-nitrophenyl carbonate 38, which is then reacted with amine 39 in the presence of a proper base to give carbamate 40. Subsequent deprotection of 40 gives carbamoyloxymethylazole N-heteroaryl-azacyclohexyl acetic acid 41.

[0423] Scheme 12

[0424]

[0425] Scheme 12 describes the synthesis of 1-azinylmethyl-piperidine-3-carboxylic acids 48, 49 and 50. In the presence of CO gas and a suitable catalyst, carbonyl insertion into azine halide 1 in methanol gives azine formate 42, which is then reduced with a suitable reducing agent to give azine methanol 43. Treatment of azine methanol 43 with MsCl in the presence of a suitable base gives the corresponding mesylate 44. Alkylation of piperidine carboxylate 45 with mesylate 44 in the presence of a suitable base gives azinylmethyl-piperidine-3-carboxylate 46. Deprotection of azinylmethyl-piperidine-3-carboxylate 46 gives hydroxymethylazole 47, which is then converted to the corresponding acids 48, 49 and 50 in several steps using methods similar to those described herein.

[0426] Pharmaceutical composition and method

[0427] The compounds used in the methods described herein can be formulated into a pharmaceutically acceptable composition together with a pharmaceutically acceptable carrier or adjuvant and then administered to a subject. In another embodiment, such pharmaceutically acceptable compositions further comprise an additional therapeutic agent in an amount effective to effect modulation of a disease or disease symptom, including those described herein.

[0428] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a subject together with a compound of the invention and that does not interfere with its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutically effective amount of the compound.

[0429] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the invention include, but are not limited to: ion exchange agents, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms such as Tween or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene block polymers, polyethylene glycol and lanolin. Cyclodextrins such as α-, β- and γ-cyclodextrins or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives can also be advantageously used to enhance the delivery of the compounds of the formula described herein.

[0430] The pharmaceutical composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, or by an implanted reservoir, preferably by oral administration or by injection. The pharmaceutical composition of the present invention can include any conventional non-toxic pharmaceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation can be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the formulated compound or its delivery form. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0431] The pharmaceutical composition can be in the form of a sterile injectable preparation, for example, in the form of a sterile injectable aqueous or oily suspension. This suspension can be formulated using suitable dispersing or wetting agents (e.g., Tween80) and suspending agents according to techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any mild fixed oil containing synthetic mono- or di-glycerides of fatty acids can be employed. Fatty acids such as oleic acid and its glyceride derivatives can be used in the preparation of injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxylated forms. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersing agent or carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. For formulating purposes, other commonly used surfactants such as Tween or Span and / or other similar emulsifying or bioavailability enhancing agents commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used.

[0432] The pharmaceutical composition of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. A lubricant such as magnesium stearate is also typically added. For oral administration in the form of capsules, useful diluents include lactose and dried corn starch. When an aqueous suspension and / or emulsion is administered orally, the active ingredient can be suspended or dissolved in the oil phase, in combination with an emulsifying and / or suspending agent. If desired, certain sweetening and / or flavoring and / or coloring agents can be added.

[0433] The pharmaceutical compositions of the present invention can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients which are solid at room temperature but liquid at rectal temperature and will thus melt in the rectum to release the active ingredient. Such materials include but are not limited to cocoa butter, beeswax and polyethylene glycols.

[0434] Local administration of the pharmaceutical compositions of the present invention is useful when the desired treatment involves an area or organ readily accessible by topical application. For topical application to the skin, the pharmaceutical compositions should be formulated with a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include but are not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with a suitable emulsifier. Suitable carriers include but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the present invention can also be topically applied to the lower intestine by rectal suppository formulations or in suitable enema formulations. The present invention also encompasses topical transdermal patches.

[0435] The pharmaceutical compositions of the present invention can be administered by nasal aerosol or inhalant. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations and can be prepared as solutions in saline with benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, fluorocarbons and / or other solubilizing or dispersing agents known in the art.

[0436] When the compositions of the present invention include a combination of a compound of the formula described herein with one or more additional therapeutic or prophylactic agents, the compound and the additional agent(s) should be present at dosage levels between about 1 to 100%, and more preferably between about 5 to 95%, of the dosages normally administered in a monotherapy regimen. As part of a multiple dosage regimen, the additional agent(s) can be administered separately from the compounds of the present invention. Alternatively, those agents can be part of a single dosage form which is mixed with the compounds of the present invention in a single composition.

[0437] The compounds described herein can be administered, for example, by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic formulation, or by inhalation, in a dosage range of from about 0.5 to about 100 mg / kg of body weight, alternatively, in a dosage between 1 mg and 1000 mg / dose, once every 4 to 120 hours, or as required by the drug. The methods herein contemplate administering an effective amount of the compound or compound composition to achieve the desired or specified effect. Generally, the pharmaceutical compositions of the invention will be administered about 1 to about 6 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated and the mode of administration. Typical formulations will contain from about 5% to about 95% active compound (w / w). Alternatively, such formulations contain from about 20% to about 80% active compound.

[0438] Doses below or above the above ranges may be required. The specific dosage and treatment regimen for any subject will depend upon a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, disease, condition or severity and course of symptoms, the subject's susceptibility to the disease, condition or symptoms, and the judgment of the treating physician.

[0439] When the condition of the subject improves, a maintenance dose of the compound, composition, or combination of the invention may be administered, if needed. Subsequently, as the symptoms change, when the symptoms have been reduced to the desired level, the dosage or frequency of administration, or both, may be reduced to a level that maintains the improved condition. However, upon any recurrence of the disease symptoms, the subject may require long-term intermittent treatment.

[0440] The pharmaceutical compositions comprising a compound of formula (I) described above may further comprise another therapeutic agent for treating a disease associated with dysregulation of lysophosphatidic acid receptor 1 (LPAi). Specifically, such combinations can be used to treat pathological fibrosis (e.g., pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, skin fibrosis, ocular fibrosis, or pancreatic fibrosis), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, or systemic sclerosis.

[0441] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0442] The following examples are provided to illustrate the advantages of the technology of the present invention and to further assist those of ordinary skill in the art in preparing or using the compounds or salts, pharmaceutical compositions, derivatives, solvates, metabolites, prodrugs, racemic mixtures or tautomeric forms thereof of the technology of the present invention. The examples herein are also presented to more fully illustrate the preferred aspects of the technology of the present invention. The examples should in no way be construed as limiting the scope of the technology of the present invention as defined by the appended claims. The examples may incorporate or include any variations, one or more aspects of the technology of the present invention as described above. The above variations, aspects or aspects may further each incorporate or include any or all other variations, aspects or aspects of the technology of the present invention.

[0443] Example

[0444] The abbreviations used herein are as follows:

[0445]

[0446] General conditions and procedures

[0447] In the following examples, chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company) and used without further purification. THF was continuously refluxed under nitrogen and freshly distilled from sodium and benzophenone, and dichloromethane was continuously refluxed under nitrogen and freshly distilled from CaH2.

[0448] Flash chromatography was performed on an Ez Purifier III through a column with 200 - 300 mesh silica gel particles. Analytical and preparative thin layer chromatography (TLC) plates were HSGF 254 (0.15 - 0.2 mm thickness, Shanghai Anbang Company, China). Unless otherwise stated, nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AMX - 300 or AMX - 400 NMR (Brucker, Switzerland) at around 20–30 °C. The following abbreviations were used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, double doublet; ddd, double doublet of doublets; dt, double triplet; bs, broad signal. Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were run using electrospray ionization (ESI) on a Waters LCT TOF mass spectrometer (Waters, USA). Compound purification was performed using various conventional methods as needed, including but not limited to preparative chromatography using normal or reverse phase HPLC or flash column or Prep - TLC plates under acidic, neutral or basic conditions.

[0449] Preparative HPLC: Unless otherwise stated, compounds were purified using a Waters Fractionlynx system equipped with a YMC Pack Pro d8 column (5 μm, 120 Å, 50×20 mm) and the following solvent systems: H2O, AcCN, and H2O containing 2% TFA. Specific elution gradients were based on the retention times obtained by analytical LC - MS. However, in general, all elution gradients of H2O and MeCN were run at a flow rate of 35 mL / min for a run time of 7 minutes. An automated mixing method was used to ensure a concentration of 0.1% TFA in each run. Specific elution gradients were based on the retention times obtained by analytical LC - MS. However, in general, all elution gradients of H2O and MeCN were run at a flow rate of 50 mL / min for a run time of 8 minutes.

[0450] Analytical LC - MS: Analytical LC - MS was performed on a Waters Acquity UPLC - MS instrument equipped with an ACQUITY UPLC BEH C18 column (2.1×50 mm, 1.7 μm) at a column temperature of 45 °C and using the following solvent systems: Solvent A: H2O containing 0.1% HCOOH; Solvent B: AcCN containing 0.1% HCOOH. All compounds were run using the same elution gradient, i.e., 5% to 95% of Solvent B in a run time of 1.5 minutes with a flow rate of 0.6 mL / min.

[0451] Preparative chiral SFC separation: Separate the stereoisomer mixture on one of the following columns using a Berger Minigram SFC instrument: ChiralPak AS-H (10×250 mm), ChiralPak IA (10×250 mm), ChiralPak AD-H (21×250 mm), Phenomenex Lux-2 (21.2×250 mm), or ChiralPak IC (10×250 mm); elute with a MeOH / CO2 solution containing 0.1% diethylamine or an EtOH / CO2 solution containing 0.1% diethylamine or an isopropanol / CO2 solution containing 0.1% diethylamine, where the flow rate is 2.5 mL / min and the column temperature is 35 °C.

[0452] Analytical chiral SFC separation: Analyze the stereoisomer mixture or single enantiomer on one of the following columns using a JASCO analytical SFC instrument: ChiralPak AS-H (4.6×250 mm), ChiralPak IA (4.6×250 mm), ChiralPak AD-H (4.6×250 mm), Phenomenex Lux-2 (4.6×250 mm), or ChiralPak IC (4.6×250 mm); elute with a MeOH / CO2 solution containing 0.1% diethylamine or an EtOH / CO2 solution containing 0.1% diethylamine or an isopropanol / CO2 solution containing 0.1% diethylamine, where the flow rate is 6.0 mL / min and the column temperature is 35 °C.

[0453] Intermediate 1: 3-Bromo-2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine

[0454]

[0455] Step 1: 3,6-Dibromo-2-ethylpyridine

[0456] At -50 °C, NaHMDS (180 mL, 0.36 mol, 2 M in THF) was added dropwise to a solution of 3,6-dibromo-2-methylpyridine (75 g, 0.299 mol) in THF (1 L), and the mixture was stirred at this temperature for 30 minutes. MeI (46.5 mL, 0.75 mol) was added to the above mixture, and the resulting mixture was stirred at -50 °C to room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (500 mL) at 0 °C and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE:DCM = 300:1 to 200:1) to give the title compound as a yellow oil (47 g, 59.1% yield). 1 H NMR (400 MHz, CD3OD) δ 7.61 - 7.59 (d, J = 8 Hz, 1H), 7.61 - 7.59 (d, J = 8.4 Hz, 1H), 2.94 - 2.88 (q, 2H), 1.38 - 1.27 (t, 3H).

[0457] Step 2: 3-(5-bromo-6-ethylpyridin-2-yl)prop-2-yn-1-ol

[0458] Propargyl alcohol (11.9 g, 0.212 mol), CuI (3.4 g, 17.7 mmol), DIPEA (35.1 mL, 0.212 mol) and Pd(PPh3)2Cl2 (12.4 g, 17.7 mmol) were added to a solution of 3,6-dibromo-2-ethylpyridine (47 g, 0.177 mol) in THF (0.65 L), and the mixture was degassed three times under N2 atmosphere and stirred at room temperature under N2 atmosphere for 16 hours. The mixture was diluted with EtOAc (500 mL) and filtered. The filtrate was washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (DCM:EtOAc = 10:1 to 4:1) to give the title compound as a brown solid (40 g, 94.1% yield). LC / MS (ESI) m / z: 240 / 242 (M+H) + 。

[0459] Step 3: (4-(5-bromo-6-ethylpyridin-2-yl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)methanol

[0460] Under a N2 atmosphere at 0 °C, cyclopentadienylbis(triphenylphosphine)ruthenium(II) (3.5 g, 4.16 mmol) and TMS-methyl azide (14 g, 0.108 mol) were added to a solution of intermediate 3-(5-bromo-6-ethylpyridin-2-yl)prop-2-yn-1-ol (20 g, 0.083 mol) in THF (400 mL). The mixture was degassed three times under a N2 atmosphere and stirred at room temperature for 16 h. The mixture was diluted with EtOAc (500 mL) and filtered. The filtrate was concentrated to dryness to give the crude product, which was triturated with PE / EtOAc (1000 mL, 10 / 1 v / v) to give the title compound as a white solid (28 g, 91.3% yield). 1 H NMR (400 MHz, CDCl3) δ 8.03 - 8.01 (d, J = 8.4 Hz, 1H), 7.95 - 7.93 (d, J = 8.4 Hz, 1H), 6.77–6.74 (t, J = 6.8 Hz, 1H), 4.79 - 4.78 (d, J = 6.8 Hz, 1H), 3.80 (s, 3H), 3.03 - 3.01 (q, 1H), 1.34–1.30 (t, J = 7.6 Hz, 3H), 0.20 (s, 9H).

[0461] Step 4: (4-(5-Bromo-6-ethylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

[0462] TBAF·3H2O (25.6 g, 81.2 mmol) was added to a solution of (4-(5-bromo-6-ethylpyridin-2-yl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)methanol (25 g, 67.7 mmol) in THF (300 mL), and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (500 mL), washed with saturated aqueous NH4Cl (3 × 50 mL) and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (DCM:EtOAc = 8:1 to 4:1) to give the title compound as a grey solid (19 g, 94.4% yield). LC / MS (ESI) m / z: 297 / 299 (M+H) + 。

[0463] Step 5: 3-Bromo-2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine

[0464] At 0 °C, DHP (10.6 g, 0.126 mol) was added to a mixture of (4-(5-bromo-6-ethylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol (25 g, 0.084 mol) and TosOH (2.2 g, 12.6 mmol) in DCM (300 mL), and the mixture was stirred at room temperature for 16 h. The mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (DCM:EtOAc = 8:1) to give the title compound as a yellow solid (30 g, 93.6% yield). LC / MS (ESI) m / z: 381 / 383 (M+H) + 。 1 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 5.36 (dd, J = 36.5, 12.8 Hz, 2H), 4.75–4.67 (m, 1H), 4.16 (s, 3H), 3.88–3.80 (m, 1H), 3.55–3.46 (m, 1H), 3.00 (q, J = 7.5 Hz, 2H), 1.84–1.67 (m, 2H), 1.65–1.58 (m, 2H), 1.54–1.45 (m, 2H), 1.34 (t, J = 7.5 Hz, 3H).

[0465] Intermediate 2: 3-Bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine

[0466]

[0467] Intermediate 2 was synthesized according to the same sequence as used for the synthesis of Intermediate 1. LC / MS (ESI) m / z: 367 / 369 (M+H) + 。 1 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 5.15 (q, J = 12.7 Hz, 2H), 4.61–4.54 (m, 1H), 3.99 (s, 3H), 3.74–3.64 (m, 1H), 3.38–3.30 (m, 1H), 2.51 (s, 3H), 1.66–1.50 (m, 2H), 1.46–1.40 (m, 2H), 1.39–1.32 (m, 2H).

[0468] Intermediate 3: (4-(6-Ethyl-5-iodopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

[0469]

[0470] Step 1: 2-Ethyl-3-iodo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine

[0471] To a mixture of 3-bromo-2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridine (7.2 g, 18.9 mmol) and NaI (14.2 g, 94.4 mmol) in 1,4-dioxane (80 mL) was added N1,N2-dimethylethane-1,2-diamine (1.55 g, 11.3 mmol) and CuI (1.80 g, 9.44 mmol), and the mixture was degassed three times under N2 atmosphere and stirred at 110 °C for 20 h. The mixture was filtered and the cake was washed with EtOAc (2 × 50 mL). The combined filtrate was washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness to give the crude product, which was purified by silica gel chromatography (PE:EtOAc = 4:1 to 1:1) to give the title compound as a pale yellow solid (6.1 g, 74.2%). LC / MS (ESI) (m / z): 429 (M+H) + 。 1 1H NMR (400 MHz, CDCl3) δ 8.11 - 8.09 (d, J = 8.4 Hz, 1H), 7.75 - 7.73 (d, J = 8.3 Hz, 1H), 5.42 - 5.29 (q, J = 12.7 Hz, 2H), 4.72–4.70 (m, 1H), 4.16 (s, 3H), 3.84–3.82 (m, 1H), 3.56–3.49 (m, 1H), 3.02 - 2.97 (q, J = 7.2 2H), 1.63–1.59 (m, 2H), 1.56–1.53 (m, 4H), 1.34–1.30 (t, J = 7.6 Hz, 3H).

[0472] Step 2: (4-(6-Ethyl-5-iodopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol (6)

[0473] To a solution of 2-ethyl-3-iodo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine (1.0 g, 2.34 mmol) in MeOH (10 mL) was added PPTS (0.59 g, 2.34 mmol), and the mixture was stirred at 60 °C for 16 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 20:1 to 2:1) to afford the title compound as a white solid (698 mg, 86.9% yield). LC / MS (ESI) m / z: 345 (M+H) + 。

[0474] Intermediate 4: 5-Bromo-4-ethyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrimidine

[0475]

[0476] Step 1: 5-Bromo-2-chloro-4-ethylpyrimidine

[0477] To a solution of 5-bromo-2-chloropyrimidine (60 g, 0.31 mol) in THF (600 mL) was added dropwise EtMgCl (186 mL, 0.37 mol, 2 M in THF) at 10 °C under N2 atmosphere, and the resulting mixture was stirred at this temperature for 1 h. TEA (43 mL, 0.31 mol) was added dropwise to the mixture at 0 °C under N2 atmosphere. After stirring at 0 °C for 20 min, a solution of iodine (79.0 g, 0.31 mol) in THF (120 mL) was added, and the resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with saturated aqueous Na2SO3 and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (EtOAc:PE = 0 to 200:1) to afford the title compound as a pale yellow solid (35.3 g, 51.4% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 2.89 - 2.83 (q, J = 7.5 Hz, 2H), 1.22 - 1.18 (t, J = 7.5 Hz, 3H).

[0478] Step 2: 5-Bromo-4-ethyl-2-iodopyrimidine

[0479] To a solution of 5-bromo-2-chloro-4-ethylpyrimidine (20 g, 0.09 mol) in DCM (50 mL) at 0 °C was added dropwise aqueous HI solution (200 mL, 57% wt), followed by NaI (30 g, 0.2 mol), and the mixture was stirred at 5 °C for 16 h. The reaction mixture was quenched with saturated aqueous Na2S2O3 (100 mL) and extracted with DCM (2 × 200 mL). The combined organic layers were concentrated under reduced pressure to give a colorless residue. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 4:1) to afford the title compound as a pale yellow solid (25.3 g, 89.8% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 2.82 - 2.75 (q, J = 7.5 Hz, 2H), 1.19 - 1.16 (t, J = 7.5 Hz, 3H).

[0480] Step 3: 5-Bromo-4-ethyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrimidine

[0481] Under N2 atmosphere, to a solution of 5-bromo-4-ethyl-2-iodopyrimidine (17.5 g, 55.9 mmol) and 1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.8 g, 46.6 mmol, prepared according to WO 2014081619) in 1,4-dioxane (300 mL) and water (60 mL) was added all at once Na2CO3 (9.9 g, 93.2 mmol), Pd(dppf)Cl2 (1.7 g, 2.3 mmol). The mixture was degassed three times under N2 and stirred at 75 °C for 16 h under N2 atmosphere. The mixture was poured into ice water and extracted with DCM (2 × 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel chromatography (PE:EtOAc = 10:1) to afford the title compound as a yellow solid (12.7 g, 59.6% yield). LC / MS (ESI) m / z: 381 / 383 (M+H) + 。 11H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.01 (s, 1H), 5.32 - 5.29 (d, J = 12 Hz, 1H), 5.14 - 5.11 (d, J = 12 Hz, 1H), 4.73 - 4.69 (m, 1H), 3.90 (s, 3H), 3.79 - 3.72 (m, 1H), 3.45 - 3.41 (m, 1H), 2.88 - 2.83 (q, J = 7.4 Hz, 2H), 1.68 - 1.55 (m, 2H), 1.55 - 1.42 (m, 4H), 1.28 - 1.24 (t, J = 7.5 Hz, 3H).

[0482] Intermediate 5: Methyl (S)-2-(5,5-difluoropiperidin-3-yl)acetate (Intermediate 5A)

[0483]

[0484] Step 1: Benzyl 5-(2-diazoacetyl)-3,3-difluoropiperidine-1-carboxylate

[0485] To a solution of 1-((benzyloxy)carbonyl)-5,5-difluoropiperidine-3-carboxylic acid (51 g, 0.17 mol) in DCM (500 mL) at 0 °C was added DMF (2 mL), followed by dropwise addition of (COCl)2 (43 g, 0.34 mol), and the mixture was stirred at 0 °C for 2 h. The reaction was concentrated to dryness and the residue was co-evaporated with toluene three times. The residue was dissolved in THF (500 mL), and a solution of TMSCHN2 (250 mL, 0.5 mol, 2 M in hexanes) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with AcOH (60 mL) at 0 °C and the mixture was concentrated to dryness to afford the title compound as a yellow oil (55 g, 100% yield), which was used directly in the next reaction without purification. LC / MS (ESI) m / z: 324 (M + H) + .

[0486] Step 2: Benzyl (S)-3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (3A) and Benzyl (R)-3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (3B)

[0487] To a solution of 5-(2-diazoacetyl)-3,3-difluoropiperidine-1-carboxylic acid benzyl ester (55 g, 0.17 mol) in MeOH (500 mL) was added AgCF3COO (7.4 g, 0.03 mol) and TEA (67.6 g, 0.67 mol), and the mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated to dryness and the residue was purified by silica gel chromatography (PE:EtOAc = 3:1) to give the title compound as a pale yellow oil (37 g, 62.9% yield). LC / MS (ESI) m / z: 328 (M+H) + The two enantiomers were separated by chiral SFC to give (S)-benzyl 3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (peak 2, retention time: 4.414 min) as a pale yellow oil (13.8 g, 24.8% yield) and (R)-benzyl 3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (peak 1, retention time: 4.109 min) (16.1 g, 28.9% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.41–7.28 (m, 5H), 5.15 (s, 2H), 4.25–3.94 (m, 2H), 3.66 (d, J = 25.3 Hz, 3H), 3.30–3.12 (m, 1H), 2.91–2.67 (m, 1H), 2.42–2.23 (m, 4H), 1.75–1.60 (m, 1H). SFC conditions: column: ChiralPak IC-H, 250×4.6 mm I.D., 5 μm; mobile phase: A is CO2 and B is methanol (0.05% NH4OH); gradient: B 5% - 40%; flow rate: 50 mL / min;

[0488] Step 3: Methyl (S)-2-(5,5-difluoropiperidin-3-yl)acetate

[0489] To a solution of (S)-benzyl 3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (4.2 g, 12.83 mmol) in EtOAc (40 mL) at 0 °C was added Pd / C (300 mg, 10% wt). The mixture was degassed three times under N2 atmosphere and stirred at room temperature under a H2 balloon for 2 h. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound as an off-white solid (2.37 g, 95.6%). LC / MS (ESI) (m / z): 194 (M+H) + 。 11H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 3.18–3.06 (m, 2H), 2.85–2.65 (m, 1H), 2.36–2.20 (m, 5H), 1.62–1.48 (m, 1H).

[0490] Intermediate 6: Methyl (R)-2-(5,5-difluoropiperidin-3-yl)acetate

[0491]

[0492] The title compound was prepared from benzyl (R)-3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate using the same procedure as for methyl (S)-2-(5,5-difluoropiperidin-3-yl)acetate. LC / MS (ESI) (m / z): 194 (M+H) + .

[0493] Intermediate 7: Methyl (S)-2-(5,5-difluoro-1-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)piperidin-3-yl)acetate

[0494]

[0495] Step 1: 2-((3S)-5,5-Difluoro-1-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid

[0496] Under a N2 atmosphere, Cs2CO3 (2.66 g, 8.2 mmol), RuPhos (381 mg, 0.82 mmol), and RuPhos-Pd-G3 (342 mg, 0.41 mmol) were added to a mixture of 3-bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine (1.5 g, 4.1 mmol) and methyl (S)-2-(5,5-difluoropiperidin-3-yl)acetate (790 mg, 4.1 mmol) in dry 1,4-dioxane (30 mL). The mixture was degassed three times under a N2 atmosphere and stirred at 100 °C for 16 h under a N2 atmosphere. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (PE containing 0–50% EtOAc) to give the title compound as a pale yellow solid (1.6 g, 81.7% yield). LC / MS (ESI) m / z: 480 (M+H) + . 11H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 5.38–5.26 (m, 2H), 4.77 (t, J = 3.2 Hz, 1H), 4.15 (s, 3H), 3.92–3.85 (m, 1H), 3.70 (s, 3H), 3.57–3.50 (m, 1H), 3.32–3.22 (m, 2H), 3.03–2.93 (m, 1H), 2.63–2.53 (m, 2H), 2.57 (s, 3H), 2.44–2.41 (m, 2H), 2.35–2.25 (m, 1H), 1.84–1.77 (m, 1H), 1.75–1.67 (m, 2H), 1.62–1.55 (m, 2H), 1.54–1.45 (m, 2H).

[0497] Step 2: Methyl (S)-2-(5,5-difluoro-1-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)piperidin-3-yl)acetate

[0498] To a solution of methyl 2-((3S)-5,5-difluoro-1-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate (1.6 g, 3.3 mmol) in MeOH (20 mL) was added PPTS (1.6 g, 6.6 mmol), and the mixture was stirred at 50 °C for 16 h. The mixture was concentrated to dryness and the residue was dissolved in EtOAc (20 mL). The mixture was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0–60% EtOAc) to afford the title compound as a pale yellow solid (1.2 g, 90.0% yield). LC / MS (ESI) m / z: 396 (M+H) + . 1 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 4.82 (s, 2H), 4.08 (s, 3H), 3.70 (s, 3H), 3.36–3.21 (m, 2H), 3.06–2.96 (m, 1H), 2.65–2.56 (m, 2H), 2.61 (s, 3H), 2.46–2.40 (m, 2H), 2.37–2.28 (m, 1H), 1.78–1.70 (m, 1H).

[0499] Intermediate 8: Methyl (S)-2-(1-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate

[0500]

[0501] Intermediate 8 was synthesized according to the same sequence as used for the synthesis of Intermediate 7. LC / MS (ESI) m / z: 410 (M+H) + 。 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 4.84 (s, 2H), 4.08 (s, 3H), 3.70 (s, 3H), 3.30–3.17 (m, 2H), 3.07–2.99 (m, 1H), 2.99–2.93 (m, 2H), 2.63–2.58 (m, 2H), 2.48–2.38 (m, 2H), 2.36–2.28 (m, 1H), 1.74–1.63 (m, 1H), 1.34 (t, J = 7.5 Hz, 3H).

[0502] Intermediate 9: Methyl (S)-2-(1-(4-ethyl-2-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)-5,5-difluoropiperidin-3-yl)acetate

[0503]

[0504] Step 1: Methyl 2-((3S)-5,5-difluoro-1-(4-methyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrimidin-5-yl)piperidin-3-yl)acetate

[0505] Under a N2 atmosphere, methyl (S)-2-(5,5-difluoropiperidin-3-yl)acetate (212 mg, 1.1 mmol) was added to a solution of 5-bromo-4-ethyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrimidine (420 mg, 1.1 mmol) in toluene (5 mL), followed by the addition of Cs2CO3 (710 mg, 2.2 mmol), BINAP (135 mg, 0.20 mmol) and Pd(OAc)2 (49 mg, 0.22 mmol). The reaction was stirred at 100 °C for 16 h under a N2 atmosphere. The mixture was diluted with EtOAc (10 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0 - 50% EtOAc) to afford the title compound as a yellow oil (160 mg, 28.7% yield). LC-MS (ESI) m / z 494 (M+H) + 。

[0506] Step 2: Methyl (S)-2-(1-(4-ethyl-2-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)-5,5-difluoropiperidin-3-yl)acetate

[0507] Intermediate 9 was synthesized according to the same sequence as used for the synthesis of Intermediate 5. LC / MS (ESI) m / z: 410 (M+H) + 。

[0508] Intermediate 10: Ethyl (R)-2-(1-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)piperidin-3-yl)acetate

[0509]

[0510] Intermediate 10 was synthesized from commercially available ethyl (R)-2-(piperidin-3-yl)acetate according to the same sequence as used for the synthesis of Intermediate 7. LC / MS (ESI) m / z: 374 (M+H) +. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.81 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 4.07 (s, 3H), 3.21–3.14 (m, 1H), 3.09–3.02 (m, 1H), 2.72–2.67 (m, 1H), 2.57 (s, 3H), 2.48–2.39 (m, 1H), 2.35–2.26 (m, 3H), 1.93–1.86 (m, 1H), 1.84–1.68 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.23–1.15 (m, 1H).

[0511] Intermediate 11: Ethyl (R)-2-(1-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate

[0512]

[0513] Intermediate 11 was synthesized from commercially available ethyl (R)-2-(piperidin-3-yl)acetate according to the same sequence as used for the synthesis of Intermediate 7. LC / MS (ESI) m / z: 388 (M+H) + . 1 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.83 (s, 2H), 4.14 (q, J = 7.5 Hz, 2H), 4.08 (d, J = 6.8 Hz, 3H), 3.12 (d, J = 10.8 Hz, 1H), 3.05–2.98 (m, 1H), 2.92 (q, J = 7.5 Hz, 2H), 2.73–2.67 (m, 1H), 2.50–2.40 (m, 1H), 2.35–2.25 (m, 3H), 1.95–1.85 (m, 1H), 1.84–1.80 (m, 1H), 1.79–1.71 (m, 1H), 1.33 (t, J = 7.5 Hz, 3H), 1.26 (t, J = 7.5, 0.7 Hz, 3H), 1.23–1.13 (m, 1H).

[0514] Intermediate 12: Methyl 5,5-difluoro-1-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)methyl)piperidine-3-carboxylate

[0515]

[0516] Step 1: Methyl 2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)nicotinate

[0517] To a solution of 3-bromo-2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridine (5.0 g, 13.6 mmol) in MeOH (50 mL) was added TEA (9.5 mL, 68.1 mmol), followed by Pd(dppf)Cl2 (1.0 g, 1.4 mmol). The mixture was degassed three times under N2 atmosphere and stirred at 70 °C under 60 psi of CO gas for 16 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (PE containing 0 - 50% EtOAc) to afford the title compound as a yellow solid (3.8 g, 80.6% yield). LC-MS (ESI) m / z 347 (M+H) + 。 1 H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 5.39 (dd, J = 29.2, 12.7 Hz, 2H), 4.77–4.75 (m, 1H), 4.17 (s, 3H), 3.93 (s, 3H), 3.90–3.83 (m, 1H), 3.55–3.50 (m, 1H), 2.86 (s, 3H), 1.84–1.66 (m, 2H), 1.65–1.57 (m, 2H), 1.55–1.48 (m, 2H).

[0518] Step 2: (2-Methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methanol

[0519] To a solution of methyl 2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)nicotinate (1.50 g, 4.33 mmol) in THF (20 mL) at 0 °C was added dropwise LiBH4 (5.20 mL, 10.40 mmol, 2 M in THF). After the addition, the mixture was stirred at 55 °C for 3 h. The mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (PE containing 0 - 50% EtOAc) to afford the title compound as a pale yellow solid (1.3 g, 94.3% yield). LC / MS (ESI) (m / z): 319 (M + H) + 。 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 5.34 (dd, J = 33.4, 12.6 Hz, 2H), 4.80–4.75 (m, 1H), 4.74 (s, 2H), 4.16 (s, 3H), 3.92–3.84 (m, 1H), 3.55–3.48 (m, 1H), 2.57 (s, 3H), 1.82–1.71 (m, 2H), 1.58–1.48 (m, 4H).

[0520] Step 3: 3-(Chloromethyl)-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine

[0521] To a solution of (2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methanol (1.3 g, 4.1 mmol) in DCM (30 mL) at 0 °C was added TEA (1.7 mL, 12.25 mmol), followed by dropwise addition of MsCl (0.70 g, 6.1 mmol). The reaction was stirred at room temperature for 2 h. The mixture was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (PE containing 0 - 50% EtOAc) to afford the title compound as a yellow solid (1.7 g, 87.3% yield). LC / MS (ESI) (m / z): 367 (M + H) + 。 11H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 5.35 (dd, J = 33.2, 12.7 Hz, 2H), 4.80–4.73 (m, 1H), 4.62 (s, 2H), 4.16 (s, 3H), 3.93–3.82 (m, 1H), 3.56–3.42 (m, 1H), 2.66 (s, 3H), 1.81–1.67 (m, 2H), 1.61–1.49 (m, 4H).

[0522] Step 4: Methyl 5,5-difluoro-1-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)piperidine-3-carboxylate

[0523] To a solution of 3-(chloromethyl)-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine (935 mg, 2.78 mmol) in CH3CN (20 mL) was added methyl 5,5-difluoropiperidine-3-carboxylate (994 mg, 3.6 mmol), followed by DIPEA (1.2 mL, 7.1 mmol), and the reaction was stirred at 80 °C for 3.5 h. The mixture was diluted with EtOAc (10 mL) and washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (PE containing 0–50% EtOAc) to afford the title compound as a yellow oil (800 mg, 60.1% yield). LC / MS (ESI) (m / z): 480 (M+H) + 。 1 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 5.43–5.30 (m, 2H), 4.78–4.76 (m, 1H), 4.15 (s, 3H), 3.93–3.85 (m, 1H), 3.68 (s, 3H), 3.65–3.57 (m, 2H), 3.56–3.49 (m, 1H), 3.12–3.01 (m, 2H), 2.92–2.85 (m, 1H), 2.81–2.75 (m, 1H), 2.58 (s, 3H), 2.42–2.35 (m, 1H), 2.32–2.22 (m, 1H), 1.93–1.86 (m, 1H), 1.82–1.66 (m, 2H), 1.62–1.48 (m, 4H).

[0524] Step 5: Methyl 5,5-difluoro-1-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)methyl)piperidine-3-carboxylate

[0525] To a solution of methyl 5,5-difluoro-1-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)piperidine-3-carboxylate (800 mg, 1.67 mmol) in MeOH (15 mL) was added PPTS (0.84 g, 3.34 mmol), and the reaction was stirred at 50 °C for 16 h. The mixture was concentrated to dryness and the residue was diluted with EtOAc (10 mL). The mixture was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0 - 60% EtOAc) to give the title compound as a yellow oil (620 mg, 94.0% yield). LC / MS (ESI) (m / z): 396 (M + H) + 。 1 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 4.85 (s, 2H), 4.09 (s, 3H), 3.69 (s, 3H), 3.62 (d, J = 3.2 Hz, 2H), 3.12–2.97 (m, 2H), 2.95–2.83 (m, 1H), 2.62 (s, 3H), 2.48–2.38 (m, 2H), 2.34–2.28 (m, 1H), 2.03–1.86 (m, 1H).

[0526] Intermediate 13: Methyl 1-((2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-5,5-difluoropiperidine-3-carboxylate

[0527]

[0528] The title compound was prepared from 3-bromo-2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine using the same sequence as in the synthesis of Intermediate 12. LC / MS (ESI) (m / z): 410 (M + H) + 。 11H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 4.85 (s, 2H), 4.10 (s, 3H), 3.69 (s, 3H), 3.64 (s, 2H), 3.12–3.00 (m, 2H), 2.94–2.88 (m, 2H), 2.44–2.37 (m, 2H), 2.33–2.27 m, 1H), 2.07–1.86 (m, 2H), 1.31 (t, J = 7.6 Hz, 3H).

[0529] Intermediate 14: 4-(Cyclopropylmethyl)-3-methylpyridin-2(1H)-one

[0530]

[0531] Step 1: Cyclopropyl(2-fluoro-3-methylpyridin-4-yl)methanol

[0532] Under N2 at 0 °C, i-Pr-MgCl (16.9 mmol, 8.4 mL, 2 M in THF) was added dropwise to a solution of 2-fluoro-4-iodo-3-methylpyridine (4 g, 16.9 mmol) in THF (40 mL), and the mixture was stirred at room temperature for 1 h. Cyclopropanecarbaldehyde (1.18 g, 16.9 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was quenched with ice water (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 100:1 to 10:1) to give the title compound as a colorless oil (2.37 g, 77.6% yield). LC / MS (ESI) m / z: 182 (M+H) + .

[0533] Step 2: 4-(Cyclopropylmethyl)-2-fluoro-3-methylpyridine

[0534] Under N2 atmosphere at 0 °C, NaI (2.68 g, 17.9 mmol) and TFA (2.61 g, 22.4 mmol) were added to a solution of cyclopropyl(2-fluoro-3-methylpyridin-4-yl)methanol (810 mg, 4.47 mmol) in CH3CN (8 mL), followed by the dropwise addition of Et3SiH (2.60 g, 22.4 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 100:1 to 10:1) to give the title compound as a colorless oil (420 mg, 56.9% yield). LC / MS (ESI) m / z: 166 (M+H) + 。

[0535] Step 3: 4-(Cyclopropylmethyl)-3-methylpyridin-2(1H)-one

[0536] HCl aqueous solution (0.84 mL, 36% wt) was added to a solution of 4-(cyclopropylmethyl)-2-fluoro-3-methylpyridine (420 mg, 2.54 mmol) in 1,4-dioxane (4.2 mL) and water (4.2 mL), and the mixture was stirred at 100 °C for 16 h. The mixture was diluted with water and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 20:1 to 2:1) to give the title compound as a pale yellow solid (322 mg, 77.6% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 6.95 (d, J = 6.8 Hz, 1H), 5.97 (d, J = 6.8 Hz, 1H), 2.19 (d, J = 6.8 Hz, 2H), 1.75 (s, 3H), 0.78 - 0.67 (m, 1H), 0.32 - 0.23 (m, 2H), 0.02 - 0.04 (m, 2H). LC / MS (ESI) m / z: 164 (M+H) + 。

[0537] Intermediate 15: 4-(Cyclopropylmethyl)-3-methylpyridin-2(1H)-one

[0538]

[0539] Step 1: 5-Allyl-2-methoxypyridine

[0540] Under a N2 atmosphere, K3PO4 (14.23 g, 67.0 mmol), Pd(dppf)Cl2 (1.63 g, 2.23 mmol) were added to a solution of 5-bromo-2-methoxypyridine (4.2 g, 22.3 mmol) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.63 g, 33.5 mmol) in 1,4-dioxane (42 mL) and water (8.4 mL), and the mixture was degassed three times under a N2 atmosphere and stirred at 100 °C for 2 h under a N2 atmosphere. The mixture was diluted with EtOAc (50 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 50:1 to 10:1) to give the title compound as a pale yellow oil (3 g, 90% yield). LC / MS (ESI) m / z: 150 (M+H) + 。

[0541] Step 2: 2-Methoxy-5-propylpyridine

[0542] Pd(OH)2 / C (0.28 g, 10% wt) was added to a solution of 5-allyl-2-methoxypyridine (3 g, 20.1 mmol) in MeOH (30 mL) under a N2 atmosphere. After the addition, the mixture was degassed three times under a N2 atmosphere and stirred at 25 °C for 16 h under a H2 balloon. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound as a colorless oil (2.74 g, 90.1% yield), which was used directly in the next step. LC / MS (ESI) m / z: 152 (M+H) + 。

[0543] Step 3: 5-Propylpyridin-2(1H)-one (4)

[0544] Aqueous HBr solution (27 mL, 40% wt) was added to a solution of 2-methoxy-5-propylpyridine (2.74 g, 18.12 mmol) in EtOH (27 mL), and the mixture was stirred at 85 °C for 16 h. The mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 10:1 to 1:1) to give the title compound as a white solid (723 mg, 29.1% yield). 11H NMR (400 MHz, CDCl3) δ 13.21 (s, 1H), 7.35 (dd, J = 9.2, 2.5 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 6.55 (d, J = 9.2 Hz, 1H), 2.35 (t, J = 7.6 Hz, 1H), 1.60 - 1.48 (m, 1H), 0.92 (t, J = 7.2 Hz, 2H). LC / MS (ESI) m / z: 138 (M + H) + 。

[0545] Intermediate 16: 5-(Cyclopropylmethyl)pyridin-2(1H)-one

[0546]

[0547] Step 1: N'-[(1E)-Cyclopropylmethylene]-4-methylbenzene-1-sulfonylhydrazide

[0548] To a solution of 4-methylbenzene-1-sulfonylhydrazide (1 g, 5.4 mmol) in MeOH (10 mL) at 0 °C was added dropwise cyclopropanecarbaldehyde (0.40 mL, 5.4 mmol), and the mixture was stirred at 70 °C for 10 minutes. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (PE containing 0 - 40% EtOAc) to give the title compound as a white solid (1.1 g, 86.0% yield). LC-MS (ESI) m / z 239 (M + H) + 。

[0549] Step 2: 5-(Cyclopropylmethyl)-2-methoxypyridine

[0550] To a mixture of N'-[(1E)-cyclopropylmethylene]-4-methylbenzene-1-sulfonylhydrazide (1 g, 4.2 mmol) and (6-methoxypyridin-3-yl)boronic acid (0.64 g, 4.2 mmol) in 1,4-dioxane (10 mL) was added K2CO3 (580 mg, 4.2 mmol), and the mixture was stirred at 110 °C for 16 hours. The mixture was diluted with EtOAc (15 mL), washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0 - 5% EtOAc) to give 5-(cyclopropylmethyl)-2-methoxypyridine as a colorless oil (210 mg, 30.7% yield). LC-MS (ESI) m / z 164 (M + H) + 。 11H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 1.9 Hz, 1H), 7.48 (dd, J = 8.4, 1.9 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H), 2.46 (d, J = 6.9 Hz, 2H), 1.01–0.84 (m, 1H), 0.57–0.46 (m, 2H), 0.20–0.17 (m, 2H).

[0551] Step 3: 5-(Cyclopropylmethyl)pyridin-2(1H)-one

[0552] To a mixture of 5-(cyclopropylmethyl)-2-methoxypyridine (200 mg, 1.2 mmol) in MeCN (5 mL) was added NaI (367 mg, 2.5 mmol) and TMSCl (0.31 mL, 2.5 mmol), and the reaction mixture was stirred at 70 °C for 16 h. The mixture was diluted with EtOAc (5 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0–50% EtOAc) to afford 5-(cyclopropylmethyl)pyridin-2(1H)-one as a colorless oil (50 mg, 27.4% yield). LC-MS (ESI) m / z 150 (M + H) + .

[0553] Intermediate 17: 5-(Cyclobutylmethyl)pyridin-2(1H)-one

[0554]

[0555] The title compound was prepared from cyclobutane carbaldehyde using the same sequence as the synthesis of Intermediate 16. LC-MS (ESI) m / z 164 (M + H) + .

[0556] Intermediate 18: 5-(Cyclobutylmethyl)pyridin-2(1H)-one

[0557]

[0558] The title compound was prepared from isobutyraldehyde using the same sequence as the synthesis of Intermediate 16. LC-MS (ESI) m / z 152 (M + H) + .

[0559] Intermediate 19: 5-Isopropylpyridin-2(1H)-one

[0560]

[0561] Step 1: 2-Methoxy-5-(prop-1-en-2-yl)pyridine

[0562] Under a N2 atmosphere, K2CO3 (1.47 g, 10.64 mmol) and Pd(PPh3)4 (0.61 g, 0.53 mmol) were added to a solution of 5-bromo-2-methoxypyridine (1.0 g, 5.32 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.34 g, 7.98 mmol) in 1,4-dioxane (10 mL) and water (2 mL). After the addition, the mixture was degassed three times under a N2 atmosphere and stirred at 100 °C for 16 h. The mixture was diluted with water and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 200:1 to 20:1) to give the title compound as a colorless oil (600 mg, 75.6% yield). LC / MS (ESI) m / z: 150 (M+H) + 。 1 H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 8.6, 2.6 Hz, 1H), 6.71 (dd, J = 8.6, 0.6 Hz, 1H), 5.29 (s, 1H), 5.05 - 5.01 (m, 1H), 3.94 (s, 1H), 2.13 (d, J = 0.5 Hz, 1H).

[0563] Step 2: 5-Isopropyl-2-methoxypyridine

[0564] Under a N2 atmosphere, Pd(OH)2 (50 mg, 10% wt) was added to a solution of 2-methoxy-5-(prop-1-en-2-yl)pyridine (600 mg, 4.02 mmol) in MeOH (6 mL). After the addition, the mixture was degassed three times under a N2 atmosphere and stirred at 25 °C under a H2 balloon for 16 h. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound as a colorless oil (290 mg, 47.7% yield), which was used directly in the next step. 1 H NMR (400 MHz, CD3OD) δ 7.95 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.6, 2.5 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 3.87 (s, 3H), 2.93 – 2.85 (m, 1H), 1.24 (d, J = 6.9 Hz, 6H). LC / MS (ESI) m / z: 152 (M+H) + 。

[0565] Step 3: 5-Isopropylpyridin-2(1H)-one

[0566] Under N2 atmosphere, aqueous HBr solution (1.5 mL, 40% wt) was added to a solution of 5-isopropyl-2-methoxypyridine (150 mg, 0.99 mmol) in EtOH (1.5 mL), and the mixture was stirred at 85 °C for 16 h. The mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford the title compound as a white solid (115 mg, 84.5% yield). LC / MS (ESI) m / z: 138 (M+H) + 。

[0567] Intermediate 20: 5-Cyclobutylpyridin-2(1H)-one

[0568]

[0569] Step 1: 1-(6-Methoxypyridin-3-yl)cyclobutan-1-ol

[0570] n-BuLi (5.5 mL, 13.8 mmol) was added dropwise to a stirred solution of 5-bromo-2-methoxypyridine (1.38 mL, 10.6 mmol) in dry THF (25 mL) at -78 °C. After stirring at this temperature for 30 min, cyclobutanone (1.2 mL, 15.9 mmol) was added, and the resulting mixture was stirred at -78 °C for 30 min and at room temperature for 30 min. The mixture was quenched with ice water and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness, and the residue was purified by flash chromatography (PE:EtOAc = 10:1) to afford the title compound (1.5 g, 78.6% yield). LC / MS (ESI) m / z: 180 (M+H) + 。 1 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.2 Hz, 1H), 7.72 (dd, J = 8.6, 2.6 Hz, 1H), 6.76 (dd, J = 8.6, 0.6 Hz, 1H), 3.94 (s, 3H), 2.62–2.46 (m, 2H), 2.41–2.32 (m, 2H), 2.08–1.94 (m, 2H), 1.69–1.59 (m, 2H).

[0571] Step 2: 5-Cyclobutyl-2-methoxypyridine

[0572] To a solution of 1-(6-methoxypyridin-3-yl)cyclobutan-1-ol (1 g, 5.5 mmol) in MeOH (3 mL) at 0 °C was added concentrated H2SO4 (1 mL), followed by Pd / C (80 mg, 10% wt). The mixture was degassed three times under a N2 atmosphere and stirred at room temperature for 1 h under a H2 balloon. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (PE:EtOAc = 10:1 to 5:1) to afford the title compound as a pale yellow oil (300 mg, 32.9% yield). LC / MS (ESI) (m / z): 164 (M+H) + 。 1 H NMR (400 MHz, CDCl3) δ 7.98 (t, J = 4.4 Hz, 1H), 7.47 (dd, J = 8.5, 2.5 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 3.91 (s, 3H), 3.46 (dd, J = 17.4, 8.7 Hz, 1H), 2.40–2.28 (m, 2H), 2.16–2.02 (m, 3H), 1.91–1.82 (m, 1H).

[0573] Step 3: 5-Cyclobutylpyridin-2-ol

[0574] To a solution of 5-cyclobutyl-2-methoxypyridine (100 mg, 0.6 mmol) in EtOH (5 mL) was added aqueous HBr solution (2 mL, 48% wt), and the mixture was stirred at 70 °C for 16 h under a N2 atmosphere. The mixture was poured into ice-cooled saturated aqueous NaHCO3 and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to afford the title compound (70 mg, 76.5% yield). LC / MS (ESI) (m / z): 150 (M+H) + 。 1 H NMR (400 MHz, CDCl3) δ 12.76 (s, 1H), 7.42 (dd, J = 9.3, 2.4 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 6.56 (d, J = 9.3 Hz, 1H), 3.34 - 3.23 (dt, J = 17.2, 8.7 Hz, 1H), 2.27 - 2.23 (m, 2H), 2.06–1.92 (m, 3H), 1.89–1.76 (m, 1H).

[0575] Intermediate 21: 5-Cyclopropyl-4-methylpyridin-2(1H)-one

[0576]

[0577] Step 1: 5-Cyclopropyl-2-methoxy-4-methylpyridine

[0578] Under N2 atmosphere, K3PO4 (6.30 g, 29.67 mmol), tricyclohexylphosphine (0.28 g, 0.99 mmol), and Pd(OAc)2 (0.11 g, 0.50 mmol) were added to a solution of 5-bromo-2-methoxy-4-methylpyridine (2 g, 9.90 mmol) and cyclopropylboronic acid (1.11 g, 12.87 mmol) in toluene (30 mL) and water (3 mL). After addition, the mixture was degassed three times under N2 atmosphere and stirred at 100 °C for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 200:1 to 10:1) to afford the title compound as a yellow oil (1.42 g, 88.1% yield). LC / MS (ESI) m / z: 164 (M+H) + 。

[0579] Step 2: 5-Cyclopropyl-4-methylpyridin-2(1H)-one (3)

[0580] NaI (1.84 g, 12.25 mmol) and TMSCl (1.33 g, 12.25 mmol) were added to a solution of 5-cyclopropyl-2-methoxy-4-methylpyridine (1 g, 6.12 mmol) in CH3CN (10 mL). The mixture was stirred overnight at 70 °C. The mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 20:1 to 1:1) to afford the title compound as a brown solid (525 mg, 57.4% yield). 1 1H-NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 6.67 (s, 1H), 5.91 (s, 1H), 1.97 (d, J = 0.6 Hz, 1H), 1.38 - 1.27 (m, 1H), 0.56 - 0.46 (m, 1H), 0.24 - 0.16 (m, 1H). LC / MS (ESI) m / z: 150 (M+H) + 。

[0581] Intermediate 22: 4-Cyclopropyl-5-methylpyridin-2(1H)-one

[0582]

[0583] Step 1: 2-Chloro-4-cyclopropyl-5-methylpyridine

[0584] Under N2 atmosphere, Pd(OAc)2 (38 mg, 0.17 mmol) and tricyclohexylphosphine (95 mg, 0.34 mmol) were added to a mixture of 4-bromo-2-chloro-5-methylpyridine (700 mg, 3.39 mmol), K3PO4 (2.15 g, 10.17 mmol) and cyclopropylboronic acid (349 mg, 4.07 mmol) in 1,4-dioxane (25 mL), and the mixture was stirred at 110 °C for 16 h. The mixture was diluted with EtOAc (10 mL) and filtered. The filtrate was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, PE containing 0 - 100% EtOAc) to give the title compound as a colorless oil (420 mg, 73.9% yield). LC / MS (ESI) m / z: 168 (M + H) + 。

[0585] Step 2: 4-Cyclopropyl-5-methyl-2-[2-(trimethylsilyl)ethoxy]pyridine

[0586] To a solution of 2-chloro-4-cyclopropyl-5-methylpyridine (250 mg, 1.49 mmol) in toluene (5 mL) were added 2-(trimethylsilyl)ethan-1-ol (2.1 mL, 14.91 mmol), Cs2CO3 (1.46 g, 4.47 mmol), Pd(OAc)2 (33 mg, 0.15 mmol), t-BuPhos (89 mg, 0.15 mmol). The mixture was degassed three times under N2 and stirred at 110 °C for 16 h. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (silica gel, PE containing 0 - 30% EtOAc) to give the title compound as a pale yellow oil (201 mg, 54.0% yield). LC / MS (ESI) m / z: 250 (M + H) + 。

[0587] Step 3: 4-Cyclopropyl-5-methylpyridin-2-ol

[0588] To a solution of 4-cyclopropyl-5-methyl-2-[2-(trimethylsilyl)ethoxy]pyridine (200 mg, 0.80 mmol) in THF (3 mL) was added TBAF (418 mg, 1.60 mmol), and the mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, DCM containing 0-20% MeOH) to afford the title compound as a white solid (56 mg, 46.8% yield). LC / MS (ESI) m / z: 150 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.08 (s, 1H), 5.83 (s, 1H), 2.08 (d, J = 0.8 Hz, 3H), 1.80–1.72 (m, 1H), 0.97–0.91 (m, 2H), 0.68–0.62 (m, 2H).

[0589] Intermediate 23: 5-(cyclopropyl ethynyl)pyridin-2(1H)-one

[0590]

[0591] Step 1: 5-(2-cyclopropyl ethynyl)-2-methoxypyridine

[0592] Under N2 and with stirring, to a solution of 5-iodo-2-methoxypyridine (1 g, 4.26 mmol) in CH3CN (20 mL) was added TEA (1.8 mL, 12.77 mmol), followed by bis(triphenylphosphine)palladium(II) chloride (0.17 g, 0.21 mmol), CuI (0.16 g, 0.85 mmol) and ethynylcyclopropane (0.43 mL, 5.11 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, PE containing 0-30% EtOAc) to afford the title compound as a white solid (700 mg, 95.0% yield). LC / MS (ESI) m / z: 174 (M+H) + .

[0593] Step 2: 5-(2-cyclopropyl ethynyl)-1,2-dihydropyridin-2-one

[0594] To a solution of 5-(2-cyclopropyl ethynyl)-2-methoxypyridine (500 mg, 2.89 mmol) in CH3CN (10 mL) was added NaI (865 mg, 5.78 mmol) and TMSCl (0.74 mL, 5.773 mmol), and the reaction mixture was stirred at 70 °C for 16 h. The mixture was diluted with EtOAc (10 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (DCM containing 0 - 5% MeOH) to afford 5-(2-cyclopropyl ethynyl)-1,2-dihydropyridin-2-one as a yellow solid (300 mg, 65.3% yield). LC / MS (ESI) m / z: 160 (M+H) + 。

[0595] Intermediate 24: 4-(cyclopropyl ethynyl)pyridin-2(1H)-one

[0596]

[0597] Intermediate 24 was prepared from 4-iodo-2-methoxypyridine using the same sequence as that used for the synthesis of Intermediate 23. LC / MS (ESI) m / z: 160 (M+H) + 。

[0598] Intermediate 25: 5-cyclopropoxypyridin-2(1H)-one

[0599]

[0600] Step 1: 2-(benzyloxy)-5-cyclopropoxypyridine

[0601] To a mixture of 6-(benzyloxy)pyridin-3-ol (300 mg, 1.5 mmol) and bromocyclopropane (1.2 mL, 14.9 mmol) in NMP (5 mL) was added Cs2CO3 (1.4 g, 4.4 mmol), and the resulting solution was stirred in an autoclave at 150 °C for 8 h. The mixture was cooled to room temperature, diluted with EtOAc (10 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0 - 50% EtOAc) to afford the title compound as a pale yellow oil (180 mg, 50% yield). LC / MS (ESI) m / z 242 [M+1] + 。

[0602] Step 2: 5-cyclopropoxypyridin-2(1H)-one

[0603] To a solution of 2-(benzyloxy)-5-cyclopropoxypyridine (180 mg, 0.7 mmol) in MeOH (3 mL) at 0 °C was added Pd / C (20 mg, 10% wt), and the mixture was degassed three times under N2 atmosphere and stirred at room temperature for 1 h under a H2 balloon. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative TLC (PE:EtOAc = 2:1) to give the title compound as a white foamy solid (40 mg, 35.4% yield). LC / MS (ESI) (m / z): 152 (M+H) + 。

[0604] Intermediate 26: 5-Propoxypyridin-2(1H)-one

[0605]

[0606] Intermediate 26 was synthesized according to the same sequence as used for the synthesis of Intermediate 25. LC / MS (ESI) (m / z): 154 (M+H) + 。

[0607] Intermediate 27: 5-Propoxypyridin-2(1H)-one

[0608]

[0609] Intermediate 27 was synthesized according to the same sequence as used for the synthesis of Intermediate 25. LC / MS (ESI) (m / z): 140 (M+H) + 。

[0610] Intermediate 28: 5-(Azetidin-1-yl)pyridin-2(1H)-one

[0611]

[0612] Step 1: 5-(Azetidin-1-yl)-2-(benzyloxy)pyridine

[0613] To a solution of 2-(benzyloxy)-5-bromopyridine (850 mg, 3.2 mmol) in 1,4-dioxane (5 mL) was added azetidine (0.65 mL, 9.6 mmol), followed by Cs2CO3 (2.1 g, 6.4 mmol), RuPhos (300 mg, 0.64 mmol) and Pd2(dba)3 (260 mg, 0.3 mmol). The mixture was degassed three times under N2 atmosphere and stirred at 100 °C for 2 h in a CEM reactor. The mixture was diluted with EtOAc (10 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0 - 50% EtOAc) to afford the title compound as a yellow oil (650 mg, 84.3% yield). LC-MS (ESI) m / z 241 (M+H) + 。

[0614] Step 2: 5-(azetidin-1-yl)pyridin-2-ol

[0615] To a solution of 5-(azetidin-1-yl)-2-(benzyloxy)pyridine (400 mg, 1.7 mmol) in MeOH (10 mL) was added Pd / C (50 mg, 10% wt). The mixture was degassed under N2 atmosphere and stirred at room temperature under a H2 balloon for 3 h. The mixture was filtered and the filtrate was concentrated to dryness to afford the title compound as a yellow solid (230 mg, 90% yield). LC-MS (ESI) m / z 151 (M+H) + 。

[0616] Intermediate 29: 5-propylpyrazin-2-ol

[0617]

[0618] Step 1: 5-allylpyrazin-2-amine

[0619] To a mixture of 5-bromopyrazin-2-amine (500 mg, 2.87 mmol) and 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane (0.81 mL, 4.31 mmol) in DMF (10 mL) were added CsF (1.3 g, 8.6 mmol) and Pd(dppf)Cl2 (430 mg, 0.57 mmol). The mixture was degassed three times under N2 atmosphere and stirred at 100 °C for 9 h under N2 atmosphere. The mixture was diluted with EtOAc (10 mL), washed with water and brine, dried and concentrated to dryness. The residue was purified by flash chromatography (PE:EtOAc = 4:1) to give the title compound as a yellow oil (250 mg, 64.1% yield). LC / MS (ESI) (m / z): 135 (M+H) + 。

[0620] Step 2: 5-propylpyrazin-2-amine

[0621] To a solution of 5-allylpyrazin-2-amine (240 mg, 1.78 mmol) in MeOH (10 mL) was added Pd / C (20 mg, 10% wt). The mixture was degassed three times under H2 atmosphere and stirred at room temperature for 16 h under a H2 balloon. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound as a yellow oil (200 mg, 82.1% yield). LC / MS (ESI) (m / z): 138 (M+H) + 。

[0622] Step 3: 5-propylpyrazin-2-ol

[0623] To a solution of NaNO2 (3 g, 43.74 mmol) in concentrated H2SO4 (10 mL) at 0 °C was added propylpyrazin-2-amine (1 g, 7.3 mmol) portionwise, and the mixture was stirred at 100 °C for 2 h. The mixture was diluted with ice water, neutralized to pH = 5 with 1 M saturated aqueous NaOH and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluting with DCM:MeOH = 15:1) to give the title compound (320 mg, 31.8% yield). LC / MS (ESI) (m / z): 139 [M+H] + .

[0624] Intermediate 30: 5-propylpyrimidin-2(1H)-one

[0625]

[0626] At 0 °C, concentrated HCl (5 mL) was added to a solution of 2-chloro-5-propylpyrimidine (500 mg, 3.19 mmol) in EtOH (5 mL), and the mixture was stirred at 100 °C for 16 h under a N2 atmosphere. The mixture was diluted with ice water (10 mL), diluted with saturated aqueous NaHCO3 to pH = 7 and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluting with DCM:MeOH = 15:1) to give the title compound as a yellow oil (200 mg, 45.3% yield). LC / MS (ESI) m / z: 139 (M+H) + 。

[0627] Intermediate 31: 6-Propylpyrimidin-4(3H)-one

[0628]

[0629] At 0 °C, MeONa (7.5 mL, 1.5 M in MeOH) was added dropwise to a mixture of ethyl 3-oxohexanoate (1.6 mL, 10 mmol) and formamidine acetate (1 g, 10 mmol) in MeOH (10 mL), and the mixture was stirred at 60 °C overnight. The reaction mixture was diluted with DCM (20 mL), washed with water, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0–100% EtOAc) to give the title compound as a white solid (410 mg, 29.0% yield). LC / MS (ESI) m / z: 139 (M+H) + 。

[0630] Intermediate 32: 4-Propylpyridazin-3(2H)-one

[0631]

[0632] Step 1: 6-Chloro-4-propylpyridazin-3(2H)-one

[0633] A solution of 3,6-dichloro-4-propylpyridazine (1.00 g, 5.23 mmol) in AcOH (10 mL) was stirred at 120 °C for 5 h under a N2 atmosphere. The mixture was concentrated to dryness and the residue was neutralized with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (2 × 20 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 8:1 to 5:1) to afford the title compound as a yellow oil (550 mg, 60.9% yield). LC / MS (ESI) m / z: 173 (M+H) + 。

[0634] Step 2: 4-propylpyridazin-3(2H)-one

[0635] To a solution of 6-chloro-4-propylpyridazin-3(2H)-one (500 mg, 2.90 mmol) in EtOAc (5 mL) was added TEA (0.05 mL, 0.360 mmol) and Pd / C (60 mg, 10% wt), and the mixture was degassed three times under a N2 atmosphere and stirred at 0 °C for 3 h under a H2 balloon. The reaction was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography (eluting with PE:EtOAc = 5:1 to 1:1) to afford the title compound as an off-white solid (75 mg, 18.7% yield). LC / MS (ESI) m / z: 139 (M+H) + 。

[0636] Intermediate 33: 6-propylpyridazin-3-ol

[0637]

[0638] Step 1: 3-allyl-6-chloropyridazine

[0639] Under N2 atmosphere, K2CO3 (1.74 g, 12.582 mmol) and Pd(dppf)Cl2 (153.44 mg, 0.210 mmol) were added to a mixture of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (705 mg, 4.2 mmol) and 3-chloro-6-iodopyridazine (1 g, 4.2 mmol) in 1,4-dioxane (10 mL) and water (2 mL). Then the mixture was stirred at 75 °C for 16 h. The mixture was diluted with water and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 5:1) to give the title compound as a yellow oil (130 mg, 20.3% yield). LC / MS (ESI) (m / z): 155 (M+H) + 。

[0640] Step 2: 6-Allylpyridazin-3-ol

[0641] A solution of 3-allyl-6-chloropyridazine (130 mg, 0.85 mmol) in AcOH (6 mL) was stirred at 120 °C for 2 h. The reaction mixture was concentrated to dryness and the residue was purified by silica gel chromatography (PE:EtOAc = 3:1) to give the title compound as a yellow solid (70 mg, 61.3% yield). LC / MS (ESI) (m / z): 137 (M+H) + 。

[0642] Step 3: 6-Propylpyridazin-3-ol

[0643] Pd / C (20 mg, 10% wt) was added to a solution of 6-allylpyridazin-3-ol (70 mg, 0.459 mmol) in MeOH (3 mL) at 0 °C. The mixture was degassed three times under N2 atmosphere and stirred at room temperature under a H2 balloon for 2 h. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound as a yellow solid (32 mg, 51.2% yield). LC / MS (ESI) (m / z): 139 (M+H) + 。

[0644] Intermediate 34: 6-(Cyclopropylmethyl)pyridazin-3-ol

[0645]

[0646] Step 1: Dimethyl (3-cyclopropyl-2-oxopropyl)phosphonate

[0647] To a solution of dimethyl methylphosphonate (652 mg, 5.25 mmol) in THF (5 mL) was added dropwise n-BuLi (2.62 mL, 5.25 mmol, 2 M in THF) at -70 °C, and the mixture was stirred at this temperature for 15 minutes. A solution of methyl 2-cyclopropylacetate (300 mg, 2.62 mmol) in THF (3 mL) was added to the above mixture at -70 °C, and the resulting mixture was stirred at -70 °C for 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl at 0 °C and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford the title compound as a yellow solid (460 mg, 84.9% yield). LC / MS (ESI) m / z: 207 (M+H) + 。

[0648] Step 2: Ethyl (2Z)-5-cyclopropyl-4-oxopent-2-enoate

[0649] To a solution of dimethyl (3-cyclopropyl-2-oxopropyl)phosphonate (460 mg, 2.23 mmol) in t-BuOH (5 mL) was added t-BuOK (250 mg, 2.23 mmol), ethyl 2-oxoacetate (0.22 mL, 2.23 mmol), and then the mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, PE containing 0 - 5% EtOAc) to afford the title compound as a yellow oil (81 mg, 19.9% yield). LC / MS (ESI) m / z: 183 (M+H) + 。 1 1H NMR (400 MHz, CDCl3) δ 6.55 (d, J = 12.1 Hz, 1H), 6.02 (d, J = 12.1 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 2.52 (d, J = 7.0 Hz, 2H), 1.29 (dd, J = 9.4, 4.8 Hz, 3H), 1.01 (dd, J = 13.9, 6.1 Hz, 1H), 0.59 (q, J = 5.3 Hz, 2H), 0.17 (q, J = 5.0 Hz, 2H).

[0650] Step 3: 6-(Cyclopropylmethyl)pyridazin-3-ol

[0651] To a solution of methyl (2Z)-5-cyclopropyl-4-oxopent-2-enoate (80 mg, 0.47 mmol) in EtOH (6 mL) and H2O (2 mL) was added hydrazine hydrate (0.1 mL), AcOH (2 mL), and the mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, DCM containing 0 - 10% MeOH) to afford the title compound as a white solid (32 mg, 44.8% yield). LC / MS (ESI) m / z: 151 (M+H) + 。 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 7.22 (d, J = 9.7 Hz, 1H), 6.63 (d, J = 9.7 Hz, 1H), 2.22 (d, J = 7.0 Hz, 2H), 0.80–0.70 (m, 1H), 0.27 (dt, J = 7.7, 4.9 Hz, 2H), -0.01 (q, J = 4.9 Hz, 2H).

[0652] Intermediate 35: 5-(1H-Pyrazol-1-yl)pyridin-2(1H)-one

[0653]

[0654] Step 1: 2-(Benzyloxy)-5-(1H-pyrazol-1-yl)pyridine

[0655] Under a N2 atmosphere, CuI (145 mg, 0.76 mmol), L-proline (87 mg, 0.757 mmol), and K2CO3 (1047 mg, 7.57 mmol) were added to a mixture of 2-(benzyloxy)-5-bromopyridine (1 g, 3.79 mmol) and 1H-pyrazole (392 mg, 5.68 mmol) in DMSO (10 mL), and the mixture was stirred at 120 °C for 16 h under a N2 atmosphere. The mixture was diluted with water and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 5:1) to afford the title compound as a white solid (350 mg, 36.8% yield). LC / MS (ESI) (m / z): 252 (M+H) + 。

[0656] Step 2: 5-(1H-Pyrazol-1-yl)pyridin-2-ol

[0657] To a solution of 2-(benzyloxy)-5-(1H-pyrazol-1-yl)pyridine (450 mg, 1.791 mmol) in MeOH (10 mL) was added Pd / C (45 mg, 10% wt), and the mixture was degassed three times under N2 atmosphere and stirred at room temperature for 3 h under a H2 balloon. The mixture was filtered and the filtrate was concentrated to dryness to afford the title compound as a colorless oil (290 mg, 100.5% yield). LC / MS (ESI) m / z: 162 (M+H) + 。

[0658] Intermediate 36: (R)-5-(cyclopropylmethyl)-1-methylimidazolidin-2-one

[0659]

[0660] Step 1: (R)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid

[0661] To a solution of (2R)-2-amino-3-cyclopropylpropanoic acid (6 g, 46.4 mmol) in THF (60 mL) and water (60 mL) at 0 °C was added NaHCO3 (11.1 g, 139.2 mmol) and di-tert-butyl dicarbonate (12.9 mL, 60.4 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to afford the title compound as a yellow oil (10 g, 93.9% yield). 1 1H NMR (400 MHz, CDCl3) δ 6.04 (s, 1H), 5.30 (d, J = 7.7 Hz, 1H), 4.35 (d, J = 6.0 Hz, 1H), 1.68 - 1.65 (m, 2H), 1.43 - 1.42 (m, 9H), 0.73 - 0.74 (m, 1H), 0.47 - 0.46 (m, 2H), 0.10 - 0.12 (m, 2H). LC / MS (ESI) (m / z): 174 (M+H-56) + 。

[0662] Step 2: (R)-(1-cyclopropyl-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester

[0663] At 0 °C, BH3-THF complex (52.3 mL, 52.3 mmol, 1 M in THF) was added dropwise to a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid (6 g, 17.4 mmol) in THF (50 mL), and the mixture was stirred at room temperature for 16 h. The reaction was quenched with MeOH at 0 °C and concentrated to dryness. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to give the title compound as a yellow oil (2 g, 35.5% yield). LC / MS (ESI) (m / z): 160 (M+H-56) + 。

[0664] Step 3: (R)-2-((tert-butoxycarbonyl)amino)-3-(methanesulfonyloxy)cyclopropylpropyl ester

[0665] At 0 °C, TEA (3.9 mL, 27.9 mmol) was added to a solution of tert-butyl (R)-(1-cyclopropyl-3-hydroxypropan-2-yl)carbamate (2.0 g, 9.3 mmol) in DCM (30 mL), followed by dropwise addition of MsCl (1.44 mL, 18.6 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water (10 mL) and extracted with DCM (2×15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 5:1) to give the title compound as a yellow oil (2.0 g, 73.4% yield). LC / MS (ESI) (m / z): 238 (M+H-56) + 。

[0666] Step 4: tert-butyl (R)-(1-azido-3-cyclopropylpropan-2-yl)carbamate

[0667] NaN3 (1.0 g, 15.3 mmol) was added to a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(methanesulfonyloxy)cyclopropylpropyl ester (1.5 g, 5.1 mmol) in DMSO (20 mL), and the mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 5:1) to give the title compound as a yellow oil (525 mg, 42.7% yield). 11H NMR (400 MHz, CDCl3) δ 4.64 (d, J = 5.2 Hz, 1H), 3.82 (s, 1H), 3.54 - 3.45 (m, 2H), 1.63 (s, 1H), 1.45 (s, 10H), 0.71 - 0.64 (m, 1H), 0.52 - 0.47 (m, 2H), 0.11 - 0.08 (m, 2H).

[0668] Step 5: (R)-(1-Azido-3-cyclopropylpropan-2-yl)(methyl)carbamic acid tert-butyl ester

[0669] To a solution of (R)-(1-azido-3-cyclopropylpropan-2-yl)carbamic acid tert-butyl ester (525 mg, 2.19 mmol) in DMF (10 mL) at 0 °C was added portionwise NaH (114 mg, 2.84 mmol, 60% dispersed in mineral oil), and the mixture was stirred at 0 °C for 1 h. Then MeI (0.33 mL, 4.37 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 5:1) to give the title compound as a white solid (480 mg, yield 86.4%). 1 1H NMR (400 MHz, CDCl3) δ 4.21 (s, 1H), 3.52 - 3.22 (m, 2H), 2.78 (s, 3H), 1.62 - 1.54 (m, 1H), 1.48 (s, 9H), 1.33 - 1.26 (m, 1H), 0.68 - 0.58 (m, 1H), 0.48 - 0.46 (m, 2H), 0.1 - 0.03 (m, 2H). LC / MS (ESI) (m / z): 199 (M + H - 56) + .

[0670] Step 6: (R)-(1-Amino-3-cyclopropylpropan-2-yl)(methyl)carbamic acid tert-butyl ester

[0671] To a solution of (R)-(1-azido-3-cyclopropylpropan-2-yl)(methyl)carbamic acid tert-butyl ester (480 mg, 1.89 mmol) in MeOH (6 mL) at 0 °C was added Pd / C (80 mg, 10% wt), and the mixture was degassed three times under N2 atmosphere and stirred at room temperature under a H2 balloon for 2 h. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound as a yellow solid (230 mg, 53.4% yield). LC / MS (ESI) (m / z): 229 (M + H)+ 。

[0672] Step 7: (R)-3-Cyclopropyl-N2-methylpropane-1,2-diamine

[0673] To a solution of (R)-(1-Amino-3-cyclopropylpropan-2-yl)(methyl)carbamic acid tert-butyl ester (230 mg, 1.0 mmol) in DCM (4 mL) at 0 °C was added TFA (4 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness under reduced pressure to afford the title compound as a yellow oil (120 mg, 92.9% yield). LC / MS (ESI) (m / z): 129 (M+H) + 。

[0674] Step 8: (S)-5-(Cyclopropylmethyl)-1-methylimidazolidin-2-one

[0675] To a solution of (R)-3-Cyclopropyl-N2-methylpropane-1,2-diamine (120 mg, 0.94 mmol) in DCM (5 mL) was added TEA (0.39 mL, 2.8 mmol) and CDI (152 mg, 0.94 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 1:2) to afford the title compound as a white solid (120 mg, 82.7% yield). LC / MS (ESI) (m / z): 155 (M+H) + 。 1 1H-NMR (400 MHz, CDCl3) δ 4.57 (s, 1H), 3.64 - 3.53 (m, 2H), 3.22 - 3.18 (m, 1H), 2.75 (s, 3H), 1.65 - 1.50 (m, 2H), 0.69 - 0.59 (m, 1H), 0.52 - 0.50 (m, 2H), 0.12 - 0.07 (m, 2H).

[0676] Intermediate 37: (S)-5-(Cyclopropylmethyl)-1-methylimidazolidin-2-one

[0677]

[0678] Intermediate 37 was prepared from (S)-2-Amino-3-cyclopropylpropanoic acid using the same synthetic sequence as used for the synthesis of Intermediate 36. LC / MS (ESI) (m / z): 155 (M+H) + 。

[0679] Intermediate 38: 1-(Cyclopropylmethyl)-1,3-dihydro-2H-imidazol-2-one

[0680]

[0681] To a solution of 1-methyl-2,3-dihydro-1H-imidazol-2-one (1 g, 10.2 mmol) in DMF (10 mL) at 0 °C was added NaH (410 mg, 10.2 mmol, 60% dispersed in mineral oil) portionwise, and the mixture was stirred at room temperature for 30 minutes. (Bromomethyl)cyclopropane (1.2 mL, 12.2 mmol) was added to the mixture and the resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 6:1) to afford the title compound as a colorless oil (450 mg, 31.9% yield). LC / MS (ESI) (m / z): 139 (M+H) + 。 1 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 6.35–6.22 (m, 2H), 3.52–3.45 (m, 2H), 1.11 (s, 1H), 0.62–0.53 (m, 2H), 0.33 (t, J = 5.3 Hz, 2H).

[0682] Intermediate 39: 1-Isobutyl-1,3-dihydro-2H-imidazol-2-one

[0683]

[0684] According to the synthesis of Intermediate 38, Intermediate 39 was prepared from 1-methyl-2,3-dihydro-1H-imidazol-2-one and 1-bromo-2-methylpropane. LC / MS (ESI) (m / z): 141 (M+H) + 。

[0685] Intermediate 40: 1-(sec-Butyl)-1,3-dihydro-2H-imidazol-2-one

[0686]

[0687] According to the synthesis of Intermediate 38, Intermediate 40 was prepared from 1-methyl-2,3-dihydro-1H-imidazol-2-one and 2-bromobutane. LC / MS (ESI) (m / z): 141 (M+H) + 。

[0688] Intermediate 41: 4-Chloro-6-(1H-pyrazol-1-yl)pyrimidine

[0689]

[0690] To a mixture of 4,6-dichloropyrimidine (1 g, 6.71 mmol) and 1H-pyrazole (457 mg, 6.71 mmol) in DMF (20 mL) was added Cs2CO3 (4.37 g, 13.4 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc (40 mL) and the mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated with EtOAc (10 mL) and filtered. The filter cake was dried under vacuum to give the title compound as a white solid (660 mg, 54.4% yield). LC / MS (ESI) m / z: 181 (M+H) + 。 1 1H NMR (400 MHz, CDCl3) δ 8.79 - 8.79 (d, J = 0.8 Hz, 1H), 8.55 - 8.57 (dd, J = 2.7, 0.5 Hz, 1H), 7.97 - 7.98 (d, J = 1.0 Hz, 1H), 7.81 (d, J = 1.0 Hz, 1H), 6.53 - 6.54 (dd, J = 2.7, 1.6 Hz, 1H).

[0691] Intermediate 42: 2-Chloro-4-cyclobutylpyrimidine

[0692]

[0693] To a mixture of 2-chloropyrimidine (3 g, 26.2 mmol) and cyclobutanecarboxylic acid (2.3 mL, 23.6 mmol) in DCM (15 mL) and water (15 mL) at room temperature was added AgNO3 (890 mg, 5.2 mmol), followed by the addition of (NH4)2S2O8 (6.0 g, 26.2 mmol) in portions, and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with DCM (50 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound as a colorless oil (2.2 g, 49.8% yield). LC / MS (ESI) m / z: 169 (M+H) + 。 1H-NMR (400 MHz, CDCl3) δ 8.49 (d, J = 5.2 Hz, 1H), 7.11 (d, J = 5.2 Hz, 1H), 3.70 - 3.53 (m, 1H), 2.41 - 2.30 (m, 4H), 2.15 - 2.03 (m, 1H), 1.99 - 1.92 (m, 1H).

[0694] Intermediate 43: 2-Chloro-4-isopropylpyrimidine

[0695]

[0696] Intermediate 43 was prepared from 2-chloropyrimidine and isobutyric acid using the same synthetic method as Intermediate 42. LC / MS (ESI) m / z: 157 (M + H) + . 1H NMR (400 MHz, CD3OD) δ 8.52 (d, J = 5.1 Hz, 1H), 7.17 (d, J = 5.1 Hz, 1H), 3.06–2.99 (m, 1H), 1.32 (d, J = 7.0 Hz, 6H).

[0697] Intermediate 44: 2-Chloro-4-cyclopropylpyrimidine

[0698]

[0699] Intermediate 44 was prepared from 2-chloropyrimidine and cyclopropanecarboxylic acid using the same synthetic method as Intermediate 42. LC / MS (ESI) m / z: 155 (M + H) + .

[0700] Intermediate 45: 4-Chloro-6-cyclobutylpyrimidine

[0701]

[0702] Step 1: 6-Propyl-3,4-dihydropyrimidin-4-one

[0703] To a solution of methyl 3-cyclobutyl-3-oxopropionate (2 g, 12.81 mmol) and formamidine acetate (1.33 g, 19.98 mmol) in MeOH (30 mL) at 0 °C was added dropwise 5 N MeONa / MeOH solution (7.7 mL, 38.5 mmol). After addition, the mixture was stirred at 70 °C for 4 h. After cooling to 0 °C, the reaction was filtered and treated with DCM (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with DCM (50 mL). The combined organics were concentrated to dryness, and the residue was purified by flash chromatography (PE containing 0 - 80% EtOAc) to give the title compound as a white solid (400 mg, 29.0% yield). LC / MS (ESI) m / z: 151 (M+H) + 。

[0704] Step 2: 4-Chloro-6-cyclobutylpyrimidine

[0705] A stirred solution of 6-cyclobutyl-3,4-dihydropyrimidin-4-one (100 mg, 0.666 mmol) in POCl3 (2 mL) was stirred at 120 °C for 2 h. The solution was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (PE containing 0 - 10% EtOAc) to give the title compound as a pale yellow oil (70 mg, 62.3% yield). LC / MS (ESI) m / z: 169 (M+H) + 。 1 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.20 (s, 1H), 3.63–3.59 (m, 1H), 2.40 - 2.30 (m, 4H), 2.12 - 2.07 (m, 1H), 1.96 - 1.93 (m, 1H).

[0706] Intermediate 46: 3-Chloro-5-cyclopropyl-1,2,4-oxadiazole

[0707]

[0708] Step 1: N-Cyanocyclopropanecarboxamide

[0709] Under a N2 atmosphere at 0 °C, cyclopropanecarbonyl chloride (1.02 g, 9.76 mmol) was added to a solution of sodium cyanamide (1.25 g, 19.51 mmol) in THF (10 mL), and the mixture was stirred at 25 °C for 16 h. The mixture was concentrated to dryness and the residue was dissolved in H2O (10 mL). The mixture was washed with EtOAc (2 × 3 mL), acidified to pH ~2 with 1 N aqueous HCl and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford the title compound as a colorless oil (564 mg, 52.5% yield), which was used directly in the next step.

[0710] Step 2: 5-Cyclopropyl-1,2,4-oxadiazol-3-amine

[0711] Under a N2 atmosphere, pyridine (1.51 g, 19.07 mmol) was added to a mixture of N-cyanocyclopropanecarboxamide (525 mg, 4.77 mmol) and hydroxylamine hydrochloride (497.0 mg, 7.15 mmol) in EtOH (6 mL), and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford the title compound as a white solid (429 mg, 71.9% yield), which was used directly in the next step. LC / MS (ESI) m / z: 126 (M+H) + . 1H NMR (400 MHz, CDCl3) δ 4.28 (s, 1H), 2.05 (tt, J = 7.0, 6.0 Hz, 1H), 1.19 - 1.12 (m, 2H).

[0712] Step 3: 3-Chloro-5-cyclopropyl-1,2,4-oxadiazole

[0713] A solution of NaNO2 (276 mg, 4.00 mmol) in water (2 mL) was added dropwise to a solution of 5-cyclopropyl-1,2,4-oxadiazol-3-amine (200 mg, 1.60 mmol) in aqueous HCl (2 mL, 36% wt), and the mixture was stirred at 0 °C for 2 h. The mixture was diluted with water and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 200:1 to 20:1) to afford the title compound as a yellow oil (78 mg, 33.8% yield). 11H NMR (400 MHz, CDCl3) δ 2.24 - 2.15 (m, 1H), 1.34 - 1.25 (m, 5H).

[0714] Intermediate 47: 3-Chloro-5-(cyclopropylmethyl)-1,2,4-oxadiazole

[0715]

[0716] The title compound was prepared from 2-cyclopropylacetyl chloride using the same procedure as for Intermediate 46. LC / MS (ESI) m / z: 159 (M+H) + .

[0717] Intermediate 48: 3-Chloro-5-cyclobutyl-1,2,4-oxadiazole

[0718]

[0719] The title compound was prepared from cyclobutanecarbonyl chloride using the same procedure as for Intermediate 46. LC / MS (ESI) m / z: 159 (M+H) + .

[0720] Intermediate 49: 5-Bromo-1-propyl-1H-1,2,4-triazole

[0721]

[0722] To a mixture of 3-bromo-4H-1,2,4-triazole (1 g, 6.76 mmol), 1-iodopropane (1.0 mL, 10.13 mmol) and TBAF (10 mg, catalyst) in toluene (10 mL) was added a solution of KOH (750 mg, 13.5 mmol) in water (2 mL), and the mixture was stirred at 60 °C for 16 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE:EtOAc = 6:1) to give the title compound as a yellow oil (400 mg, 31.3% yield). LC / MS (ESI) m / z: 190 / 192 (M+H) + . 1H-NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 4.14 (t, J = 2.4 Hz, 2H), 1.91 (m, 2H), 0.95 (t, J = 2.4 Hz, 2H).

[0723] Intermediate 50: 5-Bromo-1-(cyclopropylmethyl)-1H-1,2,4-triazole

[0724]

[0725] The title compound was prepared from 3-bromo-4H-1,2,4-triazole and (bromomethyl)cyclopropane using the same procedure as for Intermediate 49. LC / MS (ESI) m / z: 202 / 204 (M+H) + .

[0726] Intermediate 51: 5-Bromo-1-isobutyl-1H-1,2,4-triazole

[0727]

[0728] The title compound was prepared from 3-bromo-4H-1,2,4-triazole and 1-iodo-2-methylpropane using the same procedure as for Intermediate 49. LC / MS (ESI) m / z: 204 / 206 (M+H) + . 1 1H-NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 3.97 (d, J = 7.2 Hz, 2H), 2.35 - 2.86 (m, 1H), 0.95 (d, J = 6.8 Hz, 6H).

[0729] Example 1: (S)-2-(5,5-Difluoro-1-(2-methyl-6-(1-methyl-5-((3-methyl-2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid

[0730]

[0731] Step 1: Methyl (S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate

[0732] At 0 °C, TEA (20 mg, 0.2 mmol) was added to a solution of methyl (S)-2-(5,5-difluoro-1-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)piperidin-3-yl)acetate (40 mg, 0.1 mmol) in DCM (1 mL), followed by MsCl (17 mg, 0.15 mmol), and the mixture was stirred at this temperature for 2 h. The mixture was diluted with DCM (2 mL), washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to dryness to give the title compound as a pale yellow solid (43 mg, 91% yield), which was used directly in the next reaction without purification. LC / MS (ESI) (m / z): 474 (M+H) + 。

[0733] Step 2: Methyl (S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((3-methyl-2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate

[0734] To a mixture of methyl (S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate (43 mg, 0.091 mmol) and 3-methyl-5-propyl-1,2-dihydropyridin-2-one (16.5 mg, 0.11 mmol) in toluene (3 mL) and water (1 mL) were added K2CO3 (25 mg, 0.182 mmol) and TBAF (3 mg, catalytic amount), and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (3 mL) and extracted with EtOAc (2 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the title compound as a pale yellow solid (35 mg, 72.9% yield). LC / MS (ESI) (m / z): 529 (M+H) + 。

[0735] Step 3: (S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((3-methyl-2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid

[0736] At 0 °C, a solution of LiOH (15.8 mg, 0.66 mmol) in water (1 mL) was added to a solution of methyl (S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((3-methyl-2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate (35 mg, 0.066 mmol) in THF (1 mL) and methanol (2 mL). After stirring at room temperature for 2 h, the reaction mixture was concentrated to dryness and the residue was dissolved in water (3 mL). The mixture was washed twice with MTBE, and the aqueous layer was acidified to pH ~2 with 1N aqueous HCl and extracted with EtOAc (2 × 2 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (C18, 10 - 95%, H2O containing MeCN with 0.1% HCOOH) to afford the title compound as a white solid (22 mg, 64.6% yield). LC / MS (ESI) (m / z): 515 (M+H) + 。 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.17 - 7.16 (m, 1H), 5.56 (s, 2H), 4.23 (s, 3H), 3.20 - 3.04 (m, 4H), 2.60 - 2.55 (m, 4H), 2.39 - 2.27 (m, 4H), 2.15 (t, J = 7.4 Hz, 2H), 1.95 (s, 3H), 1.84 - 1.68 (m, 1H), 1.35 - 1.26 (m, 2H), 0.71 (t, J = 7.3 Hz, 3H).

[0737] Example 2: (S)-2-(1-(6-(5-((4-(Cyclopropylmethyl)-3-methyl-2-oxopyridin-1(2H)-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetic acid

[0738]

[0739] Step 1: 3-Bromo-6-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridine

[0740] To a solution of (4-(5-bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol (500 mg, 1.76 mmol) in DCM (10 mL) at 0 °C was added dropwise PBr3 (717 mg, 2.65 mmol), and the mixture was stirred at 0 °C to room temperature for 3 h. The mixture was diluted with DCM (10 mL), washed with ice-cooled saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the crude product, which was purified by flash chromatography (silica gel, PE containing 0 - 30% EtOAc) to give the title compound as a white solid (510 mg, 83.7% yield). LC / MS (ESI) m / z: 347 (M+H) + 。

[0741] Step 2: 1-((4-(5-bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-4-(cyclopropylmethyl)-3-methylpyridin-2(1H)-one

[0742] To a mixture of 3-bromo-6-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridine (200 mg, 0.58 mmol) and 4-(cyclopropylmethyl)-3-methyl-1,2-dihydropyridin-2-one (136 mg, 0.83 mmol) in toluene (5 mL) and H2O (1 mL) was added K2CO3 (230 mg, 1.66 mmol) and TBAF (10 mg, catalyst), and the mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with EtOAc (5 mL), washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, PE containing 0 - 56% EtOAc) to give the title compound as a white solid (220 mg, 88.9% yield). LC / MS (ESI) m / z: 428 / 430 (M+H) + 。

[0743] Step 3: Methyl (S)-2-(1-(6-(5-((4-(cyclopropylmethyl)-3-methyl-2-oxopyridin-1(2H)-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate

[0744] To a mixture of 1-((4-(5-bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-4-(cyclopropylmethyl)-3-methylpyridin-2(1H)-one (78 mg, 0.18 mmol), methyl 2-[(3S)-5,5-difluoropiperidin-3-yl]acetate (35 mg, 0.18 mmol), Cs2CO3 (177 mg, 0.54 mmol) and Ru-phos (17 mg, 0.036 mmol) in 1,4-dioxane (2 mL) was added Ru-phos-Pd-G3 (30 mg, 0.036 mmol). The mixture was then degassed three times under N2 atmosphere and stirred at 110 °C for 16 h under N2 atmosphere. The reaction mixture was poured into ice water and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, PE containing 0 - 50% EtOAc) to afford the title compound as a yellow solid (35 mg, 35.5% yield). LC / MS (ESI) m / z: 541 (M+H) + 。

[0745] Step 4: (S)-2-(1-(6-(5-((4-(cyclopropylmethyl)-3-methyl-2-oxopyridin-1(2H)-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetic acid

[0746] To a solution of methyl (S)-2-(1-(6-(5-((4-(cyclopropylmethyl)-3-methyl-2-oxopyridin-1(2H)-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate (35 mg, 0.065 mmol) in MeOH (1 mL), H2O (1 mL), THF (4 mL) was added LiOH (50 mg, 2.1 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was acidified to pH ~ 3 with 1N aqueous HCl and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (C18, 10 - 95%, H2O containing MeCN with 0.1% HCOOH) to afford the title compound as a white solid (15 mg, 43.8% yield). LC / MS (ESI) m / z: 527 (M+H) + 。 11H NMR (400 MHz, CD3OD) δ 7.83 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.1 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 6.30 (d, J = 7.2 Hz, 1H), 5.73 (s, 2H), 4.21 (s, 3H), 3.28 - 3.23 (m, 2H), 3.15 - 3.00 (m, 1H), 2.62 - 2.56 (m, 1H), 2.59 (s, 3H), 2.54 - 2.48 (m, 1H), 2.43 - 2.39 (m, 4H), 2.36 - 2.26 (m, 1H), 2.04 (s, 3H), 1.81 - 1.64 (m, 1H), 0.90 - 0.87 (m, 1H), 0.52 - 0.46 (m, 2H), 0.18 - 0.14 (m, 2H).

[0747] The examples in the following table were prepared by the specified method using similar reactants.

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761] Example 43: (S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((4-oxo-3-propylpyridin-1(4H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid

[0762]

[0763] Step 1: 4-(Benzyloxy)-3-bromopyridine

[0764] Under a N2 atmosphere at 0 °C, NaH (92 mg, 2.30 mmol, 60% dispersed in mineral oil) was added portionwise to a solution of 3-bromopyridin-4-ol (0.13 mL, 1.16 mmol) in DMF (2 mL), and the reaction was stirred at 0 °C for 20 minutes. BnBr (0.21 mL, 1.76 mmol) was added to the above mixture, and the resulting mixture was stirred at 25 °C for 16 hours. The reaction was quenched with water (20 mL) at 0 °C and the mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography (PE:EtOAc = 50:1 to 20:1) to give the title compound as a pale yellow solid (300 mg, 98.6% yield). LC / MS (ESI) m / z: 264 (M+H) + 。

[0765] Step 2: 3-Allyl-4-(benzyloxy)pyridine

[0766] Under a N2 atmosphere, Pd(PPh3)4 (132 mg, 0.114 mmol) was added to a mixture of 4-(benzyloxy)-3-bromopyridine (300 mg, 1.14 mmol), titanium butyl(vinyl)tin (0.53 mL, 1.71 mmol) and LiCl (121 mg, 2.85 mmol). After addition, the mixture was degassed at 100 °C for 16 hours under a N2 atmosphere. The mixture was diluted with EtOAc (10 mL), washed with saturated aqueous KF solution and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 50:1 to 20:1) to give the title compound 3 as a yellow oil (205 mg, 80.2% yield). LC / MS (ESI) m / z: 226 (M+H) + 。

[0767] Step 3: 3-Propylpyridin-4-ol

[0768] Under N2 atmosphere at 25 °C, Pd(OH)2 / C (20 mg, 10% wt) was added to a solution of 3-allyl-4-(benzyloxy)pyridine (150 mg, 0.67 mmol) in MeOH (3 mL), and the mixture was degassed three times under N2 atmosphere and stirred at 25 °C under a H2 balloon for 5 h. The mixture was filtered and the filter cake was washed with MeOH (2 × 5 mL). The filtrate was concentrated to dryness, and the residue was purified by column chromatography (DCM:MeOH = 20:1 to 10:1) to give compound 4 as a colorless oil (50 mg, 54.7% yield). LC / MS (ESI) m / z: 138 (M+H) + 。

[0769] Step 4: Methyl (R)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((4-oxo-3-propylpyridin-1(4H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate

[0770] To a mixture of 3-propylpyridin-4-ol (15.7 mg, 0.114 mmol) and methyl (S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate (36 mg, 0.076 mmol) in toluene (2 mL) and H2O (1 mL) was added K2CO3 (31.5 mg, 0.23 mmol), followed by TBAF (2 mg, 0.008 mmol), and the reaction mixture was heated to 80 °C for 16 h. The mixture was diluted with EtOAc (3 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the title compound as a yellow solid (50 mg, 100% yield), which was used directly in the next reaction. LC / MS (ESI) m / z: 515 (M+H) + 。

[0771] Step 5: (R)-2-(5,5-Difluoro-1-(2-methyl-6-(1-methyl-5-((4-oxo-3-propylpyridin-1(4H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid

[0772] At 25 °C, LiOH·H2O (42 mg, 1.00 mmol) was added to a solution of methyl (R)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((4-oxo-3-propylpyridin-1(4H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate (50 mg, 0.097 mmol) in THF (2 mL), MeOH (0.50 mL) and water (0.5 mL), and the mixture was stirred at 25 °C for 16 h. The reaction was concentrated to dryness and the residue was diluted with water (5 mL). The mixture was basified to pH ~14 with 1 N aqueous NaOH and washed with EtOAc (2 × 2 mL). The aqueous layer was acidified to pH ~3 with 1 N aqueous HCl and extracted with DCM (2 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC to give the title compound as a white solid (5.2 mg, 10.7%). LC / MS (ESI) m / z: 501 (M+H) + 。 1 H NMR (400 MHz, DMSO) δ 7.90 (d, J = 8.3 Hz, 1H), 7.84–7.75 (m, 2H), 7.59 (d, J = 8.4 Hz, 1H), 6.03 (d, J = 7.3 Hz, 1H), 5.69 (s, 2H), 4.10 (s, 3H), 3.21–3.07 (m, 3H), 2.59–2.56 (m, 1H), 2.52 (s, 3H), 2.40–2.25 (m, 4H), 2.22–2.15 (m, 2H), 2.03–1.95 (m, 1H), 1.80–1.73 (m, 1H), 1.40–1.31 (m, 2H), 0.78 (t, J = 7.4 Hz, 3H).

[0773] Example 44: 2-[5,5-Difluoro-1-(2-methyl-6-{1-methyl-5-[2-(6-oxo-5-propyl-1,6-dihydropyridazin-1-yl)ethyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)piperidin-3-yl]acetic acid

[0774]

[0775] Step 1: 2-[4-(5-Bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl]acetonitrile

[0776] To a solution of 3-bromo-6-[5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl]-2-methylpyridine (1.1 g, 3.18 mmol) in CH3CN (10 mL) was added DMSO (10 mL) containing NaCN (260 mg, 5.31 mmol), and the reaction mixture was stirred at room temperature for 30 minutes and then partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic extracts were concentrated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0% to 100% EtOAc) to afford the title compound as a white solid (680 mg, 73.2% yield). 1 H NMR (400 MHz, CDCl3) δ 7.92 (q, J = 8.4 Hz, 2H), 4.64 (s, 2H), 4.19 (s, 3H), 2.69 (s, 3H), 1.66 (s, 2H).

[0777] Step 2: 2-[4-(5-bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl]acetic acid

[0778] To a solution of 2-[4-(5-bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl]acetonitrile (630 mg, 2.16 mmol) in ethanol (10 mL) and H2O (10 mL) was added KOH (483 mg, 8.63 mmol), and the resulting mixture was refluxed for 16 hours. The ethanol was removed under reduced pressure, then the solution was cooled to below 10 °C and acidified to pH ~ 1 with aqueous concentrated HCl. The mixture was extracted with EtOAc (2 × 10 mL), and the combined organic extracts were concentrated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford the title compound as a white solid (680 mg, 101.4% yield). LC / MS (ESI) m / z: 312 / 314 (M + H) + 。

[0779] Step 3: 2-[4-(5-bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl]ethan-1-ol

[0780] To a mixture of 2-[4-(5-bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl]acetic acid (450 mg, 1.45 mmol) in THF was added dropwise BH3·THF complex (4.3 mL, 1 M in THF) at 0 °C, and the mixture was stirred at room temperature for 6 h. The reaction mixture was quenched by adding dropwise MeOH (5 mL) at 0 °C, and the resulting mixture was concentrated to dryness to afford the title compound as a white solid (250 mg, 58.2% yield). LC / MS (ESI) m / z: 298 / 300 (M+H) + 。

[0781] Step 4: 2-[4-(5-bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl]ethyl methanesulfonate

[0782] To a stirred solution of 2-[4-(5-bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl]ethan-1-ol (250 mg, 0.84 mmol) in DCM (10 mL) was added MsCl (0.1 mL, 1.26 mmol) and TEA (0.35 mL, 2.52 mmol) at 0 °C under N2 atmosphere. After stirring at room temperature for 3 h, the reaction mixture was quenched with H2O (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 9:1 to 4:1) to afford the title compound as a yellow solid (270 mg, 85.5% yield). LC / MS (ESI) m / z: 376 / 378 (M+H) + 。

[0783] Step 5: 2-{2-[4-(5-bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl]ethyl}-4-propyl-2,3-dihydropyridazin-3-one

[0784] To a solution of 2-[4-(5-bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl]ethyl methanesulfonate (120 mg, 0.32 mmol) and 4-propyl-2,3-dihydropyridazin-3-one (66 mg, 0.48 mmol) in toluene (2 mL) was added H2O (2 mL) containing K2CO3 (132 mg, 0.96 mmol), followed by TBAF (8 mg, 0.03 mmol), and the mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0 - 25% EtOAc) to afford the title compound as a brown solid (40 mg, 30.0% yield). LC / MS (ESI) m / z: 418 / 420 (M+H) + 。

[0785] Step 6: Methyl 2-[(3R)-5,5-difluoro-1-(2-methyl-6-{1-methyl-5-[2-(6-oxo-5-propyl-1,6-dihydropyridazin-1-yl)ethyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)piperidin-3-yl]acetate

[0786] Under N2 atmosphere, to a mixture of 2-{2-[4-(5-bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl]ethyl}-4-propyl-2,3-dihydropyridazin-3-one (40 mg, 0.10 mmol) and methyl 2-[(3R)-5,5-difluoropiperidin-3-yl]acetate (22 mg, 0.12 mmol) in toluene (2 mL) was added Cs2CO3 (62 mg, 0.19 mmol), followed by BINAP (6 mg, 0.01 mmol) and Pd(OAc)2 (2 mg, 0.01 mmol). The reaction was degassed three times under N2 atmosphere and stirred at 110 °C for 2 h in a CEM microwave reactor. The mixture was diluted with EtOAc (5 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0 - 55% EtOAc) to afford the title compound as a yellow solid (10 mg, 19.7% yield). LC / MS (ESI) m / z: 531 (M+H) + 。

[0787] Step 7: 2-[5,5-Difluoro-1-(2-methyl-6-{1-methyl-5-[2-(6-oxo-5-propyl-1,6-dihydropyridazin-1-yl)ethyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)piperidin-3-yl]acetic acid

[0788] To a solution of 2-[5,5-difluoro-1-(2-methyl-6-{1-methyl-5-[2-(6-oxo-5-propyl-1,6-dihydropyridazin-1-yl)ethyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)piperidin-3-yl]acetic acid (10 mg, 0.02 mmol) in THF (5 mL) and MeOH (1 mL) was added a solution of LiOH (8 mg, 0.2 mmol) in H2O (1 mL). The mixture was stirred at room temperature for 2 h. The mixture was acidified to pH ~3 with 1N aqueous HCl and extracted with DCM (2×2 mL). The combined organic layers were washed with brine and concentrated to dryness. The residue was purified by preparative HPLC (C18, H2O containing 0 - 90% acetonitrile with 0.1% formic acid) to afford 2-[5,5-difluoro-1-(2-methyl-6-{1-methyl-5-[2-(6-oxo-5-propyl-1,6-dihydropyridazin-1-yl)ethyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)piperidin-3-yl]acetic acid as a white solid (2.2 mg, 22.6% yield). LC / MS (ESI) m / z: 517 (M+H) + 。 1 H NMR (400 MHz, CD3OD) δ 7.65 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 4.2 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 4.2 Hz, 1H), 4.61 (s, 3H), 4.50 (t, J = 7.3 Hz, 2H), 4.06 (s, 3H), 3.78 (t, J = 6.6 Hz, 2H), 3.14–2.99 (m, 1H), 2.56 (s, 3H), 2.54–2.47 (m, 1H), 2.42–2.35 (m, 4H), 2.34–2.25 (m, 1H), 1.83–1.64 (m, 1H), 1.57–1.45 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0789] Examples 45 and 46: 2-((3R,5R) or (3S,5S)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetic acid and 2-((3S,5S) or (3R,5R)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetic acid

[0790]

[0791] Step 1: Methyl cis-5-hydroxypiperidine-3-carboxylate

[0792] To a solution of cis-1-benzyl 3,5-hydroxypiperidine-1,3-dicarboxylate (8 g, 27.3 mmol) in EtOAc (100 mL) was added Pd / C (1 g, 10% wt), and the mixture was degassed three times under a N2 atmosphere and stirred at room temperature for 16 h under a H2 balloon. The mixture was filtered and the filtrate was concentrated to dryness to afford the title compound as a colorless oil (4.3 g, 99% yield). LC / MS (ESI) m / z: 160 (M+1) + .

[0793] Step 2: Methyl cis-1-benzyl-5-hydroxypiperidine-3-carboxylate

[0794] To a mixture of methyl cis-5-hydroxypiperidine-3-carboxylate (4.3 g, 27.0 mmol) and K2CO3 (7.5 g, 54.1 mmol) in DMF (50 mL) was added BnBr (7.4 g, 40.5 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (100 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0 - 100% EtOAc) to afford the title compound as a yellow oil (3.85 g, 57.2% yield). LC / MS (ESI) m / z: 250 (M+1) + .

[0795] Step 3: Methyl trans-1-benzyl-5-fluoropiperidine-3-carboxylate

[0796] To a mixture of methyl cis-1-benzyl-5-hydroxypiperidine-3-carboxylate (3.85 g, 15.4 mmol) in DCM (50 mL) at -78 °C was added dropwise DAST (4.1 mL, 30.9 mmol), and the mixture was stirred at -78 °C to room temperature for 16 h. The mixture was quenched with saturated aqueous NaHCO3 at 0 °C and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0 - 100% EtOAc) to give the title compound as a yellow oil (3.2 g, 82.5% yield). LC / MS (ESI) m / z: 252 (M+1) + 。

[0797] Step 4: Methyl trans-5-fluoropiperidine-3-carboxylate

[0798] To a mixture of methyl trans-1-benzyl-5-fluoropiperidine-3-carboxylate (3.2 g, 12.7 mmol) in MeOH (50 mL) was added Pd(OH)2 (400 mg, 10% wt) and AcOH (3 drops of water), and the mixture was degassed three times under N2 and stirred at room temperature under a H2 balloon for 16 h. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound as a colorless oil (2.5 g, 100% yield). LC / MS (ESI) m / z: 162 (M+1) + 。

[0799] Step 5: Methyl trans-1-benzyl 3-5-fluoropiperidine-1,3-dicarboxylate

[0800] To a mixture of methyl trans-5-fluoropiperidine-3-carboxylate (2.5 g, 15.5 mmol) in THF (30 mL) and saturated aqueous NaHCO3 (15 mL) at 0 °C was added dropwise CbzCl (5.27 g, 31.0 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was extracted with EtOAc (2 × 20 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0 - 50% EtOAc) to give the title compound as a yellow oil (3.7 g, 80.8% yield). LC / MS (ESI) m / z: 296 (M+1) + 。

[0801] Step 6: trans-1-((Benzyloxy)carbonyl)-5-fluoropiperidine-3-carboxylic acid

[0802] To a solution of trans-1-benzyl 3-(5-fluoropiperidine-1,3-dicarboxylate) (3.7 g, 12.5 mmol) in MeOH (40 mL), THF (20 mL) and H2O (20 mL) was added LiOH·H2O (2.63 g, 62.6 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to dryness and the residue was dissolved in water (50 mL) and washed with EtOAc (2 × 10 mL). The aqueous layer was acidified to pH ~4 with 1N aqueous HCl and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford the title compound as a white solid (3.1 g, 88% yield). LC / MS (ESI) m / z: 282 (M+1) + 。

[0803] Step 7: Benzyl trans-3-(chlorocarbonyl)-5-fluoropiperidine-1-carboxylate

[0804] To a solution of 1-[(benzyloxy)carbonyl]-5-fluoropiperidine-3-carboxylic acid (3.1 g, 11.0 mmol) and DMF (0.085 mL, 1.10 mmol) in DCM (31 mL) at 0 °C was added oxalyl chloride (2.80 g, 22.0 mmol) dropwise, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness and the residue was dissolved in THF (40 mL). A solution of TMSCHN2 (16.5 mL, 2 M in toluene) was added to the above mixture and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with AcOH (6 mL) and concentrated to dryness to afford a yellow residue. The residue was dissolved in MeOH (50 mL), and F3CCOOAg (0.48 g, 2.16 mmol) and TEA (6 mL) were added. The reaction mixture was sonicated at room temperature for 1 h. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel (40 g), 0 - 100%, PE containing EtOAc) to afford the title compound as a yellow oil (2.0 g, 60% yield). LC / MS (ESI) m / z: 310 (M+1) + 。

[0805] Step 8: Methyl trans-2-(5-fluoropiperidin-3-yl)acetate

[0806] To a mixture of benzyl trans-3-fluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (2 g, 6.46 mmol) in EtOAc (50 mL) was added Pd / C (200 mg, 10% wt). The mixture was degassed three times under N2 atmosphere and stirred at room temperature for 2 h under a H2 balloon. The reaction mixture was filtered and the filtrate was concentrated to dryness to afford the title compound as an off-white solid (1.1 g, 97% yield). LC / MS (ESI) m / z: 176 (M+1) + 。

[0807] Step 9: Methyl trans-2-(1-(2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetate

[0808] To a mixture of 3-bromo-2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridine (600 mg, 1.57 mmol), methyl trans-2-(5-fluoropiperidin-3-yl)acetate (276 mg, 1.58 mmol), Ru-phos (147 mg, 0.315 mmol) and Cs2CO3 (1.0 mg, 3.14 mmol) in 1,4-dioxane (15 mL) was added Pd2(dba)3 (216 mg, 0.236 mmol). The mixture was degassed three times under N2 and stirred at 120 °C for 3 h. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, PE containing 0 - 40% EtOAc) to afford the title compound as a yellow solid (430 mg, 57.5% yield). LC / MS (ESI) m / z: 476 (M+1) + 。

[0809] Step 10: Methyl 2-((3S,5S) or (3R,5R)-1-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetate (14-P1) and

[0810] Methyl 2-((3R,5R) or (3S,5S)-1-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetate (14-P2)

[0811] To a mixture of methyl 2-[1-(2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)-5-fluoropiperidin-3-yl]acetate (430 mg, 0.904 mmol) in MeOH (10 mL) was added PPTS (454 mg, 1.81 mmol). After stirring at 50 °C for 16 h, the mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (C 18 , 10 - 95%, H2O containing MeCN with 0.1% HCOOH) to give the racemic product, which was purified by chiral SFC to give compound 14-P1 as a white solid (peak 1, retention time: 5.48 min) (64 mg, 18% yield) and 14-P2 (peak 2, retention time: 5.83 min) (92 mg, 26% yield). LC / MS (ESI) m / z: 392.5 (M+1) + . SFC conditions: column: ChiralPak OJ, 250×21.2 mm I.D., 5 μm; mobile phase: A represents CO2 and B represents methanol (0.1% NH4OH); gradient: B 40%; flow rate: 50 mL / min; column temperature: 35 °C.

[0812] Step 11: Methyl 2-((3S,5S) or (3R,5R)-1-(2-ethyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetate

[0813] To a mixture of compound 14-P1 (64 mg, 0.16 mmol) and TEA (0.07 mL, 0.510 mmol) in DCM (3 mL) at 0 °C was added MsCl (0.025 mL, 0.33 mmol). After stirring at 0 °C for 1 h, the reaction mixture was diluted with DCM (5 mL), washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the title compound as a yellow solid (76 mg, 99% yield). LC / MS (ESI) m / z: 470 (M+1) + .

[0814] Step 12: Methyl 2-((3S,5S) or (3R,5R)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetate

[0815] To a mixture of compound 15 (35 mg, 0.075 mmol) and K2CO3 (21 mg, 0.151 mmol) in toluene (2 mL) and H2O (0.4 mL) was added 5-propyl-1,2-dihydropyridin-2-one (12 mg, 0.089 mmol). After stirring at 100 °C for 2 h, the reaction mixture was diluted with EtOAc (5 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a yellow solid (38 mg, 99.8% yield). LC / MS (ESI) m / z: 511 (M+1) + 。

[0816] Step 13: 2-((3S,5S) or (3R,5R)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetic acid

[0817] To a solution of compound 16 (38 mg, 0.074 mmol) in THF (2 mL), H2O (0.5 mL) and MeOH (0.5 mL) was added LiOH·H2O (31 mg, 0.740 mmol). After stirring at room temperature for 16 h, the reaction mixture was acidified to pH ~ 6 with 1N aqueous HCl and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (C 18 , 10 - 95%, H2O containing MeCN with 0.1% HCOOH) to afford the title compound as a white solid (8.5 mg, 23% yield). LC / MS (ESI) m / z: 497 (M+1) +.1H NMR (400 MHz, CD3OD) δ 7.88 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 9.3, 2.4 Hz, 1H), 6.52 (d, J = 9.2 Hz, 1H), 5.87 (s, 2H), 4.82–4.63 (m, 1H), 4.16 (s, 3H), 3.21–3.12 (m, 1H), 3.02–2.90 (m, 2H), 2.89–2.79 (m, 1H), 2.54–2.40 (m, 3H), 2.39–2.27 (m, 2H), 2.21 (t, J = 7.5 Hz, 2H), 1.48–1.28 (m, 7H), 0.76 (t, J = 7.3 Hz, 3H).

[0818] Example 46: 2-((3R,5R) or (3S,5S)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetic acid

[0819] The title compound was prepared from Compound 14-P2 using the same sequence as in the synthesis of Example 45. LC / MS (ESI) m / z: 497 (M+1) + . 1 1H NMR (400 MHz, CD3OD) δ 7.88 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 9.3, 2.5 Hz, 1H), 6.52 (d, J = 9.2 Hz, 1H), 5.87 (s, 2H), 4.73 (d, J = 4.6 Hz, 1H), 4.16 (s, 3H), 3.33 (s, 1H), 3.20–3.14 (m, 1H), 3.01–2.90 (m, 2H), 2.88–2.81 (m, 1H), 2.54–2.40 (m, 3H), 2.39–2.26 (m, 2H), 2.21 (t, J = 7.6 Hz, 2H), 1.50–1.40 (m, 1H), 1.39–1.33 (m, 2H), 1.31 (t, J = 7.5 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H).

[0820] Example 47: 2-(1-(4-fluoro-2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid

[0821]

[0822] Step 1: 6-Bromo-3-fluoro-2-methylpyridine 1-oxide

[0823] Under a nitrogen atmosphere at 0 °C, hydrogen peroxide (40 mL, 353 mmol) was added to a solution of 6-bromo-3-fluoro-2-methylpyridine (10 g, 52.6 mmol) in TFA (100 mL), and the mixture was stirred at 70 °C for 20 hours. The reaction was cooled to 0 °C and quenched with saturated aqueous Na2S2O3. The mixture was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 10:1 to 0:1) to give the title compound as a yellow solid (8.2 g, 75.6% yield).

[0824] Step 2: 6-Bromo-3-fluoro-2-methyl-4-nitropyridine 1-oxide

[0825] Potassium nitrate (1.96 g, 19.4 mmol) was added portionwise to a solution of 6-bromo-3-fluoro-2-methylpyridine 1-oxide (7 g, 34.0 mmol) in concentrated H2SO4 (70 mL, 731 mmol) at 0 °C, and the mixture was stirred at 120 °C for 6 hours. The reaction mixture was poured into ice water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was recrystallized from EtOAc to give the title compound as a yellow solid (2.57 g, 30.1% yield). LC / MS (ESI) m / z: 251 (M+H) + 。

[0826] Step 3: 6-Bromo-3-(3-(2-ethoxy-2-oxoethyl)piperidin-1-yl)-2-methyl-4-nitropyridine 1-oxide

[0827] At 0 °C, a solution of TEA (0.7 mL, 5.04 mmol) and ethyl 2-(piperidin-3-yl)acetate (0.9 g, 5.26 mmol) in THF (5 mL) was added to a solution of 6-bromo-3-fluoro-2-methyl-4-nitropyridine 1-oxide (1.2 g, 4.78 mmol) in THF (5 mL), and the reaction was stirred at 25 °C for 24 h. The mixture was diluted with EtOAc (20 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 10:1 to 3:1) to give the title compound as a red solid (1.55 g, 82.8% yield). LC / MS (ESI) m / z: 402 (M+H) + 。

[0828] Step 4: Ethyl 2-(1-(6-bromo-2-methyl-4-nitropyridin-3-yl)piperidin-3-yl)acetate

[0829] Under a N2 atmosphere at 0 °C, a solution of PBr3 (0.91 mL, 9.63 mmol) in DCM (2 mL) was added to a solution of 6-bromo-3-(3-(2-ethoxy-2-oxoethyl)piperidin-1-yl)-2-methyl-4-nitropyridine 1-oxide (1.55 g, 4.13 mmol) in DCM (15 mL), and the mixture was stirred at 16 °C for 3 h. The reaction was poured into ice-cooled saturated aqueous NaHCO3 and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 30:1 to 10:1) to give the title compound as a red oil (1.52 g, 93.9% yield). LC / MS (ESI) m / z: 386 (M+H) + 。

[0830] Step 5: Ethyl 2-(1-(6-bromo-4-fluoropyridin-3-yl)piperidin-3-yl)acetate

[0831] To a solution of ethyl 2-(1-(6-bromo-2-methyl-4-nitropyridin-3-yl)piperidin-3-yl)acetate (1.5 g, 3.88 mmol) in DMSO (15 mL) was added KF (1.13 g, 19.4 mmol), and the reaction mixture was stirred at 140 °C for 3 h under a N2 atmosphere. The mixture was poured into ice water and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 20:1 to 10:1) to afford the title compound as a yellow solid (700 mg, 50.2% yield). LC / MS (ESI) m / z: 359 (M+H) + 。

[0832] Step 6: Ethyl 2-(1-(4-fluoro-6-(3-hydroxyprop-1-yn-1-yl)-2-methylpyridin-3-yl)piperidin-3-yl)acetate

[0833] To a mixture of ethyl 2-(1-(6-bromo-4-fluoro-2-methylpyridin-3-yl)piperidin-3-yl)acetate (830 mg, 2.31 mmol) and TEA (0.96 mL, 6.93 mmol) in MeCN (8 mL) at 16 °C under a N2 atmosphere were added CuI (10 mg, 0.046 mmol) and Pd(PPh3)2Cl2 (32.4 mg, 0.046 mmol). Then propargyl alcohol (0.27 mL, 4.62 mmol) was added, and the resulting mixture was degassed three times under a N2 atmosphere and stirred at 25 °C for 22 h. The mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was concentrated to dryness, and the residue was purified by silica gel chromatography (PE:EtOAc = 10:1 to 1:1) to afford the title compound as a yellow oil (430 mg, 55.7% yield). LC / MS (ESI) m / z: 335 (M+H) + 。

[0834] Step 7: Ethyl 2-(1-(4-fluoro-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)piperidin-3-yl)acetate

[0835] Under a N2 atmosphere, TMSCH2N3 (332 mg, 2.57 mmol), Cp*RuCl(PPh3)2 (51 mg, 0.064 mmol), and copper(I) iodide (12.25 mg, 0.064 mmol) were added to a solution of ethyl 2-(1-(4-fluoro-6-(3-hydroxyprop-1-yn-1-yl)-2-methylpyridin-3-yl)piperidin-3-yl)acetate (430 mg, 1.29 mmol) in 1,4-dioxane (10 mL). The mixture was degassed three times under a N2 atmosphere and stirred at 50 °C for 16 h under a N2 atmosphere. The mixture was concentrated to dryness and the residue was dissolved in THF (10 mL) and TBAF (336 mg, 1.29 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (10 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (DCM:EtOAc = 6:1) to give the title compound as a yellow solid (200 mg, 39.7% yield). LC / MS (ESI) (m / z): 392 (M+H) + 。

[0836] Step 8: Ethyl 2-(1-(4-fluoro-2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate

[0837] At 0 °C, TEA (0.213 mL, 1.53 mmol) and MsCl (0.079 mL, 1.02 mmol) were added to a solution of ethyl 2-(1-(4-fluoro-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)piperidin-3-yl)acetate (200 mg, 0.511 mmol) in DCM (10 mL), and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid (210 mg, 87.5% yield). LC / MS (ESI) (m / z): 470 (M+H) + 。

[0838] Step 9: Ethyl 2-(1-(4-fluoro-2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate

[0839] Under a N2 atmosphere, K2CO3 (80 mg, 0.57 mmol) and TBAF (7.5 mg, 0.03 mmol) N were added to a mixture of methyl 2-(1-(4-fluoro-2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate (135 mg, 0.29 mmol) and 5-propyl-1,2-dihydropyridin-2-one (59 mg, 0.43 mmol) in toluene (4 mL) and H2O (1 mL), and the mixture was stirred at 70 °C for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 5:1 to 2:1) to give the title compound as a yellow oil (70 mg, 47.7% yield). LC / MS (ESI) (m / z): 511 (M+H) + 。

[0840] Step 10: 2-(1-(4-Fluoro-2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid

[0841] A solution of LiOH (23.5 mg, 0.98 mmol) in water (1 mL) was added to a solution of ethyl 2-(1-(4-fluoro-2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate (50 mg, 0.098 mmol) in THF (2 mL) and MeOH (3 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to 1 / 5 volume, diluted with water and washed twice with ethyl acetate. The aqueous layer was acidified to pH ~3 with 1N HCl aqueous solution and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C18, 25-95%, H2O containing MeCN with 0.1% HCOOH) to give the title compound as a white solid (10 mg, 21.2% yield). LC / MS (ESI) m / z: 483 (M+H) + 。 11H NMR (400 MHz, CD3OD) δ 7.83 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 13.0 Hz, 1H), 7.38 (dd, J = 9.2, 2.5 Hz, 1H), 6.47 (d, J = 9.2 Hz, 1H), 5.72 (s, 2H), 4.23 (s, 3H), 3.14 (t, J = 11.7 Hz, 2H), 3.06 - 3.03 (m, 2H), 2.63 (s, 3H), 2.31 - 2.26 (m, 4H), 1.96 - 1.90 (m, 1H), 1.84 (d, J = 12.9 Hz, 2H), 1.51 - 1.36 (m, 4H), 0.80 (t, J = 7.3 Hz, 3H).

[0842] Example 48: 2-(1-(2-Ethyl-4-fluoro-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid

[0843]

[0844] Step 1: 6-Bromo-2-ethyl-3-fluoropyridine

[0845] Under N2 atmosphere at -70 °C, LDA (27 mL, 54.1 mmol, 2 M in THF) was added dropwise to a mixture of 6-bromo-3-fluoro-2-methylpyridine (7.9 g, 41.6 mmol) and DMPU (6.5 mL, 54.1 mmol) in THF (80 mL), and the mixture was stirred at -70 °C for 1 hour. MeI (3.37 mL, 54.1 mmol) was added to the above mixture, and the resulting mixture was stirred at -70 °C for 3 hours and at room temperature for 16 hours. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE) to give the title compound as a colorless oil (2 g, 21.2% yield). LC / MS (ESI) m / z: 204 / 206 (M + H) + .

[0846] Step 2: 6-Bromo-2-ethyl-3-fluoropyridine 1-oxide

[0847] To a solution of 6-bromo-2-ethyl-3-fluoropyridine (2 g, 10.5 mmol) in TFA (20 mL) was added H2O2 (8 mL, 70.6 mmol), and the mixture was stirred at 70 °C for 16 h under a N2 atmosphere. The reaction was cooled to 0 °C and quenched with saturated aqueous Na2S2O3. The mixture was extracted with EtOAc (3 × 50 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 and brine (50 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography (PE:EtOAc = 10:1 to 5:1) to afford the title compound as a yellow solid (1.5 g, 65.0% yield). LC / MS (ESI) m / z: 220 / 222 (M+H) + 。

[0848] Step 3: 6-Bromo-2-ethyl-3-fluoro-4-nitropyridine 1-oxide

[0849] To a solution of 6-bromo-2-ethyl-3-fluoropyridine 1-oxide (5.0 g, 22.7 mmol) in concentrated H2SO4 (50 mL) at 0 °C was added KNO3 (9.19 g, 90.9 mmol) portionwise, and the mixture was stirred at 120 °C for 4 h. The mixture was poured into ice water and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 5:1 to 3:1) to afford the title compound as a yellow solid (380 mg, 6.31% yield). LC / MS (ESI) m / z: 265 / 267 (M+H) + 。

[0850] Step 4: 6-Bromo-3-(3-(2-ethoxy-2-oxoethyl)piperidin-1-yl)-2-ethyl-4-nitropyridine 1-oxide

[0851] To a solution of 6-bromo-2-ethyl-3-fluoro-4-nitropyridine 1-oxide (380 mg, 1.43 mmol) and ethyl 2-(piperidin-3-yl)acetate (318 mg, 1.86 mmol) in THF (5 mL) was added TEA (0.60 mL, 4.30 mmol), and the mixture was stirred at 25 °C for 4 h. The mixture was concentrated to dryness, and the residue was purified by silica gel chromatography (PE:EtOAc = 10:1 to 3:1) to afford the title compound as a yellow oil (480 mg, 80.4% yield). LC / MS (ESI) m / z: 416 / 418 (M+H) + 。

[0852] Step 5: Ethyl 2-(1-(6-bromo-2-ethyl-4-nitropyridin-3-yl)piperidin-3-yl)acetate

[0853] Under a N2 atmosphere at 0 °C, a solution of PBr3 (0.11 mL, 1.15 mmol) in DCM (1 mL) was added to a solution of 6-bromo-3-(3-(2-ethoxy-2-oxoethyl)piperidin-1-yl)-2-ethyl-4-nitropyridine 1-oxide (480 mg, 1.15 mmol) in DCM (5 mL), and the mixture was stirred at room temperature for 5 h. The reaction mixture was poured into ice-cooled saturated aqueous NaHCO3 and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 30:1 to 20:1) to give the title compound as a yellow solid (435 mg, 94.3% yield). LC / MS (ESI) m / z: 400 / 402 (M+H) + 。

[0854] Step 6: Ethyl 2-(1-(6-bromo-2-ethyl-4-fluoropyridin-3-yl)piperidin-3-yl)acetate

[0855] TBAF (5.43 mL, 5.43 mmol, 1 M in THF) was added to a solution of ethyl 2-(1-(6-bromo-2-ethyl-4-nitropyridin-3-yl)piperidin-3-yl)acetate (435 mg, 1.09 mmol) in DMF (5 mL), and the reaction was stirred at 50 °C for 1 h. The mixture was poured into ice water and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 30:1 to 20:1) to give the title compound as a yellow solid (220 mg, 54.2% yield). LC / MS (ESI) m / z: 373 / 375 (M+H) + 。

[0856] Step 7: Ethyl 2-(1-(2-ethyl-4-fluoro-6-(3-hydroxyprop-1-yn-1-yl)pyridin-3-yl)piperidin-3-yl)acetate

[0857] Under a N2 atmosphere at 0 °C, TEA (0.25 mL, 1.77 mmol), Pd(PPh3)2Cl2 (41.4 mg, 0.059 mmol), and CuI (11.2 mg, 0.059 mmol) were added to a mixture of ethyl 2-(1-(6-bromo-2-ethyl-4-fluoropyridin-3-yl)piperidin-3-yl)acetate (220 mg, 0.59 mmol) and prop-2-yn-1-ol (0.10 mL, 1.77 mmol) in CH3CN (5 mL), and the mixture was stirred at 25 °C for 16 h under a N2 atmosphere. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography (PE:EtOAc = 10:1 to 2:1) to afford the title compound as a yellow solid (167 mg, 81.3% yield). LC / MS (ESI) m / z: 349 (M+H) + 。

[0858] Step 8: Ethyl 2-(1-(2-ethyl-4-fluoro-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate

[0859] Under a N2 atmosphere, Cp*RuCl(PPh3)2 (38 mg, 0.05 mmol) and CuI (9.1 mg, 0.05 mmol) were added to a mixture of ethyl 2-(1-(2-ethyl-4-fluoro-6-(3-hydroxyprop-1-yn-1-yl)pyridin-3-yl)piperidin-3-yl)acetate (167 mg, 0.48 mmol) and TMSCH2N3 (0.14 mL, 0.96 mmol) in 1,4-dioxane (3 mL). The reaction mixture was degassed and stirred at 50 °C for 16 h under a N2 atmosphere. The mixture was concentrated to dryness and the residue was dissolved in THF (10 mL), followed by the addition of TBAF (1.5 mL, 3 mmol, 2 M in THF). The mixture was diluted with EtOAc (10 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (DCM:EtOAc = 100:0 to 1:1) to afford the title compound as a yellow oil (100 mg, 51.4% yield). LC / MS (ESI) m / z: 406 (M+H) + 。

[0860] Step 9: Ethyl 2-(1-(2-ethyl-4-fluoro-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate

[0861] Under N2 atmosphere at 0 °C, TEA (0.10 mL, 0.719 mmol) and MsCl (0.05 mL, 0.646 mmol) were added to a solution of ethyl 2-(1-(2-ethyl-4-fluoro-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate (40 mg, 0.099 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with DCM (5 mL) and washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness to give the title compound (50 mg, 100% yield), which was used directly in the next step. LC / MS (ESI) m / z: 484 (M+H) + 。

[0862] Step 10: 2-(1-(2-Ethyl-4-fluoro-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid

[0863] The title compound was prepared according to the procedure described for the synthesis of Example 47. LC / MS (ESI) m / z: 497 (M+H) + 。 1 1H NMR (400 MHz, CD3OD) δ 7.69–7.62 (m, 2H), 7.48–7.30 (m, 1H), 6.53–6.49 (d, J = 9.2 Hz, 1H), 5.84 (s, 2H), 4.16 (s, 3H), 3.21–3.13 (m, 2H), 3.06–2.98 (m, 4H), 2.31–2.28 (d, J = 7.0 Hz, 2H), 2.21-2.26 (m, 2H), 1.98–1.88 (m, 1H), 1.80-1.86 (m, 2H),, 1.51–1.36 (m, 4H), 1.32–1.26 (m, 3H), 0.80–0.75 (m, 3H).

[0864] Example 49: (S)-2-(1-(2-Cyano-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetic acid

[0865]

[0866] Step 1: 3,6-Dibromopicolinoyl chloride

[0867] A solution of 3,6-dibromopicolinic acid (1 g, 3.56 mmol) in SOCl2 (10 mL) was stirred at 85 °C for 3 h. The reaction mixture was concentrated to dryness to afford the title compound as a yellow oil (1.0 g, 95.0% yield), which was used directly in the next step.

[0868] Step 2: 3,6-Dibromopicolinamide

[0869] NH4OH (10 mL) was added dropwise to a solution of 3,6-dibromopyridine-2-carbonyl chloride (1 g, 3.34 mmol) in DCM (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. The mixture was poured into ice water and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford the title compound (900 mg, 90% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 5.59 (s, 2H). LC / MS (ESI) m / z: 281 (M+H) + 。

[0870] Step 3: 3,6-Dibromopicolinonitrile

[0871] Pyridine (1.3 mL, 16 mmol) was added to a solution of 3,6-dibromopicolinamide (900 mg, 3.21 mmol) in DCM (10 mL) at 0 °C, followed by TFAA (1.25 mL, 9 mmol), and the mixture was stirred at this temperature for 1 h. The mixture was poured into ice water and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE:EtOAc = 30:1 to 5:1) to afford the title compound as a white solid (650 mg, 77.2% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H).

[0872] Step 3: 3-Bromo-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)picolinonitrile

[0873] To a mixture of 3,6-dibromopicolinonitrile (2.3 g, 8.7 mmol) and 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (1.5 g, 10.54 mmol) in MeCN (20 mL) was added TEA (3.7 mL, 26.34 mmol), CuI (84 mg, 0.44 mmol), and Pd(PPh3)2Cl2 (310 mg, 0.44 mmol). The mixture was degassed three times under a N2 atmosphere and stirred at room temperature for 16 h under a N2 atmosphere. The mixture was diluted with ice water and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 2:1) to afford the title compound as a yellow solid (2.2 g, 54.4% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 4.86 (t, J = 3.2 Hz, 1H), 4.50 (q, J = 16.4 Hz, 2H), 3.93 - 3.81 (m, 1H), 3.62 - 3.51 (m, 1H), 1.91 - 1.72 (m, 2H), 1.75 - 1.60 (m, 3H). LC (ESI) m / z: 238 (M+H - 84) + 。

[0874] Step 4: 3-Bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)picolinonitrile

[0875] To a solution of 3-bromo-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)picolyl nitrile (2.2 g, 6.85 mmol) in 1,4-dioxane (5 mL) was added (azidomethyl)trimethylsilane (1.1 g, 8.22 mmol), CuI (65 mg, 0.34 mmol), Cp*RuCl(PPh3)2 (270 mg, 0.34 mmol). The mixture was degassed three times under N2 atmosphere and stirred at 50 °C for 16 h under N2 atmosphere. The mixture was concentrated to dryness and the residue was dissolved in THF (10 mL). TBAF (1.8 g, 13.7 mmol) was added to the above mixture, and the resulting mixture was stirred at 0 °C for 10 min. The mixture was diluted with EtOAc (5 mL) and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the crude product, which was purified by flash chromatography (PE:EtOAc = 4:1) to give the title compound as a white solid (1.6 g, 51.8% yield). LC / MS (ESI) (m / z): 294 (M+H-84) + 。

[0876] Step 6: Methyl 2-((3S)-1-(2-cyano-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate

[0877] Under N2 atmosphere, Cs2CO3 (137.8 mg, 0.42 mmol), Ru-Phos Pd G3 (35 mg, 0.04 mmol), Ru-phos (20 mg, 0.04 mmol) were added to a mixture of 3-bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)picolyl nitrile (80 mg, 0.21 mmol) and (S)-methyl 2-(5,5-difluoropiperidin-3-yl)acetate (40.9 mg, 0.21 mmol) in 1,4-dioxane (7.5 mL). The mixture was degassed three times under N2 atmosphere and stirred at 110 °C overnight under N2 atmosphere. The mixture was diluted with EtOAc (5 mL), and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (PE:EtOAc = 2:1) to give the title compound as a yellow solid (70 mg, 67.5% yield). LC / MS (ESI) m / z: 491 (M+H) + 。

[0878] Step 7: Methyl (S)-2-(1-(2-cyano-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate

[0879] To a solution of methyl 2-((3S)-1-(2-cyano-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate (70 mg, 0.14 mmol) in MeOH (5 mL) was added PPTS (72 mg, 0.28 mmol), and the mixture was stirred at 50 °C for 16 h. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography (eluting with PE:EtOAc = 1:1) to afford the title compound as a yellow solid (55 mg, 94.8% yield). LC / MS (ESI) m / z: 407 (M+H) + 。

[0880] Step 8: Methyl (S)-2-(1-(2-cyano-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate

[0881] To a solution of methyl (S)-2-(1-(2-cyano-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate (60 mg, 0.15 mmol) in DCM (2 mL) at 0 °C was added TEA (0.06 mL, 0.44 mmol), followed by MsCl (25 mg, 0.22 mmol), and the reaction mixture was stirred at 0 °C for 1 h. The mixture was diluted with ice water and extracted with DCM (2 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford the title compound as a yellow solid (65 mg, 90.8% yield). LC / MS (ESI) m / z: 485 (M+H) + 。

[0882] Step 9: Methyl (S)-2-(1-(2-cyano-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate

[0883] To a mixture of methyl (S)-2-(1-(2-cyano-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate (70 mg, 0.14 mmol) and 5-propylpyridin-2(1H)-one (20 mg, 0.14 mmol) in toluene (5 mL) and water (1 mL) was added K2CO3 (40 mg, 0.29 mmol) and TBAF (3.4 mg, catalyst), and the mixture was stirred at 110 °C for 1.5 h. The reaction mixture was diluted with EtOAc (5 mL) and washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford the title compound as a yellow solid (65 mg, 88.4% yield). LC / MS (ESI) m / z: 526 (M+H) + 。

[0884] Step 10: (S)-2-(1-(2-Cyano-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetic acid (12)

[0885] To a solution of methyl (S)-2-(1-(2-cyano-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate (35 mg, 0.067 mmol) in MeOH (1 mL), water (1 mL) and THF (4 mL) was added LiOH (28 mg, 0.67 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was acidified with 1 M aqueous HCl and extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC to afford the title compound as a white solid (20 mg, 58.7% yield). 11H NMR (400 MHz, CD3OD) δ 8.21 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.39 (dd, J = 9.2, 2.0 Hz, 1H), 6.41 (d, J = 9.2 Hz, 1H), 5.55 (s, 2H), 4.31 (s, 3H), 3.98 - 3.74 (m, 2H), 3.57 - 3.32 (m, 4H), 3.03 - 2.91 (m, 1H), 2.59 - 2.32 (m, 6H), 1.90 - 1.74 (m, 6H), 1.55 - 1.45 (m, 1H), 0.88 (t, J = 7.2, 3H). LC / MS (ESI) m / z: 512 (M + H) + 。

[0886] Example 50: (R)-2-(1-(2-Cyano-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid

[0887]

[0888] The title compound was prepared according to the procedure described for the synthesis of Example 49. LC / MS (ESI) m / z: 476 (M + H) + 。 1 1H NMR (400 MHz, CD3OD) δ 8.17 - 8.14 (d, J = 8.9 Hz, 1H), 7.91 (s, 1H), 7.71 - 7.68 (d, J = 9.0 Hz, 1H), 7.41 - 7.37 (m, 1H), 6.42 - 6.39 (d, J = 9.2 Hz, 1H), 5.54 (s, 2H), 4.30 (s, 3H), 3.77 - 3.65 (m, 2H), 3.02 - 2.96 (m, 1H), 2.81 - 2.74 (m, 1H), 2.46 - 2.39 (m, 3H), 2.27 - 2.24 (m, 2H), 1.99 - 1.81 (m, 3H), 1.59 - 1.46 (m, 3H), 0.89 - 0.85 (m, 3H).

[0889] Example 51: (S)-2-(1-(2-Cyano-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid

[0890]

[0891] The title compound was prepared according to the procedure described for the synthesis of Example 49. LC / MS (ESI) m / z: 476 (M+H) + 。 1 H NMR (400 MHz, CD3OD) δ 8.21 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.39 (dd, J = 9.2, 2.0 Hz, 1H), 6.41 (d, J = 9.2 Hz, 1H), 5.55 (s, 2H), 4.31 (s, 3H), 3.98 - 3.74 (m, 2H), 3.57 - 3.32 (m, 4H), 3.03 - 2.91 (m, 1H), 2.59 - 2.32 (m, 6H), 1.90 - 1.74 (m, 6H), 1.55 - 1.45 (m, 1H), 0.88 (t, J = 7.2, 3H).

[0892] Examples 52 and 53: (R) or (S)-2-(1-(2-Ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetic acid and (S) or (R)-2-(1-(2-Ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetic acid

[0893]

[0894] Step 1: Methyl (4-(6-ethyl-5-iodopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanesulfonate

[0895] To a solution of (4-(6-ethyl-5-iodopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol (1 g, 2.91 mmol) in DCM (10 mL) at 0 °C was added TEA (590 mg, 5.8 mmol), followed by the dropwise addition of MsCl (0.40 g, 3.49 mmol), and the mixture was stirred at 0 °C for 2 h. The mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the title compound as a yellow oil (1.27 g, 103.5% yield), which was used directly in the next step. LC / MS (ESI) m / z: 423 (M+H) + 。

[0896] Step 2: 1-((4-(6-Ethyl-5-iodopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-5-propylpyridin-2(1H)-one

[0897] To a mixture of methyl (4-(6-ethyl-5-iodopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanesulfonate (1.27 g, 3.01 mmol) and 5-propylpyridin-2(1H)-one (0.54 g, 3.91 mmol) in toluene (15 mL) and water (3 mL) was added K2CO3 (1.25 g, 9.02 mmol), TBAF (80 mg, 0.30 mmol), and the mixture was stirred at 100 °C for 16 h. The mixture was diluted with EtOAc (20 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 20:1 to 1:1) to afford the title compound as a yellow solid (1.06 g, 76.1% yield). LC / MS (ESI) m / z: 464 (M+H) + 。

[0898] Step 3: Ethyl (R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetate and Ethyl (S)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetate

[0899] Under a N2 atmosphere, Cs2CO3 (253 mg, 0.78 mmol), N1,N2-dimethylethane-1,2-diamine (2.3 mg, 0.026 mmol), and CuI (9.9 mg, 0.052 mmol) were added to a mixture of 1-((4-(6-ethyl-5-iodopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-5-propylpyridin-2(1H)-one (120 mg, 0.26 mmol) and ethyl 2-(2-oxopiperidin-3-yl)acetate (48 mg, 0.26 mmol) in 1,4-dioxane (3 mL). After the addition, the mixture was degassed three times under a N2 atmosphere and stirred at 110 °C for 16 h under a N2 atmosphere. The mixture was diluted with EtOAc (10 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by chiral SFC to obtain the title compounds as white solids: methyl (R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetate (peak 1, retention time: 6.782 min) (37 mg, yield 27.4%) and ethyl (S)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetate (peak 2, retention time: 7.367 min) (37 mg, yield 27.4%). LC / MS (ESI) m / z: 521 (M+H) + . SFC instrument: Waters Thar80 preparative SFC, column: ChiralPak IA, 250×21.2 mm I.D., 5 μm; mobile phase: A represents CO2 and B represents MeOH + 0.1% NH3H2O, gradient: B 35%, flow rate: 50 mL / min, column temperature: 35 °C, wavelength: 220 nm.

[0900] Step 4: (R)- or (S)-2-(1-(2-Ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetic acid

[0901] To a solution of ethyl (R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetate (37 mg, 0.071 mmol) in THF (2 mL), MeOH (0.5 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (30 mg, 0.71 mmol), and the reaction mixture was stirred at 25 °C for 2 h. The mixture was concentrated to dryness and the residue was dissolved in water. The mixture was washed with EtOAc (2 × 3 mL), and the aqueous layer was acidified to pH = 3 with 1N aqueous HCl and extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (C18, 10 - 95%, H2O containing MeCN with 0.1% HCOOH) to give the title compound as a white solid (14.7 mg, 42.0% yield). LC / MS (ESI) m / z: 493 (M + H) + 。 1 H NMR (400 MHz, CD3OD) δ 8.03 (dd, J = 8.2, 1.9 Hz, 1H), 7.76 - 7.65 (m, 1H), 7.41 (dd, J = 9.3, 2.5 Hz, 1H), 6.55 (d, J = 9.2 Hz, 1H), 5.91 (s, 1H), 4.14 (s, 1H), 3.82 - 3.46 (m, 1H), 2.88 - 2.68 (m, 2H), 2.27 - 2.22 (m, 1H), 2.15 - 1.96 (m, 1H), 1.47 - 1.36 (m, 1H), 1.31 - 1.25 (m, 1H), 0.79 (t, J = 7.2 Hz, 1H).

[0902] Example 53: (S) or (R)-2-(1-(2-Ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetic acid

[0903] The title compound was prepared according to the procedure described for the synthesis of Example 53. LC / MS (ESI) m / z: 493 (M + H) + 。 11H NMR (400 MHz, CD3OD) δ 8.03 (dd, J = 8.3, 1.8 Hz, 1H), 7.77 - 7.64 (m, 2H), 7.41 (dd, J = 9.2, 2.5 Hz, 1H), 6.55 (d, J = 9.2 Hz, 1H), 5.91 (s, 2H), 4.14 (s, 3H), 3.81 - 3.46 (m, 2H), 2.89 - 2.70 (m, 5H), 2.25 (t, J = 7.6 Hz, 2H), 2.16 - 1.93 (m, 4H), 1.47 - 1.37 (m, 2H), 1.31 - 1.25 (m, 3H), 0.79 (t, J = 7.2 Hz, 3H).

[0904] Examples 54 and 55: (R) or (S)-2-(1-(2-Ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-6-oxopiperidin-3-yl)acetic acid and (S) or (R)-2-(1-(2-Ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-6-oxopiperidin-3-yl)acetic acid

[0905]

[0906] Step 1: tert-Butyl 3-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate

[0907] TEA (1.6 mL, 11.7 mmol) was added to a mixture of ethyl 2-(piperidin-3-yl)acetate (1 g, 5.8 mmol) in DCM (25 mL) and di-tert-butyl dicarbonate (1.9 mL, 8.8 mmol) at 0 °C, and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (PE solution containing 0 - 20% EtOAc) to give the title compound as a yellow oil (1.3 g, 82.3% yield). LC-MS (ESI) m / z 272 (M+H) + .

[0908] Step 2: tert-Butyl 5-(2-ethoxy-2-oxoethyl)-2-oxopiperidine-1-carboxylate

[0909] To a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (1.3 g, 4.8 mmol) in EtOAc (10 mL) at 0 °C was added a solution of NaIO4 (5.1 g, 24.0 mmol) in H2O (10 mL), followed by ruthenium(IV) hydrate (70 mg, 0.45 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through a Celite pad, and the cake was washed with EtOAc (2 × 5 mL). The filtrate was washed with saturated aqueous Na2SO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0–30% EtOAc) to give the title compound as a yellow oil (1.1 g, 80.1% yield). LC-MS (ESI) m / z 286 (M+H) + 。

[0910] Step 3: Ethyl 2-(6-oxopiperidin-3-yl)acetate

[0911] To a solution of tert-butyl 5-(2-ethoxy-2-oxoethyl)-2-oxopiperidine-1-carboxylate (1.1 g, 3.9 mmol) in 1,4-dioxane (5 mL) at 0 °C was added HCl / 1,4-dioxane (4.8 mL, 4 M), and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness, and the residue was basified with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (2 × 10 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness to give the title compound as a yellow syrup (640 mg, 89.6% yield). LC-MS (ESI) m / z186 (M+H) + 。

[0912] Step 4: Ethyl (R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-6-oxopiperidin-3-yl)acetate and Ethyl (S)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-6-oxopiperidin-3-yl)acetate

[0913] To a solution of 1-{[4-(6-ethyl-5-iodopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl]methyl}-5-propyl-1,2-dihydropyridin-2-one (250 mg, 0.5 mmol) in 1,4-dioxane (10 mL) was added ethyl 2-(6-oxopiperidin-3-yl)acetate (150 mg, 0.8 mmol), followed by Cs2CO3 (527 mg, 1.6 mmol), CuI (21 mg, 0.11 mmol), and N1,N2-dimethylethane-1,2-diamine (15 mg, 0.11 mmol), and the reaction mixture was stirred at 120 °C for 16 h. The mixture was filtered through a pad of Celite and the cake was washed with EtOAc (10 mL). The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (PE containing 0–50% EtOAc) and further separated by chiral SFC to afford the title compounds as white solids: methyl 2-[(3R)-1-(2-ethyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)-6-oxopiperidin-3-yl]acetate (peak 1, retention time: 4.123 min) (35 mg, 9.2% yield) and methyl 2-[(3S)-1-(2-ethyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)-6-oxopiperidin-3-yl]acetate (peak 2, retention time: 4.669 min) (40 mg, 10.3% yield). LC-MS (ESI) m / z 521 (M+H) + . SFC conditions: column: ChiralPak IA, 250×21.2 mm I.D., 5 μm; mobile phase: A represents CO2 and B represents methanol (0.1% NH4OH); gradient: B 30%; flow rate: 50 mL / min; column temperature: 35 °C.

[0914] Step 5: (R)- or (S)-2-(1-(2-Ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-6-oxopiperidin-3-yl)acetic acid

[0915] To a solution of ethyl 2-[(3R)-1-(2-ethyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)-6-oxopiperidin-3-yl]acetate (35 mg, 0.06 mmol) in THF (4 mL) and MeOH (1 mL) was added H2O (1 mL) containing LiOH (28 mg, 0.7 mmol), and the reaction was stirred at room temperature for 2 h. The mixture was concentrated to dryness and the residue was diluted with water (5 mL) and washed twice with EtOAc (2 × 3 mL). The aqueous layer was acidified to pH ~ 3 with 1N aqueous HCl and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (C18, 0 - 90%, H2O containing acetonitrile with 0.1% formic acid) to afford the title compound as a white solid (7 mg, 21.2% yield). LC-MS (ESI) m / z 493 (M+H) + 。 1 H NMR (400 MHz, CD3OD) δ 8.06–8.03 (m, 1H), 7.78–7.71 (m, 1H), 7.66 - 7.65 (t, J = 2.6 Hz, 1H), 7.442 - 7.29 (dd, J = 9.3, 2.5 Hz, 1H), 6.55 (d, J = 9.3 Hz, 1H), 5.91 (d, J = 1.8 Hz, 2H), 4.15 (s, 3H), 3.87 - 3.41 (m, 2H), 2.81 - 2.67 (m, 3H), 2.62 - 2.49 (m, 1H), 2.45 - 2.43 (m, 2H), 2.35 - 2.32 (m, 1H), 2.26 - 2.22 (t, J = 7.5 Hz, 2H), 2.20 - 2.09 (m, 1H), 1.89 - 1.78 (m, 1H), 1.47 - 1.36 (m, 2H), 1.32 - 1.26 (q, J = 7.6 Hz, 3H), 0.80 - 0.77 (t, J = 7.3 Hz, 3H).

[0916] Example 55: (S) or (R)-2-(1-(2-Ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-6-oxopiperidin-3-yl)acetic acid

[0917] The title compound was prepared according to the procedure described for the synthesis of Example 54. 11H NMR (400 MHz, CD3OD) δ 7.98 - 7.91 (m, 1H), 7.67 - 7.60 (m, 1H), 7.56 (t, J = 2.6 Hz, 1H), 7.34 - 7.27 (m, 1H), 6.45 (d, J = 9.3 Hz, 1H), 5.81 (d, J = 1.7 Hz, 2H), 4.05 (s, 3H), 3.76 - 3.34 (m, 2H), 2.72 - 2.58 (m, 3H), 2.53 - 2.39 (m, 1H), 2.39 - 2.32 (m, 2H), 2.28 - 2.18 (m, 1H), 2.15 (t, J = 7.5 Hz, 2H), 2.06 (d, J = 13.6 Hz, 1H), 1.82 - 1.65 (m, 1H), 1.38 - 1.26 (m, 2H), 1.19 (q, J = 7.6 Hz, 3H), 0.69 (t, J = 7.3 Hz, 3H). LC / MS (ESI) m / z: 493 (M + H) + 。

[0918] Example 56: (R)-2-(5,5-Difluoro-1-(5-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)piperidin-3-yl)acetic acid

[0919]

[0920] Step 1: 3-(5-Bromopyrazin-2-yl)prop-2-yn-1-ol

[0921] Under N2 atmosphere, TEA (2.0 g, 20.18 mmol), CuI (30 mg, 0.14 mmol), Pd(PPh3)2Cl2 (90 mg, 0.14 mmol) were added to a solution of 2,5-dibromopyrazine (1.6 g, 6.73 mmol) and prop-2-yn-1-ol (0.38 g, 6.73 mmol) in MeCN (16 mL). After addition, the mixture was degassed three times under N2 atmosphere and stirred at 25 °C for 16 h. The mixture was diluted with water and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 20:1 to 2:1) to give the title compound as a yellow solid (453 mg, 31.6% yield). LC / MS (ESI) m / z: 213 / 215 (M + H) + 。

[0922] Step 2: (4-(5-Bromopyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

[0923] Under a N2 atmosphere, CuI (20.3 mg, 0.11 mmol) and chloro(pentamethylcyclopentadienyl)bis(triphenylphosphine)ruthenium(II) (84.7 mg, 0.11 mmol) were added to a solution of 3-(5-bromopyrazin-2-yl)prop-2-yn-1-ol (453 mg, 2.13 mmol) and TMSCH2N3 (493.76 mg, 3.83 mmol) in 1,4-dioxane (5 mL). After the addition, the mixture was degassed three times under a N2 atmosphere and stirred at 50 °C for 16 h. The mixture was concentrated to dryness and the residue was dissolved in THF (5 mL). TBAF (1 M in THF, 4.3 mL) was added and the resulting mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 20:1 to 2:1) to give the title compound as a yellow solid (205 mg, 35.7% yield). LC / MS (ESI) m / z: 270 / 272 (M+H) + 。

[0924] Step 3: Methyl (4-(5-bromopyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanesulfonate

[0925] Under a N2 atmosphere at 0 °C, TEA (230.4 mg, 2.28 mmol) and MsCl (104.3 mg, 0.91 mmol) were added to a solution of (4-(5-bromopyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol (205 mg, 0.76 mmol) in DCM (2 mL), and the mixture was stirred at 0 °C for 2 h. The mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the title compound as a yellow solid (295 mg, 111.6% yield), which was used directly in the next step. LC / MS (ESI) m / z: 348 / 350 (M+H) + 。

[0926] Step 4: 1-((4-(5-bromopyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-5-propylpyridin-2(1H)-one

[0927] Under a N2 atmosphere at room temperature, K2CO3 (351 mg, 2.54 mmol) and TBAF (22 mg, 0.085 mmol) were added to a solution of methyl (4-(5-bromopyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanesulfonate (295 mg, 0.85 mmol) and 5-propylpyridin-2(1H)-one (174.3 mg, 1.27 mmol) in toluene (5 mL) and H2O (1 mL), and the mixture was stirred at 100 °C for 16 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluting with PE:EtOAc = 20:1 to 2:1) to afford the title compound 6 as a yellow solid (130 mg, 39.4% yield). LC / MS (ESI) m / z: 389 / 391 (M+H) + 。

[0928] Step 5: Methyl (S)-2-(5,5-difluoro-1-(5-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)piperidin-3-yl)acetate

[0929] Under a N2 atmosphere, Cs2CO3 (49 mg, 0.15 mmol), Ru-Phos Pd G3 (13 mg, 0.015 mmol), and Ru-Phos (7.2 mg, 0.015 mmol) were added to a solution of 1-((4-(5-bromopyrazin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)-5-propylpyridin-2(1H)-one (30 mg, 0.077 mmol) and methyl (S)-2-(5,5-difluoropiperidin-3-yl)acetate (14.9 mg, 0.077 mmol) in 1,4-dioxane (2 mL). After addition, the mixture was degassed three times under a N2 atmosphere and stirred at 110 °C for 16 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford the title compound as a white solid (30 mg, 77.6% yield), which was used directly in the next step. LC / MS (ESI) m / z: 502 (M+H) + 。

[0930] Step 6: (S)-2-(5,5-Difluoro-1-(5-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)piperidin-3-yl)acetic acid

[0931] To a solution of methyl (S)-2-(5,5-difluoro-1-(5-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)piperidin-3-yl)acetate (30 mg, 0.06 mmol) in THF (2 mL), MeOH (0.5 mL) and H2O (0.5 mL) at 25 °C was added LiOH.H2O (25 mg, 0.60 mmol). The reaction was stirred at 25 °C for 2 h. The mixture was concentrated to dryness and the residue was dissolved in water (5 mL). The mixture was washed with EtOAc (2 × 3 mL), and the aqueous layer was acidified to pH = 4 with 1N HCl aqueous solution and extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (C18, 10 - 95%, H2O containing MeCN with 0.1% HCOOH) to give the title compound as a white solid (3.6 mg, 12.3% yield). LC / MS (ESI) m / z: 488 (M+H) + 。 1 1H NMR (400 MHz, CD3OD) δ 8.68 (s, 1H), 8.41 (s, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 12.0, 2.6 Hz, 1H), 6.43 (d, J = 9.6 Hz, 1H), 5.60 (s, 2H), 4.25 (s, 4H), 3.29 - 3.19 (m, 3H), 3.02 - 2.91 (m, 1H), 2.40 - 2.27 (m, 7H), 1.91 - 1.75 (m, 1H), 1.49 - 1.40 (m, 2H), 0.86 - 0.78 (m, 3H).

[0932] Example 57: 2-(1-(5-(1-Methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)piperidin-3-yl)acetic acid

[0933]

[0934] The title compound was prepared according to the procedure described for...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: L 1 is a covalent bond or CH2 optionally substituted with 1 or 2 methyl groups; L 2 is a covalent bond or (CR 7 R 7 ) p ; L 3 is a covalent bond, O or NR 7 , provided that L 2 and L 3 at least one of which is not a covalent bond; Q is C(=O)NR 9 R 10 、C(=O)OR 10 or a ring selected from 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclic groups, wherein said ring comprises at least one carbon atom, at least one nitrogen atom and optionally 1 to 4 additional heteroatoms selected from nitrogen, oxygen and sulfur, wherein oxygen can be a ring member and / or an oxo group attached to a ring member, and wherein said ring is substituted by (R 3 ) n and one R 4 substituted; X 1 is N, O or CR 6a ; X 2 is N or NR 6 ; X 3 is N, NR 6 or CR 6 , where the dashed circle represents a bond forming a five-membered aromatic ring; Y 1 , Y 2 , Y 3 and Y 4 Each independently is N or CR 5 , the condition is that Y 1 , Y 2 , Y 3 and Y 4 At least one but no more than two of them are N; Z is CH2 or O; R 1 is independently, at each occurrence, hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, halo C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b , C 1-6 alkyl-NR a R b or a 4- to 6-membered heterocyclic group, or two R 1 groups together with the carbon atom to which they are attached form C=O; R 2 is (CR 7 R 7 ) q -R 8 ; R 3 is independently, at each occurrence, hydrogen, halogen, CN, C 1-6 alkyl or C 3-7 cycloalkyl; R 4 independently is hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, optionally substituted by 1 to 4 R 11 substituted (CH2) q -5- to 6-membered heteroaryl ring, optionally substituted by 1 to 4 R 11 substituted (CH2) q -5- to 7-membered heterocyclic ring, where each phenyl is independently optionally substituted by 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy; R 5 is, independently at each occurrence, hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, OH, C 1-6 alkyl-OH, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy, halo-C 1-6 alkoxy, CN, C 3-7 cycloalkyl, NR a R b or C 1-6 alkyl-NR a R b ; R 6a and R 6 is, independently at each occurrence, hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl; R 7 is independently, at each occurrence, hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or two R 7 groups together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring; R 8 is C(=O)OR 7 、C(=O)NR a R b 、CN、C(=O)NHC(=O)R 7 、C(=O)NHS(=O)2R 7 、 C(=O)NHS(=O)R 7 、S(=O)2R 7 、P(=O)(OH)2 or R 9 and R 10 is independently, at each occurrence, hydrogen, C 11 alkyl substituted with 1 to 4 R 1-6 groups, (CR 11 R 12 R 12 ) q -C 2-6 alkenyl substituted with 1 to 4 R 11 groups, (CR 12 R 12 ) q -C 2-6 alkynyl substituted with 1 to 4 R 11 groups, (CR 12 R 12 ) q -C 3-7 cycloalkyl substituted with 1 to 4 R 11 groups, (CR 12 R 12 ) q -phenyl substituted with 1 to 4 R 11 groups, (CR 12 R 12 ) q -a 5- to 6-membered heteroaryl ring substituted with 1 to 4 R 11 groups, (CR 12 R 12 ) q -a 5- to 7-membered heterocyclic ring; or R 9 and R 10 together with the nitrogen atom to which they are attached form a saturated or unsaturated 3- to 7-membered heterocycle substituted with 1 to 4 R 11 groups, said ring optionally containing an additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; R 11 is independently, at each occurrence, hydrogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, where each phenyl is independently optionally substituted with 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy; R 12 is independently, at each occurrence, hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, or two R 12 groups together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl ring; R a and R b is independently hydrogen or C 1-6 alkyl each time it appears, or R a and R b together with the nitrogen atom to which it is attached form a saturated or unsaturated heterocyclic ring containing three to seven ring atoms, said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally being substituted by one to three groups which may be the same or different and are selected from the group consisting of C 1-4 alkyl, phenyl and benzyl; m is 1 or 2; n is 0, 1 or 2; p is independently 1, 2, 3 or 4 each time it appears; and q is independently 0, 1, 2, 3 or 4 each time it appears.

2. The compound according to claim 1, wherein Z is CH2.

3. The compound according to claim 1, wherein Z is O.

4. The compound according to any one of claims 1 to 3, wherein L 1 is a covalent bond.

5. A compound according to any one of claims 1 to 3, wherein L 1 is CH2 optionally substituted with 1 or 2 methyl groups.

6. The compound according to any one of claims 1 to 3, wherein L 1 is CH2.

7. A compound according to any one of claims 1 to 3, wherein R 1 is independently hydrogen at each occurrence.

8. A compound according to any one of claims 1 to 3, wherein R 1 is independently halogen at each occurrence.

9. A compound according to any one of claims 1 to 3, wherein m is 2, one R 1 is hydrogen and the other R 1 is halogen.

10. The compound according to any one of claims 1 to 3, wherein m is 2, one R 1 is hydrogen, and the other R 1 is F.

11. The compound according to any one of claims 1 to 3, wherein m is 2 and R 1 is F each time it appears.

12. The compound according to any one of claims 1 to 3, wherein Y 2 is N, and each of Y 1 , Y 3 and Y 4 is independently CR 5 .

13. The compound according to any one of claims 1 to 3, wherein Y 1 is CR 5 , Y 2 is N, and each of Y 3 and Y 4 is independently CH.

14. The compound according to any one of claims 1 to 3, wherein Y 1 is CR 5 , Y 2 is N, Y 3 is N, and Y 4 CH.

15. The compound according to any one of claims 1 to 3, wherein R 5 is independently, in each occurrence, hydrogen, methyl or ethyl.

16. The compound according to any one of claims 1 to 3, wherein R 5 is independently hydrogen, CHF2 or CF3 each time it appears.

17. The compound according to any one of claims 1 to 3, wherein R 5 is independently hydrogen or CN each time it appears.

18. A compound according to any one of claims 1 to 3, wherein X 1 is N, X 2 is N, and X 3 is NR 6 .

19. The compound according to any one of claims 1 to 3, wherein X 1 is CH, X 2 is N, and X 3 is NR 6 .

20. The compound according to any one of claims 1 to 3, wherein X 1 is O, X 2 is N, and X 3 is CR 6 .

21. The compound according to any one of claims 1 to 3, wherein R 6 is methyl.

22. The compound according to any one of claims 1 to 3, wherein L 2 is a covalent bond.

23. The compound according to any one of claims 1 to 3, wherein L 2 is (CR 7 R 7 ) p .

24. The compound according to any one of claims 1 to 3, wherein L 2 is CH2.

25. The compound according to any one of claims 1 to 3, wherein L 3 is a covalent bond.

26. The compound according to any one of claims 1 to 3, wherein L 3 is O.

27. The compound according to any one of claims 1 to 3, wherein L 3 is NR 7 .

28. The compound according to any one of claims 1 to 3, wherein q is 0.

29. The compound according to any one of claims 1 to 3, wherein q is 1.

30. The compound according to any one of claims 1 to 3, wherein q is 2.

31. The compound according to any one of claims 1 to 3, wherein R 8 is COOH.

32. The compound according to any one of claims 1 to 3, wherein R 9 is C 1-4 alkyl.

33. The compound according to any one of claims 1 to 3, wherein R 10 is C 11 alkyl substituted with 1 to 4 R 1-6 , (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkynyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 3-7 cycloalkyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -phenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -a 5- to 6-membered heteroaryl ring, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -a 5- to 7-membered heterocyclic ring.

34. The compound according to any one of claims 1 to 3, wherein R 10 is C 1-6 alkyl.

35. The compound according to any one of claims 1 to 3, wherein R 10 is (CH2) p -C 3-7 cycloalkyl.

36. The compound according to any one of claims 1 to 3, wherein R 9 and R 10 together with the nitrogen atom to which they are attached form a saturated or unsaturated 3- to 7-membered heterocycle substituted with 1 to 4 R 11 , and the ring can optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

37. A compound according to any one of claims 1 to 3, wherein Q is C(=O)NR 9 R 10 .

38. A compound according to any one of claims 1 to 3, wherein Q is a ring selected from a 5-membered heteroaryl or heterocyclic group and a 6-membered heteroaryl or heterocyclic group, wherein the ring comprises at least one carbon atom, at least one nitrogen atom and optionally 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, wherein oxygen may be a ring member and / or a carbonyl group attached to a ring member, and wherein the ring is substituted by (R 3 ) n and R 4 substituted.

39. The compound according to claim 38, wherein Q is: and each of which is substituted at any available carbon or nitrogen position by (R 3 ) n and an R 4 substituent.

40. The compound according to claim 38, wherein Q is: Each of which is substituted at any available carbon or nitrogen position by (R 3 ) n and an R 4 substituent.

41. A compound according to any one of claims 1 to 3, wherein R 3 is independently, in each occurrence, hydrogen, halogen or C 1-4 alkyl.

42. The compound according to any one of claims 1 to 3, wherein R 3 is independently C 1-4 alkyl each time it appears.

43. The compound according to any one of claims 1 to 3, wherein R 3 is independently methyl at each occurrence.

44. A compound according to any one of claims 1 to 3, wherein R 4 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, wherein each phenyl is independently optionally substituted with 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy.

45. A compound according to any one of claims 1 to 3, wherein R 4 is independently (CH2) 11 substituted with 1 to 4 R q -5- to 6-membered heteroaryl ring or (CH2) 11 substituted with 1 to 4 R q -5- to 7-membered heterocyclic ring.

46. A compound according to any one of claims 1 to 3, wherein R 4 is independently C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl or C 2-6 alkenyl-C 3-7 cycloalkyl.

47. The compound according to claim 1, which has the structure of formula (II), wherein: Q is a ring selected from the group consisting of: 5-membered heteroaryl, 5-membered heterocyclic, 6-membered heteroaryl, and 6-membered heterocyclic, wherein said ring includes at least one carbon atom, at least one nitrogen atom, and optionally 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein oxygen can be a ring member and / or an oxo attached to a ring member, and wherein said ring is substituted by (R 3 ) n and one R 4 ; X 1 is N or CR 6a ; R 6a is hydrogen or methyl; R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl or cyclopropyl; R 13 is independently, at each occurrence, hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl; and t is 0, 1, 2 or 3; and w is 0 or 1, provided that when L 1 is a covalent bond, w is 1; and further provided that when L 1 is CH2 optionally substituted with 1 or 2 methyl groups, w is 0.

48. The compound according to claim 47, wherein Z is CH2.

49. The compound according to claim 47, wherein Z is O.

50. A compound according to any one of claims 47 to 49, wherein L 1 is a covalent bond.

51. A compound according to any one of claims 47 to 49, wherein L 1 is CH2 optionally substituted with 1 or 2 methyl groups.

52. The compound according to any one of claims 47 to 49, wherein L 1 is CH2.

53. A compound according to any one of claims 47 to 49, wherein R 1 is independently hydrogen at each occurrence.

54. A compound according to any one of claims 47 to 49, wherein R 1 is independently halogen at each occurrence.

55. A compound according to any one of claims 47 to 49, wherein one R 1 is hydrogen and the other R 1 is halogen.

56. A compound according to any one of claims 47 to 49, wherein one R 1 is hydrogen and the other R 1 is F.

57. A compound according to any one of claims 47 to 49, wherein R 1 is independently F at each occurrence.

58. A compound according to any one of claims 47 to 49, wherein moiety is 59. A compound according to any one of claims 47 to 49, wherein each R 5 is independently hydrogen, halogen, C 1-6 alkyl or halo-C 1-6 alkyl.

60. A compound according to any one of claims 47 to 49, wherein each R 5 is independently C 1-6 alkyl.

61. A compound according to any one of claims 47 to 49, wherein each R 5 is independently methyl or ethyl.

62. A compound according to any one of claims 47 to 49, wherein each R 5 is independently CHF2 or CF3.

63. A compound according to any one of claims 47 to 49, wherein X 1 is N.

64. The compound according to any one of claims 47 to 49, wherein X 1 is CH.

65. A compound according to any one of claims 47 to 49, wherein R 6 is methyl.

66. A compound according to any one of claims 47 to 49, wherein L 2 is (CR 7 R 7 ) p .

67. A compound according to any one of claims 47 to 49, wherein L 2 is CH2.

68. A compound according to any one of claims 47 to 49, wherein L 3 is a covalent bond.

69. A compound according to any one of claims 47 to 49, wherein L 3 is O.

70. A compound according to any one of claims 47 to 49, wherein L 3 is NR 7 .

71. The compound according to any one of claims 47 to 49, wherein Q is: Each of which is substituted at any available carbon or nitrogen position by (R 3 ) n and an R 4 and n is 0, 1 or 2.

72. The compound according to claim 71, wherein Q is substituted at any available carbon or nitrogen position by (R 3 ) n and one R 4 substituted and n is 0, 1 or 2.

73. The compound according to any one of claims 47 to 49, wherein Q is: each of which is substituted at any available carbon or nitrogen position by an (R 3 ) n and an R 4 and n is 0, 1 or 2.

74. A compound according to any one of claims 47 to 49, wherein R 3 is, independently at each occurrence, hydrogen, halogen or C 1-4 alkyl.

75. A compound according to any one of claims 47 to 49, wherein R 3 is independently, at each occurrence, C 1-4 alkyl.

76. A compound according to any one of claims 47 to 49, wherein R 3 is independently methyl at each occurrence.

77. A compound according to any one of claims 47 to 49, wherein R 4 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl, C 2-6 alkenyl-C 3-7 cycloalkyl, C 2-6 alkynyl-C 3-7 cycloalkyl, O(CH2) p -C 3-7 cycloalkyl, wherein each phenyl is independently optionally substituted with 1 to 3 of halogen, C 1-6 alkyl or C 1-6 alkoxy.

78. A compound according to any one of claims 47 to 49, wherein R 4 is independently a (CH2) 11 substituted with 1 to 4 Rs q -5- to 6-membered heteroaryl ring or a (CH2) 11 substituted with 1 to 4 Rs q -5- to 7-membered heterocyclic ring.

79. A compound according to any one of claims 47 to 49, wherein R 4 is independently C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH2) p -C 1-6 alkoxy, C 3-7 cycloalkyl, (CH2) p -C 3-7 cycloalkyl or C 2-6 alkynyl-C 3-7 cycloalkyl.

80. A compound according to any one of claims 47 to 49, wherein is part of 81. A compound according to any one of claims 47 to 49, wherein R 13 is hydrogen.

82. A compound according to any one of claims 47 to 49, wherein R 13 is methyl.

83. A compound according to any one of claims 47 to 49, wherein R 13 is cyclopropyl.

84. The compound according to claim 1, which has the structure of formula (III), wherein: X 1 is N or CR 6a ; R 6a is hydrogen or methyl; R 6 is hydrogen, a halogen, CN, methyl, ethyl, propyl or cyclopropyl; R 13 is independently, at each occurrence, hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl; and t is 0, 1, 2 or 3; and w is 0 or 1, provided that when L 1 is a covalent bond, w is 1, and further provided that when L 1 is CH2 optionally substituted by one or two methyl groups, w is 0.

85. The compound according to claim 84, wherein Z is CH2.

86. The compound according to claim 84, wherein Z is O.

87. A compound according to any one of claims 84 to 86, wherein L 1 is a covalent bond.

88. A compound according to any one of claims 84 to 86, wherein L 1 is CH2 optionally substituted with 1 to 2 methyl groups.

89. A compound according to any one of claims 84 to 86, wherein L 1 is CH2.

90. A compound according to any one of claims 84 to 86, wherein R 1 is independently hydrogen at each occurrence.

91. A compound according to any one of claims 84 to 86, wherein R 1 is independently halogen at each occurrence.

92. A compound according to any one of claims 84 to 86, wherein one R 1 is hydrogen and the other R 1 is halogen.

93. A compound according to any one of claims 84 to 86, wherein one R 1 is hydrogen and the other R 1 is F.

94. A compound according to any one of claims 84 to 86, wherein R 1 is independently F at each occurrence.

95. A compound according to any one of claims 84 to 86, wherein the moiety is 96. A compound according to any one of claims 84 to 86, wherein each R 5 is independently hydrogen, halogen or C 1-6 alkyl.

97. A compound according to any one of claims 84 to 86, wherein each R 5 is independently C 1-6 alkyl.

98. A compound according to any one of claims 84 to 86, wherein each R 5 is independently methyl or ethyl.

99. A compound according to any one of claims 84 to 86, wherein X 1 is N.

100. A compound according to any one of claims 84 to 86, wherein X 1 is CH.

101. A compound according to any one of claims 84 to 86, wherein R 6 is methyl.

102. A compound according to any one of claims 84 to 86, wherein L 2 is (CR 7 R 7 ) p .

103. A compound according to any one of claims 84 to 86, wherein L 2 is CH2.

104. A compound according to any one of claims 84 to 86, wherein L 3 is a covalent bond.

105. A compound according to any one of claims 84 to 86, wherein L 3 is O.

106. A compound according to any one of claims 84 to 86, wherein L 3 is NR 7 .

107. A compound according to any one of claims 84 to 86, wherein R 9 is C 1-4 alkyl.

108. A compound according to any one of claims 84 to 86, wherein R 10 is C 11 alkyl substituted with 1 to 4 R 1-6 , (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 2-6 alkynyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -C 3-7 cycloalkyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -phenyl, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -a 5- to 6-membered heteroaryl ring, (CR 11 substituted with 1 to 4 R 12 R 12 ) q -a 5- to 7-membered heterocyclic ring.

109. A compound according to any one of claims 84 to 86, wherein R 10 is C 1-6 alkyl.

110. A compound according to any one of claims 84 to 86, wherein R 10 is (CH2) q -C 3-7 cycloalkyl.

111. A compound according to any one of claims 84 to 86, wherein R 9 and R 10 together with the nitrogen atom to which they are attached form a saturated or unsaturated 3- to 7-membered heterocycle substituted with 1 to 4 R 11 and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

112. A compound according to any one of claims 84 to 86, wherein is part of 113. A compound according to any one of claims 84 to 86, wherein R 13 is hydrogen.

114. A compound according to any one of claims 84 to 86, wherein R 13 is methyl.

115. A compound according to any one of claims 84 to 86, wherein R 13 is cyclopropyl.

116. The compound according to claim 1, which is selected from:

117. The compound according to claim 1, which is selected from:

118. The compound according to claim 1, which is selected from:

119. The compound according to claim 1, which is selected from:

120. A pharmaceutical composition comprising the compound according to any one of claims 1 to 119 and a pharmaceutically acceptable carrier.

121. Use of the compound according to any one of claims 1 to 119 in the preparation of a drug for the treatment or prevention of a disease associated with an imbalance of lysophosphatidic acid receptor 1 (LPAi), wherein the disease is pulmonary fibrosis, liver fibrosis or kidney fibrosis.

122. The use according to claim 121, wherein the disease is idiopathic pulmonary fibrosis.

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