Novel substituted bicyclic azaheterocycles as sos1 inhibitors

Abstract

The present application relates to novel substituted bicyclic azaheterocycles and analogs, their preparation, pharmaceutical compositions comprising the novel substituted bicyclic azaheterocycles and analogs, and the use of the novel substituted bicyclic azaheterocycles and analogs as medicaments for the treatment of diseases associated with the RAS (Rat Sarcoma Virus) family of proteins in mammals.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to PCT International Application No. PCT / CN2021 / 078596, filed on March 2, 2021, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to novel substituted bicyclic azaheterocyclic compounds and analogues, their preparation, pharmaceutical compositions comprising said novel substituted bicyclic azaheterocyclic compounds and analogues, and the use of said novel substituted bicyclic azaheterocyclic compounds and analogues as pharmaceuticals for treating diseases associated with mammalian RAS (rat sarcoma virus) family proteins. Background Technology

[0004] RAS (rat sarcoma virus) proteins belong to the small GTPase superfamily and act as "binary switches" in cell signal transduction. For example, in... Figure 1 As described in *Biomark Cancer*, 2016; 8(Supplement 1): 27-35., the RAS protein exerts its function through the GDP / GTP cycle (nucleotide exchange cycle). GEF (guanine nucleotide exchange factor) stimulates GDP / GTP exchange, leading to the formation of the RAS-GTP complex, which interacts with and activates downstream effector pathways. Since the cellular concentration of GTP is much higher than GDP (up to 10 times higher), as a net result, active RAS-GTP is in the RAS-on state. Conversely, GAP (GTPase activator protein) enhances GTP hydrolysis, leading to the formation of the RAS-GDP complex, which cannot bind to downstream effectors, resulting in the RAS-off or inactive state. Mutations in the RAS gene promote the formation of the RAS-GTP complex, and the apparent "active state" promotes tumor cell proliferation and survival; however, due to altered tumor metabolism and drug resistance, it leads to poor prognosis in several cancer types.

[0005] The RAS gene encodes four highly homologous RAS proteins (83% to 85% amino acid sequence identity): HRAS (Harvey rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), KRAS4A (Kirsten rat sarcoma toxic oncogene homolog 4A), and KRAS4B [Cell. June 29, 2017; 170(1):17-33; Sci. Signal. 2020, 13, eaay 6013]. Since the discovery of the mutated activated human RAS gene as an important oncogene, mutations in KRAS, HRAS, and NRAS have been associated with poor prognosis in various forms of human cancer [RAShistory, Small GTPases, 2010, 1:1, 2-27, DOI:10.4161 / sgtp.1.1.12178]. To date, activating mutations in the RAS protein have been found in approximately 24% of all cancers, with KRAS mutations being a major driver in 90% of pancreatic ductal adenocarcinoma (PDAC), 43% of colorectal cancer (CRC), and 26% of non-small cell carcinoma (NSCLC), thereby affecting pathways involved in cell proliferation, differentiation, and apoptosis [Cell, 29 June 2017; 170(1):17-33; Oncogene, 37(18):2444-2455]. Due to the high cellular concentration of GTP and the small / shallow binding pocket in the RAS-GTP complex, competitive inhibition of GTP binding sites through direct targeting in the discovery and development of RAS inhibitors (specifically KRAS inhibitors) as antitumor agents has not yet yielded results. The RAS signaling pathway is associated with multiple upstream promoters (such as RTK, receptor tyrosine kinases), downstream effectors, and binding chaperones (chaperone proteins). For example, in... Figure 2As shown in the figure [Oncotarget 2014 Sep 15; 5(17):7285-302; Science Signal Transduction 2020, 13, eaay6013], SOS (Son of Seven, GEF) plays a key role in converting RAS-GDP (off) to RAS-GTP (on), thus activating downstream effector pathways RAF / MEK / ERK and / or PI3K / AKT / mTOR and promoting tumor cell proliferation and survival [Oncotarget 2014 Sep 15; 5(17):7285-302; Cell 2017 June 29; 170(1):17-33]. Therefore, various stages of RAS:SOS interaction and / or RAS signaling have been explored to identify tumor vulnerability to therapeutic interventions for various RAS mutation-driven cancers [Biochemical Journal (2019) 476 365–374; Science Signal Transduction 2020 March 24; 13(624):eaay 6013].

[0006] SOS1 (SOS1 homolog) is the most studied GEF involved in RAS signaling. RAS:SOS1 interactions, specifically KRAS:SOS1 interactions, have been explored as key vulnerabilities in KRAS mutation-driven cancers. It has been shown that SOS1-mediated cross-activation of oncogenic RAS is essential for tumorigenesis, and that the absence of SOS1 reduces the proliferation and survival of tumor cells carrying KRAS mutations [Nature Communications 2012; 3:1168. doi:10.1038 / ncomms 2173.]. The study also showed that the RAS:SOS1 interaction can be disrupted / inhibited by small molecules, as illustrated by BAY-293 and BI-2852 [Proceedings of the National Academy of Sciences of the United States of America, February 12, 2019; 116(7):2551-2560; Proceedings of the National Academy of Sciences of the United States of America, August 6, 2019; 116(32):15823-15829]. BAY-293, a selective inhibitor of the KRAS:SOS1 interaction, prevents the formation of the KRAS:SOS1 complex and blocks the reloading of KRAS with GTP, thereby producing antiproliferative activity [Proceedings of the National Academy of Sciences of the United States of America, February 12, 2019; 116(7):2551-2560]. In contrast, BI-2852, a KRAS inhibitor, binds with nanomolar affinity to the pocket between switches I and II on the RAS, blocking all interactions of GEF, GAP, and effectors with KRAS, thereby inhibiting downstream signaling and antiproliferative effects. This suggests that the RAS switch I / II pocket can be treated with small molecules [Proceedings of the National Academy of Sciences, August 6, 2019; 116(32):15823-15829]. These findings clearly demonstrate the important role of SOS1 as a GEF in KRAS-mutant cancers, and that the KRAS:SOS1 interaction in RAS signaling can serve as a target for therapeutic intervention.

[0007] Besides cancer, abnormal activity of the RAS protein is associated with a variety of diseases commonly referred to as RAS diseases [J Hum Genet. 2016 Jan; 61(1):33-9.]. In contrast to cancers driven by RAS mutations, RAS diseases are a group of clinical syndromes caused by hyperactivation of the RAS / MAPK pathway [Cell 2017 6J; 170(1):17-33.]. There is evidence that somatic mutations in the RAS and SOS genes play an important role in the pathogenesis of these developmental disorders, including neurofibromatosis type 1, Noonan syndrome, Noonan multiple slow sperm syndrome, Costello syndrome, cardiofaciocutaneous syndrome, and capillary malformation arteriovenous syndrome [Annals of Oncology 2020 3M; S0923-7534(20)36378-X.]. Therefore, RAS:SOS inhibitors can be used not only to treat RAS mutation-driven cancers but also to treat RAS diseases caused by abnormal RAS signaling activity. Furthermore, a recent study showed that knocking down KRAS expression with antisense oligonucleotides reduced fibrosis by 50% and prevented loss of kidney function in a mouse model of chronic folate nephropathy [Scientific Reports, September 30, 2019; 9(1):14010], demonstrating that targeting KRAS expression and activity can be used to treat fibrosis-related kidney dysfunction. Summary of the Invention

[0008] The present invention provides novel RAS:SOS (e.g., KRAS:SOS1) small molecule inhibitors that disrupt the interaction between RAS and SOS and prevent the activation of RAS proteins, specifically KRAS. Inhibition of RAS:SOS (e.g., KRAS:SOS1) complex formation results in significant inhibition of downstream effector pathways, leading to a significant reduction in the proliferation and survival of RAS or KRAS mutation-driven cancers. The described RAS:SOS (e.g., KRAS:SOS1) inhibitors can be used to treat various RAS mutation-driven cancers, including PDAC, NSCLC, CRC, and RAS diseases. Furthermore, the small molecule compounds disclosed herein exhibit favorable pharmaceutical properties including solubility, ADME (absorption, distribution, metabolism, and excretion), pharmacokinetics, CYP inhibition, and other safety characteristics. Finally, RAS:SOS (e.g., KRAS:SOS1) inhibitors can be combined with upstream RTK or SHP2 and downstream RAF, MEK, ERK, PI3K, AKT, or mTOR inhibitory pathways to achieve better antitumor efficacy.

[0009] On the one hand, the technology of the present invention relates to a compound of formula (I)-(IV),

[0010]

[0011]

[0012] Or its pharmaceutically acceptable salts, tautomers, or stereoisomers.

[0013] in:

[0014] Q is independently selected from phenyl or 5- or 6-membered heteroaryl rings each time it appears, wherein the heteroaryl ring comprises at least one carbon atom and 1 to 4 additional heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0015] X is CH or N;

[0016] R 1 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, OH, C 1-6 Alkyl-OH, Halogenated C 1-6 Alkyl-OH, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, C 3-7 cycloalkyl, C 3-7 cycloalkyl-OH, C 3-7 Cycloalkoxy groups, -S(O) t -C 1-6 Alkyl group, -S(O) t -NR a R b , phenyl or 3-7 membered heterocyclic group, wherein the phenyl and the 3-7 membered heterocyclic group are optionally substituted by 1-4 independent substituents selected from the following C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl groups -OH, OH, halogens, CN, -S(O) t -C 1-6 Alkyl group, -S(O) t -NR a R b -NR a R b and C 1-4 Alkyl-NRa R b ; or two adjacent R 1 The group, together with the carbon atom it is attached to, forms a 5-7 membered carbon ring or heterocycle, optionally substituted by 1-3 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b C 1-4 Alkyl-NR a R b And oxy groups (=O);

[0017] R 2 Each time it appears, it is independently hydrogen, halogen, CN, or -OR. a -NR a R b C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl groups, the halogenated C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkenyl, the C 3-7 Each of the cycloalkyl group, the 3-7 membered heterocyclic group, the phenyl group, and the 5-6 membered heteroaryl group is optionally surrounded by 1-5 R groups. 8 replace;

[0018] R 3 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-OH, CN, C 3-7 cycloalkyl, C 3-7 cycloalkyl-OH, C 3-7 Cycloalkoxy, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl) 2- or 3-7 membered cyclic amines;

[0019] R 4 Each time it appears, it is independently hydrogen, halogen, or carbon.1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, NH2, C 3-7 cycloalkyl or C 3-7 Cycloalkoxy;

[0020] R 5 Each time it appears, it is independently hydrogen and C. 1-4 Alkyl or halogenated C 1-4 alkyl;

[0021] R 6 Each time it appears, it is independently hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 3-7 cycloalkyl;

[0022] R 8 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-7 cycloalkyl, C 3-7 Cycloalkoxy, 3-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -OR a -SR a S(O) t R a -S(O) t NR a R b -OC(O)-R a -NR a R b -C(O)R a -C(O)OR a -OC(O)NR a R b 2. -C(O)NR a R b -N(R) a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)NR a R b -N(R) a )C(NR a )NR a R b -N(R) aS(O) t NR a R b -P(=O)(R a (R) b -OP(=O)(OR) a (OR) b ) or oxo group (=O);

[0023] R a and R b Each time it appears, it is independently hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 1-6 Alkyl-NH2, C 1-6 Alkyl-NHC 1-4 Alkyl, C 1-6 Alkyl-N(C) 1-4 Alkyl)2 or C 1-6 Alkyl-(3-7 membered cyclic amine); wherein each of the aforementioned groups may optionally be substituted by one to three independent substituents selected from the group consisting of: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, halogen, OH, NH2, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, CN and -C(O)C 1-4 Alkyl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a saturated or unsaturated heterocycle containing three to seven ring atoms, said ring optionally containing one or two additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally one to three independently selected from carbon. 1-4 Alkyl, -C(O)C 1-4 Substituents in the group consisting of alkyl, phenyl, and benzyl groups;

[0024] n is independently 1, 2, or 3 each time it appears; and

[0025] t is 1 or 2 independently each time it appears.

[0026] The present invention also relates to pharmaceutical compositions comprising compounds of formulas (I)-(IV), their preparation, and their use as medicines for treating or preventing diseases or symptoms mediated by mammalian Ras family proteins. Therefore, compounds of formulas (I)-(IV) can be used to treat or prevent cancers including: breast cancer, leukemia, prostate cancer, ovarian cancer, pancreatic cancer, colon cancer, lung cancer, endometrial cancer, thyroid cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, hepatocellular carcinoma, glioblastoma, renal cancer, sarcoma, bladder cancer, urothelial carcinoma, gastric cancer, or cervical cancer. Therefore, compounds of formulas (I)-(IV) can be used to treat or prevent RAS diseases. Attached Figure Description

[0027] Figure 1 This diagram illustrates how the RAS protein functions through the GDP / GTP cycle (nucleotide exchange cycle), resulting in RAS-GDP (off) and RAS-GTP (on) states. Mutations in the RAS gene that promote the latter can drive tumor cell proliferation and survival.

[0028] Figure 2 This schematically demonstrates how SOS (Son of the Seven, GEF) plays a crucial role in converting RAS-GDP (off) to RAS-GTP (on), thereby activating downstream effector pathways RAF / MEK / ERK and / or PI3K / AKT / mTOR and promoting tumor cell proliferation and survival. Detailed Implementation

[0029] 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.

[0030] On the other hand, the technology of the present invention provides methods for treating and / or controlling various diseases and conditions, said methods comprising administering to a patient a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable form thereof (e.g., salt, hydrate, solvate, isomer, stereoisomer, enantiomer, prodrug, and isotopically labeled derivative). Non-limiting examples of diseases and conditions are described herein.

[0031] On the other hand, the technology of the present invention provides methods for preventing various diseases and conditions, the methods comprising administering to a patient requiring such prevention a preventatively effective amount of the compound provided herein or a pharmaceutically acceptable form thereof (e.g., salt, hydrate, solvate, isomer, stereoisomer, prodrug, and isotopically labeled derivative). Non-limiting examples of diseases and conditions are described herein.

[0032] On the other hand, the compounds provided herein or their pharmaceutically acceptable forms (e.g., salts, hydrates, solvates, isomers, stereoisomers, prodrugs, and isotopically labeled derivatives) may be administered in combination with another drug (“second activator”) or a treatment. Second activators comprise small molecules and large molecules (e.g., proteins and antibodies).

[0033] This document 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 the compounds provided herein or pharmaceutically acceptable forms thereof (e.g., salts, hydrates, solvates, isomers, stereoisomers, prodrugs, and isotopically labeled derivatives), and optionally one or more second active agents.

[0034] While specific embodiments have been discussed, this specification is illustrative and not restrictive. Many variations of this disclosure will become apparent to those skilled in the art upon reading this specification.

[0035] 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 pertains.

[0036] definition

[0037] As used in the specification and claims, the singular forms “a / an” and “the” include plural objects unless the context clearly indicates otherwise.

[0038] As used herein, “pharmaceutical,” “bioactive agent,” or “secondary active agent” refers to a biological, pharmaceutical, or chemical compound or part thereof. 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) as well as synthetic organic compounds based on various core structures. Additionally, various natural sources can provide active compounds, such as plant or animal extracts. Those skilled in the art will readily recognize that there are no limitations on the structural properties of the pharmaceutical agents of this disclosure.

[0039] "Administration" of the disclosed compounds encompasses the delivery to a subject of the compound described herein or its prodrug or other pharmaceutically acceptable derivative using any suitable formulation or route of administration as discussed herein.

[0040] As used herein, the terms “co-administration,” “combination administration,” and their grammatical equivalents cover the administration of 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 as an independent composition, administration as an independent composition at independent times, or administration as a composition in which two agents are present simultaneously.

[0041] The term "effective amount" or "therapeutic effective amount" refers to the amount of a compound or pharmaceutical composition described herein that is sufficient to affect the intended application (including, but not limited to, the treatment of a disease), as shown below. In some embodiments, the amount is an effective amount for detectable inhibition of SOS1, which may be determined, for example, in a KRAS:SOS1 binding assay. Therapeutic effective amounts can vary depending on the intended application (in vitro or in vivo) or the treated subject and condition (e.g., subject's weight and age, severity of the condition, method of administration, etc.) that can be readily determined by a person skilled in the art. The term also applies to doses that will induce a response in target cells, such as reduced cell migration. The specific dose will vary depending on, for example, the compound selected, the species of the subject and their age / pre-existing health condition or health risk, the dosing regimen followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system on which it is carried.

[0042] Unless otherwise stated in this document or clearly contradicted by the context, all methods described herein may be performed in any suitable order.

[0043] As used herein, the terms “treatment,” “treating,” “mitigation,” “control,” and “improvement” are used interchangeably. These terms refer to methods of achieving a beneficial or desired outcome, including, but not limited to, therapeutic and / or preventive benefits. A “therapeutic benefit” means the eradication or improvement of the underlying condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition, resulting in an observed improvement in the patient, although the patient may still have the underlying condition. For preventive benefits, pharmaceutical compounds and / or compositions may be administered to patients at risk of developing the disease, or to patients who report one or more physiological symptoms of the disease, even if the disease has not yet been diagnosed.

[0044] As used herein, the terms “preventing” and “prophylaxis” refer to the administration of a drug compound or drug, or a composition containing a drug compound or drug, to a subject before the disease, condition, or symptom fully manifests itself, in order to prevent the occurrence and / or reduce the severity of one or more symptoms of the disease, condition, or symptom. Those skilled in the art will recognize that the term “preventing” is not an absolute term. In the medical field, “prevention” should be understood as the prophylactic administration of a drug to reduce the likelihood or severity of a disease, condition, or symptom, or its symptoms, and this is the meaning of the use of such terms in this disclosure.

[0045] As used herein, the term "therapeutic effect" encompasses the therapeutic and / or preventive benefits described above. Preventive effects include delaying or eliminating the onset of a disease or symptom, delaying or eliminating the onset of symptoms of a disease or symptom, slowing, stopping, or reversing the progression of a disease or symptom, or any combination thereof.

[0046] The “subjects” to be considered for administration include, but are not limited to, humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged or elderly)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats and / or dogs; and / or poultry, including commercially relevant poultry such as chickens, ducks, geese, quails and / or turkeys.

[0047] The term "in vivo" refers to events that occur within the body of a subject. In vivo also includes events that occur in rodents such as rats, mice, and guinea pigs.

[0048] The term "in vitro" refers to an event that occurs outside the subject's body. For example, in vitro assays encompass any assay performed outside the subject's body. In vitro assays include cell-based assays, in which live or dead cells are used. In vitro assays also include cell-free assays, in which intact cells are not used.

[0049] As used herein, the term "pharmaceutically acceptable salt" means that salts suitable for contact with a subject's tissues within the bounds of reasonable medical judgment without excessive toxicity, irritation, allergic response, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. described pharmaceutically acceptable salts in detail in the *Journal of Pharmaceutical Sciences* (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds presented herein include those derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (such as ion exchange). For example, pharmaceutically acceptable salts include adipic acid salts, alginate salts, ascorbate salts, aspartate salts, benzenesulfonate salts, besylate salts, benzoate salts, hydrogen sulfate salts, borate salts, butyrate salts, camphorate salts, camphor sulfonate salts, citrate salts, cyclopentanepropionate salts, diglucuronate salts, dodecyl sulfate salts, ethanesulfonate salts, formate salts, fumarate salts, glucohepanoate salts, glycerophosphate salts, glucuronate salts, hemisulfate salts, heptanate salts, and caproic acid salts. Salts, hydroiodates, 2-hydroxyethanesulfonates, lacturonates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pyrates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, neopentanoates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. In some embodiments, organic acids from which 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.

[0050] Salts can be prepared in situ or separately during the isolation and purification of the disclosed compounds, 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 suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N2 salts. + (C 1-4 alkyl) 4Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Pharmaceutically acceptable salts also include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. 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, pharmaceutically acceptable base addition salts may be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0051] As used herein, the term "solvent" refers to a compound that further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. A 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 may contain, for example, 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, as well as mixtures thereof.

[0052] 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. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, through hydrolysis (e.g., hydrolysis in the blood). In some cases, a prodrug has improved physical and / or delivery properties compared to the parent compound. Administering a prodrug to a subject may increase the bioavailability of the compound (e.g., by allowing enhanced absorption into the bloodstream 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 comprise derivatives of the disclosed compound that have enhanced water solubility or active transport via the intestinal membrane relative to the parent compound.

[0053] Prodrug compounds often offer advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14; and “Bioreversible Carriers in Drug Design,” ed. Edward B. Roche, American Pharmaceutical Association and Pergamon. A discussion of prodrugs is provided in the Press (1987), both of which are incorporated herein by reference in their entirety. Exemplary advantages of prodrugs may include, but are not limited to, their physical properties, such as enhanced water solubility at physiological pH when administered parenterally compared to the parent compound, or their ability to enhance absorption from the digestive tract, or their ability to enhance the stability of the drug during long-term storage.

[0054] The term "prodrug" is also intended to include any covalently bonded carrier that, when administered to an animal subject, releases the active compound in vivo. Prodrugs of the active compounds described herein can be prepared by modifying functional groups present in the active compound in such a manner that the modified compound cleaves to the parent active compound under normal handling or in vivo. Prodrugs comprise compounds in which a hydroxyl, amino, or thiol group is bonded to any group that, when administered to a subject, cleaves to form a free hydroxyl, free amino, or free thiol group. Examples of prodrugs include, but are not limited to, acetates, formates, and benzoates of alcohols or acetamides in the active compound, and formamide and benzamide derivatives with amine functional groups. Other examples of prodrugs include compounds comprising -NO, -NO2, -ONO, or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described in Burger's *Medicinal Chemistry and Drug Discovery*, 172-178, 949-982 (edited by Manfred E. Wolff, 5th edition, 1995) and *Prodrug Design* (edited by H. Bundgaard, Elselvier, New York, 1985).

[0055] For example, if the disclosed compound or a pharmaceutically acceptable form of the compound contains a carboxylic acid functional group, the prodrug may comprise 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 Alkyloxymethyl, 1-(alkoxyoxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkoxyoxy)-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-phthaloyl, 4-crotonic acid lactone, 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 )alkylcarbamoyl-(C 1-2 )alkyl and piperidin-, pyrrolidine-, or morpholino (C 2-3 )alkyl.

[0056] Similarly, if the disclosed compound contains an alcohol functional group, the prodrug can be formed by replacing the hydrogen atom of the alcohol group with groups such as the following: (C 1-6 )alkyl oxymethyl, 1-((C 1-6 )alkylyloxy)ethyl, 1-methyl-1-((C 1-6 )alkylyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 )alkoxycarbonylaminomethyl, succinoyl, (C 1-6 ) alkyl acyl group, α-amino (C 1-4 ) alkyl acyl, aryl acyl and α-amino acyl or α-amino acyl-α-amino acyl, wherein each α-amino acyl is independently selected from naturally occurring L-amino acids, -P(O)(OH)2, -P(O)(O(C 1-6 Alkyl groups or glycosyl groups (free radicals generated by removing the hydroxyl groups of hemiacetal carbohydrates).

[0057] If the disclosed compound incorporates an amine functional group, the prodrug can be formed by replacing the hydrogen atom in the amine group with groups such as R-carbonyl, RO-carbonyl, and NRR'-carbonyl, where R and R' are each independently selected from (C 1–10 )alkyl, (C3-7 )cycloalkyl, benzyl, native α-aminoacyl or native α-aminoacyl-native-α-aminoacyl, -C(OH)C(O)OY 1 , where Y 1 It is H, (C 1-6 )alkyl or benzyl, -C(OY 2 )Y 3 , where Y 2 Yes (C) 1-4 )alkyl, and Y 3 Yes (C) 1-6 )alkyl, carboxyl (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 , where Y 4 It is H or methyl, and Y 5 It is mono-N- or di-N-(C16)alkylamino, morpholino, piperidin-1-yl, or pyrrolidine-1-yl.

[0058] In some embodiments, the disclosed compounds may encompass isomers. An "isomer" is a different compound having the same molecular formula. A "stereoisomer" is an isomer that differs only in the spatial arrangement of its atoms. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomers" include geometric double-bonded cis and trans isomers, also known as E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure.

[0059] Geometric isomers can be identified by symbols The symbols indicated herein represent bonds that can be single, double, or triple bonds as described herein. This document provides various geometric isomers and mixtures thereof resulting from substituent arrangements around a carbon-carbon double bond or around a carbon ring. Substituents around the 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 stated, the structures depicting the double bond encompass both the “E” and “Z” isomers.

[0060] Substituents around carbon-carbon double bonds can alternatively be referred to as "cis" or "trans," where "cis" indicates a substituent on the same side of the double bond and "trans" indicates a substituent on opposite sides of the double bond. The arrangement of substituents around a carbon cyclic ring can also be specified as "cis" or "trans." The term "cis" indicates a substituent on the same side of the ring plane and "trans" indicates a substituent on opposite sides of the ring plane. Mixtures of compounds in which substituents are arranged on both sides of the ring plane are specified as "cis / trans."

[0061] An enantiomer is a pair of stereoisomers that are not mirror images of each other. A mixture of a pair of enantiomers in any proportion may be called a racemic mixture. The term "(±)" is used to denote racemic mixtures where appropriate. A diastereomer is a stereoisomer having at least two asymmetric atoms but not being mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is an enantiomer, the stereochemistry at each chiral carbon may be specified by R or S. Resolved compounds with unknown absolute configuration may be specified as (+) or (-) depending on the direction of their rotation of plane-polarized light at the sodium D line wavelength (dextrorotatory or levorotatory). Some of the compounds described herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomers defined as (R)- or (S)- based on 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 intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0062] In some embodiments, the provided enantiomer portion is substantially free of the corresponding enantiomer and may be referred to as “optically enriched,” “enantiomer-rich,” “enantiomer-pure,” and “non-racemic,” as used interchangeably herein. The “enantiomer excess” or “enantiomer excess %” of the compound can be calculated using the equation shown below. In the examples shown below, the composition contains one enantiomer, for example 90% of the S enantiomer, and another enantiomer, for example 10% of the R enantiomer.

[0063] ee = (90-10) / 100 = 80%.

[0064] Therefore, a composition containing 90% of one enantiomer and 10% of another enantiomer is referred to as having an 80% enantiomer excess. In some embodiments, the compositions described herein contain an S enantiomer excess 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 and including any two of the foregoing values ​​(e.g., 50-99.5%ee). In other words, the composition contains an S enantiomer excess relative to the R enantiomer. In other embodiments, some compositions described herein contain an enantiomer excess of the following R enantiomers: 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 contains an enantiomer excess of the R enantiomer relative to the S enantiomer. When the enrichment of one enantiomer is much greater than about 80% by weight, the composition is referred to as a “substantially enantiomer-enriched,” “substantially enantiomer-pure,” or “substantially non-racemic” formulation.

[0065] Therefore, a composition containing 90% of one enantiomer and 10% of another enantiomer is referred to as having an 80% enantiomer excess. In some embodiments, the compositions described herein contain an S enantiomer excess 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 and including any two of the foregoing values ​​(e.g., 50-99.5%ee). In other words, the composition contains an S enantiomer excess relative to the R enantiomer. In other embodiments, some compositions described herein contain an enantiomer excess of the following R enantiomers: 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 contains an enantiomer excess of the R enantiomer relative to the S enantiomer. When the enrichment of one enantiomer is much greater than about 80% by weight, the composition is referred to as a “substantially enantiomer-enriched,” “substantially enantiomer-pure,” or “substantially non-racemic” formulation.

[0066] Optical isomers can be obtained by resolving racemic mixtures using conventional methods, such as by forming diastereomer salts or by treatment with optically active acids or bases. Examples of suitable acids include, but are not limited to, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, benzoyltartaric acid, and camphorsulfonic acid. The isomers are separated by crystallization of the mixture of diastereomers, followed by the release of an optically active base from these salts. Another method involves synthesizing covalent diastereomer molecules by reacting the disclosed compound 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, followed by hydrolysis to provide an enantiomer-enriched compound. Optically active compounds can also be obtained by using active starting materials. In some embodiments, these isomers can be in the form of free acids, free bases, esters, or salts.

[0067] In any embodiment, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" is an isomer of a type comprising two or more interconvertible compounds, produced by at least one formal hydrogen atom migration and at least one valence change (e.g., single to double, triple to single, or vice versa). "Tautomerization" includes proton heterogeneity or proton shift tautomerization, which is considered a subset of acid-base chemistry. "Proton heterogeneity tautomerization" or "proton shift 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. Tautomer chemical equilibrium can be reached where tautomerization may occur (e.g., in solution). Tautomerization (i.e., the reaction that provides tautomer pairs) can be catalyzed by acid or base, or can occur without the action or presence of external reagents. Exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactam; enamine-imide; and enamine-(different)enamine tautomerizations. Specific examples of keto-enol tautomerization are the interconversions of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. Specific examples of phenol-keto tautomerization are the interconversions of pyridine-4-ol and pyridine-4(1H)-keto tautomers.

[0068] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, those having hydrogen replaced by deuterium or tritium, or those with... 13 C or 14 Compounds of the present invention with C-enriched carbon replacing carbon other than carbon are within the scope of this disclosure.

[0069] This disclosure also includes pharmaceutically acceptable forms of "isotopically labeled derivatives," wherein the isotopically labeled derivatives are the same compounds as those described herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may 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 36 Cl. Disclosed compounds labeled with certain isotopes (e.g., using...) 3 H and 14 C-labeled compounds can be used for the determination of compound and / or substrate tissue distribution. Tritized isotopes (i.e., 3 H) and carbon-14 isotopes (i.e., ... 14 C) It can be easily prepared and detected. Furthermore, heavier isotopes (such as deuterium, i.e., 2 H) Substitution can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement). Disclosed isotopically labeled compounds can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents. In some embodiments, compounds are provided herein that may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. All isotopic variations (whether radioactive or non-radioactive) of the compounds disclosed herein are covered within the scope of this disclosure. In some embodiments, radiolabeled compounds can be used to study the metabolism and / or tissue distribution of the compound or to alter metabolic rates or pathways or other aspects of biological function.

[0070] "Pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption retardants. Pharmaceutically acceptable carriers or excipients do not impair the pharmacological activity of the disclosed compound and are non-toxic when administered in doses sufficient to deliver a therapeutic 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 should be considered. Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered astragalus; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; and Ringer's solution. (solution); ethanol; phosphate buffer solutions; non-toxic and compatible lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coating agents; sweeteners, flavorings and aromas; preservatives; antioxidants; ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS) such as d-tocopherol polyethylene glycol 1000 succinate; surfactants used in drug dosage forms such as Tween or other similar polymer delivery matrices; serum proteins such as human serum albumin; glycine; sorbic acid; potassium sorbate; mixtures of metaglycerides 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 substances; polyacrylates; waxes; and polyethylene-polyoxypropylene-block polymers. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins (including 2- and 3-hydroxypropyl-cyclodextrins) or other soluble derivatives can also be used to enhance the delivery of the compounds described herein.

[0071] The following section describes in more detail the definitions of specific functional groups and chemical terms. 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 in this article. In addition, the general principles of organic chemistry, as well as specific functional components and reactivity, are described in the following literature: *Organic Chemistry*, Thomas Sorrell, University Science Books, Sansalito, 1999; *March's Advanced Organic Chemistry*, 5th ed., John Wiley & Sons, Inc., New York, 2001; *Comprehensive Organic Transformations*, Larock, VCH Publishers, Inc., New York, 1989; and *Some Modern Methods of Organic Synthesis*, 3rd ed., Cambridge University Press, Cambridge, 1987.

[0072] Unless otherwise indicated herein, the description of value ranges herein serves only as a shorthand for each individual value and subrange belonging to the range, and each individual value and subrange is incorporated into this specification as if described separately herein. For example, "C 1-6 "Alkyl" will be understood 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 5-6Alkyl. Similarly, 1-4 substituents will be understood to encompass 1, 2, 3, 4, 1-2, 1-3, 1-4, 2-3, 2-4 or 3-4 substituents.

[0073] "alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, wherein the straight-chain or branched hydrocarbon chain group is unsaturated and has one to ten carbon atoms (e.g., C64 ... 1-10 Alkyl group. When used herein, numerical ranges such as “1 to 10” refer to each integer within a given range; for example, “1 to 10 carbon atoms” means that an alkyl group can consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, but the definition of this invention also covers the occurrence of the term “alkyl” without a specified numerical range. In some embodiments, an 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 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, etc. Alkyl groups are linked to the parent molecule by single bonds. Unless otherwise stated in the specification, alkyl groups may optionally be substituted with one or more substituents disclosed herein. In non-limiting embodiments, the substituted alkyl group may be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0074] "Alkenyl" refers to a group consisting only of carbon and hydrogen atoms, containing at least one double bond, and having two to ten carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C7 ... 2-10 An alkenyl group is a straight-chain or branched hydrocarbon chain group. Whenever it appears herein, numerical ranges such as “2 to 10” refer to each integer within a given range; for example, “2 to 10 carbon atoms” means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., and at most and contain 10 carbon atoms. In any embodiment, the alkenyl group comprises two to eight carbon atoms. In other embodiments, the alkenyl group comprises two to six carbon atoms (e.g., C64 ... 2-6 Alkenyl groups are connected to the parent molecule via single bonds. Examples include ethenyl (i.e., vinyl), propyl-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. One or more carbon-carbon double bonds can be located internally (e.g., in a 2-butenyl group) or terminally (e.g., in a 1-butenyl group). 2-4Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), 2-methylprop-2-enyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the C group mentioned above. 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and 2,3-dimethyl-2-butenyl (C6). Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), and octetrinyl (C8). Unless otherwise specified in the specification, alkenyl groups may optionally be substituted with one or more of the substituents disclosed herein.

[0075] "Alkyne" refers to a group consisting only of carbon and hydrogen atoms, containing at least one triple bond, and having two to ten carbon atoms (i.e., C2H2O). 2-10 A straight-chain or branched hydrocarbon chain group (alkynyl). Whenever it appears herein, numerical ranges such as "2 to 10" refer to each integer within a given range; for example, "2 to 10 carbon atoms" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., and at most and contain 10 carbon atoms. In any embodiment, the alkynyl group comprises two to eight carbon atoms. In other embodiments, the alkynyl group has two to six carbon atoms (e.g., C64 ... 2-6 (Alynyl group). The alkynyl group is linked to the parent molecule structure via a single bond, for example, ethynyl, propynyl, butynyl, pentyynyl, 3-methyl-4-pentynyl, hexynyl, etc. Unless otherwise stated in the specification, the alkynyl group may optionally be substituted with one or more of the substituents disclosed herein.

[0076] "Alkoxy" refers to an -O-alkyl group comprising 1 to 10 straight-chain, branched, saturated cyclic carbon atoms and combinations thereof connected to the parent molecule via oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, cyclopropoxy, cyclohexyloxy, etc. "Lower alkoxy" refers to an alkoxy group containing one to six carbon atoms. In some embodiments, C 1-4 An alkoxy group is an alkoxy group comprising both straight-chain and branched alkyl groups having 1 to 4 carbon atoms. Unless otherwise stated in the specification, an alkoxy group may optionally be substituted with one or more substituents disclosed herein. The terms “alkenoxy” and “alkynoxy” are very similar to the above description of “alkoxy”, wherein the prefix “alkane” is replaced by “alken” or “alkyn” respectively, and the parent terms “alkenyl” or “alkynyl” are as described herein.

[0077] "Aromatic" or "aryl" refers to a group having 6 to 14 ring atoms (e.g., C14, C24, C34, C44, C54, C6 ... 6-14Aromatic or C614 aryl), the group having at least one ring having a carbocyclic conjugated π-electron system (e.g., phenyl, fluorenyl, and naphthyl). In some embodiments, the aryl group is C614 aryl. 6-10 Aryl groups. 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 group. In other embodiments, divalent groups derived from monovalent polycyclic hydrocarbon groups whose names end in "-" are named by removing a hydrogen atom from a carbon atom having a free valence, and are named by adding "idene" to the name of the corresponding monovalent group. For example, a naphthyl group with two connection points is called a naphthylene group. Whenever it appears herein, numerical ranges such as "6 to 14 aryl groups" refer to each integer within a given range; for example, "6 to 14 ring atoms" means that an aryl group can consist of 6 ring atoms, 7 ring atoms, etc., up to and including 14 ring atoms. The term encompasses monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent ring atom pairs) groups. Polycyclic aromatic groups include bicyclic, tricyclic, tetracyclic, etc. In polycyclic groups, only one ring needs to be aromatic; therefore, groups such as indanyl are covered in the definition of aryl. Non-limiting examples of aryl groups include phenyl, benzenatyl, naphthyl, tetrahydronaphthyl, phenanthryl, anthraceneyl, fluorenyl, indolyl, indenyl, etc. Unless otherwise stated in the specification, aryl groups may optionally be substituted with one or more substituents disclosed herein.

[0078] "Cycloalkyl" and "carbocyclic" refer to monocyclic or polycyclic free radicals containing only carbon and hydrogen, and can be saturated or partially unsaturated. A partially unsaturated cycloalkyl group can be called a "cycloalkenyl" if the carbide ring contains at least one double bond, or a partially unsaturated cycloalkyl group can be called a "cycloynyl" if the carbide ring contains at least one triple bond. Cycloalkyl groups comprise groups having 3 to 13 ring atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-13 (Cycloalkyl). Whenever it appears herein, numerical ranges such as “3 to 10” refer to each integer within a given range; for example, “3 to 13 carbon atoms” means that a cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., and at most and contain 13 carbon atoms. The term “cycloalkyl” also includes bridged and spirofused cyclic structures that do not contain heteroatoms. The term also includes monocyclic or fused polycyclic (i.e., rings sharing adjacent ring atom pairs) groups. Polycyclic aromatic groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, “cycloalkyl” can be C 3-8 Cycloalkyl. In some embodiments, "cycloalkyl" can be C 3-5 Cycloalkyl groups. Illustrative examples of cycloalkyl groups include, but are not limited to, the following portions: C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6).3-7 Examples of carbocyclic groups include norbornyl (C7). 3-8 Examples of carbocyclic groups include the aforementioned C 3-7 Carbocyclic groups, as well as cycloheptyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, etc. 3-13 Examples of carbocyclic groups include the C mentioned above. 3-8 Carbocyclic groups, as well as octahydro-1H indenyl, decahydronaphthyl, spiro[4.5]decyl, etc. Unless otherwise stated in the specification, cycloalkyl groups may optionally be substituted with one or more substituents disclosed herein. The terms “cycloalkenyl” and “cycloynyl” are very similar to the above description of “cycloalkyl”, wherein the prefix “alkane” is replaced by “alken” or “ynyne” respectively, and the parent terms “alkenyl” or “ynyne” are as described herein. For example, a cycloalkenyl group may have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloynyl group may have 5 to 13 ring atoms.

[0079] The terms “halogenated,” “halide,” or alternatively “halogen” refer to fluorine, chlorine, bromine, or iodine. The terms “halogenated alkyl,” “halogenated alkenyl,” “halogenated alkynyl,” and “halogenated alkoxy” comprise an alkyl, alkenyl, alkynyl, or alkoxy structure substituted with one or more halogen groups or combinations thereof, preferably substituted with one, two, or three halogen groups. For example, the terms “fluoroalkyl” and “fluoroalkoxy” comprise halogenated alkyl and halogenated alkoxy, respectively, wherein the halogen is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, -O-CHF2, etc. Each of the alkyl, alkenyl, alkynyl, and alkoxy groups is as defined herein and may optionally be further substituted as defined herein.

[0080] "Heteroaryl" or alternatively "heteroaromatic" refers to a group having a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) of one or more ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-18 membered heteroaryl"). A heteroaryl polycyclic system may contain one or more heteroatoms in one or two rings. Whenever it appears herein, numerical ranges such as "5 to 18" refer to each integer within a given range; for example, "5 to 18 ring atoms" means that a heteroaryl can consist of 5 ring atoms, 6 ring atoms, etc., and at most contain 18 ring atoms. In some instances, a heteroaryl can have 5 to 14 ring atoms. In some embodiments, a heteroaryl group has a divalent group derived from a monovalent heteroaryl group whose name ends with "-" by removing a hydrogen atom from an atom having a free valence, the divalent group being named by adding "-ene" to the name of the corresponding monovalent group. For example, a pyridyl group with two connection points is a pyridine group.

[0081] For example, the N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. One or more heteroatoms in the heteroaryl group may optionally be oxidized. One or more nitrogen atoms (if present) may also optionally be quaternized. Heteroaryl groups also comprise ring systems substituted with one or more oxynitride (-O-) substituents, such as pyridyl N-oxide. The heteroaryl group is linked to the parent molecular structure through any atom of the ring.

[0082] "Heteroaryl" also includes a ring system in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the connection point to the parent molecule is on the aryl group or on the heteroaryl ring, or in which a heteroaryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point to the parent molecule is on the heteroaryl ring. For polycyclic heteroaryl, one ring does not contain a heteroatom (e.g., indole, quinolinyl, carbazolyl, etc.), and the connection point to the parent molecule can be on either ring, i.e., a ring with a heteroatom (e.g., 2-indole) or a ring without a heteroatom (e.g., 5-indole). In some embodiments, a heteroaryl is a 5- to 10-membered aromatic ring system having one or more ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur (“5-6 membered heteroaryl”). In some embodiments, a 5-6 membered heteroaryl group has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0083] Examples of heteroaryl groups include, but are not limited to, azacyclic, acridine, benzimidazolyl, benzoindolyl, 1,3-benzo[1,4]dioxazinyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxane, benzonaphthofuranyl, benzooxazolyl, benzo[1,4]dioxazinyl, benzo[2,4]dioxazinyl, benzo[3,2-d]pyrimidinyl, benzo[4,6]imidazolyl [1,2-a]pyridyl, carbazolyl, cyclopenten[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenten[4,5]thiophene[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazoline, 5,6-dihydrobenzo[h]cyrinyl, 6,7-dihydro-5Hbenzo[6,7]cycloheptane[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiopheneyl, furanyl, furazolidyl, furanoneyl, furano[3,2-c]pyridyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d] Pyridyl, isothiazolyl, imidazolyl, indazole, indole, indazole, isoindole, indole, isoindole, isoquinolinyl, indoleazinyl, isoxazolyl, 5,8-methanol-5,6,7,8-tetrahydroquinazolinyl, naphridyl, 1,6-naphridinone, oxadiazolyl, 2-oxoazonyl heterocyclic, oxazolyl, ethylene oxide, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenthiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purine, pyranyl, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl The following groups are included: pyrazinyl, pyrimidinyl, pyridazinyl, pyrroloyl, 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-cycloheptane[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyridin[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 (i.e., thienoyl). Unless otherwise stated in the specification, the heteroaryl group may optionally be substituted with one or more of the substituents disclosed herein.

[0084] The terms “heterocyclic group,” “heterocyclic alkyl group,” or “heterocyclic carbocyclic group” each refer to any 3- to 18-membered non-aromatic monocyclic or polycyclic moiety comprising at least one carbon atom and at least one heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. Heterocyclic groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, wherein polycyclic ring systems can be fused rings, bridged rings, or spirocyclic systems. Heterocyclic polycyclic systems may contain one or more heteroatoms in one or two rings. Heterocyclic groups can be saturated or partially unsaturated. If a heterocyclic group contains at least one double bond, a partially unsaturated heterocyclic alkyl group may be referred to as a “heterocyclic alkenyl group,” or if a heterocyclic group contains at least one triple bond, a partially unsaturated heterocyclic alkyl group may be referred to as a “heterocyclic ynyl group.” Whenever used herein, numerical ranges such as “5 to 18” refer to each integer within a given range; for example, “5 to 18 ring atoms” means that a heterocyclic group may consist of 5 ring atoms, 6 ring atoms, etc., and at most and contain 18 ring atoms. For example, a divalent group derived from a monovalent heterocyclic group whose name ends with "-" is named by removing a hydrogen atom from an atom with a free valence, and named by adding "-ene" to the name of the corresponding monovalent group. For example, a piperidinyl group with two connection points is a piperidinyl group.

[0085] A nitrogen-containing heterocyclic moiety is a non-aromatic group in which at least one ring atom is a nitrogen atom. The heteroatoms in the heterocyclic moiety may optionally be oxidized. One or more nitrogen atoms (if present) may optionally be quaternized. The heterocyclic moiety also comprises a ring system substituted with one or more oxynitride (-O-) substituents, such as piperidinyl N-oxide. The heterocyclic moiety is linked to the parent molecular structure through any atom of any ring within the ring.

[0086] "Heterocyclic group" also includes ring systems in which a heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic group or the heterocyclic ring or the ring system, wherein the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point with the parent molecular structure is on the heterocyclic ring. In some embodiments, a heterocyclic group is a 5-14 membered nonaromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-14 membered heterocyclic group"). In some embodiments, a heterocyclic group is a 3-10 membered nonaromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("3-10 membered heterocyclic group"). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0087] A "heterocyclic group" may contain one or more ketone groups (-C(=O)-) as part of a ring. Examples of ketone-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-imidazolidin-2-one, 2,4-dihydro-3H-1,2,4-triazol-3-one, oxazol-2(3H)-one, and oxazollidin-2-one. A ketone-containing heterocyclic group can be obtained by removing a hydrogen atom from its corresponding ketone-containing heterocycle at any available NH or CH position.

[0088] 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, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-diketone. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxopentyl, oxothiophenyl, tetrahydrothiazolyl, and dithiophenyl. 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, dihydropyridinyl, and thiocyclohexyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, thiomorpholinyl, dithiaalkyl, dioxaneyl, 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, indole, isoindole, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, benzoxyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, benzothianyl, tetrahydroindole, 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, phenanthridine, indole, and phthalimide. Naphthalimide, benzodihydropyranyl, benzothiophene, 1H-benzo[e][1,4]diazapyridyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrole, 5,6-dihydro-4H-furano[3,2-b]pyrrole, 6,7-dihydro-5H-furano[3,2-b]pyranyl, 5,7-dihydro-4H-thiopheno[2,3-c]pyran The compounds include 2,3-dihydro-1H-pyrrolo[2,3-b]pyridyl, hydrofuranolo[2,3-b]pyridyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridyl, 4,5,6,7-tetrahydrofuranolo[3,2-c]pyridyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridyl, and 1,2,3,4-tetrahydro-1,6-naphthidyl.

[0089] Unless otherwise stated in the specification, the heterocyclic group may optionally be substituted with one or more of the substituents disclosed herein.

[0090] When a substituent is specified by its conventional chemical formula (written from left to right), it equally covers the chemically identical substituents produced when the structure is written from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0091] "Leaving group or atom" is any group or atom that, under reaction conditions, will cleave the starting material to facilitate a reaction at a specific site. Unless otherwise stated, suitable non-limiting examples of such groups include halogen atoms, methanesulfonyloxy, p-nitrobenzenesulfonyloxy, trifluoromethoxy, and toluenesulfonyloxy.

[0092] The term "protecting group" has the meaning commonly associated with organic synthesis: a group that selectively blocks one or more reactive sites in a polyfunctional compound, allowing a chemical reaction to selectively occur at another unprotected reactive site, and enabling the group to be easily removed after the selective reaction is complete. Non-limiting examples of functional groups that can be masked by protecting groups include amines, hydroxyl groups, thiols, carboxylic acids, and aldehydes. For example, hydroxyl protection is the protection of at least one hydroxyl group present in a compound by a hydroxyl protecting group. Various protecting groups are disclosed, for example, in 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, Complex Organic Transformations, VCH Publishing (1989); Green's Organic Synthesis, 5th Edition, Willy Publishing (2014); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Willy & Sons (1994); and L. Paquette (ed.), Encyclopedia of Reagents for Organic Synthesis, John Willy & Sons (1995). These references are incorporated herein by reference in their entirety.

[0093] The terms “substituted” or “substituted” mean that at least one hydrogen atom present on a group atom (e.g., carbon or nitrogen atom) is substituted by a permissible substituent, such as a substituent that, when substituted, produces a stable compound, for example, a compound that does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, or other reactions. Unless otherwise stated, a “substituted” group may have substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents may be the same or different at each position. Substituents comprise one or more groups individually and independently selected from the following: acyl, alkyl, alkenyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidine, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphonite, silyl, sulfinyl, sulfonyl, sulfonamide, hyposulfite, 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 -OP(=O)(OR a )2, where each R aIndependently, these are hydrogen, alkyl, haloalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties (except hydrogen) may optionally be substituted by one or more substituents selected from the following (up to six, depending on valence): OH, NH2, oxo, halogen, nitro, COOH, C(O)NH2, or cyano. For example, cycloalkyl substituents may have halides substituted at one or more ring carbons, etc. Protecting groups that can form protective derivatives of the above-mentioned substituents are known to those skilled in the art and can be found in references such as Greene and Wuts above.

[0094] Suitable substituents include, but are not limited to, haloalkyl and trihaloalkyl, alkoxyalkyl, halophenyl, -M-heteroaryl, -M-heterocyclic, -M-aryl, and -M-OR. a -M-SR a -MN(R) a )2、-M-OC(O)N(R a )2、-MC(=NR a )N(R a )2、-MC(=NR a OR a -MP(O)(R a )2、Si(R a )3、-M-NR a C(O)R a -M-NR a C(O)OR a -MC(O)R a -MC(=S)R a -MC(=S)NR a R a -MC(O)N(R) a )2、-MC(O)NR a -MN(R a )2、-M-NR a C(NR a )N(R a )2、-M-NR a C(S)N(R a )2、-MS(O)2R a -MC(O)R a -M-OC(O)R a -MC(O)SR a -MS(O)2N(R) a )2、-C(O)-MC(O)R a -MCO2R a-MC(=O)N(R) a )2、-MC(=NH)N(R a )2 and -M-OC(=NH)N(R a )2 (where M is C) 1-6 alkyl).

[0095] When a ring system (e.g., cycloalkyl, heterocyclic, aryl, or heteroaryl) is substituted with several substituents varying within a well-defined range, it should be understood that the total number of substituents does not exceed the normal usable valence under existing conditions. Thus, for example, a phenyl ring substituted with a "p" substituent (where "p" ranges from 0 to 5) can have 0 to 5 substituents, while it should be understood that a pyridyl ring substituted with a "p" substituent has several substituents ranging from 0 to 4. The maximum number of substituents that a group in a disclosed compound can have can be readily determined. Substituted groups only encompass combinations of substituents and variations that produce stable or chemically viable compounds. A stable or chemically viable compound is one that, among other things, possesses stability sufficient to allow its preparation and detection. In some embodiments, the disclosed compounds are stable enough that when kept at 40°C or lower under conditions of no 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 reactions for at least, for example, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 4 weeks, or at least about 6 weeks, the compounds do not undergo substantial changes.

[0096] The term "combine, combining, to combine, combination" refers to the act of adding at least one chemical substance sequentially or simultaneously to another chemical substance. In some embodiments, combining these chemicals may result in the initial chemical substance being transformed into one or more different chemical substances. This transformation can occur through one or more chemical reactions, such as covalent bond formation, breaking, rearrangement, etc. A non-limiting example may include the hydrolysis of esters into alcohols and carboxylic acids, which can be produced by combining esters with suitable bases. In another non-limiting example, aryl fluorides may combine with amines to provide aryl amines through a substitution process. These terms also include changes in the association of charged chemical substances and the production of charged chemical substances, such as, but not limited to, N-oxide formation, acid addition salt formation, base addition salt formation, etc. These terms include the production and / or transformation of free radical chemical substances and isotopically labeled chemical substances.

[0097] The term "converting" refers to a subset of "combinations" and its syntactic equivalents, in which the action of one or more agents transforms one or more functional groups on a chemical substance into another functional group. For example, conversion includes, but is not limited to, the conversion of a nitro functional group on a chemical substance into an amine using a reducing agent. Conversion also includes changes in charged chemicals, free radical chemicals, and isotopically labeled chemicals. However, the term "conversion" does not include changes in conserved bonds within the disclosed genus and compounds.

[0098] compound

[0099] On the one hand, the technology of the present invention relates to a compound of formula (I)-(IV),

[0100]

[0101] Or its pharmaceutically acceptable salts, tautomers, or stereoisomers.

[0102] in:

[0103] Q is independently selected from phenyl or 5- or 6-membered heteroaryl rings each time it appears, wherein the heteroaryl ring comprises at least one carbon atom and 1 to 4 additional heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0104] X is CH or N;

[0105] R 1 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl, -NR a R b OH, C 1-6 Alkyl-OH, Halogenated C 1-6 Alkyl-OH, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, C 3-7 cycloalkyl, C 3-7 cycloalkyl-OH, C 3-7 Cycloalkoxy groups, -S(O) t -C 1-6 Alkyl group, -S(O) t -NR a R b , phenyl or 3-7 membered heterocyclic group, wherein the phenyl and the 3-7 membered heterocyclic group are optionally substituted by 1-4 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl groups -OH, OH, halogens, CN, -S(O) t -C 1-6 Alkyl group, -S(O) t -NR a R b -NR a R b and C 1-4 Alkyl-NR a R b ; or two adjacent R 1 The group, together with the carbon atom it is attached to, forms a 5-7 membered carbon ring or heterocycle, optionally substituted by 1-3 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b C 1-4 Alkyl-NR a R b And oxy groups (=O);

[0106] R 2 Each time it appears, it is independently hydrogen, halogen, CN, or -OR. a -NR a R b C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl groups, the halogenated C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkenyl, the C 3-7 Each of the cycloalkyl group, the 3-7 membered heterocyclic group, the phenyl group, and the 5-6 membered heteroaryl group is optionally surrounded by 1-5 R groups. 8 replace;

[0107] R 3 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-OH, CN, C 3-7 cycloalkyl, C 3-7 cycloalkyl-OH, C 3-7 Cycloalkoxy, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl) 2- or 3-7 membered cyclic amines;

[0108] R 4 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, NH2, C 3-7 cycloalkyl or C 3-7 Cycloalkoxy;

[0109] R 5 Each time it appears, it is independently hydrogen and C. 1-4 Alkyl or halogenated C 1-4 alkyl;

[0110] R 6 Each time it appears, it is independently hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 3-7 cycloalkyl;

[0111] R 8 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-7 cycloalkyl, C 3-7 Cycloalkoxy, 3-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -OR a -SR a S(O) t R a -S(O) t NR a R b -OC(O)-R a -NR a R b -C(O)R a -C(O)OR a -OC(O)NR a R b 2. -C(O)NR aR b -N(R) a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)NR a R b -N(R) a )C(NR a )NR a R b -N(R) a S(O) t NR a R b -P(=O)(R a (R) b -OP(=O)(OR) a (OR) b ) or oxo group (=O);

[0112] R a and R b Each time it appears, it is independently hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 1-6 Alkyl-NH2, C 1-6 Alkyl-NHC 1-4 Alkyl, C 1-6 Alkyl-N(C) 1-4 Alkyl)2 or C 1-6 Alkyl-(3-7 membered cyclic amine); wherein each of the aforementioned groups may optionally be substituted by one to three substituents that are the same as or different from the substituents selected from the group consisting of: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, halogen, OH, NH2, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, CN and -C(O)C 1-4 Alkyl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a saturated or unsaturated heterocycle containing three to seven ring atoms, said ring optionally containing one or two additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally one to three independently selected from carbon. 1-4 Alkyl, -C(O)C 1-4 Substituents in the group consisting of alkyl, phenyl, and benzyl groups;

[0113] n is independently 1, 2, or 3 each time it appears; and

[0114] t is 1 or 2 independently each time it appears.

[0115] In some embodiments, the technology of the present invention relates to compounds of formula (I):

[0116]

[0117] Or its pharmaceutically acceptable salts, tautomers or stereoisomers, wherein Q, R 1 R 2 R 4 R 8 R a R b n and t are each as defined above, or may have any of the values ​​disclosed herein.

[0118] In some embodiments, the technology of the present invention relates to compounds of formula (II):

[0119]

[0120] Or its pharmaceutically acceptable salts, tautomers, or stereoisomers.

[0121] Among them, Q and R 1 R 2 R 4 R 5 R 8 R a R b n and t are each as defined above, or may have any of the values ​​disclosed herein.

[0122] In some embodiments, the technology of the present invention relates to compounds of formula (III):

[0123]

[0124] Or its pharmaceutically acceptable salts, tautomers, or stereoisomers.

[0125] Among them, Q, X, R 1 R 2 R 3 R 4 R 8 R a R b n and t are each as defined above, or may have any of the values ​​disclosed herein.

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

[0127]

[0128] Or its pharmaceutically acceptable salts, tautomers, or stereoisomers.

[0129] Among them, Q and R 1 R 2 R 5 R 6 R 8 R a R b n and t are each as defined above, or may have any of the values ​​disclosed herein.

[0130] In any embodiment of the compounds of the present invention (including, but not limited to, compounds of formulas I, II, III, and IV), Q is phenyl in each occurrence. In some embodiments, Q is independently a 5-membered heteroaryl in each occurrence. In some embodiments, Q is independently a 6-membered heteroaryl in each occurrence. In some embodiments, Q is phenylthio in each occurrence. In some embodiments, Q is pyridyl in each occurrence.

[0131] In any embodiment of the compounds of the present invention, R 1 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, OH, C 1-6 Alkyl-OH, Halogenated C 1-6 Alkyl-OH, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, C 3-7 cycloalkyl, C 3-7 cycloalkyl-OH, C 3-7 Cycloalkoxy or -S(O) t -C 1-6 Alkyl group. In some embodiments, R 1 Each time it appears, it is independently a phenyl or a 3-7 membered heterocyclic group, wherein the phenyl and the 3-7 membered heterocyclic group are optionally substituted by 1-4 substituents independently selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl groups -OH, OH, halogens, CN, -S(O) t -C 1-6 Alkyl group, -S(O) t -NRa R b -NR a R b and C 1-4 Alkyl-NR a R b In some embodiments, two adjacent R 1 Each time the group appears, it forms a 5-7 membered carbon ring or heterocycle with the carbon atom it is attached to, optionally substituted by 1-3 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b C 1-4 Alkyl-NR a R b and oxo groups (=O). In some embodiments, two adjacent R groups 1 Each time the group appears, it forms a 5-6 membered carbon ring with the carbon atom it is attached to, optionally substituted by 1-3 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b C 1-4 Alkyl-NR a R b and oxo groups (=O). In some embodiments, two adjacent R groups 1 Each time the group appears, it forms a 5-6 membered heterocycle with the carbon atom it is attached to, optionally substituted by 1-3 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b C 1-4 Alkyl-NR a R b And oxo groups (=O).

[0132] In any embodiment of the compounds disclosed herein, Q is related to its substituent (R). 1 ) n , It has independent characteristics each time it appears. The structure, wherein:

[0133] R 1a Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, OH, C 1-6 Alkyl-OH, Halogenated C 1-6 Alkyl-OH, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, C 3-7 cycloalkyl, C 3-7 cycloalkyl-OH, C 3-7 Cycloalkoxy groups, -S(O) t -C 1-6 Alkyl group, -S(O) t -NR a R b Or a 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is optionally substituted by 1-4 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl groups -OH, OH, halogens, CN, -S(O) t -C 1-6 Alkyl group, -S(O) t -NR a R b -NR a R b and C 1-4 Alkyl-NR a R b ;

[0134] R 1b Each time it appears, it is independently hydrogen, halogen, or carbon. 1-4 Alkyl or C 3-6 cycloalkyl;

[0135] Or R 1a and R 1b Each time it appears, it forms a 5-7 membered carbon ring or heterocycle with the carbon atom it is attached to, optionally substituted by 1-3 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b C 1-4 Alkyl-NR a R b and oxo groups (=O); and

[0136] R 1c Each time it appears, it is independently hydrogen, halogen, NH2, or C. 1-4 alkyl.

[0137] In some embodiments, the compound of formula (I) comprises the compound of formula (Ia),

[0138]

[0139] Where R 1a R 1b R 1c R 2 and R 4 Each as defined above, or may have any value disclosed herein, including but not limited to R as defined herein. a R b R 8 and t groups.

[0140] In some embodiments, the compound of formula (II) comprises the compound of formula (IIa).

[0141]

[0142] Where R 1a R 1b R 1c R 2 R 4 and R 5 Each as defined above, or may have any value disclosed herein, including but not limited to R as defined herein. a R b R 8 and t groups.

[0143] In some embodiments, the compound of formula (III) comprises the compound of formula (IIIa).

[0144]

[0145] Where R1a R 1b R 1c R 2 R 3 and R 5 Each as defined above, or may have any value disclosed herein, including but not limited to R as defined herein. a R b R 8 and t groups.

[0146] In some embodiments, the compound of formula (IV) comprises the compound of formula (IVa).

[0147]

[0148] Where R 1a R 1b R 1c R 2 R 5 and R 6 Each as defined above, or may have any value disclosed herein, including but not limited to R as defined herein. a R b R 8 and t groups.

[0149] In any embodiment, R 1a Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, OH, C 1-6 Alkyl-OH, Halogenated C 1-6 Alkyl-OH, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, C 3-7 cycloalkyl, C 3-7 cycloalkyl-OH, C 3-7 Cycloalkoxy or -S(O) t -C 1-6 Alkyl group. In some embodiments, R 1a Each time it appears, it is independently and optionally substituted by 1-4 substituents selected independently from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl groups -OH, OH, halogens, CN, -S(O)t -C 1-6 Alkyl group, -S(O) t -NR a R b -NR a R b and C 1-4 Alkyl-NR a R b In some embodiments, R 1a Each occurrence is independently CHF2, CH2F, CF3, CF2CH3, or CF2CH2OH. In some embodiments, R 1a and R 1b Each time it appears, it forms a 5- or 6-membered carbon ring with the carbon atom it is attached to, optionally substituted with 1-3 halogens. In some embodiments, R 1a and R 1b Each time it appears, it forms a structure together with the carbon atom it is attached to, possessing... The structure of carbon rings.

[0150] In any embodiment, R 1b It is hydrogen independently each time it appears. In some embodiments, R 1b It is a halogen, occurring independently each time. In some embodiments, R 1b It is C independently each time it appears. 1-4 Alkyl group. In some embodiments, R 1b Each time it appears, it is independently either F or methyl.

[0151] In any embodiment, R 1c It is hydrogen independently each time it appears. In some embodiments, R 1c It is a halogen, occurring independently each time. In some embodiments, R 1c It is NH2 independently each time it appears. In some embodiments, R 1c It is C independently each time it appears. 1-4 alkyl.

[0152] In any embodiment, Q and its substituent (R) 1 ) n , It has independent characteristics each time it appears. The structure, wherein:

[0153] R 1d and R 1e Each time it appears, it is independently hydrogen, halogen, or carbon. 1-4 Alkyl or halogenated C 1-4 Alkyl; and R 1fEach time it appears, it is independently a phenyl, a 5-6-membered heteroaryl, or a 3-7-membered heterocyclic group, wherein the phenyl, the 5-6-membered heteroaryl, and the 3-7-membered heterocyclic group are optionally substituted by 1-4 substituents independently selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b and C 1-4 Alkyl-NR a R b .

[0154] In some embodiments, the compound of formula (I) comprises the compound of formula (Ib).

[0155]

[0156] Where R 1d R 1e R 1f R 2 and R 4 Each as defined above, or may have any value disclosed herein, including but not limited to R as defined herein. a R b R 8 and t groups.

[0157] In some embodiments, the compound of formula (II) comprises the compound of formula (IIb).

[0158]

[0159] Where R 1d R 1e R 1f R 2 R 4 and R 5 Each as defined above, or may have any value disclosed herein, including but not limited to R as defined herein. a R b R 8 and t groups.

[0160] In some embodiments, the compound of formula (III) comprises the compound of formula (IIIb).

[0161]

[0162] Where R 1d R 1e R 1r R 2 R 3 and R 5 Each as defined above, or may have any value disclosed herein, including but not limited to R as defined herein. a R b R 8 and t groups.

[0163] In some embodiments, the compound of formula (IV) comprises the compound of formula (IVb).

[0164]

[0165] Where R 1d R 1e R 1f R 2 R 5 and R 6 Each as defined above, or may have any value disclosed herein, including but not limited to R as defined herein. a R b R 8 and t groups.

[0166] In any embodiment, R 1d and R 1e It is either hydrogen or methyl each time it appears. In some embodiments, R 1d and R 1e It is hydrogen each time it appears.

[0167] In any embodiment, R 1f Each time it appears, it is independently, optionally, a phenyl group substituted with 1 to 4 substituents independently selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b and C 1-4 Alkyl-NR a R b In some embodiments, R 1f Each time it appears, it is independently and arbitrarily C. 1-4 Alkyl-NR a R bSubstituted phenyl groups. In some embodiments, R 1f Each time it appears, it is independently and arbitrarily C. 1-4 Alkyl-NH-C 1-4 Alkyl-substituted phenyl. In some embodiments, R 1f Each time it appears, it is independently and arbitrarily C. 1-3 Alkyl-NH-C 1-3 Alkyl-substituted phenyl. In some embodiments, R 1f Each time it appears, it is independently and arbitrarily C. 1-2 Alkyl-NH-C 1-2 Alkyl-substituted phenyl. In some embodiments, R 1f Each time it appears, it is independently and arbitrarily C. 1-2 Alkyl-N(C) 1-2 alkyl)-C 1-2 Alkyl-substituted phenyl groups.

[0168] In any embodiment, R 2 Each time it appears, it is independently hydrogen, halogen, CN, or -OR. a -NR a R b C 1- 6-alkyl or halogenated C 1-6 Alkyl, wherein the C 1-6 Alkyl groups and the halo-C 1-6 Each of the alkyl groups is optionally surrounded by 1-5 R groups. 8 Replacement. In some embodiments, R 2 Each time it appears, it is independently and optionally assigned 1-5 R's. 8 Replacement C 3-7 Cycloalkyl groups. For example, R 2 It can be cyclopropyl or cyclobutyl. In some embodiments, R 2 Each time it appears, it is independently and optionally assigned 1-5 R's. 8 Substituted 3-7 membered heterocyclic groups. For example, R 2 It can be tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazineyl, or morpholinyl. In some embodiments, R 2 Each time it appears, it is independently and optionally assigned 1-5 R's. 8 Substituted phenyl groups. In some embodiments, R 2 Each time it appears, it is independently and optionally assigned 1-5 R's. 8 Substituted 5-membered heteroaryl. In some embodiments, R 2 Each time it appears, it is independently and optionally assigned 1-5 R's. 8 Substituted 6-membered heteroaryl group.

[0169] In any embodiment, R 3Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl or halogenated C 1-6 Alkyl or CN. In some embodiments, R 3 It is C independently each time it appears. 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 1-6 Alkyl-OH. In some embodiments, R 3 It is C independently each time it appears. 3-7 cycloalkyl or C 3-7 Cycloalkyl-OH. In some embodiments, R 3 Each time it appears, it is independently -NH2 or -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl) 2 or 3-7 membered cyclic amines.

[0170] In any embodiment, X is CH. In some embodiments, X is N.

[0171] In any embodiment, R 4 It is hydrogen independently each time it appears. In some embodiments, R 4 It is a halogen, occurring independently each time. In some embodiments, R 4 It is C independently each time it appears. 1-6 Alkyl group. In some embodiments, R 4 It is independently methyl each time it appears. In some embodiments, R 4 It is ethyl, occurring independently each time. In some embodiments, R 4 It is propyl, occurring independently each time. In some embodiments, R 4 It is an isopropyl group each time it appears.

[0172] In any embodiment, R 5 Each time it appears, it is independently either hydrogen or C. 1-4 Alkyl; in some embodiments, R 5 It is hydrogen independently each time it appears. In some embodiments, R 5 It is independently methyl each time it appears. In some embodiments, R 5 It is ethyl, occurring independently each time. In some embodiments, R 5 It is propyl, occurring independently each time. In some embodiments, R 5 It is an isopropyl group each time it appears.

[0173] In any embodiment, R 6 Each time it appears, it is independently either hydrogen or C. 1-4 Alkyl; in some embodiments, R 6It is hydrogen independently each time it appears. In some embodiments, R 6 It is C independently each time it appears. 1-4 Alkyl group. In some embodiments, R 6 It is independently methyl each time it appears. In some embodiments, R 6 It is ethyl, occurring independently each time. In some embodiments, R 6 It is propyl, occurring independently each time. In some embodiments, R 6 It is an isopropyl group each time it appears.

[0174] In any embodiment, R 8 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 1-4 Alkoxy. In some embodiments, R 8 It is C independently each time it appears. 3-7 Cycloalkyl or 3-7 membered heterocyclic groups. In some embodiments, R 8 Each time it appears, it is independently phenyl or a 5-6 membered heteroaryl group. In some embodiments, R 8 It is -OR independently each time it appears. a -SR a -S(O) t R a -S(O) t -NR a R b -OC(O)-R a -NR a R b -C(O)R a -C(O)OR a -OC(O)NR a R b -C(O)NR a R b -N(R) a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)NR a R b -N(R) a )C(NR a )NR a R b -N(R) a S(O) t NR a R b -P(=O)(Ra (R) b -OP(=O)(OR) a (OR) b ) or an oxo group (=O). In some embodiments, R 8 Each time it appears, it is independently an oxo group (=O). In some embodiments, R 8 It is -NR independently each time it appears. a R b In some embodiments, R 8 It is -NR independently each time it appears. a R b Wherein -NR a R b Independently, they are NH2 and -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2 or 3-7 membered cyclic amines. In some embodiments, R 8 It is -S(O) independently each time it appears. t -C 1-4 alkyl.

[0175] In any embodiment, the compound is selected from:

[0176]

[0177] In any embodiment, the compound is selected from:

[0178]

[0179] In some embodiments, the technology of the present invention relates to compounds of formulas (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), and (IVb), comprising each exemplary compound wherein at least one hydrogen (H) is substituted with deuterium (D). Enrichment of deuterium can provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or can provide compounds that can be used as standards for characterizing biological samples. In some other embodiments, the isotopic enrichment factor of the compounds provided herein for each deuterium at the site designated as a potential deuteration site on the compound may be at least 3500 (52.5% deuterium doping), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0180] On the other hand, the technology of the present invention relates to a pharmaceutical composition comprising the compounds disclosed herein (including, but not limited to, compounds of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) and / or (IVb)) and a pharmaceutically acceptable carrier.

[0181] In another aspect, the technology of the present invention relates to a method for treating or preventing diseases or symptoms mediated by mammalian Ras family proteins in a subject of need, the method comprising administering to the subject an effective amount of the compounds disclosed herein (including, but not limited to, compounds of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) and / or (IVb)).

[0182] In another aspect, the present invention relates to a method for treating or preventing cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound disclosed herein (including, but not limited to, compounds of formulas (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), and / or (IVb)). In some embodiments, the cancer is breast cancer, leukemia, prostate cancer, ovarian cancer, pancreatic cancer, colon cancer, lung cancer, endometrial cancer, thyroid cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, hepatocellular carcinoma, glioblastoma, kidney cancer, sarcoma, bladder cancer, urothelial carcinoma, gastric cancer, or cervical cancer.

[0183] In another aspect, the technology of the present invention relates to a method for treating or preventing RAS disease caused by abnormal RAS signaling activity in a subject in need, the method comprising administering to the subject an effective amount of the compounds disclosed herein (including, but not limited to, compounds of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) and / or (IVb)).

[0184] In another aspect, the present invention relates to a method for treating a condition or symptom in a subject in need, the method comprising administering to the subject an effective amount of a compound disclosed herein (including, but not limited to, compounds of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) and / or (IVb), wherein the condition or symptom is selected from neurofibromatosis type 1, Noonan syndrome, Noonan multiple chronic spermatic syndrome, Costyle syndrome, cardiofacial skin syndrome, and capillary malformation arteriovenous syndrome.

[0185] In another aspect, the technology of the present invention relates to a method for treating or preventing fibrosis-related renal dysfunction in a subject of need, the method comprising administering to the subject an effective amount of the compounds disclosed herein (including, but not limited to, compounds of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) and / or (IVb)).

[0186] In another aspect, the technology of the present invention relates to a method for preparing compounds of formulas (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa) and (IVb), said method comprising each of the illustrative compounds and intermediates described herein.

[0187] Example

[0188] General Synthesis Method

[0189] The compounds of the present invention can be synthesized using the methods described herein, in conjunction with synthetic methods known in the field of synthetic organic chemistry, or by variations thereof 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 stated, all substituents are as defined above. Reactions are carried out in solvents or solvent mixtures suitable for the reagents and materials used and suitable for the proposed transformation. This may sometimes require judgment to modify the order of synthetic steps or to select a particular method scheme instead of another to obtain the desired compounds of the present invention.

[0190] It will be recognized that another major consideration in the planning of any synthetic route in this field is the prudent choice of protecting groups for protecting reactive functional groups present in the compounds described in the techniques of this invention. An authoritative account describing the many alternatives for trained practitioners is Greene et al., Protecting Groups in Greene's Organic Synthesis, 5th Edition, Wiley Publishers (2014). It will also be recognized that the compound names mentioned in the descriptions of schemes 1-5 are for convenience only and do not necessarily reflect the actual chemical names of those compounds.

[0191] Option 1

[0192]

[0193] Scheme 1 describes the synthesis of pyrrolo-pyridone amide 13. 2,2,6-trimethyl-4H-1,3-dioxin-4-one is reacted with an amine R2-NH2 to give acetoacetamide 1, which is then treated with DMF-DMA to provide intermediate 2. 2 is converted under POCl3 conditions to give pyridine-aldehyde 3. After treating 3 with hydrazine at high temperature, a pyrazolo-pyridone derivative 4 is obtained. 4 is reacted with NIS or NBS to give intermediate 5, which can be subjected to Suzuki conditions or a nucleophilic aromatic substitution reaction with R4 boric acid using a suitable catalyst (e.g., Pd(PPh3)4) to provide 7. 7 is protected with a protecting group such as SEM to provide 8. 8 is iodinated with NIS to give an iodinated intermediate 9, which is then carbonylated using a suitable catalyst such as MeOH containing Pd(dppf)Cl2 to give the corresponding ester 10. Hydrolyzing 10 under alkaline conditions yields acid 11, and then coupling 11 with amine 12 to obtain the desired amide 13 after deprotection with TFA.

[0194] Option 2

[0195]

[0196] Scheme 2 describes the general synthetic route for pyrrolo-pyridone amide 26. After treatment of 14 with DMF-DMA, followed by acid treatment, an aldehyde intermediate 15 is obtained. This aldehyde intermediate is then reacted with an amine R2-NH2, and subsequently under basic conditions, yields a hydroxy-pyridone derivative 16. The conversion of 16 to a bromine derivative 17 is carried out under POBr3 conditions. 17 is reacted with a diphenylimine 18 under Buckwald catalysis such as Pd2(dba)3 / xantphose, followed by acid treatment, to give an amino-pyridone 19. 19 is iodinated with NIS, followed by a Suzuki coupling reaction with a borate ester 21 to give intermediate 22. Pyrrolo-pyridone 23 is formed after treatment of 22 under acidic conditions. After treatment of 23 with NBS or NIS, 23 can be further substituted with an R4 group, and the resulting aryl halide undergoes a Suzuki coupling reaction to provide 24. After hydrolysis of ester 24, acid 25 is then coupled with amine 12 under coupling conditions such as HATU / DIPEA to obtain the desired pyrrolo-pyridinone amide 26.

[0197] Option 3

[0198]

[0199] Scheme 3 describes the general synthetic route for indazole-amide 35. Lithification of 27 at the ortho position, followed by treatment with DMF, yields aldehyde 28, which is reacted with hydrazine at high temperature to give indazole 29. Carbonylation of 29 under Pd(dppf)Cl2 / TEA / MeOH conditions forms methyl ester 30. Bromination of 30 with NBS produces 31, which can undergo a Suzuki coupling reaction with an R4-bonic acid to give 33. Hydrolysis of 33 under basic conditions provides acid 34, which is coupled with amine 12 to give the desired indazole-amide 35.

[0200] Option 4

[0201]

[0202] Scheme 4 describes the synthesis of the aza-indazole amide derivative 45. Aldehyde intermediate 37 was prepared by ortho-lithiation of LDA at low temperature followed by treatment with DMF. Aza-indazole 38 was obtained by treatment of 37 with hydrazine. SEM protection of 38 was achieved using NaH / SEMCl. Aza-indazole chloride 39 was treated with R2-NH2 (Buckwald reaction) or R2-B(OH)2 (Suzuki coupling reaction) to give 40. After treatment with m-CPBA, 40 was converted to 41, which reacts with POBr3, to give aza-indazole bromide 42. Pd-catalyzed carbonylation of 42 containing MeOH provided ester 43. The ester was hydrolyzed under basic conditions to produce acid 44. Acid 44 was coupled to amine 12 using a coupling agent such as HATU / DIPEA, and subsequently deprotected by SEM using TFA to obtain the desired product 45.

[0203] Option 5

[0204]

[0205] Scheme 5 describes the synthesis of a urea-containing pyrimidine derivative 52. Nucleophilic substitution of 46 with R4-NH2 yields 47, which is then subjected to aldehyde reduction to give 48. Chlorination and substitution with R2-NH2 provide 50. 50 is treated with CDI at high temperature to give a urea-containing pyrimidine chloride derivative 51, which is then subjected to nucleophilic substitution with amine 12 to obtain the desired target 52.

[0206] Pharmaceutical Compositions and Methods

[0207] The compounds used in the methods described herein can be formulated together with pharmaceutically acceptable carriers or adjuvants into pharmaceutically acceptable compositions, which are then administered to subjects. In another embodiment, such pharmaceutically acceptable compositions further include additional therapeutic agents, comprising those described herein, that effectively achieve the modulation of the disease or disease symptoms.

[0208] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a subject together with the compound of the present invention without interfering with its pharmacological activity, and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound.

[0209] Pharmaceutically acceptable carriers, adjuvants, and mediators that can be used in pharmaceutical compositions of the present invention include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants for drug formulations such as Tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in the form of glycerides, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene 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-cyclodextrins, or other dissolved derivatives, can also be advantageously used to enhance the delivery of compounds of the formula described herein.

[0210] The pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, or orally, via implanted receptacles, preferably orally or by injection. The pharmaceutical compositions of the present invention may include any conventionally non-toxic, pharmaceutically acceptable carrier, adjuvant, or mediator. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form. As used herein, the term parenterally includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0211] Pharmaceutical compositions can be in the form of sterile injectable formulations, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic parenteral diluents or solvents, such as a solution in 1,3-butanediol. Acceptable mediators and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild non-volatile oil containing synthetic monoglycerides or diglycerides can be used. Fatty acids such as oleic acid and their glyceride derivatives can be used to prepare injectables, as can natural, pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethyleneized form. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, such as emulsions and / or suspensions. Other commonly used surfactants such as Tween or Spans and / or other similar emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0212] The pharmaceutical compositions 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. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When administered orally in aqueous suspensions and / or emulsions, the active ingredient can be suspended or dissolved in the oil phase in combination with emulsifiers and / or suspending agents. Sweeteners and / or flavoring agents and / or coloring agents may be added if desired.

[0213] The pharmaceutical compositions of the present invention can be administered in the form of rectal suppositories. These compositions can be prepared by mixing compounds of the present invention with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature, thus melting in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0214] Topical application of the pharmaceutical compositions of the present invention is useful when the desired treatment involves an area or organ easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing an active ingredient suspended or dissolved in a carrier. Carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene / polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing an active compound suspended or dissolved in a carrier having a suitable emulsifier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, hexadecyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention can also be applied topically to the lower intestine via rectal suppository formulations or as suitable enema formulations. The present invention also includes topical transdermal patches.

[0215] The pharmaceutical compositions of the present invention can be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulations and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers for improving bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art.

[0216] When the composition of the present invention comprises a compound of the formula described herein combined with one or more other therapeutic or preventative agents, the compound and the other agents should be present at a dose level between about 1% and 100%, and more preferably between about 5% and 95%, of the dose typically administered in a single therapy regimen. As part of a multi-dose regimen, the additional agents may be administered separately from the compound of the present invention. Alternatively, those agents may be part of a single dosage form mixed together with the compound of the present invention in a single composition.

[0217] The compounds described herein can be administered, for example, by injection, intravenous, intra-arterial, subdermal, intraperitoneal, intramuscular, or subcutaneous routes; or orally, orally, nasally, via mucosae, topically, as ophthalmic preparations, or by inhalation, at doses ranging from about 0.5 to about 100 mg / kg of body weight, alternatively, at doses between 1 mg and 1000 mg per dose, every 4 to 120 hours, or as required by the medicine. The methods described herein contemplate administering an effective amount of the compound or a composition of compounds to achieve the desired or prescribed effect. Typically, the pharmaceutical compositions of the present invention will be administered about 1 to about 6 times daily, 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 a carrier material to produce a single dosage form will vary depending on the host being treated and the mode of administration. Typical formulations will contain about 5% to about 95% (w / w) of the active compound. Alternatively, such formulations contain about 20% to about 80% of the active compound.

[0218] Doses lower or higher than those listed above may be required. The specific dosage and treatment regimen for any subject will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, combination of drugs, disease, severity and duration of symptoms, the subject's predisposition to the disease, symptoms, and the judgment of the treating physician.

[0219] As the subject's symptoms improve, a maintenance dose of the compounds, compositions, or combinations of the present invention may be administered, if necessary. Subsequently, as symptoms change and have lessened to a desired level, the dose or frequency, or both, may be reduced to a level that maintains the improved symptoms. However, in the event of any recurrence of disease symptoms, the subject may require long-term intermittent treatment.

[0220] The pharmaceutical compositions described above, comprising compounds of formulas (I)-(IV), may further comprise another therapeutic agent for the treatment or prevention of diseases or symptoms mediated by mammalian Ras family proteins. Specifically, such combinations may be used to treat or prevent cancers including: breast cancer, leukemia, prostate cancer, ovarian cancer, pancreatic cancer, colon cancer, lung cancer, endometrial cancer, thyroid cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, hepatocellular carcinoma, glioblastoma, renal cancer, sarcoma, bladder cancer, urothelial carcinoma, gastric cancer, or cervical cancer.

[0221] 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 herein by reference. In case of conflict, the definition contained herein shall prevail.

[0222] Examples are provided herein to illustrate the advantages of the technology of the present invention and to further assist those skilled in the art in preparing or using compounds or salts, pharmaceutical compositions, derivatives, solvates, metabolites, prodrugs, racemic mixtures, or tautomeric forms thereof. Examples are also presented herein to illustrate preferred aspects of the technology of the present invention more fully. The examples should not in any way be construed as limiting the scope of the technology of the present invention as defined by the appended claims. Examples may include or incorporate any variations, aspects, or aspects of the technology of the present invention described above. The variations, aspects, or aspects described above may further each include or incorporate any or all other variations, aspects, or modifications of the technology of the present invention.

[0223] Example

[0224] The abbreviations used in this article are as follows:

[0225]

[0226]

[0227] General conditions and procedures

[0228] In the following examples, the chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Company) and were ready for use 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.

[0229] Rapid chromatography was performed on an Ez Purifier III column with silica gel particles of 200–300 mesh. Analytical and preparative thin-layer chromatography (TLC) plates were HSGF 254 (0.15–0.2 mm thickness, Shanghai Anbang Company, China). Unless otherwise specified, nuclear magnetic resonance (NMR) spectra were recorded using a Bruker AMX-300 or AMX-400 NMR spectroscopy system at approximately 20–30 °C. The following abbreviations were used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet; ddd, doublet of doublet; dt, doublett; bs, broad signal. Chemical shifts from the low field of tetramethylsilane were reported in parts per million (ppm, δ). Mass spectrometry was run using an electrospray ionization (ESI) system 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-phase or reversed-phase HPLC, fast columns, or Prep-TLC plates under acidic, neutral, or alkaline conditions.

[0230] Preparative HPLC: Unless otherwise specified, compounds were purified using a Waters Fractionlynx system equipped with a YMC Pack Pro d8 column (5 μm, 120A, 50 x 20 mm) and the following solvent systems: H2O, AcCN, and H2O containing 2% TFA. Specific elution gradients were based on retention times obtained using analytical LC-MS; however, generally all elution gradients for H2O and AcCN 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 TFA concentration of 0.1% in each run. Specific elution gradients were based on retention times obtained using analytical LC-MS; however, generally all elution gradients for H2O and AcCN were run at a flow rate of 50 mL / min for a run time of 8 minutes.

[0231] Analytical LC-MS: Analytical LC-MS was performed on a Waters Acquity UPLC-MS instrument equipped with an ACQUITY UPLC BEH Ci8 column (2.1 x 50 mm, 1.7 μm), at a column temperature of 45 °C, 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 over a 1.5-minute run at a flow rate of 0.6 mL / min.

[0232] Preparative chiral SFC separation: Stereoisomeromer mixtures were separated on one of the following columns using a Berger Minigram SFC instrument: ChiralPak AS-H (10 x 250 mm), ChiralPak IA (10 x 250 mm), ChiralPak AD-H (21 x 250 mm), Phenomenex Lux-2 (21.2 x 250 mm), or ChiralPak IC (10 x 250 mm); eluted 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, at a flow rate of 2.5 mL / min and a column temperature of 35 °C.

[0233] Analytical chiral SFC separation: Mixtures of stereoisomers or single enantiomers were analyzed using a JASCO analytical SFC instrument on one of the following columns: ChiralPak AS-H (4.6 x 250 mm), ChiralPak IA (4.6 x 250 mm), ChiralPak AD-H (4.6 x 250 mm), Phenomenex Lux-2 (4.6 x 250 mm), or ChiralPak IC (4.6 x 250 mm); eluted with MeOH / CO2 containing 0.1% diethylamine, or EtOH / CO2 containing 0.1% diethylamine, or isopropanol / CO2 containing 0.1% diethylamine, at a flow rate of 6.0 mL / min and a column temperature of 35 °C.

[0234] Intermediate 1: Synthesis of (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethylamine

[0235]

[0236] Step A. 1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-one

[0237] Tributyl(1-ethoxyvinyl)stanane (3.3 g, 9.2 mmol), TEA (3.5 mL, 25.1 mmol), and Pd(PPh3)2Cl2 (0.3 g, 0.4 mmol) were added to a solution of 1-bromo-2-methyl-3-(trifluoromethyl)benzene (1.3 mL, 8.4 mmol) in dry dioxane (20 mL). After stirring at 100 °C for 2 hours, 12N HCl (15 mL) was added and stirred for 30 minutes. The cooled mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by chromatography (silica gel, 0-25%, EtOAc / PE) to give 1-[2-methyl-3-(trifluoromethyl)phenyl]ethane-1-one (1.4 g, 7.1 mmol, 85.1%) as a brown oil. LC-MS(ESI)m / z196(M+H) + .

[0238] Step B. (S,E)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide

[0239] (R)-2-methylpropane-2-sulfinamide (1.29 g, 10.7 mmol) and titanium ethoxide (3 mL, 14.2 mmol) were added to a stirred solution of 1-[2-methyl-3-(trifluoromethyl)phenyl]ethane-1-one (1.44 g, 7.1 mmol) in THF (15 mL) at room temperature. After stirring overnight at 80 °C, the cooled mixture was poured into water (50 mL) and filtered. The filtrate was extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-50%, EtOAc / PE) to give 2-methyl-N-[(1E)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethylidene]propane-2-sulfinamide (1.2 g, 3.9 mmol, 55.2%) as a brown oil.

[0240] Step C. (S)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide

[0241] NaBH4 (0.26 g, 7.07 mmol) was added to a stirred solution of 2-methyl-N-[(1E)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethylene]propane-2-sulfinamide (1.2 g, 3.9 mmol) in THF (64 mL) at 0 °C. After stirring at room temperature for 3.5 hours, the mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-60%, EtOAc / PE) to give 2-methyl-N-{1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}propane-2-sulfinamide (0.6 g, 1.95 mmol, 49.7%) as a yellow oil.

[0242] Step D. (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine

[0243] Dioxane / HCl (5 mL, 4 mol / L) was added to a stirred solution of 2-methyl-N-{1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}propane-2-sulfinamide (60 mg, 0.2 mmol) in dioxane (5 mL) at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated to give crude (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethane-1-amine (100 mg, 0.15 mmol, 75.6%) as a yellow solid. LC-MS (ESI) m / z 204 (M+H) + .

[0244] Intermediate 2:

[0245] Synthesis of (1R)-1-[3-(1,1-difluoroethyl)-2-fluorophenyl]ethane-1-amine

[0246]

[0247] Step A. 1-{2-fluoro-3-[2-(trimethylsilyl)ethynyl]phenyl}ethane-1-one.

[0248] At room temperature, ethynyltrimethylsilane (5 mL, 34.5 mmol), CuI (880 mg, 4.6 mmol), Pd(dppf)Cl2 (1.7 g, 2.3 mmol), and TEA (9.6 mL, 69.1 mmol) were added to a stirred solution of 1-(3-bromo-2-fluorophenyl)ethane-1-one (5 g, 23.1 mmol) in THF (30 mL). After stirring overnight at 80 °C, the cooled mixture was poured into water (30 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-20%, EtOAc / PE) to give 1-{2-fluoro-3-[2-(trimethylsilyl)ethynyl]phenyl}ethane-1-one (5 g, 21.3 mmol, 92%) as a yellow oil. LCMS: m / z 235(M+H) + .

[0249] Step B. 1-(3-ethynyl-2-fluorophenyl)ethane-1-one.

[0250] At room temperature, K₂CO₃ (8.8 g, 64.1 mmol) was added to a stirred solution of 1-{2-fluoro-3-[2-(trimethylsilyl)ethynyl]phenyl}ethane-1-one (5 g, 21.3 mmol) in DCM (20 mL) / MeOH (20 mL). After stirring at room temperature for 2 hours, the cooled mixture was poured into water (30 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give 1-(3-ethynyl-2-fluorophenyl)ethane-1-one (3.2 g, 19.7 mmol, 92%) as a brown solid. LCMS: m / z 163 (M+H) + .

[0251] Step C.1-[3-(1,1-difluoroethyl)-2-fluorophenyl]ethane-1-one.

[0252] At room temperature, pyridine (8 mL) containing 70% HF was added to a stirred solution of 1-(3-ethynyl-2-fluorophenyl)ethane-1-one (2.7 g, 16.6 mmol) in CHOH(CF3)2 (8 mL). After stirring at room temperature for a weekend, the cooled mixture was poured into water (30 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-20%, EtOAc / PE) to give 1-[3-(1,1-difluoroethyl)-2-fluorophenyl]ethane-1-one (1.4 g, 6.9 mmol, 41%) as a brown solid. LCMS: m / z 203 (M+H) + .

[0253] Step DN-[(1E)-1-[3-(1,1-difluoroethyl)-2-fluorophenyl]ethylene]-2-methylpropane-2-sulfinamide.

[0254] At room temperature, 2-methylpropane-2-sulfinamide (629 mg, 5.2 mmol) and Ti(OEt)4 (2 mL) were added to a stirred solution of 1-[3-(1,1-difluoroethyl)-2-fluorophenyl]ethane-1-one (700 mg, 3.4 mmol) in THF (10 mL). After stirring at 80 °C for 4 hours, the cooled mixture was poured into water (30 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-30%, EtOAc / PE) to give N-[(1E)-1-[3-(1,1-difluoroethyl)-2-fluorophenyl]ethylene]-2-methylpropane-2-sulfinamide (700 mg, 2.3 mmol, 66%) as a yellow oil. LCMS: m / z 236(M+H) + .

[0255] Step EN-{1-[3-(1,1-difluoroethyl)-2-fluorophenyl]ethyl}-2-methylpropane-2-sulfinamide.

[0256] At 0 °C, NaBH4 (116 mg, 3.44 mmol) was added to a stirred solution of N-[(1E)-1-[3-(1,1-difluoroethyl)-2-fluorophenyl]ethylene]-2-methylpropane-2-sulfinamide (700 mg, 2.3 mmol) in THF (5 mL). After stirring at room temperature for 2 hours, the cooled mixture was poured into water (30 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-30%, EtOAc / PE) to give N-{1-[3-(1,1-difluoroethyl)-2-fluorophenyl]ethyl}-2-methylpropane-2-sulfinamide (380 mg, 1.2 mmol, 54%) as a yellow solid. LCMS: m / z 308 (M+H) + .

[0257] 1 H NMR (400MHz, DMSO) δ7.70 (s, 1H), 7.45 (d, J = 7.3Hz, 1H), 7.31 (t, J = 7.7Hz, 1H), 5.86 (d, J = 7.7 Hz, 1H), 4.75–4.62 (m, 1H), 2.00 (dd, J=21.9, 16.3Hz, 3H), 1.42 (d, J=6.8Hz, 3H), 1.11 (s, 9H).

[0258] Step F. (1R)-1-[3-(1,1-difluoroethyl)-2-fluorophenyl]ethane-1-amine.

[0259] At room temperature, 4N HCl / dioxane (3 mL) was added to a stirred mixture of N-{1-[3-(1,1-difluoroethyl)-2-fluorophenyl]ethyl}-2-methylpropane-2-sulfinamide (100 mg, 0.32 mmol) and dioxane (3 mL). After stirring at room temperature for 2 hours, the mixture was concentrated to give crude product (1R)-1-[3-(1,1-difluoroethyl)-2-fluorophenyl]ethane-1-amine (60 mg, 0.29 mmol, 91%) as a yellow solid. LCMS: m / z 204 (M+H) + .

[0260] Intermediate 3:

[0261] Synthesis of (R)-1-(6-(trifluoromethyl)pyridin-2-yl)ethylamine

[0262]

[0263] Step A: 1-(6-(trifluoromethyl)pyridin-2-yl)ethane-1-one

[0264] At room temperature, DMA (0.23 mL, 2.4 mmol) was added to a solution of 2-bromo-6-(trifluoromethyl)pyridine (0.5 g, 2.2 mmol) in THF (5 mL). The mixture was cooled to -60 °C, and N-BuLi (0.23 g, 3.54 mmol) was added dropwise. The reaction was stirred at -20 °C for 3 h. After complete conversion of the starting material, the mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: 0–10% EtOAc / PE) to give a product of 1-[6-(trifluoromethyl)pyridin-2-yl]ethane-1-one as a yellow oil (0.09 g, 0.48 mmol, 21.5%). LCMS (ESI) m / z 190 (M+H) +

[0265] Step B: (S,E)-2-methyl-N-(1-(6-(trifluoromethyl)pyridin-2-yl)ethylidene)propane-2-sulfinamide

[0266] At room temperature, (R)-2-methylpropane-2-sulfinamide (0.67 g, 5.55 mmol) and titanium ethoxide (2.33 mL, 11.1 mmol) were added to a stirred solution of 1-[6-(trifluoromethyl)pyridin-2-yl]ethane-1-one (0.7 g, 3.7 mmol) in THF (15 mL). After stirring overnight at 80 °C, the cooled mixture was poured into ice water (25 mL) and filtered. The filtrate was extracted with EtOAc (25 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-100%, EtOAc / PE) to obtain 2-methyl-N-[(1E)-1-[6-(trifluoromethyl)pyridin-2-yl]ethylene]propane-2-sulfinamide (0.74 g, 2.53 mmol, 68.4%) as a brown oil.

[0267] Step C: (S)-2-methyl-N-(1-(6-(trifluoromethyl)pyridin-2-yl)ethyl)propane-2-sulfinamide

[0268] At 0 °C, NaBH4 (0.14 mL, 4.31 mmol) was added to a stirred solution of 2-methyl-N-[(1E)-1-[6-(trifluoromethyl)pyridin-2-yl]ethylene]propane-2-sulfinamide (0.7 g, 2.4 mmol) in THF (7 mL). After stirring at room temperature for 3 hours, the mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-60%, EtOAc / PE) to give 2-methyl-N-{1-[6-(trifluoromethyl)pyridin-2-yl]ethyl}propane-2-sulfinamide (0.3 g, 1.0 mmol, 42.6%) as a yellow oil.

[0269] Step D: (R)-1-(6-(trifluoromethyl)pyridin-2-yl)ethane-1-amine

[0270] At room temperature, dioxane / HCl (3 mL, 4 mol / L) was added to a solution of 2-methyl-N-{1-[6-(trifluoromethyl)pyridin-2-yl]ethyl}propane-2-sulfinamide (0.08 g, 0.27 mmol) in dioxane (5 mL). After stirring at room temperature for 1 hour, the mixture was concentrated to give crude product (1R)-1-[6-(trifluoromethyl)pyridin-2-yl]ethane-1-amine (60 mg, 0.25 mmol, 93%) as a yellow solid. LC-MS (ESI) m / z 191 (M+H) + .

[0271] Intermediate 4:

[0272] Synthesis of (R)-2-(5-(1-aminoethyl)thiophen-2-yl)benzyl(methyl)carbamate

[0273]

[0274] Step A: 1-(2-bromophenyl)-N-methylmethylamine

[0275] At room temperature, a solution of 1-bromo-2-(bromomethyl)benzene (10 g, 40.0 mmol) in MeOH was added to a solution of MeNH2 (10.8 g, 160 mmol) in MeOH over 30 minutes. After stirring at room temperature for 2 hours, the mixture was concentrated and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. The crude product was purified by silica gel column chromatography (gradient elution: 0–20% MeOH / DCM) to give the product of [(2-bromophenyl)methyl](methyl)amine (2.7 g, 13.5 mmol, 33.7%). LC-MS (ESI) m / z: 249 + .

[0276] Step B: N-[(2-bromophenyl)methyl]-N-methylcarbamate benzyl ester

[0277] At room temperature, TEA (5.6 mL, 40.5 mmol) was added to a solution of [(2-bromophenyl)methyl](methyl)amine (2.7 g, 13.5 mmol) in DCM (30 mL). Cb2Cl (2.76 g, 16.2 mmol) was added dropwise to a solution of DCM (20 mL). After stirring at room temperature for 1.5 hours, the reaction was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: 0–10% EtOAc / PE) to give N-[(2-bromophenyl)methyl]-N-methylcarbamate benzyl ester (3 g, 8.976 mmol, 66.5%) as a colorless oil. LC-MS (ESI) m / z: 334 +

[0278] Step C: N-methyl-N-{[2-(tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl]methyl} benzyl carbamate

[0279] At room temperature and under N2, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhexacyclopentane) (3.95 g, 15.6 mmol), Pd(dppf)Cl2 (0.44 g, 0.598 mmol), and KOAc (3.52 g, 35.9 mmol) were added to a solution of N-[(2-bromophenyl)methyl]-N-methylcarbamate (4 g, 11.9 mmol) in dioxane (40 mL). After stirring overnight at 100 °C, the cooled mixture was concentrated. The filtrate was diluted with water and then extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, and then concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc / PE) to give N-methyl-N-{[2-(tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]methyl} benzyl carbamate (4.35 g, 11.4 mmol, 95.3%) as a green oil. LC-MS (ESI) m / z 382 (M+H) + .

[0280] Step D: N-{[2-(5-acetylthiophen-2-yl)phenyl]methyl}-N-methylcarbamate benzyl ester

[0281] At room temperature, 1-(5-bromothiophene-2-yl)ethane-1-one (1.87 g, 9.13 mmol), Pd(dppf)Cl2 (0.83 g, 1.14 mmol), and K2CO3 (6.31 g, 45.636 mmol) were added to a solution of N-methyl-N-{[2-(tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]methyl}carbamate (4.35 g, 11.4 mmol), dioxane (40 mL), and H2O (10 mL). After stirring at 100 °C for 1.5 hours, the mixture was filtered. The filtrate was extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, and then concentrated. The mixture was purified by chromatography (silica gel, 0-50%, EtOAc / PE) to give N-{[2-(5-acetylthiophene-2-yl)phenyl]methyl}-N-methylcarbamate (0.38 g, 1.00 mmol, 8.78%) as a white solid. LC-MS (ESI) m / z 380 (M+H) + .

[0282] Step E: N-methyl-N-[(2-{5-[(1E)-1-[(2-methylpropane-2-sulfinyl)imino]ethyl]thiophen-2-yl}phenyl)methyl]benzyl carbamate

[0283] At room temperature, (R)-2-methylpropane-2-sulfinamide (1.17 g, 9.68 mmol) and titanium ethoxide (4.061 mL, 19.369 mmol) were added to a solution of N-{[2-(5-acetylthiophene-2-yl)phenyl]methyl}-N-methylcarbamate (2.45 g, 6.46 mmol) in THF (30 mL). After stirring at 80 °C for 5 hours, the mixture was quenched with ice water and filtered. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The mixture was purified by chromatography (silica gel, 0-80%, EtOAc / PE) to give N-methyl-N-[(2-{5-[(1E)-1-[(2-methylpropane-2-sulfinyl)imino]ethyl]thiophen-2-yl}phenyl)methyl]carbamate (2 g, 4.14 mmol, 64.2%) as a white solid.

[0284] Step F: N-methyl-N-[(2-{5-[(1R)-1-[(2-methylpropane-2-sulfinyl)amino]ethyl]thiophen-2-yl}phenyl)methyl]benzyl carbamate

[0285] At 0 °C, NaBH4 (0.541 mL, 16.6 mmol) was added to a solution of N-methyl-N-[(2-{5-[(1E)-1-[(2-methylpropane-2-sulfinyl)imino]ethyl]thiophen-2-yl}phenyl)methyl]carbamate (2 g, 4.14 mmol) in THF (20 mL). After stirring at room temperature for 2 hours, the mixture was quenched with ice water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The mixture was purified by chromatography (silica gel, 0-100%, EtOAc / PE) to give N-methyl-N-[(2-{5-[(1R)-1-[(2-methylpropane-2-sulfinyl)amino]ethyl]thiophen-2-yl}phenyl)methyl]carbamate (1.76 g, 3.63 mmol, 87.6%) as a white solid.

[0286] Step G: N-[(2-{5-[(1R)-1-aminoethyl]thiophen-2-yl}phenyl)methyl]-N-methylcarbamate benzyl ester

[0287] At room temperature, 4NHCl / dioxane (2 mL) was added to a solution of N-methyl-N-{[2-(5-{1-[(2-methylpropane-2-sulfinyl)amino]ethyl}thiophen-2-yl)phenyl]methyl}benzyl carbamate (180 mg, 0.371 mmol) in dioxane (5 mL). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give crude N-[(2-{5-[(1R)-1-aminoethyl]thiophen-2-yl}phenyl)methyl]-N-methylcarbamate (165 mg, 0.325 mmol, 87.6%) as a white solid. LC-MS (ESI) m / z: 381 + .

[0288] Example 1: Synthesis of (R)-N-(1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-4-oxo-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0289]

[0290] Step A. 3-Oxo-N-(Tetrahydro-2H-pyran-4-yl)butyramide

[0291] Add oxane-4-amine (3.28 mL, 31.7 mmol) and NaOAc (1.90 g, 23.2 mmol) to a stirred solution of 2,2,6-trimethyl-2,4-dihydro-1,3-dioxin-4-one (2.8 mL, 21.1 mmol) in dry THF (30 mL). Stir the reaction mixture at 70 °C for 16 hours. Pour the reaction mixture into water, extract with EtOAc, wash with brine, dry to Na₂SO₄, and concentrate under vacuum. Purify the residue by column chromatography (silica gel, 40 g, 0–100% EtOAc / PE) to N-(oxane-4-yl)-3-oxobutyramide (3.80 g, 20.5 mmol, 97.1%) as a yellow oil. LCMS: m / z 186 (M+H) + .

[0292] Step B. (E)-2-((dimethylamino)methylene)-3-oxo-N-(tetrahydro-2H-pyran-4-yl)butyramide

[0293] DMF-DMA (2.46 g, 20.5 mmol) was added dropwise to a stirred solution of N-(oxapan-4-yl)-3-oxobutyramide (3.80 g, 20.5 mmol) in DMF (20 mL) over 5 minutes. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (silica gel, 40 g, 0–10% MeOH / DCM) to give (2E)-2-[(dimethylamino)methylene]-N-(oxapan-4-yl)-3-oxobutyramide (4 g, 16.6 mmol, 81.1%) as a yellow oil. LCMS: m / z 241 (M+H) + .

[0294] Step C. 4-Chloro-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridine-3-carboxaldehyde

[0295] At 0 °C, 10 mL of DMF was added dropwise to 20 mL of POCl3, and the mixture was stirred for 15 minutes. Then, 40 mL of DMF containing (2E)-2-[(dimethylamino)methylene]-N-(oxan-4-yl)-3-oxobutyramide (4 g, 16.6 mmol) was added. The reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was poured into water and neutralized with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 40 g, 0–100% EtOAc / PE) to give 4-chloro-1-(oxan-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxaldehyde (2.1 g, 8.69 mmol, 52.2%) as a yellow oil. LCMS: m / z 242(M+H) + .

[0296] Step D. 5-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0297] N₂H₄·H₂O (4.34 g, 86.9 mmol) was added to a solution of 4-chloro-1-(oxan-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxaldehyde (2.1 g, 8.69 mmol) in dioxane (20 mL). The reaction mixture was stirred at 120 °C for 16 hours. The reaction mixture was concentrated under vacuum and purified by column chromatography (silica gel, 24 g, 0–10% MeOH / DCM) to give 5-(oxan-4-yl)-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (1.6 g, 7.3 mmol, 83.9%) as a yellow solid. LCMS: m / z 220 (M+H) + .

[0298] Step E.5-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0299] At 0 °C, NaH (0.53 g, 21.9 mmol) was added to a stirred solution of 5-(oxaalkyl-4-yl)-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (1.6 g, 7.3 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 0.5 h, and then SEMCl (1.46 g, 8.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (silica gel, 24 g, 0–70% EtOAc / PE) to give 5-(oxacan-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (2.1 g, 6.0 mmol, 82.3%) as a pale yellow solid. LCMS: m / z 350 (M+H) + .

[0300] Step E.7-Iodo-5-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0301] Iodo(thionyl)amine (519.6 mg, 3.0 mmol) was added to a stirred solution of 5-(oxapan-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (700 mg, 2.003 mmol) in AcOH (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EtOAc, washed with NaHCO3, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 24 g, 0–50% EtOAc / PE) to give 7-iodo-5-(oxapan-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (400 mg, 0.84 mmol, 42.0%) as a pale yellow oil. LCMS: m / z 476 (M+H) + .

[0302] Step G. 4-oxo-5-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid methyl ester

[0303] Pd(dppf)Cl2 (123 mg, 0.17 mmol) and TEA (0.35 mL, 2.5 mmol) were added to a stirred solution of 7-iodo-5-(oxan-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (400 mg, 0.841 mmol) in MeOH (10 mL). The reaction mixture was stirred at 80 °C for 16 hours under a CO atmosphere. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (silica gel, 24 g, 0–40% EtOAc / PE) to give methyl 5-(oxaconitine-4-yl)-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylate (250 mg, 0.61 mmol, 72.9%) as a pale yellow oil. LCMS: m / z 408 (M+H) + .

[0304] Step H.4-oxo-5-(tetrahydro-2H-pyran-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxylic acid

[0305] To a stirred solution of methyl 5-(oxapan-4-yl)-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (250 mg, 0.61 mmol) in MeOH (5 mL), H₂O (5 mL) containing sodium hydroxide (245 mg, 6.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 3–4 and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give crude 5-(oxapan-4-yl)-4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (150 mg, 0.38 mmol, 62.1%) as a pale yellow solid. LCMS: m / z 394(M+H) + .

[0306] Step I. (R)-N-(1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-4-oxo-5-(tetrahydro-2H-pyran-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0307] To a stirred solution of 5-(oxapan-4-yl)-4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (20 mg, 0.05 mmol) in N,N-dimethylformamide (3 mL), 2-{3-[(1R)-1-aminoethyl]phenyl}-2,2-difluoroethane-1-ol (11.2 mg, 0.05 mmol), DIPEA (33.0 mg, 0.2 mmol), and HATU (28.9 mg, 0.07 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted by adding water and extracting with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain a residue. The residue was purified by TLC (100% EtOAc) to give N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-5-(oxan-4-yl)-4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (15 mg, 0.02 mmol, 51.1%) as a white solid. LCMS: m / z 577 (M+H) + .

[0308] Step J.(R)-N-(1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-4-oxo-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0309] Add N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-5-(oxan-4-yl)-4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (15 mg, 0.03 mmol) to a stirred solution of TFA (2 mL). Stir the reaction mixture at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to obtain a residue, which was then purified by preparative HPLC (phase A: H₂O (0.1% FA); phase B: MECN) to give N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-5-(oxan-4-yl)-4-oxo-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (3 mg, 0.007 mmol, 25.8%) as a white solid. 1 HNMR (400MHz, DMSO): δ13.41(s,1H),8.89(d,J=7.6Hz,1H),8.14(d,J=111.7Hz,2H),7. 54(d,J=8.9Hz,2H),7.48(t,J=7.6Hz,1H),7.41(d,J=7.6Hz,1H),5.63(t,J=6.3Hz,1H), 5.35–5.18(m,1H),5.08(s,1H),4.04(d,J=8.0Hz,2H),3.85(td,J=14.2,6.1Hz,3H),3.5 3(t,J=11.3Hz,2H),2.04(s,3H),1.74(d,J=9.1Hz,3H),1.55(d,J=7.0Hz,4H).LCMS:m / z 447(M+H) + .

[0310] The examples in Table 1 below were prepared using methods similar to those used to prepare the examples as described herein.

[0311] Table 1

[0312]

[0313]

[0314]

[0315] Example 10: Synthesis of (R)-5-(4-acetylcyclohexyl)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0316]

[0317] Step A. 4-Chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]pyridine.

[0318] At 0 °C, NaH (2.08 g, 52.1 mmol) was added to a stirred solution of 4-chloro-1H-pyrazolo[4,3-c]pyridine (4 g, 26.1 mmol) in THF (50 mL). After stirring at 0 °C for 20 min, SEMCl (6.47 g, 39.1 mmol) was added at 0 °C. After 2 hours, the mixture was poured into ice water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-50%, EtOAc / PE) to give 4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]pyridine (6.2 g, 21.8 mmol, 83.9%) as a brown solid. LC-MS(ESI)m / z284(M+H) + .

[0319] Step B. 4-Methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]pyridine.

[0320] At room temperature, NaOMe (13.1 mL, 65.5 mmol, 5 mol / L in MeOH) was added to a stirred solution of 4-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]pyridine (6.2 g, 21.8 mmol) in MeOH (100 mL). After stirring at 60 °C for 2 hours, the cooled mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-50%, EtOAc / PE) to give 4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]pyridine (5.5 g, 19.7 mmol, 90.1%) as a yellow solid. LC-MS(ESI) m / z 280(M+H)+ .

[0321] Step C.2-((2-(trimethylsilyl)ethoxy)methyl)-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0322] TMSI (6.34 mL, 42.9 mmol) was added to a stirred solution of 4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]pyridine (6 g, 21.4 mmol) in MeCN (15 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, 40 g, 0–3% MeOH / DCM) to give 2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (3.5 g, 13.2 mmol, 61.4%) as a yellow solid. LCMS: m / z 266 (M+H) + .

[0323] Step D.

[0324] 5-(1-acetylpiperidin-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0325] To a stirred solution of 2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (200 mg, 0.75 mmol) in toluene (10 mL), 1-(4-hydroxypiperidin-1-yl)ethane-1-one (108 mg, 0.75 mmol) and CMBP (782 mg, 2.26 mmol) were added. The reaction mixture was stirred at 120 °C for 3 hours. The reaction mixture was concentrated under vacuum and extracted with DCM. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to obtain a residue, which was then purified by TLC (0–2% MeOH / DCM) to give 5-(1-acetylpiperidin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (80 mg, 0.20 mmol, 27.2%) as a yellow solid. LCMS: m / z 391 (M+H) + .

[0326] Step E.5-(1-acetylpiperidin-4-yl)-7-iodo-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0327] NIS (55.4 mg, 0.24 mmol) was added to a stirred solution of 5-(4-acetylcyclohexyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (80 mg, 0.20 mmol) in AcOH (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with NaHCO3, dried over Na2SO4, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (silica gel, 4 g, 0–100% EtOAc / PE) to give 5-(4-acetylcyclohexyl)-7-iodo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (80 mg, 0.15 mmol, 75.6%) as a pale yellow oil. LCMS: m / z 517 (M+H) + .

[0328] Step F. methyl 5-(1-acetylpiperidin-4-yl)-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrrolo[3,2-c]pyridine-7-carboxylate

[0329] Pd(dppf)Cl2.CH2Cl2 (12.6 mg, 0.01 mmol) and TEA (0.06 mL, 0.46 mmol) were added to a stirred solution of 5-(4-acetylcyclohexyl)-7-iodo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (80 mg, 0.15 mmol) in MeOH (5 mL). The reaction mixture was stirred at 70 °C for 3 hours under a CO atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue, which was then purified by column chromatography (silica gel, 24 g, 0–40% EtOAc / PE) to give methyl 5-(4-acetylcyclohexyl)-4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylate (60 mg, 0.13 mmol, 86.5%) as a pale yellow solid. LCMS: m / z 448 (M+H) + .

[0330] Step G.5-(1-acetylpiperidin-4-yl)-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxylic acid

[0331] To a stirred solution of methyl 5-(4-acetylcyclohexyl)-4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (60 mg, 0.13 mmol) in MeOH (3 mL), 2 mL of H₂O containing NaOH (53.74 mg, 1.34 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 3–4 and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give crude 5-(4-acetylcyclohexyl)-4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (50 mg, 0.11 mmol, 85.8%) as a white solid. LCMS: m / z 434(M+H) + .

[0332] Step H.(R)-5-(1-acetylpiperidin-4-yl)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0333] To a stirred solution of 5-(4-acetylcyclohexyl)-4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (50 mg, 0.11 mmol) in DMF (10 mL), (1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethane-1-amine (27 mg, 0.13 mmol), DIEA (0.057 mL, 0.345 mmol), and HATU (65 mg, 0.17 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (silica gel, 24 g, 0–100% EtOAc / PE) to give 5-(4-acetylcyclohexyl)-N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (50 mg, 0.08 mmol, 70.7%) as a white solid. LCMS: m / z 614 (M+H) + .

[0334] Step I. (R)-5-(1-acetylpiperidin-4-yl)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0335] Add 5-(1-acetylpiperidin-4-yl)-N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (50 mg, 0.081 mmol) to a stirred solution in 4N HCl / dioxane (3 mL). Stir the reaction mixture at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to obtain a residue, which was then purified by preparative HPLC (phase A: H2O (0.1% TFA), phase B: MeCN) to give 5-(1-acetylpiperidin-4-yl)-N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethyl]-4-oxo-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (11 mg, 0.023 mmol, 27.9%) as a white solid. 1 H NMR(400MHz,DMSO)δ13.45(s,1H),8.86(t,J=6.9Hz,1H),8.31(s,1H),8.16(s,1H ),7.57(d,J=6.4Hz,1H),7.49–7.37(m,3H),5.24(dd,J=7.0,4.8Hz,1H),5.04(s,1 H),4.61(d,J=12.1Hz,1H),4.01(d,J=15.6Hz,1H),3.17(dd,J=36.0,7.2Hz,6H),2 .73–2.55(m,4H),2.07(s,5H),1.94–1.74(m,6H),1.53(d,J=7.0Hz,4H).LCMS:m / z 484(M+H) + .

[0336] Example 11: Synthesis of N-((R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-5-((1s,4S)-4-((2-hydroxyethyl)(methyl)carbamoyl)cyclohexyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0337]

[0338] Step A. (1s,4s)-4-((E)-2-((dimethylamino)methylene)-3-oxobutamido)cyclohexane-1-carboxylic acid methyl ester

[0339] To a stirred solution of (1s,4s)-4-aminocyclohexane-1-carboxylate (5 g, 31.8 mmol) in THF (50 mL), 2,2,6-trimethyl-2,4-dihydro-1,3-dioxin-4-one (6.23 mL, 47.7 mmol) and NaOAc (7.83 g, 95.4 mmol) were added. The reaction mixture was stirred at 75 °C for 16 hours. The reaction mixture was concentrated, diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 45 g, 0–100% EtOAc / PE) to give methyl 4-(3-oxobutamido)cyclohexane-1-carboxylate (4.19 g, 17.3 mmol, 54.6%) as a yellow oil. LCMS: m / z 242 (M+H) + .

[0340] Step B. Methyl 4-hydroxy-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

[0341] DMF-DMA (4.21 mL, 31.4 mmol) was added to a stirred solution of methyl 4-(3-oxobutamido)cyclohexane-1-carboxylate (3.8 g, 15.7 mmol) in DMF (15 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, 40 g, 0–5% MeOH / DCM) to give methyl 4-[(2E)-2-[(dimethylamino)methylene]-3-oxobutamido]cyclohexane-1-carboxylate (4.2 g, 14.171 mmol, 89.9%) as a yellow solid. LCMS: m / z 297 (M+H) + .

[0342] Step C. (1s,4s)-4-(4-chloro-3-formyl-2-oxopyridin-1(2H)-yl)cyclohexane-1-carboxylic acid methyl ester

[0343] At 0 °C, POCl3 (6.605 mL, 70.857 mmol) was added dropwise to DMF (15 mL), and the mixture was stirred for 15 minutes. Then, 15 mL of DMF containing methyl 4-[(2E)-2-[(dimethylamino)methylene]-3-oxobutamido]cyclohexane-1-carboxylate (4.2 g, 14.1 mmol) was added. The reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was concentrated under vacuum to remove excess POCl3. The residue was poured into water and neutralized with a saturated aqueous solution of NaHCO3, and then extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, concentrated under vacuum, and purified by column chromatography (silica gel, 40 g, 0–100% EtOAc / PE) to give methyl (1S,4S)-4-(4-chloro-3-formyl-2-oxo-1,2-dihydropyridin-1-yl)cyclohexane-1-carboxylate (2.3 g, 7.7 mmol, 54.5%) as a yellow oil. LCMS: m / z 298 (M+H) + .

[0344] Step D. (1s,4s)-4-(4-oxo-1,4-dihydro-5H-pyrazolo[4,3-c]pyridin-5-yl)cyclohexane-1-carboxylic acid methyl ester

[0345] A solution of (1s,4s)-4-(4-chloro-3-formyl-2-oxo-1,2-dihydropyridin-1-yl)cyclohexane-1-carboxylate (2.2 g, 7.3 mmol) in dioxane (20 mL) was mixed with N₂H₄·H₂O (3.69 g, 73.8 mmol). The reaction mixture was stirred at 120 °C for 2 h. The cooled reaction mixture was concentrated under vacuum and purified by column chromatography (silica gel, 24 g, 0–10% MeOH / DCM) to give (1s,4s)-4-{4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-5-yl}cyclohexane-1-carboxylate (2.0 g, 7.26 mmol, 98.3%) as a yellow solid. LCMS: m / z 276 (M+H) + .

[0346] Step E. (1s,4s)-4-(4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydro-5H-pyrazolo[4,3-c]pyridin-5-yl)cyclohexane-1-carboxylic acid methyl ester

[0347] At 0 °C, NaH (130.7 mg, 5.4 mmol) was added to a stirred solution of (1s,4s)-4-{4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-5-yl}cyclohexane-1-carboxylate (500 mg, 1.81 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 0.5 h, and then SEM-Cl (0.38 mL, 2.17 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 24 g, 0–70% EtOAc / PE) to give methyl (1S,4S)-4-(4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrazolo[4,3-c]pyridin-5-yl)cyclohexane-1-carboxylate (600 mg, 1.48 mmol, 81.5%) as a pale yellow solid. LCMS: m / z 406 (M+H) + .

[0348] Step F. (1s,4s)-4-(4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydro-5H-pyrazolo[4,3-c]pyridin-5-yl)cyclohexane-1-carboxylic acid

[0349] Add 2 mL of H₂O containing 296 mg (7.39 mmol) to a stirred solution of (1s,4s)-4-(4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrazolo[4,3-c]pyridin-5-yl)cyclohexane-1-carboxylate (600 mg, 1.48 mmol) in MeOH (3 mL). Stir the reaction mixture at room temperature for 2 hours. Adjust the pH of the reaction mixture to 3–4 and extract with EA. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give the crude product (1s,4s)-4-(4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrazolo[4,3-c]pyridin-5-yl)cyclohexane-1-carboxylic acid (500 mg, 1.277 mmol, 86.3%) as a pale yellow solid. LCMS: m / z 392 (M+H) + .

[0350] Step G.(1s,4s)-N-(2-hydroxyethyl)-N-methyl-4-(4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-2,4-dihydro-5H-pyrazolo[4,3-c]pyridin-5-yl)cyclohexane-1-carboxamide

[0351] To a stirred solution of (1s,4s)-4-(4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrazolo[4,3-c]pyridin-5-yl)cyclohexane-1-carboxylic acid (500 mg, 1.2 mmol) in DCM (10 mL), 2-(methylamino)ethane-1-ol (84.42 mg, 1.40 mmol), DIEA (0.42 mL, 2.55 mmol), and HATU (728 mg, 1.91 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a residue. This residue was purified by column chromatography (silica gel, 24 g, 0–100% EtOAc / PE) to give (1s,4s)-N-(2-hydroxyethyl)-N-methyl-4-(4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridin-5-yl)cyclohexane-1-carboxamide (550 mg, 1.23 mmol, 96.0%) as a white solid. LCMS: m / z 449 (M+H) + .

[0352] Step H.(1s,4s)-N-(2-hydroxyethyl)-4-(7-iodo-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-2,4-dihydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-N-methylcyclohexane-1-carboxamide

[0353] NIS (330 mg, 1.47 mmol) was added to a stirred solution of (1s,4s)-N-(2-hydroxyethyl)-N-methyl-4-(4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridin-5-yl)cyclohexane-1-carboxamide (600 mg, 1.33 mmol) in AcOH (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, extracted with EtOAc, washed with NaHCO3, and dried over Na2SO4. The residue was concentrated under vacuum and purified by column chromatography (silica gel, 24 g, 0–50% EtOAc / PE) to give (1s,4s)-N-(2-hydroxyethyl)-4-(7-iodo-4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridin-5-yl)-N-methylcyclohexane-1-carboxamide (400 mg, 0.69 mmol, 52.1%) as a pale yellow oil. LCMS: m / z 575 (M+H)+ .

[0354] Step I. Methyl 5-((1s,4s)-4-((2-hydroxyethyl)(methyl)carbamoyl)cyclohexyl)-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxylic acid

[0355] Pd(dppf)Cl2.CH2Cl2 (20 mg, mmol) and TEA (0.14 mL, 1.04 mmol) were added to a stirred solution of (1s,4s)-N-(2-hydroxyethyl)-4-(7-iodo-4-oxo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridin-5-yl)-N-methylcyclohexane-1-carboxamide (200 mg, 0.348 mmol) in MeOH (5 mL). The reaction mixture was stirred at 80 °C for 16 hours under a CO atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue, which was then purified by column chromatography (silica gel, 24 g, 0–40% EtOAc / PE) to give methyl 4-oxo-5-[(1s,4s)-4-[(2-hydroxyethyl)(methyl)carbamoyl]cyclohexyl]-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylate (60 mg, 0.11 mmol, 34.0%) as a pale yellow solid. LCMS: m / z 507 (M+H) + .

[0356] Step J.5-((1s,4s)-4-((2-hydroxyethyl)(methyl)carbamoyl)cyclohexyl)-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxylic acid

[0357] Add 2 mL of H₂O containing sodium hydroxide (23.6 mg, 0.59 mmol) to a stirred solution of methyl 4-oxo-5-[(1s,4s)-4-[(2-hydroxyethyl)(methyl)carbamoyl]cyclohexyl]-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylate (60 mg, 0.118 mmol) in MeOH (3 mL). Stir the reaction mixture at room temperature for 2 hours. Adjust the pH of the reaction mixture to 3–4 and extract with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give the crude product 4-oxo-5-[(1s,4s)-4-[(2-hydroxyethyl)(methyl)carbamoyl]cyclohexyl]-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (50 mg, 0.101 mmol, 85.7%) as a pale yellow solid. LCMS: m / z 493 (M+H) + .

[0358] Step KN-((R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-5-((1s,4S)-4-((2-hydroxyethyl)(methyl)carbamoyl)cyclohexyl)-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0359] To a stirred solution of 4-oxo-5-[(1s,4s)-4-[(2-hydroxyethyl)(methyl)carbamoyl]cyclohexyl]-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (50 mg, 0.101 mmol) in DCM (10 mL), (1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethane-1-amine (30.0 mg, 0.15 mmol), DIEA (0.05 mL, 0.30 mmol), and HATU (38.6 mg, 0.10 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (silica gel, 24 g, 0–100% EtOAc / PE) to give N-[(1S)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-oxo-5-[(1S,4S)-4-[(2-hydroxyethyl)(methyl)carbamoyl]cyclohexyl]-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (50 mg, 0.07 mmol, 73.3%) as a white solid. LCMS: m / z 671 (M+H) + .

[0360] Step LN-((R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-5-((1s,4S)-4-((2-hydroxyethyl)(methyl)carbamoyl)cyclohexyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0361] A stirred solution of N-[(1S)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-oxo-5-[(1S,4S)-4-[(2-hydroxyethyl)(methyl)carbamoyl]cyclohexyl]-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (50 mg, 0.074 mmol) in 4N HCl / dioxane (3 mL) was prepared. The reaction mixture was stirred at room temperature for 1 hour and concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (phase A: H₂O (0.1% TFA), phase B: MeCN) to give N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-oxo-5-[(1s,4s)-4-[(2-hydroxyethyl)(methyl)carbamoyl]cyclohexyl]-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (10 mg, 0.018 mmol, 24.8%) as a white solid. NMR(400MHz,MeOD)δ8.34(d,J=132.2Hz,1H),8.14(s,1H),7.56(s,1H),7.44–7.34 (m,2H),5.39–5.31(m,1H),4.58(s,1H),3.71(t,J=5.6Hz,2H),3.52(s,1H),3.17( s,1H),3.11(d,J=17.3Hz,1H),2.97(s,1H),2.60(dq,J=20.7,6.8Hz,2H),2.32–2. 17(m,2H),2.10(s,2H),1.85(s,2H),1.74(s,2H),1.61(d,J=7.0Hz,2H).LCMS:m / z 542(M+H) + .

[0362] Example 12: Synthesis of (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-5-(1-(methanesulfonyl)piperidin-4-yl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0363]

[0364] Step AN-(1-(methanesulfonyl)piperidin-4-yl)-3-oxobutyramide

[0365] 2,2,6-trimethyl-4H-1,3-dioxin-4-one (123 mmol) and NaOAc (18.5 g, 224 mmol) were added to a stirred solution of 1-(methanesulfonyl)piperidin-4-amine (12.0 g, 112 mmol) in dry THF (50 mL). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was poured into water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (silica gel, 40 g, 0–100% EtOAc / PE) to give N-(1-(methanesulfonyl)piperidin-4-yl)-3-oxobutyramide (3.4 g, 21.9 mmol, 18.5%) as a yellow oil. LCMS: m / z 263 (M+H) + .

[0366] Step B. (E)-2-((dimethylamino)methylene)-N-(1-(methanesulfonyl)piperidin-4-yl)-3-oxobutyramide was added dropwise to a stirred solution of N-(1-(methanesulfonyl)piperidin-4-yl)-3-oxobutyramide (3.4 g, 21.9 mmol) in DMF (20 mL) over 5 minutes. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (silica gel, 40 g, 0–10% MeOH / DCM) to give (E)-2-((dimethylamino)methylene)-N-(1-(methanesulfonyl)piperidin-4-yl)-3-oxobutyramide (4.3 g, 20.47 mmol, 97.4%) as a yellow oil. LCMS: m / z 318 (M+H) + .

[0367] Step C. 4-Chloro-1-(1-(methanesulfonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxaldehyde

[0368] At 0 °C, POCl3 (5.0 equivalents) was added dropwise to DMF (20 mL) and the mixture was stirred for 15 minutes. (E)-2-((dimethylamino)methylene)-N-(1-(methanesulfonyl)piperidin-4-yl)-3-oxobutyramide (4.3 g, 20.5 mmol) was added to DMF (10 mL). The reaction mixture was stirred at 100 °C for 1 hour. The cooled reaction mixture was concentrated under vacuum to remove POCl3. The residue was poured into water, neutralized with a saturated aqueous solution of NaHCO3, and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, concentrated under vacuum, and purified by column chromatography (silica gel, 40 g, 0–100% EtOAc / PE) to give 4-chloro-1-(1-(methanesulfonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxaldehyde (1.3 g, 6.03 mmol, 29.4%) as a yellow oil. LCMS: m / z 319 (M+H) + .

[0369] Step D. 5-(1-(methanesulfonyl)piperidin-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0370] N₂H₄·H₂O (60.3 mmol) was added to a solution of 4-chloro-1-(1-(methanesulfonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxaldehyde (1.3 g, 6.03 mmol) in dioxane (20 mL). The reaction mixture was stirred at 120 °C for 4 hours. The reaction mixture was concentrated under vacuum and purified by column chromatography (silica gel, 24 g, 0–10% MeOH / DCM) to give 5-(1-(methanesulfonyl)piperidin-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (900 mg, 4.76 mmol, 78.1%) as a yellow solid. LCMS: m / z 297 (M+H) + .

[0371] Step E.5-(1-(methanesulfonyl)piperidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0372] At 0 °C, NaH (571 mg, 14.3 mmol) was added to a stirred solution of 5-(1-(methanesulfonyl)piperidin-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (900 mg, 4.76 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 0.5 h, and then SEMCl (948 mg, 5.71 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by column chromatography (silica gel, 24 g, 0–70% EtOAc / PE) to give 5-(1-(methanesulfonyl)piperidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (1.2 g, 3.76 mmol, 79.3%) as a pale yellow solid. LCMS: m / z 427 (M+H) + .

[0373] Step E.7-Iodo-5-(1-(methanesulfonyl)piperidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0374] NIS (930 mg, 4.13 mmol) was added to a stirred solution of 5-(1-(methanesulfonyl)piperidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (1.2 g, 3.76 mmol) in AcOH (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 24 g, 0–50% EtOAc / PE) to give 7-iodo-5-(1-(methanesulfonyl)piperidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (1.4 g, 3.13 mmol, 83.7%) as a pale yellow oil. LCMS: m / z 553 (M+H) + .

[0375] Step G. 5-(1-(methanesulfonyl)piperidin-4-yl)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid methyl ester

[0376] Pd(dppf)Cl2 (495 mg, 0.616 mmol) and TEA (6.16 mmol) were added to a stirred solution of 7-iodo-5-(1-(methanesulfonyl)piperidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (1.4 g, 3.13 mmol) in MeOH (5 mL). The reaction mixture was stirred at 80 °C for 16 hours under a CO atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue, which was then purified by column chromatography (silica gel, 24 g, 0–40% EtOAc / PE) to give methyl 5-(1-(methanesulfonyl)piperidin-4-yl)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxylate (530 mg, 1.41 mmol, 44.3%) as a pale yellow solid. LCMS: m / z 485 (M+H) + .

[0377] Step H.5-(1-(methanesulfonyl)piperidin-4-yl)-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxylic acid

[0378] Add 2 mL of H₂O containing 52.80 mg (1.32 mmol) of NaOH to a stirred solution of methyl 5-(1-(methanesulfonyl)piperidin-4-yl)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxylate (50 mg, 0.132 mmol) in MeOH (5 mL). Stir the reaction mixture at room temperature for 2 hours. Adjust the pH of the reaction mixture to 3–4 and extract with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give the crude product 5-(1-(methanesulfonyl)piperidin-4-yl)-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (40 undefined, 0.11 mmol, 80.0%) as a pale yellow solid. LCMS: m / z 471 (M+H) + .

[0379] Step I. (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-5-(1-(methanesulfonyl)piperidin-4-yl)-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0380] To a stirred solution of 5-(1-(methanesulfonyl)piperidin-4-yl)-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (20 mg, 0.055 mmol) in DMF (3 mL), (1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethane-1-amine (16.3 mg, 0.08 mmol), DIPEA (21.46 mg, 0.16 mmol), and HATU (41.84 mg, 0.11 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain a residue. The residue was purified by TLC (100% EtOAc) to give (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-5-(1-(methanesulfonyl)piperidin-4-yl)-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide (20 mg, 0.04 mmol, 66.9%) as a white solid. LCMS: m / z 650 (M+H) + .

[0381] Step J.(R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-5-(1-(methanesulfonyl)piperidin-4-yl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0382] (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-5-(1-(methanesulfonyl)piperidin-4-yl)-4-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide (20 mg, 0.04 mmol) was added to a stirred solution in 4N HCl / dioxane (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to obtain a residue, which was then purified by preparative HPLC (phase A: H₂O (0.1% TFA), phase B: MeCN) to give (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-5-(1-(methanesulfonyl)piperidin-4-yl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxamide (5.3 mg, 0.01 mmol, 35.5%) as a white solid. LCMS: m / z 520 (M+H) + . 1 H NMR (400MHz, MeOD) δ8.54(s,1H),8.28(s,1H),8.14(s,1H),7.54(d,J=7.3Hz,1H),7.44–7.32(m,2H),5.35(q,J=6.7Hz,1H),5.05(d,J=48. 2Hz,1H),3.92(s,2H),3.13(s,2H),2.99(t,J=10.3Hz,2H),2.90(s,3H),2.59(dq,J=21.2,7.0Hz,2H),2.00(s,4H),1.61(d,J=6.7Hz,3H).

[0383] Example 13: Synthesis of (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-5-(3,3-difluorocyclobutyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0384]

[0385] Step A: N-(3,3-difluorocyclobutyl)-3-oxobutyramide

[0386] At room temperature, 3,3-difluorocyclobutane-1-amine (4.56 mL, 49.8 mmol) and NaOAc (12.3 g, 150 mmol) were added to a solution of 2,2,6-trimethyl-2,4-dihydro-1,3-dioxin-4-one (7.87 mL, 59.8 mmol) in THF (60 mL). After stirring overnight at 75 °C, the mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 0-100%, EtOAc / PE) to give N-(3,3-difluorocyclobutyl)-3-oxobutyramide (2.5 g, 13.1 mmol, 26.2%) as a white oil. LC-MS (ESI) m / z: 191 + .

[0387] Step B: (2E)-N-(3,3-difluorocyclobutyl)-2-[(dimethylamino)methylene]-3-oxobutyramide

[0388] At room temperature, DMF-DMA (3.5 mL, 26.2 mmol) was added dropwise to a solution of N-(3,3-difluorocyclobutyl)-3-oxobutyramide (2.5 g, 13.1 mmol) in DMF (30 mL). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 0–10%, MeOH / DCM) to give (2E)-N-(3,3-difluorocyclobutyl)-2-[(dimethylamino)methylene]-3-oxobutyramide (2.5 g, 10.2 mmol, 77.6%) as a white solid. LC-MS (ESI) m / z: 247 + .

[0389] Step C: 4-Chloro-1-(3,3-difluorocyclobutyl)-2-oxo-1,2-dihydropyridine-3-carboxaldehyde

[0390] POCl3 (8.14 mL, 87.3 mmol) was added dropwise to a solution of DMF (70 mL) at 0 °C. After stirring at 0 °C for 15 min, (2E)-N-(3,3-difluorocyclobutyl)-2-[(dimethylamino)methylene]-3-oxobutyramide (4.3 g, 17.5 mmol) was added to a solution of DMF (40 mL) at 0 °C. The reaction mixture was heated to 100 °C and stirred for 1 h. After complete conversion, the mixture was concentrated under reduced pressure. The residue was washed with NaHCO3 and extracted with EtOAc. The mixture was purified by chromatography (silica gel, 0-50%, EtOAc / PE) to give a product of 4-chloro-1-(3,3-difluorocyclobutyl)-2-oxo-1,2-dihydropyridine-3-carboxaldehyde (2.75 g, 11.1 mmol, 63.6%) as a colorless oil. LC-MS(ESI) m / z: 248 + .

[0391] Step D: 5-(3,3-difluorocyclobutyl)-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one

[0392] At room temperature, a solution of N₂H₄ (9.5 g, 190 mmol) was added to a solution of 4-chloro-1-(3,3-difluorocyclobutyl)-2-oxo-1,2-dihydropyridine-3-carboxaldehyde (2.1 g, 8.48 mmol) in dioxane (37 mL). After stirring overnight at 120 °C, the mixture was concentrated and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and then concentrated under reduced pressure. The mixture was purified by chromatography (silica gel, 0–20%, DCM / MeOH) to give a product of 5-(3,3-difluorocyclobutyl)-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (1.8 g, 8.0 mmol, 94.7%) as a colorless oil. LC-MS (ESI) m / z: 226 + .

[0393] Step E: 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one

[0394] At room temperature, TsOH·H₂O (0.08 g, 0.444 mmol) and 3,4-dihydro-2H-pyran (1.12 g, 13.3 mmol) were added to a solution of 5-(3,3-difluorocyclobutyl)-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (1 g, 4.44 mmol) in MeCN (15 mL). After stirring at room temperature for 15 minutes, the mixture was concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 0-50%, EtOAc / PE) to give the product 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (0.9 g, 2.91 mmol, 65.5%) as a white oil. LC-MS (ESI) m / z: 310 + .

[0395] Step F: 5-(3,3-difluorocyclobutyl)-7-iodo-1-(oxan-2-yl)-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one was added to a solution of 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (0.9 g, 2.91 mmol) in AcOH (5 mL) at room temperature. After stirring for 1 hour at room temperature, the mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The mixture was purified by chromatography (silica gel, 0-40%, EtOAc / PE) to give a product of 5-(3,3-difluorocyclobutyl)-7-iodo-1-(oxan-2-yl)-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (0.45 g, 1.03 mmol, 35.5%) as a brown solid. LC-MS (ESI) m / z: 436 + .

[0396] Step G: Methyl 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylate

[0397] Under a CO atmosphere at room temperature, TEA (0.383 mL, 2.76 mmol) and Pd(dppf)Cl2 (0.13 g, 0.184 mmol) were added to a solution of 5-(3,3-difluorocyclobutyl)-7-iodo-1-(oxan-2-yl)-1H,4H,5H-pyrazolo[4,3-c]pyridin-4-one (0.4 g, 0.92 mmol) in MeOH (5 mL). After stirring overnight at 60 °C, the reaction was concentrated. The filtrate was concentrated and purified by chromatography (silica gel, 0-50%, EtOAc / PE) to give methyl 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylate (0.18 g, 0.49 mmol, 53.3%) as a brown oil. LC-MS (ESI) m / z: 368 + .

[0398] Step H: 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylic acid

[0399] At room temperature, a solution of NaOH (1.5 mL, 1.27 mol / L) was added to a solution of methyl 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylate (0.07 g, 0.19 mmol) in MeOH (5 mL). After stirring at room temperature for 1.5 hours, the pH of the mixture was adjusted to 3–4 with 2N HCl (3 mL), and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 0-100%, EtOAc / PE) to give 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (0.06 g, 0.17 mmol, 89.1%) as a white solid. LC-MS (ESI) m / z: 354 + .

[0400] Step I: N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-5-(3,3-difluorocyclobutyl)-2-(oxan-2-yl)-4-oxo-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0401] At room temperature, (R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethane-1-amine (0.02 g, 0.102 mmol), DIPEA (0.04 g, 0.283 mmol), and HATU (0.04 g, 0.113 mmol) were added to a solution of 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (0.02 g, 0.057 mmol) in DMF (2 mL). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-5-(3,3-difluorocyclobutyl)-2-(oxan-2-yl)-4-oxo-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (0.03 g, 0.045 mmol, 79.6%) as a white solid. LC-MS (ESI) m / z: 534 + .

[0402] Step J: N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-5-(3,3-difluorocyclobutyl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0403] At room temperature, 4N HCl / dioxane (2 mL, 8 mmol) was added to a stirred solution of N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-5-(3,3-difluorocyclobutyl)-2-(oxan-2-yl)-4-oxo-2H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (0.06 g, 0.09 mmol) in dioxane (5 mL). After stirring at room temperature for 10 minutes, the mixture was concentrated. The crude product was purified by preparative HPLC (C18, 30–80% MeCN / H2O containing 0.1% HCOOH) to give N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-5-(3,3-difluorocyclobutyl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (0.02 g, 0.045 mmol, 49.5%) as a white solid. LC-MS (ESI) m / z 449 (M+H) + . 1H NMR (400MHz, DMSO) δ8.87(d,J=7.1Hz,1H),8.08(s,1H),7.58(d,J=6.8Hz,1H),7.50–7.39(m,2H),5. 25(p,J=7.0Hz,1H),4.96–4.84(m,1H),3.20–3.07(m,5H),2.68–2.54(m,2H),1.54(d,J=7.0Hz,3H).

[0404] Example 14: Synthesis of (R)-5-(3,3-difluorocyclobutyl)-4-oxo-N-(1-(3-(trifluoromethyl)phenyl)ethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (The subject compound was synthesized from compound 9 in Example 13.)

[0405]

[0406] Step E: 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0407] At room temperature, (R)-1-(3-(trifluoromethyl)phenyl)ethane-1-amine (67.4 mg, 0.357 mmol), DIPEA (128 mg, 0.991 mmol), and HATU (151 mg, 0.396 mmol) were added to a solution of 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (70 mg, 0.198 mmol) in DMF (0.5 mL). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure to give 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (70 mg, 0.08 mmol, 40.4%) as a white solid. LC-MS (ESI) m / z: 534 + .

[0408] Step F: 5-(3,3-difluorocyclobutyl)-4-oxo-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0409] At room temperature, 4N HCl / dioxane (4 mol / L, 5 mL) was added to a stirred solution of 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (70 mg, 0.08 mmol) in dioxane (5 mL). After stirring at room temperature for 1 hour, the mixture was concentrated. The residue was purified by preparative HPLC (C18, 30–80% MeCN / H₂O containing 0.1% TFA) to give the product as a white solid, 5-(3,3-difluorocyclobutyl)-4-oxo-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (15 mg, 0.034 mmol, 42.5%). LC / MS (ESI) m / z: 556 (M+H) + . 1 H NMR(400MHz,MeOD)δ8.38(s,1H),8.14(s,1H),7.69(dd,J=8.5,3.6Hz,2H),7.54(d,J=6.4H z, 2H), 5.33 (q, J = 7.0Hz, 1H), 5.04–4.92 (m, 2H), 3.23–3.02 (m, 4H), 1.63 (d, J = 7.0Hz, 3H).

[0410] Example 15: 5-(3,3-difluorocyclobutyl)-N-[(1R)-1-(4-{2-[(methylamino)methyl]phenyl}thiophen-2-yl)ethyl]-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide. (The subject compound was synthesized from compound 9 in Example 13.)

[0411]

[0412] Step B: N-[(2-{5-[(1R)-1-{[5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-7-yl]carbamate}ethyl]thiophen-3-yl}phenyl)methyl]-N-methylcarbamate

[0413] To a stirred solution of 5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (100 mg, 0.283 mmol) in DMF (2 mL), N-[(2-{5-[(1R)-1-aminoethyl]thiophen-3-yl}phenyl)methyl]-N-methylcarbamate (161 mg, 0.425 mmol), HATU (161 mg, 0.425 mmol), and DIPEA (109 mg, 0.849 mmol) were added. The reaction mixture was stirred at 25 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was then poured into ice water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product purified by silica gel column chromatography (DCM:MeOH = 100:1 to 30:1) to obtain N-[(2-{5-[(1R)-1-{[5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-7-yl]carbamate}ethyl]thiophen-3-yl}phenyl)methyl]-N-methylcarbamate (170 mg, 83%) as a yellow liquid. LC / MS (ESI) m / z: 716.0 (M+H) + .

[0414] Step C: N-[(2-{5-[(1S)-1-{[5-(3,3-difluorocyclobutyl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-7-yl]carbamate}ethyl]thiophen-3-yl}phenyl)methyl]-N-methylcarbamate

[0415] Add HCl (2 mL, 4N) to a stirred solution of N-[(2-{5-[(1R)-1-{[5-(3,3-difluorocyclobutyl)-1-(oxan-2-yl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-7-yl]carbamate}ethyl]thiophen-3-yl}phenyl)methyl]-N-methylcarbamate (80 mg, 0.112 mmol) in DCM (2 mL). Stir the reaction mixture at 25 °C for 1 hour. Dilute the reaction mixture with water (10 mL). Extract the following mixture with DCM (10 mL * 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to obtain N-[(2-{5-[(1S)-1-{[5-(3,3-difluorocyclobutyl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-7-yl]carbamate}ethyl]thiophen-3-yl}phenyl)methyl]-N-methylcarbamate (60 mg, 85%) as a white solid. LC / MS (ESI) m / z: 632.0 (M+H) +

[0416] Step D: N-[(2-{5-[(1S)-1-{[5-(3,3-difluorocyclobutyl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-7-yl]carbamate}ethyl]thiophen-3-yl}phenyl)methyl]-N-methylcarbamate tert-butyl

[0417] Add Pd / C (6 mg, 10% wt) and Boc2O (27 mg, 0.127 mmol) to a solution of N-[(2-{5-[(1S)-1-{[5-(3,3-difluorocyclobutyl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-7-yl]carbamate}ethyl]thiophen-3-yl}phenyl)methyl]-N-methylcarbamate (40 mg, 0.063 mmol) in MeOH (5 mL). The reaction mixture was concentrated to obtain a crude product purified by silica gel column chromatography (DCM:MeOH = 100:1 to 30:1) to give N-[(2-{5-[(1S)-1-{[5-(3,3-difluorocyclobutyl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-7-yl]carbamate}ethyl]thiophen-3-yl}phenyl)methyl]-N-methylcarbamate tert-butyl ester (20 mg, 53%) as a yellow solid. LC / MS (ESI) m / z: 598 (M+H) + .

[0418] Step E: 5-(3,3-difluorocyclobutyl)-N-[(1R)-1-(4-{2-[(methylamino)methyl]phenyl}thiophen-2-yl)ethyl]-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0419] At 0°C, 4N HCl / dioxane (2 mL) was added to a stirred solution of N-[(2-{5-[(1S)-1-{[5-(3,3-difluorocyclobutyl)-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-7-yl]carbamate}ethyl]thiophen-3-yl}phenyl)methyl]-N-methylcarbamate tert-butyl ester (20 mg, 0.033 mmol) in DCM (2 mL). The reaction mixture was stirred at 25°C for 1 hour. The mixture was extracted with EtOAc (5 mL x 3). The combined organic phases were washed with saturated NaHCO3 and water, as well as brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 5-(3,3-difluorocyclobutyl)-N-[(1R)-1-(4-{2-[(methylamino)methyl]phenyl}thiophene-2-yl)ethyl]-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridine-7-carboxamide (10 mg, 60%) as a yellow solid. LC / MS (ESI) m / z: 498 (M+H) + . 1 H NMR (400MHz, CD3OD-d4) δ8.41(s,1H),8.19(s,1H),7.57-7.53(m,1H),7.51–7.41(m,3H),7.14(dd,J=3.6,0.8Hz,1H),7.00(d ,J=3.6Hz,1H),5.59(q,J=6.9Hz,1H),5.05–4.98(m,1H),4.26(s,2H),3.18-3.08(m,4H),2.59(s,3H),1.75(d,J=6.9Hz,3H).

[0420] Example 16: Synthesis of N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-methoxy-5-(oxan-4-yl)-2H-indazole-7-carboxamide

[0421]

[0422] Step A. 3-Bromo-2-fluoro-6-methoxybenzaldehyde.

[0423] LDA (30 mL, 60 mmol, 2 M in THF) was added to a stirred solution of 1-bromo-2-fluoro-4-methoxybenzene (10 g, 48.7 mmol) in 100 mL THF at -70 °C. After stirring at -70 °C for 20 min, DMF (5 mL, 64.6 mmol) was added at -70 °C. After stirring at -70 °C for 20 min, the mixture was poured into NH4Cl (200 mL aqueous solution) and extracted with EtOAc (200 mL * 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give 3-bromo-2-fluoro-6-methoxybenzaldehyde (11 g, 47.2 mmol, 96.8%) as a yellow solid. LC-MS (ESI) m / z 234 (M + H) + .

[0424] Step B. 7-Bromo-4-methoxy-2H-indazole.

[0425] At room temperature, NH₂NH₂·H₂O (36.8 g, 515 mmol, 70% in water) was added to a stirred solution of 3-bromo-2-fluoro-6-methoxybenzaldehyde (12 g, 51.4 mmol) in dioxane (50 mL). After stirring overnight at 110 °C, the cooled mixture was concentrated. The crude product was purified by column chromatography (silica gel, 30–100%, EtOAc / PE) to give 7-bromo-4-methoxy-2H-indazole (10 g, 44.04 mmol, 85%) as a white solid. LC-MS (ESI) m / z 228 (M+H) + .

[0426] Step C. Methyl 4-methoxy-2H-indazole-7-carboxylate.

[0427] Pd(dppf)Cl2 (64 mg, 0.088 mmol) and TEA (0.4 mL, 2.7 mmol) were added to a stirred solution of 7-bromo-4-methoxy-2H-indazole (200 mg, 0.88 mmol) in MeOH (5 mL) at room temperature. After stirring overnight at 70 °C under a CO atmosphere, the cooled mixture was filtered and concentrated. The crude product was purified by chromatography (silica gel, 30-100%, EtOAc / PE) to give methyl 4-methoxy-2H-indazole-7-carboxylate (150 mg, 0.72 mmol, 82%) as a white solid. LC-MS (ESI) m / z 207 (M+H) + .

[0428] Step D. 5-Bromo-4-methoxy-2H-indazole-7-carboxylate.

[0429] NBS (142 mg, 0.80 mmol) was added to a stirred solution of methyl 4-methoxy-2H-indazole-7-carboxylate (150 mg, 0.72 mmol) in DCM (5 mL) and HOAc (5 mL) at room temperature. After stirring overnight at room temperature, the mixture was concentrated. The crude product was poured into NaHCO3 (aqueous solution, 20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 50-100%, EtOAc / PE) to give methyl 5-bromo-4-methoxy-2H-indazole-7-carboxylate (130 mg, 0.45 mmol, 62%) as a white solid. LC-MS (ESI) m / z 286 (M+H) + .

[0430] Step E.5-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-2H-indazole-7-carboxylic acid methyl ester.

[0431] At room temperature, methyl 5-bromo-4-methoxy-2H-indazole-7-carboxylate (200 mg, 0.70 mmol) was added to a stirred solution of dioxane (2 mL) and water (0.5 mL) with (3,6-dihydro-2H-pyran-4-yl)boronic acid (135 mg, 1.052 mmol), Pd(dppf)Cl2 (103 mg, 0.140 mmol), and K2CO3 (291 mg, 2.10 mmol). After stirring at 100 °C for 2 hours, the cooled mixture was filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0-20%, MeOH / DCM) to give methyl 5-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-2H-indazole-7-carboxylate (150 mg, 0.52 mmol, 74%) as a yellow solid. LC-MS(ESI) m / z 289(M+H) + .

[0432] Step F. Methyl 4-methoxy-5-(oxan-4-yl)-2H-indazole-7-carboxylate.

[0433] PtO2 (30 mg, 0.69 mmol) was added to a stirred solution of methyl 5-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-2H-indazole-7-carboxylate (150 mg, 0.52 mmol) in MeOH (10 mL) at room temperature. After stirring at 50 °C for 2 hours under an H2 balloon, the cooled mixture was filtered and concentrated to give methyl 4-methoxy-5-(oxan-4-yl)-2H-indazole-7-carboxylate (120 mg, 0.413 mmol, 79%) as a brown solid. LC-MS (ESI) m / z 291 (M+H) + .

[0434] Step G: 4-methoxy-5-(oxan-4-yl)-2H-indazole-7-carboxylic acid.

[0435] At room temperature, LiOH (173 mg, 4.13 mmol) was added to a stirred solution of methyl 4-methoxy-5-(oxan-4-yl)-2H-indazole-7-carboxylic acid (120 mg, 0.41 mmol) in MeOH (5 mL) and water (5 mL). After stirring at 40 °C for 2 hours, the cooled mixture was concentrated to give crude 4-methoxy-5-(oxan-4-yl)-2H-indazole-7-carboxylic acid (115 mg, 0.41 mmol, 100%) as a brown solid. LC-MS (ESI) m / z 300 (M+H) + .

[0436] Step HN-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethyl]-4-methoxy-5-(oxane-4-yl)-2H-indazole-7-carboxamide.

[0437] At room temperature, (1R)-1-(1,1-difluoro-2,3-dihydro-1H-indazole-7-carboxylic acid (115 mg, 0.41 mmol) in acetonitrile (10 mL) and DMF (5 mL) with stirring was added with (1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethane-1-amine (123 mg, 0.62 mmol), HATU (316 mg, 0.83 mmol), and DIPEA (0.5 mL, 2.8 mmol). After stirring overnight at 70 °C, the cooled mixture was poured into water (30 mL) and extracted with EtOAc (30 mL * 2). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-20%, MeOH / DCM) and then by preparative HPLC (C18, 30-80% MeCN / H2O containing 0.1% HCOOH) to give N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-methoxy-5-(oxan-4-yl)-2H-indazole-7-carboxamide (7 mg, 0.015 mmol, 3%). LC-MS (ESI) m / z 456 (M+H) + . 1 H NMR (400MHz, MeOD) δ8.33(s,1H),7.94(s,1H),7.59(d,J=6.3Hz,1H),7.38(d,J=6.7Hz,2H),5.40(d,J=7.0Hz,1H),4.30(s,3H),4.07(d,J=8.7Hz,2H ),3.61(t,J=11.6Hz,2H),3.13(s,1H),2.64–2.55(m,2H),2.03–1.94(m,2 H), 1.71 (d, J = 12.6Hz, 2H), 1.61 (d, J = 6.9Hz, 3H), 1.33 (d, J = 25.3Hz, 2H).

[0438] Example 17: Synthesis of N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-methoxy-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-indazole-7-carboxamide. (The subject compound was synthesized from compound 5 in Example 16.)

[0439]

[0440] Step A. Methyl 4-methoxy-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-indazole-7-carboxylate.

[0441] At room temperature, 1-methyl-5-(tetramethyl-1,3,2-dioxaborhexane-7-carboxylate 130 mg, 0.456 mmol), Pd(dppf)Cl2 (67 mg, 0.091 mmol), and K2CO3 (189 mg, 1.368 mmol) were added to a stirred solution of methyl 5-bromo-4-methoxy-2H-indazole-7-carboxylate (130 mg, 0.456 mmol) in dioxane (2 mL) and water (0.5 mL). After stirring at 100 °C for 2 hours, the cooled mixture was filtered and concentrated. The crude product was purified by chromatography (silica gel, 0-20%, MeOH / DCM) to give methyl 4-methoxy-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-indazole-7-carboxylate (120 mg, 0.383 mmol, 84%) as a yellow solid. LC-MS (ESI) m / z 314 (M+H) + .

[0442] Step B: 4-Methoxy-5-(1-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-indazole-7-carboxylic acid.

[0443] At room temperature, LiOH (160 mg, 3.830 mmol) was added to a stirred solution of methyl 4-methoxy-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-indazole-7-carboxylic acid (120 mg, 0.383 mmol) in MeOH (5 mL) and water (5 mL). After stirring at 40 °C for 2 hours, the cooled mixture was concentrated to give crude 4-methoxy-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-indazole-7-carboxylic acid (115 mg, 0.384 mmol, 100%) as a white solid. LC-MS (ESI) m / z 300 (M+H) + .

[0444] Step CN-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethyl]-4-methoxy-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-indazole-7-carboxamide.

[0445] At room temperature, (1R)-1-(1,1-difluoro-2,3-dihydro-1H-indazole-7-carboxylic acid (115 mg, 0.384 mmol) was added to a stirred solution of 4-methoxy-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-indazole-7-carboxylic acid (115 mg, 0.384 mmol), HATU (292 mg, 0.768 mmol), and DIPEA (0.5 mL, 2.810 mmol) in acetonitrile (10 mL) and DMF (5 mL). After stirring overnight at 70 °C, the cooled mixture was poured into water (30 mL) and extracted with EtOAc (30 mL * 2). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was subjected to chromatography (silica gel, 0-20%, MeOH / DCM) and then purified by preparative HPLC (C18, 30-80% MeCN / H2O containing 0.1% HCOOH) to give N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-methoxy-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-indazole-7-carboxamide (2 mg, 0.004 mmol, 1%). LC-MS (ESI) m / z 479 (M+H) + . 1 H NMR (400MHz, MeOD) δ8.43(s,2H),7.97(s,1H),7.88–7.78(m,2H),7.59–7.46(m,2H),7.37(d,J=7.9Hz,2H),6.61(d,J=9.1 Hz, 1H), 5.39 (d, J = 6.8Hz, 1H), 4.27 (s, 3H), 3.65 (s, 3H), 3.00 (s, 2H), 2.60 (dd, J = 14.3, 7.1Hz, 2H), 1.59 (d, J = 6.7Hz, 3H).

[0446] Example 18: Synthesis of N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-methoxy-5-(morpholin-4-yl)-2H-indazole-7-carboxamide (The title compound was synthesized from compound 5 in Example 16.)

[0447]

[0448] Step A. Methyl 5-bromo-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylic acid.

[0449] At 0 °C, methyl 5-bromo-4-methoxy-2H-indazole-7-carboxylate (900 mg, 3.16 mmol) was added to a stirred solution of methyl 5-bromo-4-methoxy-2H-indazole-7-carboxylate (900 mg, 3.16 mmol) in 20 mL of THF. After stirring at 0 °C for 20 min, SEM-Cl (0.9 mL, 4.735 mmol) was added at 0 °C. After stirring at 0 °C for 1 hour, the mixture was poured into ice water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-50%, EtOAc / PE) to give methyl 5-bromo-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylate (700 mg, 1.68 mmol, 53%) as a white solid. LC-MS(ESI) m / z 415(M+H) + .

[0450] Step B. 5-Bromo-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylic acid.

[0451] At room temperature, LiOH (202 mg, 4.81 mmol) was added to a stirred solution of methyl 5-bromo-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylic acid (200 mg, 0.48 mmol) in MeOH (5 mL) and water (5 mL). After stirring at 40 °C for 2 hours, the cooled mixture was concentrated to give crude 5-bromo-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylic acid (193 mg, 0.48 mmol, 99.87%) as a white solid. LC-MS (ESI) m / z 401 (M+H) + .

[0452] Step C. 5-Bromo-N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethyl]-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxamide.

[0453] At room temperature, (1R)-1-(1,1-difluoro-2,3-dihydro-1H-indazole-7-carboxylic acid (193 mg, 0.481 mmol) was added to a stirred solution of 5-bromo-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylic acid (193 mg, 0.481 mmol), HATU (365 mg, 0.96 mmol), and DIPEA (0.5 mL, 2.81 mmol) in acetonitrile (10 mL) and DMF (5 mL). After stirring overnight at 70 °C, the cooled mixture was poured into water (30 mL) and extracted with EtOAc (30 mL * 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-20%, MeOH / DCM) to give 5-bromo-N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxamide (120 mg, 0.20 mmol, 43%) as a brown solid. LC-MS (ESI) m / z 456 (M+H) + .

[0454] Step DN-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethyl]-4-methoxy-5-(morpholin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxamide.

[0455] At room temperature, morpholine (0.1 mL, 0.62 mmol), Ru-phos (20 mg, 0.04 mmol), RuPhosPd G3 (17 mg, 0.02 mmol), and Cs2CO3 (135 mg, 0.41 mmol) were added to a stirred solution of 5-bromo-N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethyl]-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxamide (120 mg, 0.20 mmol) in dioxane (5 mL). After stirring at 100 °C for 1 hour, the cooled mixture was filtered and concentrated. The crude product was purified by chromatography (silica gel, 0-20%, MeOH / DCM) to give N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-methoxy-5-(morpholin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxamide (55 mg, 0.09 mmol, 45%) as a yellow solid. LC-MS (ESI) m / z 587 (M+H) + .

[0456] Step EN-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethyl]-4-methoxy-5-(morpholin-4-yl)-2H-indazole-7-carboxamide.

[0457] At room temperature, 4N dioxane / HCl (2 mL, 2 M) was added to a stirred solution of N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-methoxy-5-(morpholin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxamide (55 mg, 0.094 mmol) in dioxane (5 mL). After stirring at 40 °C for 1 hour, the cooled mixture was concentrated. The crude product was purified by preparative HPLC (C18, 30–80% MeCN / H2O containing 0.1% NH3·H2O) to give N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-methoxy-5-(morpholin-4-yl)-2H-indazole-7-carboxamide (17 mg, 0.037 mmol, 40%) as a white solid. LC-MS (ESI) m / z 457 (M+H) + . 1H NMR (400MHz, DMSO) δ12.87(s,1H),8.93(d,J=7.1Hz,1H),8.26(s,1H),7.87(s,1H),7.61(d,J=5.3Hz,1H),7.43(d,J=6.2Hz,2H),5 .30(t,J=7.1Hz,1H),4.21(s,3H),3.80–3.76(m,4H),3.15(d,J=6.0Hz,2H),3.03(s,4H),2.68–2.59(m,2H),1.54(d,J=7.0Hz,3H).

[0458] Example 19: Synthesis of N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxamide. (The subject compound was synthesized from compound 5 in Example 16.)

[0459]

[0460] Step A. Methyl 5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxylic acid.

[0461] At room temperature, methyl 5-bromo-4-methoxy-2H-indazole-7-carboxylate (500 mg, 1.75 mmol) was added to a stirred solution of dioxane (4 mL) and water (1 mL) along with 1150655-04-1 (434 mg, 2.63 mmol), S-Phos (144 mg, 0.35 mmol), Pd(OAc)2 (40 mg, 0.17 mmol), and K3PO4 (1.11 g, 5.26 mmol). After stirring at 100 °C for 2 hours, the cooled mixture was filtered and concentrated. The crude product was purified by chromatography (silica gel, 0-40%, MeOH / DCM) to give methyl 5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxylate (85 mg, 0.32 mmol, 18%) as a brown solid. LC-MS (ESI) m / z 264 (M+H) + .

[0462] Step B: 5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxylic acid.

[0463] At room temperature, LiOH (135 mg, 3.22 mmol) was added to a stirred solution of methyl 5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxylic acid (85 mg, 0.32 mmol) in MeOH (5 mL) and water (5 mL). After stirring at 40 °C for 2 hours, the cooled mixture was concentrated to give crude 5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxylic acid (80 mg, 0.32 mmol, 99%) as a white solid. LC-MS (ESI) m / z 250 (M+H) + .

[0464] Step CN-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethyl]-5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxamide.

[0465] At room temperature, (1R)-1-(1,1-difluoro-2,3-dihydro-1H-indazole-7-carboxylic acid (40 mg, 0.16 mmol) was added to a stirred solution of 5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxylic acid (40 mg, 0.16 mmol) in DMF (10 mL), along with diphenyl ether (DPEA) (0.2 mL, 1.12 mmol) and HATU (122 mg, 0.32 mmol). After stirring at 70 °C for 2 hours, the cooled mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (C18, 30–80% MeCN / H2O containing 0.1% HCOOH) to give N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxamide (8 mg, 0.019 mmol, 12%) as a white solid. LC-MS (ESI) m / z 429 (M+H) + . 1 H NMR(400MHz,MeOD)δ8.51(s,1H),7.95(s,1H),7.59(d,J=6.9Hz,1H),7.42–7.35(m,2H),5.40(q,J=7.0Hz,1H),4.46( s,3H),4.30(s,2H),3.25(d,J=7.0Hz,1H),3.16–3.09(m,1H),2.81(s,6H),2.65–2.54(m,2H),1.61(d,J=7.0Hz,3H).

[0466] Example 20: Synthesis of N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxamide. (The subject compound was synthesized from compound 7 in Example 19.)

[0467]

[0468] Step AN-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxamide.

[0469] At room temperature, 2-{3-[(1R)-1-aminoethyl]phenyl}-2,2-difluoroethane-1-ol (32 mg, 0.16 mmol), DIPEA (0.2 mL, 1.12 mmol), and HATU (122 mg, 0.32 mmol) were added to a stirred solution of 5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxylic acid (40 mg, 0.16 mmol) in DMF (10 mL). After stirring at 70 °C for 2 hours, the cooled mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (DCM containing 10% MeOH) and then by preparative HPLC (C18, 30–80% MeCN / H2O containing 0.1% HCOOH) to give N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-5-[(dimethylamino)methyl]-4-methoxy-2H-indazole-7-carboxamide (7 mg, 0.016 mmol, 10%) as a white solid. LC-MS (ESI) m / z 433 (M+H) + . 1 H NMR(400MHz,MeOD)δ8.53(s,1H),7.92(s,1H),7.61(s,1H),7.57(d,J=7.0Hz,1H),7.47–7.41(m,2H),5.3 7(d,J=7.1Hz,1H),4.48(s,3H),4.38(s,2H),3.88(t,J=13.5Hz,2H),2.88(s,6H),1.63(d,J=7.1Hz,3H).

[0470] Example 21: Synthesis of (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-3-methyl-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide. (The subject compound was synthesized from compound 5 in Example 16.)

[0471]

[0472] Step A. Methyl 3-bromo-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate

[0473] NBS (47.7 mg, 0.27 mmol) was added to a stirred solution of methyl 5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylate (60 mg, 0.24 mmol) in AcOH (1 mL) and DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with aqueous NaHCO3 solution, dried over Na2SO4, and concentrated under vacuum to obtain a residue, which was purified by column chromatography (silica gel, 24 g, 0–100% EtOAc / PE) to give methyl 3-bromo-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylate (60 mg, 0.19 mmol, 75.7%) as a colorless solid. LCMS: m / z 326(M+H) + .

[0474] Step B. Methyl 3-methyl-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate

[0475] To a stirred solution of methyl 3-bromo-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylate (60 mg, 0.185 mmol) in dioxane (3 mL) and H₂O (1 mL), trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (0.08 mL, 0.55 mmol), Pd(dppf)Cl₂ (13.5 mg, 0.02 mmol), and K₂CO₃ (76.5 mg, 0.55 mmol) were added. The reaction mixture was stirred at 70 °C for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue, which was then purified by column chromatography (silica gel, 24 g, 0–80% EtOAc / PE) to give methyl 3-methyl-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylate (10 mg, 0.04 mmol, 20.8%) as a pale yellow solid. LCMS: m / z 261 (M+H) + .

[0476] Step C. 3-Methyl-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid

[0477] To a stirred solution of methyl 3-methyl-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (10 mg, 0.04 mmol) in MeOH (3 mL), 2 mL of H₂O containing LiOH (15.37 mg, 0.38 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 3–4 and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give crude 3-methyl-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (6 mg, 0.02 mmol, 63.4%) as a pale yellow solid. LCMS: m / z 247 (M+H) + .

[0478] Step D.(R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-3-methyl-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide

[0479] To a stirred solution of 3-methyl-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (6 mg, 0.024 mmol) in DMF (3 mL), (1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethane-1-amine (5.77 mg, 0.03 mmol), DIPEA (15.84 mg, 0.12 mmol), and HATU (13.9 mg, 0.037 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a residue. The residue was purified by TLC (100% EtOAc) to obtain a crude product, which was then purified by preparative HPLC to obtain N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-3-methyl-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxamide (5 mg, undefined, 0.01 mmol, 48.2%) as a white solid. 1 HNMR(400MHz,MeOD)δ8.08(s,1H),7.62–7.51(m,1H),7.48–7.31(m,2H),6.35(d,J=0.9Hz,1H),5.40–5.14(m,1H),3.10(ddd,J=16.9,9.3,5.3Hz,1 H),2.60(tt,J=14.4,7.2Hz,2H),2.33(d,J=0.7Hz,3H),1.58(d,J=7.1Hz,3H),1.55(s,3H),1.18(d,J=6.8Hz,2H),1.04(t,J=5.9Hz,2H).LCMS:m / z 426(M+H) + .

[0480] Example 22: Synthesis of N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxamide. (The subject compound was synthesized from compound 5 in Example 16.)

[0481]

[0482] Step A. Methyl 4-methoxy-5-(tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2H-indazole-7-carboxylate.

[0483] At room temperature, KOAc (516 mg, 5.26 mmol), Pd(dppf)Cl2 (128 mg, 0.17 mmol), and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-oxaborhexacyclopentane (0.7 mL, 2.63 mmol) were added to a stirred solution of methyl 5-bromo-4-methoxy-2H-indazole-7-carboxylate (500 mg, 1.21 mmol, 69%) in dioxane (20 mL). After stirring overnight at 100 °C, the cooled mixture was concentrated to give the crude product methyl 4-methoxy-5-(tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2H-indazole-7-carboxylate (400 mg, 1.21 mmol, 69%) as a brown solid. LCMS:m / z 333(M+H) + .

[0484] Step B. Methyl 5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxylate.

[0485] At room temperature, methyl 4-methoxy-5-(tetramethyl-1,3,2-dioxaborpine-2-yl)-2H-indazole-7-carboxylate (300 mg, 0.91 mmol) was added to a stirred solution of methyl 4-methoxy-5-(tetramethyl-1,3,2-dioxaborpine-2-yl)-2H-indazole-7-carboxylate (300 mg, 0.09 mmol) in H₂O (3 mL) / dioxane (5 mL). After stirring at 100 °C for 3 hours, the cooled mixture was poured into water (20 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-20%, MeOH / DCM) to give methyl 5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxylate (100 mg, 0.367 mmol, 40%) as a brown solid. LCMS: m / z 273 (M+H) + .

[0486] Step C. 5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxylic acid.

[0487] At room temperature, LiOH (88 mg, 3.67 mmol) was added to a stirred mixture of methyl 5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxylic acid (100 mg, 0.37 mmol) in MeOH (3 mL) / H₂O (3 mL). After stirring at room temperature for 2 hours, the mixture was concentrated to give 5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxylic acid (90 mg, 0.35 mmol, 95%) as a white solid. LCMS: m / z 259 (M+H) + .

[0488] Step DN-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethyl]-5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxamide.

[0489] At room temperature, (1R)-1-(1,1-difluoro-2,3-dihydro-1H-indazole-7-carboxylic acid (40 mg, 0.155 mmol) was added to a stirred mixture of 5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxylic acid (40 mg, 0.155 mmol) in DMF (5 mL). After stirring at 60 °C for 2 hours, the cooled mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM:MeOH = 10:1) and then by preparative HPLC (C18, H₂O containing 40–90% MeCN and 0.1% HCOOH) to give N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxamide (2 mg, 0.005 mmol, 3%) as a white solid. LCMS: m / z 438 (M+H) + . 1 H NMR(400MHz,MeOD)δ8.46(d,J=17.3Hz,2H),8.14(s,1H),7.66–7.59(m,2H),7.41–7.34(m,2H),5.40(q,J=7.0Hz, 1H), 4.42 (s, 3H), 3.27 (s, 1H), 3.12 (dd, J = 15.9, 5.8Hz, 1H), 2.61 (dt, J = 20.7, 6.9Hz, 2H), 1.62 (d, J = 7.0Hz, 3H).

[0490] Example 23: Synthesis of N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxamide. (The subject compound was synthesized from compound 8 in Example 22.)

[0491]

[0492] Step AN-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxamide.

[0493] At room temperature, 2-{3-[(1R)-1-aminoethyl]phenyl}-2,2-difluoroethane-1-ol (37 mg, 0.18 mmol), HATU (118 mg, 0.31 mmol), and DIPEA (0.7 mL, 0.77 mmol) were added to a stirred mixture of 5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxylic acid (40 mg, 0.15 mmol, from N201220-7) in DMF (3 mL). After stirring at 60 °C for 2 hours, the cooled mixture was poured into water (20 mL) and extracted with EtOAc (20 mL * 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM:MeOH = 8:1) and then by preparative HPLC (C18, H₂O containing 40–90% MeCN and 0.1% HCOOH) to give N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-5-(1H-imidazol-5-yl)-4-methoxy-2H-indazole-7-carboxamide (2 mg, 0.005 mmol, 3%) as a white solid. LCMS: m / z 442 (M+H) + . 1 H NMR(400MHz,MeOD)δ8.50(s,1H),8.37(s,2H),7.71(s,1H),7.63(s,1H),7.58(d,J=7.3Hz,1H),7 .47–7.41(m,2H),5.39–5.34(m,1H),4.44(s,3H),3.88(t,J=13.5Hz,2H),1.64(d,J=7.0Hz,3H).

[0494] Example 24: Synthesis of 5-(1-aminoethyl)-N-((R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-4-methoxy-2H-indazole-7-carboxamide. (The subject compound was synthesized from compound 5 in Example 16.)

[0495]

[0496] Step A. Methyl 5-acetyl-4-methoxy-2H-indazole-7-carboxylate.

[0497] At room temperature, TEA (1.4 mL, 10.5 mmol) and Pd(PPh3)2Cl2 (245 mg, 351 mmol) were added to a stirred solution of methyl 5-bromo-4-methoxy-2H-indazole-7-carboxylate (1.00 g, 3.51 mmol) in dioxane (15 mL). The resulting mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The cooled reaction mixture was diluted with 2 mol / L HCl (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-40%, EtOAc / PE) to give methyl 5-acetyl-4-methoxy-2H-indazole-7-carboxylate (420 mg, 1.69 mmol, 48.2%) as a white solid. LC-MS(ESI) m / z 249(M+H) + .

[0498] Step B. Methyl 5-acetyl-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate

[0499] At 0 °C, methyl 5-acetyl-4-methoxy-2H-indazole-7-carboxylate (500 mg, 2.01 mmol) was added to a stirred solution of methyl 5-acetyl-4-methoxy-2H-indazole-7-carboxylate (500 mg, 2.01 mmol) in 10 mL of THF. After stirring at 0 °C for 20 min, SEMCl (503 mg, 3.02 mmol) was added. The resulting mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into a saturated NaHCO3 solution and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-5% MeOH / DCM containing 0.5% TEA) to give methyl 5-acetyl-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate (260 mg, 0.69 mmol, 34.1%) as a brown solid. LC-MS(ESI) m / z 378.9(M+1) + .

[0500] Step C. Methyl 5-(1-hydroxyethyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate.

[0501] At 0 °C, methyl 5-acetyl-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate (200 mg, 0.529 mmol) was added to a stirred solution in DCM / MeOH (10 mL / 2 mL). After stirring at 0 °C for 20 min, the reaction mixture was quenched with water and extracted with DCM (30 mL * 2). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give methyl 5-(1-hydroxyethyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate (200 mg, 0.526 mmol) as a brown oil. LC-MS (ESI) m / z 381.1 (M+1) + .

[0502] Step D. Methyl 5-(1-azidoethyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate

[0503] At room temperature, DBU (240 mg, 1.57 mmol) and DPPA (275 mg, 434 mg) were added to a stirred solution of methyl 5-(1-hydroxyethyl)-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylate (200 mg, 0.526 mmol) in toluene (8 mL). The resulting mixture was stirred at 55 °C for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-30%, EtOAc / PE) to give methyl 5-(1-azidoethyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate (35 mg, 0.086 mmol, 16.4%) as a white solid. LC-MS(ESI) m / z 406.1(M+1) + .

[0504] Step E. 5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylic acid methyl ester

[0505] At room temperature, methyl 5-(1-azidoethyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate (35 mg, 0.086 mmol) was added to a stirred solution of methyl 5-(1-azidoethyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate (30 mg, 0.063 mmol, 72.4%) in THF (8 mL) with Boc₂O (94.3 mg, 0.432 mmol) and Pd / C (50 mg, 20% wet). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered. The filtrate was concentrated. The crude product was purified by preparative TLC (PE / EA = 3 / 1) to give methyl 5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate (30 mg, 0.063 mmol, 72.4%) as a white solid. LC-MS (ESI) m / z 480.1 (M+1) + .

[0506] Step F. 5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylic acid.

[0507] At room temperature, LiOH (11.0 mg, 0.26 mmol) was added to a stirred solution of methyl 5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate (25 mg, 0.052 mmol) in MeOH / THF / H₂O (2:2:1) (8 mL). The resulting mixture was stirred at 40 °C for 40 min. The reaction mixture was concentrated. The residue was diluted with water (3 mL) and the pH was adjusted to 6 with 1 N HCl. The mixture was extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give 5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylic acid (20 mg, 0.043 mmol, 82.4%) as a white solid. LC-MS (ESI) m / z 466.1 (M+1) + .

[0508] Step G. (1-(7-(((R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)carbamoyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethyl)tert-butyl carbamate

[0509] At room temperature, DIPEA (17 mg, 0.129 mmol) and (1R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethane-1-amine (13 mg, 0.065 mmol) were added to a stirred solution of 5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indole-7-carboxylic acid (20 mg, 0.043 mmol) in DMF (8 mL). Then, HATU (25 mg, 0.065 mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes and quenched with saturated NaHCO3 solution, and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (PE / EA = 3 / 1) to give tert-butyl (1-(7-(((R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)carbamoyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethyl)carbamate (18 mg, 0.028 mmol, 65%) as a white solid. LC-MS (ESI) m / z 645.1 (M+1) + .

[0510] Step H.5-(1-aminoethyl)-N-((R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethyl)-4-methoxy-2H-indazole-7-carboxamide.

[0511] Add 4 mol / L 4NHCl / dioxane (0.07 mL, 0.280 mmol) to a stirred solution of (1-(7-((((R)-1-(1,1-difluoro-2,3-dihydro-1H-indene-4-yl)ethyl)carbamoyl)-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethyl)carbamate (18 mg, 0.028 mmol) in dioxane (2 mL). Stir the resulting mixture at room temperature for 30 min. Quench the reaction mixture with saturated NaHCO3 solution and extract with EtOAc (20 mL * 2). Wash the combined organic phases with brine, dry over Na2SO4, filter, and concentrate. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1) to give 5-(1-aminoethyl)-N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-methoxy-2H-indazole-7-carboxamide (5 mg, 0.012 mmol, 43.2%) as a white solid. LC-MS (ESI) m / z 413.1 (M⁻¹) - . 1 H NMR (400MHz, DMSO) δ13.13(s,1H),8.93(d,J=14.3Hz,1H),8.49(s,1H),8.28(d,J=52Hz,3H),7.68(s,1H),7.42(d,J= 6.5Hz,2H),5.39-5.16(m,1H),4.70(s,1H),4.33(s,3H),3.17(d,J=1.1Hz,2H),2.85-2.54(m,2H),1.74–1.46(m,6H),

[0512] Example 25: Synthesis of (R)-5-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-1,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0513]

[0514] Step A. 4-Chloro-2-methyl-6-(methylamino)pyrimidine-5-carboxaldehyde

[0515] At room temperature, 2 mol / L MeNH₂ / THF (11.6 mL, 23.2 mmol) was added to a stirred solution of 4,6-dichloro-2-methylpyrimidin-5-carboxaldehyde (4 g, 20.9 mmol) in THF (40 mL). After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (100 mL). The mixture was extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated to give 4-chloro-2-methyl-6-(methylamino)pyrimidin-5-carboxaldehyde (3.8 g, 19.4 mmol, 92.9%) as a yellow solid. LC-MS (ESI) m / z 186 (M+H) + .

[0516] Step B. (4-chloro-2-methyl-6-(methylamino)pyrimidin-5-yl)methanol

[0517] To a stirred solution of 3.8 g (19.4 mmol) of 4-chloro-2-methyl-6-(methylamino)pyrimidin-5-carboxaldehyde in 40 mL of MeOH, NaBH4 (810 mg, 21.4 mmol) was added at room temperature. After stirring for 60 minutes at room temperature, the mixture was quenched with 10 mL of water and concentrated. The residue was extracted with DCM (50 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give (4-chloro-2-methyl-6-(methylamino)pyrimidin-5-yl)methanol (3.6 g, 0.184 mmol, 98.2%) as a yellow solid. LC-MS (ESI) m / z 188 (M+H) + .

[0518] Step C. 6-Chloro-5-(chloromethyl)-N,2-dimethylpyrimidin-4-amine

[0519] SOCl2 (2.3 mL, 31.9 mmol) was added to a stirred solution of (4-chloro-2-methyl-6-(methylamino)pyrimidin-5-yl)methanol (120 mg, 0.428 mmol) in DCM (30 mL) at room temperature. After stirring at room temperature for 2 hours, the mixture was poured into NaHCO3 (30 mL) and extracted with DCM (50 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-10%, MeOH / DCM) to give 6-chloro-5-(chloromethyl)-N,2-dimethylpyrimidin-4-amine (3.00 g, 14.557 mmol, 91.0%) as a yellow solid. LC-MS (ESI) m / z 206 (M+H) + .

[0520] Step D. 6-Chloro-N,2-Dimethyl-5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)pyrimidin-4-amine

[0521] At room temperature, K₂CO₃ (2.3 mL, 31.9 mmol) and tetrahydro-2H-pyran-4-amine (1.55 g, 15.2 mmol) were added to a stirred solution of 6-chloro-5-(chloromethyl)-N,2-dimethylpyrimidin-4-amine (3 g, 14.5 mmol) in DMA (30 mL). The resulting mixture was stirred at 50 °C for 2 h. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0–10%, MeOH / DCM) to give 6-chloro-N,2-dimethyl-5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)pyrimidin-4-amine (1.8 g, 6.65 mmol, 45.6%) as a brown solid. LC-MS(ESI) m / z 271(M+H) + .

[0522] Step E. 5-Chloro-1,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0523] CDI (4.68 g, 33.2 mmol) was added to a stirred solution of 6-chloro-N,2-dimethyl-5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)pyrimidin-4-amine (1.8 g, 6.65 mmol) in anhydrous DME (20 mL). The resulting mixture was stirred overnight at 100 °C. After cooling to room temperature, the mixture was poured into NaHCO3 (aqueous solution) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (silica gel, 0-7%, MeOH / DCM) to give 5-chloro-1,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one (600 mg, 2.02 mmol, 30.4%) as a white solid. LC-MS (ESI) m / z 297 (M+H) + .

[0524] Step F.(R)-5-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-1,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0525] At room temperature, K₂CO₃ (30.7 mg, 0.222 mmol) and (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol (60 mg, 0.298 mmol) were added to a stirred solution of 5-chloro-1,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (60 mg, 0.202 mmol) in anhydrous DMA (3 mL). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The cooled reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 15 / 1) to obtain a crude product further purified by preparative HPLC (C18, 20% acetonitrile / H2O containing 0.1% formic acid) to give (R)-5-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-1,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one (3 mg, 0.007 mmol, 3.22%) as a white solid. LC-MS (ESI) m / z 462 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.32 (s, 1H), 7.68 (s, 1H), 7.58 (d, J = 6.6Hz, 1H), 7.54 ~ 7.46 (m, 2H), 4.95 (t, J=13.1Hz, 2H), 4.33 (dd, J=14.0, 10.0Hz, 1H), 4.21 (d, J=6.7Hz, 1H), 4. 10(s,2H),3.94(dd,J=11.1,3.8Hz,2H),3.36(s,2H),3.21(s,3H),2.42(s,3H),2.42 (s, 3H), 1.76 (qd, J = 12.2, 4.6Hz, 2H), 1.52 (d, J = 10.0Hz, 2H), 1.33 (d, J = 6.6Hz, 3H).

[0526] Example 26: Synthesis of (R)-5-((1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)amino)-1,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one. (The subject compound was synthesized from compound 6 in Example 25.)

[0527]

[0528] Step A. 7-(R)-5-((1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)amino)-1,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0529] At room temperature, K₂CO₃ (57.9 mg, 0.420 mmol) and (R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethylamine (50 mg, 0.254 mol) were added to a stirred solution of 5-chloro-1,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (50 mg, 0.168 mmol) in anhydrous DMA (3 mL). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The cooled reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 15 / 1) to obtain a crude product further purified by preparative HPLC (C18, 30% MeOH / H2O containing 0.1% formic acid) to give (R)-5-((1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)amino)-1,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one (1.5 mg, 0.003 mmol, 1.95%) as a white solid. LC-MS (ESI) m / z 458 (M+H) + . 1H NMR (400MHz, DMSO) δ7.71~7.51(m,1H),7.39(d,J=5.3Hz,2H),7.01(d,J=7.5Hz ,1H),5.66~5.25(m,1H),4.45(t,J=12.0Hz,1H),4.17(s,2H),3.98(dd,J=11.1 ,3.9Hz,2H),3.43(d,J=11.4Hz,2H),3.14(s,3H),2.68(s,3H),2.35~2.19(m,5 H), 1.96 (dd, J=12.3, 4.5Hz, 6H), 1.49 (d, J=7.0Hz, 6H), 0.86. (t, J=6.8Hz, 1H).

[0530] Example 27: Synthesis of 4-methoxy-5-(((S)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-2H-indazole-7-carboxamide. (The subject compound was synthesized from compound 5 in Example 16.)

[0531]

[0532] Step E. methyl 5-bromo-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate

[0533] At 0 °C, NaH (0.51 g, 21.0 mmol) was added to a stirred solution of methyl 5-bromo-4-methoxy-2H-indazole-7-carboxylate (2 g, 7.0 mmol) in THF (20 mL). After stirring at 0 °C for 20 min, SEM-Cl (1.4 mL, 8.4 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was poured into NH4Cl (aqueous solution, 50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give methyl 5-bromo-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylate (2.2 g, 5.2 mmol, 75.5%) as a yellow solid. LCMS: m / z 415 (M+H) + .

[0534] Step F. 4-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylic acid methyl ester

[0535] To a stirred solution of methyl 5-bromo-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylate (1.5 g, 3.6 mmol) in dioxane (5 mL), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentane (1.8 mL, 7.2 mmol), Pd(dppf)Cl2 (2.6 g, 3.6 mmol), and AcOK (1.1 g, 10.8 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The cooled reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (silica gel, 25 g, 0–50% EtOAc / PE) to give methyl 4-methoxy-5-(tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylate (1.2 g, 2.5 mmol, 71.8%) as a white solid. LCMS: m / z 463 (M+H) + .

[0536] Step G. Methyl 5-hydroxy-4-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate

[0537] To a stirred solution of methyl 4-methoxy-5-(tetramethyl-1,3,2-dioxaborphane-2-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylate (1.2 g, 2.5 mmol) in MeCN (4 mL), urea hydrogen peroxide (0.3 g) and H₂O (1 mL) containing citric acid (0.1 g, 0.52 mmol) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain a residue. This residue was purified by column chromatography (silica gel, 5 g, 0–4% MeOH / DCM) to give methyl 5-hydroxy-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylate (320 mg, 0.9 mmol, 34.9%) as a pale yellow solid. LCMS: m / z 353 (M+H) + .

[0538] Step H.(S)-4-methoxy-5-((tetrahydrofuran-3-yl)oxy)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylic acid methyl ester

[0539] To a stirred solution of methyl 5-hydroxy-4-methoxy-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylate (320 mg, 0.9 mmol) in DMF (10 mL), oxacyclopentan-3-yl-4-methylbenzene-1-sulfonate (329 mg, 1.3 mmol) and Cs₂CO₃ (887 mg, 2.7 mmol) were added. The reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain a residue. This residue was purified by column chromatography (silica gel, 25 g, 0–50% PE / EtOAc) to give methyl 4-methoxy-5-(oxacyclopentan-3-yloxy)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylate (300 mg, 0.71 mmol, 78.2%) as a white solid. LCMS: m / z 423 (M+H) + .

[0540] Step I. (S)-4-methoxy-5-((tetrahydrofuran-3-yl)oxy)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylic acid

[0541] Methyl 4-methoxy-5-(oxepane-3-yloxy)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylic acid (300 mg, 0.71 mmol) was added to a stirred solution of 4-methoxy-5-(oxepane-3-yloxy)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylic acid (240 mg, 0.58 mmol, 82.7%) in MeOH (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 3–4 and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give crude 4-methoxy-5-(oxepane-3-yloxy)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylic acid (240 mg, 0.58 mmol, 82.7%) as a white solid. LCMS: m / z 409 (M+H) + .

[0542] Step G. 4-Methoxy-5-(((S)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxamide

[0543] To a stirred solution of 4-methoxy-5-(oxepane-3-yloxy)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxylic acid (50 mg, 0.12 mmol) in DMF (3 mL), (1R)-1-[3-(trifluoromethyl)phenyl]ethane-1-amine (27.7 mg, 0.15 mmol), DIEA (0.06 mL, 0.36 mmol), and HATU (69.8 mg, 0.18 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a residue. The residue was purified by TLC (50% EtOAc / PE) to obtain a crude product, which was then purified by preparative HPLC to give 4-methoxy-5-(oxacyclopentan-3-yloxy)-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxamide (60 mg, 0.10 mmol, 84.5%) as a white solid. LCMS: m / z 580 (M+H) + .

[0544] Step K. 4-Methoxy-5-(((S)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-2H-indazole-7-carboxamide

[0545] A stirred solution of 4-methoxy-5-(oxepane-3-yloxy)-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-7-carboxamide (50 mg, 0.086 mmol) was prepared in 4N HCl / dioxane (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (phase A: H₂O (0.1% FA), phase B: MeCN) to give 4-methoxy-5-(oxepane-3-yloxy)-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]-2H-indazole-7-carboxamide (11 mg, 0.02 mmol, 28.3%) as a white solid. LCMS: m / z 450 (M+H) + . 1H NMR(400MHz,MeOD)δ8.26(s,1H),7.85(s,1H),7.75–7.66(m,2H),7.57–7.49(m,2H),5.44–5.31(m,1H),5.04(t,J=4.6Hz,1H),4.26(s,3H),4.11 –4.01(m,2H),3.92(td,J=8.3,3.8Hz,1H),3.85(dd,J=10.1,4.1Hz,1H),2.22(dd,J=12.6,6.1Hz,1H),2.17–2.06(m,1H),1.63(d,J=7.1Hz,3H).

[0546] The examples in Table 2 below were prepared using methods similar to those used to prepare the examples as described herein.

[0547] Table 2

[0548]

[0549]

[0550] Example 32: Synthesis of N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(4-methylpiperazin-1-yl)-1H-indazole-7-carboxamide. (The subject compound was synthesized from compound 5 in Example 16.)

[0551]

[0552] Step E. 5-Bromo-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxylate

[0553] To a solution of methyl 5-bromo-4-methoxy-1H-indazole-7-carboxylate (3 g, 10.5 mmol) in THF (30 mL), NaH (0.63 g, 15.7 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (2.79 mL, 15.7 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was quenched in a saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was subjected to silica gel chromatography (DCM:MeOH = 20:1) to give methyl 5-bromo-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxylate (3 g, 68%) as a yellow solid. LC / MS (ESI) (m / z): 415 (M+H) + .

[0554] Step F. 5-Bromo-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxylic acid

[0555] At 0 °C, methyl 5-bromo-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxylic acid (1 g, 2.408 mmol) in a solution of H₂O (10 mL) / MeOH (10 mL) was added to NaOH (4.815 mL, 1 N). The reaction mixture was stirred at 25 °C for 2 hours. The mixture was concentrated to dryness and the residue was washed with diethyl ether and dried under vacuum to give 5-bromo-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxylic acid (900 mg, 2.24 mmol, 93.2%) as a brown solid, which was used directly in the next step. LC / MS (ESI) (m / z): 401 (M+H) + .

[0556] Step G. 5-Bromo-N-{1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl}-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxamide

[0557] At 0 °C, HATU (1.89 g, 4.98 mmol) and DIEA (1.64 mL, 9.96 mmol) were added to a mixture of 5-bromo-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxylic acid (1 g, 2.49 mmol) and 2-{3-[(1R)-1-aminoethyl]phenyl}-2,2-difluoroethane-1-ol (1.00 g, 4.98 mmol) in DMF (20 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (DCM:MeOH = 97:3) to give 5-bromo-N-{1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl}-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxamide (500 mg, 34%) as a brown solid. LC / MS (ESI) (m / z): 584 (M+H) + .

[0558] Step HN-[(1S)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(4-methylpiperazin-1-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxamide

[0559] Under a nitrogen atmosphere, RuPhos-Pd-G3 (14 mg, 0.017 mmol), RuPhos (16 mg, 0.034 mmol), and Cs2CO3 (167 mg, 0.513 mmol) were added to a mixture of 5-bromo-N-{1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl}-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxamide (100 mg, 0.171 mmol) and 1-methylpiperazine (34 mg, 0.34 mmol) in dioxane (10 mL). The mixture was degassed three times under a nitrogen atmosphere and stirred at 120 °C for 12 hours under a nitrogen atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried, and concentrated to dryness to give a crude product. The crude product was purified by rapid chromatography (DCM:MeOH = 20:1 to 10:1) to give N-[(1S)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(4-methylpiperazin-1-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxamide (10 mg, 9%) as a yellow solid. LC / MS (ESI) (m / z): 604 (M+H) + .

[0560] Step JN-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(4-methylpiperazin-1-yl)-1H-indazole-7-carboxamide

[0561] To a solution of N-[(1S)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(4-methylpiperazin-1-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxamide (10 mg, 0.017 mmol) in DCM (3 mL), HCl (1 mL, 4N) was added and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to give N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(4-methylpiperazin-1-yl)-1H-indazole-7-carboxamide (2.6 mg, 0.005 mmol, 33.2%) as a white solid. LC / MS (ESI) (m / z): 474 (M+H) + . 1 HNMR(400MHz,MeOD-d4)δ8.45(s,1H),8.32(s,1H),7.84(s,1H),7.62(s,1H),7.56(d,J=7.1Hz,1H),7.43(p,J=7.8Hz,2H),5.37 (q,J=7.0Hz,1H),4.31(s,3H),3.88(t,J=13.5Hz,2H),3.31-3.27(m,4H),3.25-3.10(M,4H),2.76(s,3H),1.63(d,J=7.1Hz,3H).

[0562] Example 33: N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(4-methylpiperazin-1-yl)-1H-indazole-7-carboxamide. (The subject compound was synthesized from compound 9 in Example 32.)

[0563]

[0564] Step A. 4-(7-{[(1S)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]carbamoyl}-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-5-yl)piperazine-1-carboxylic acid tert-butyl ester

[0565] Under a nitrogen atmosphere, RuPhos-Pd-G3 (14 mg, 0.017 mmol), RuPhos (15 mg, 0.034 mmol), and Cs2CO3 (167 mg, 0.513 mmol) were added to a mixture of 5-bromo-N-{1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl}-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxamide (100 mg, 0.171 mmol) and piperazine-1-carboxylic acid tert-butyl ester (63 mg, 0.342 mmol) in dioxane (5 mL). The mixture was degassed three times under a nitrogen atmosphere and stirred at 120 °C for 12 hours under a nitrogen atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried, and concentrated to dryness to give a crude product. The crude product was purified by rapid chromatography (DCM:MeOH = 20:1 to 10:1) to give tert-butyl piperazine-1-carboxylate (10 mg, 0.014 mmol, 8.47%) as a yellow solid. LC / MS (ESI) (m / z): 689 (M+H) + .

[0566] Step B: N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(4-methylpiperazin-1-yl)-1H-indazole-7-carboxamide

[0567] Add HCl (1 mL, 4.00 mmol) to a solution of tert-butyl piperazine-1-carboxylate (10 mg, 0.014 mmol) in DCM (3 mL). Stir the reaction mixture at room temperature for 1 hour. Dilute the mixture with DCM, wash with saturated aqueous NaHCO3 solution and brine, dry over anhydrous Na2SO4, filter, and concentrate to dryness. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to give N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(4-methylpiperazin-1-yl)-1H-indazole-7-carboxamide (2.6 mg, 37%) as a white solid. LC / MS (ESI) (m / z): 460 (M+H) + . 1HNMR(400MHz,MeOD-d4)δ8.53(s,1H),8.36(s,1H),7.85(s,1H),7.68-7.62(m,1H),7.60-7.55(m,1H),7.5 0-7.40(m,2H),5.39(m,1H),4.35(s,3H),3.90(t,J=13.5Hz,2H),3.42-3.35(m,8H),1.66(d,J=7.0Hz,3H).

[0568] Example 34: N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1-methylpiperidin-4-yl)-1H-indazole-7-carboxamide. (The subject compound was synthesized from compound 5 in Example 16.)

[0569]

[0570] Step A: 5-Bromo-4-methoxy-1H-indazole-7-carboxylic acid

[0571] To a solution of methyl 5-bromo-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxylic acid (400 mg, 0.963 mmol) in MeOH (5 mL) and water (1 mL), NaOH (77 mg, 1.92 mmol) and THF (5 mL) were added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to 1 / 5 volume, diluted with water, and washed twice with MTBE. The aqueous layer was acidified to pH ~3 with 1N HCl aqueous solution and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give 5-bromo-4-methoxy-1H-indazole-7-carboxylic acid (230 mg, 88%) as a white solid. LC / MS (ESI) (m / z): 271 (M+H) + .

[0572] Step B: 5-Bromo-N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-1H-indazole-7-carboxamide

[0573] At 25 °C, DIEA (0.42 mL, 2.54 mmol) and HATU (483 mg, 1.27 mmol) were added to a mixture of 5-bromo-4-methoxy-1H-indazole-7-carboxylic acid (230 mg, 0.848 mmol) and 2-{3-[(1R)-1-aminoethyl]phenyl}-2,2-difluoroethane-1-ol (170 mg, 0.848 mmol) in DMF (5 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was diluted with EtOAc and washed with saturated NH4Cl aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (DCM:MeOH = 97:3) to give 5-bromo-N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-1H-indazole-7-carboxamide (230 mg, 59%) as a white solid. LC / MS (ESI) (m / z): 454 (M+H) + .

[0574] Step C: N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-7-carboxamide

[0575] Under a nitrogen atmosphere, Pd(dppf)Cl2 (9 mg, 0.013 mmol) and Na2CO3 (42 mg, 0.396 mmol) were added to a mixture of 5-bromo-N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-1H-indazole-7-carboxamide (60 mg, 0.132 mmol) and 1-methyl-4-(tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,6-tetrahydropyridine (58 mg, 0.264 mmol) in 1,4-dioxane (2.4 mL) and water (0.3 mL). The mixture was degassed three times under a nitrogen atmosphere and stirred at 95 °C for 12 hours under a nitrogen atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried, and concentrated to dryness to give a crude product. The crude product was purified by rapid chromatography (DCM:MeOH = 20:1 to 10:2) to give N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-7-carboxamide (40 mg, 64%) as a white solid. LC / MS (ESI) (m / z): 471 (M+H) + .

[0576] Step D: N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1-methylpiperidin-4-yl)-1H-indazole-7-carboxamide

[0577] At 25°C, PtO2 (3 mg) was added to a solution of N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-7-carboxamide (30 mg, 0.064 mmol) in MeOH (5 mL), and the mixture was degassed three times under N2 atmosphere and stirred for 1 hour at room temperature under H2 balloon. The mixture was filtered and the filtrate was concentrated to dryness to obtain the residue. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to give N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1-methylpiperidin-4-yl)-1H-indazole-7-carboxamide (15 mg, 0.032 mmol, 49.7%) as a white solid. LC / MS (ESI) (m / z): 473 (M+H) + .

[0578] 1 HNMR(400MHz,MeOD)δ8.38(s,1H),7.84(s,1H),7.62(s,1H),7.57(d,J=7 .0Hz,1H),7.49-7.37(m,2H),5.42-5.31(m,1H),4.35(s,3H),3.88(t,J=1 3.5Hz,2H),3.60(d,J=11.9Hz,2H),3.38-3.35(m,1H),3.20-3.13(m,2H), 2.91(s,3H),2.28-2.16(m,2H),2.15-2.03(d,2H),1.64(d,J=7.1Hz,3H).

[0579] Example 35: N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(piperidin-4-yl)-1H-indazole-7-carboxamide. (The subject compound was synthesized from compound 9 in Example 32.)

[0580]

[0581] Step A. 4-(7-{[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]carbamoyl}-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-5-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester

[0582] Under a nitrogen atmosphere, Pd(dppf)Cl2 (5 mg, 0.007 mmol) and K2CO3 (56 mg, 0.411 mmol) were added to a mixture of 5-bromo-N-[(1S)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxamide (80 mg, 0.137 mmol) and 4-(tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (63.5 mg, 0.20 mmol) in 1,4-dioxane (5 mL) and water (1 mL). The mixture was degassed three times under a nitrogen atmosphere and stirred at 95 °C for 12 hours under a nitrogen atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried, and concentrated to dryness to give a crude product. The crude product was purified by rapid chromatography (DCM:MeOH = 20:1) to give 4-(7-{[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]carbamoyl}-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-5-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (80 mg, 85%) as a yellow solid. LC / MS (ESI) (m / z): 687 (M+H) + .

[0583] Step B: N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-7-carboxamide

[0584] At 0 °C, 4N HCl / dioxane (1 mL, 0.116 mmol) was added to a solution of 4-(7-{[(1S)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]carbamoyl}-4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-5-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (80 mg, 0.11 mmol) in DCM (2 mL), and the mixture was stirred at 25 °C for 2 hours. The mixture was concentrated to dryness, and the residue was washed with diethyl ether and dried under vacuum to give N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-7-carboxamide (50 mg, 94%) as a brown solid, which was used directly in the next step. LC / MS (ESI) (m / z): 457 (M+H) + .

[0585] Step C: N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(piperidin-4-yl)-1H-indazole-7-carboxamide

[0586] At 25 °C, PtO2 (5 mg) was added to a solution of N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-7-carboxamide (50 mg, 0.11 mmol) in CF3CH2OH (5 mL), and the mixture was degassed three times under N2 atmosphere and stirred at room temperature for 2 hours under H2 balloon. The mixture was filtered and the filtrate was concentrated to dryness to give N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(piperidin-4-yl)-1H-indazole-7-carboxamide (5 mg, 10%) as a white solid. LC / MS (ESI) (m / z): 459 (M+H) + . 1H NMR (400MHz, CD3OD-d4) δ8.56(s,1H),8.42(s,1H),7.85(s,1H),7.62(s,1H),7.56(d,J=7.0Hz,1H),7.48-7.35(m,2H),5.37(q,J=7.0Hz,1H),4.34 (s,3H),3.88(t,J=13.5Hz,2H),3.50(d,J=12.7Hz,2H),3.40-3.30(m,1H ), 3.14(td,J=12.4,3.6Hz,2H),2.17–1.96(m,4H),1.64(d,J=7.1Hz,3H).

[0587] Example 36: Synthesis of N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-4-methoxy-5-(piperidin-3-yl)-1H-indazole-7-carboxamide. (The subject compound was synthesized from compound 3 in Example 34.)

[0588]

[0589] Step A. (R)-5-(7-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)carbamoyl)-4-methoxy-1H-indazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0590] To a stirred solution of 5-bromo-N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-1H-indazole-7-carboxamide (100 mg, 0.2 mmol) in dioxane (2 mL) and H₂O (0.5 mL), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (81.6 mg, 0.264 mmol), Pd(dppf)Cl₂ (32.1 mg, 0.04 mmol), and K₂CO₃ (91.2 mg, 0.6 mmol) were added. The reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to obtain a residue, which was then purified by preparative TLC (50% EtOAc / PE) to give (R)-5-(7-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)carbamoyl)-4-methoxy-1H-indazole-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol, 65.4%) as a white solid. LCMS: m / z 557 (M+H) + .

[0591] Step B. (R)-N-(1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-4-methoxy-5-(1,4,5,6-tetrahydropyridin-3-yl)-1H-indazole-7-carboxamide

[0592] To a stirred solution of (R)-5-(7-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)carbamoyl)-4-methoxy-1H-indazole-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (80 mg, 0.2 mmol) in 4N HCl / dioxane (3 mL), the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give a residue of N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1,4,5,6-tetrahydropyridine-3-yl)-1H-indazole-7-carboxamide (60 mg, 0.13 mmol, 91.4%) as a colorless oil. LCMS: m / z 457 (M+H) + .

[0593] Step CN-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-4-methoxy-5-(piperidin-3-yl)-1H-indazole-7-carboxamide

[0594] Platinum dioxide (15 mg, 0.1 mmol) was added to a stirred solution of N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1,4,5,6-tetrahydropyridin-3-yl)-1H-indazole-7-carboxamide (30 mg, 0.1 mmol) in 2,2,2-trifluoroethanol (3 mL). The reaction mixture was stirred at 60 °C for 5 hours using an H2 balloon. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue. The residue was purified by preparative HPLC to give N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(piperidin-3-yl)-1H-indazole-7-carboxamide (3.1 mg, 0.01 mmol, 10.3%) as a white solid. LCMS: m / z 459 (M+H) + . 1H NMR (400MHz, MeOD) δ8.36(d,J=5.6Hz,1H),7.97–7.83(m,1H),7.62(s,1H),7.56(d,J=7.2Hz,1H),7.47–7.39(m,2H),5.44–5.28(m,1H),3.88(t, J=13.5Hz,2H),3.14(t,J=12.4Hz,2H),2.78(dt,J=23.0,12.3Hz,2H),1.90(dd,J=15.6,6.3Hz,4H),1.75(d,J=7.7Hz,2H),1.63(t,J=8.6Hz,4H).

[0595] Example 37: Synthesis of N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-4-methoxy-5-(1-methylpiperidin-3-yl)-1H-indazole-7-carboxamide. (The subject compound was synthesized from compound 3 in Example 36.)

[0596]

[0597] Step AN-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-4-methoxy-5-(1-methylpiperidin-3-yl)-1H-indazole-7-carboxamide

[0598] PtO2 (7.5 mg, 0.1 mmol) and paraformaldehyde (10 mg, 0.1 mmol) were added to a stirred solution of N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1,4,5,6-tetrahydropyridin-3-yl)-1H-indazole-7-carboxamide (30 mg, 0.1 mmol) in 2,2,2-trifluoroethanol (3 mL). The reaction mixture was stirred at 60 °C for 5 hours under an H2 balloon. The reaction mixture was filtered and the filtrate was concentrated under vacuum to obtain a residue, which was then purified by preparative HPLC to give N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-4-methoxy-5-(1-methylpiperidin-3-yl)-1H-indazole-7-carboxamide (2.6 mg, 0.006 mmol, 8.3%) as a white solid. LCMS: m / z 473 (M+H) + . 1H NMR(400MHz,MeOD)δ8.45(s,1H),7.89(s,1H),7.62(s,1H),7.56(d,J=7.1Hz,1H),7.44(q,J =7.8Hz,2H),5.37(dt,J=17.3,8.6Hz,1H),4.37(s,3H),3.88(t,J=13.5Hz,2H),3.57(dd,J= 23.4,11.5Hz,3H),3.12(td,J=12.0,7.6Hz,1H),2.97(d,J=26.7Hz,1H),2.91(d,J=2.4Hz,3 H), 2.18 (dd, J = 16.2, 8.3Hz, 1H), 1.97 (dd, J = 18.7, 8.5Hz, 4H), 1.64 (dd, J = 7.0, 1.2Hz, 4H).

[0599] Example 38: Synthesis of (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-4-oxo-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide

[0600]

[0601] Step A. Dimethyl 2-formyl-3-oxoglutarate

[0602] At 0 °C, DMF-DMA (6.8 g, 57.4 mmol) was added to a stirred solution of 1,5-dimethyl 3-oxoglutaric acid (10 g, 57.4 mmol) in 100 mL of 2-methyltetrahydrofuran. The reaction mixture was stirred at 0 °C for 1.5 h under a nitrogen atmosphere before adding 4 M HCl (28 mL, 13.1 mmol). The resulting solution was warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with water (100 mL). The following mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to obtain 1,5-dimethyl 2-formyl-3-oxoglutaric acid (9.6 g, 47.5 mmol, yield 82.7%) as a colorless oil. LC / MS (ESI) m / z: 203.0 (M+H) +

[0603] Step B: Methyl 4-hydroxy-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate

[0604] Oxalide-4-amine (5.0 g, 49.4 mmol) was added to a stirred solution of 1,5-dimethyl 2-formyl-3-oxoglutaric acid (12.0 g, 59.3 mmol) in CH3OH (80 mL) at 0 °C. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 h before adding MeONa (40 mL, 59.3 mmol, 30% in CH3OH). The resulting solution was stirred at room temperature for 2 h. The reaction mixture was poured into ice water (100 mL). CH3OH was removed by reducing the power. The precipitate was filtered and dried to give the crude desired product. The filtrate was extracted with DCM (80 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The combined crude products were ground in 100 mL of PE:DCM = 10:1 to obtain the desired product (11 g, 43.5 mmol, 73.3%) as a grayish-white solid. LC / MS (ESI) m / z: 253.9 (M+H) + .

[0605] Step C. Methyl 4-bromo-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate

[0606] A solution of methyl 4-hydroxy-1-(oxan-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (7 g, 27.64 mmol) in DMF (20 mL) was added to POBr3 (11.9 g, 41.40 mmol). The reaction mixture was stirred at 100 °C for 5 hours. The cooled reaction mixture was poured into water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (silica gel, 24 g, 0–60% EA / PE) to give methyl 4-bromo-1-(oxan-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (5 g, 15.8 mmol, 57.2%) as a pale yellow solid. LCMS: m / z 316 (M+H) + .

[0607] Step D. Methyl 4-amino-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate

[0608] To a stirred solution of methyl 4-bromo-1-(oxan-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (5 g, 15.82 mmol) in dioxane (30 mL), diphenylmethyleneimine (2.65 mL, 15.82 mmol), Pd₂(dba)₃ (1.45 g, 1.58 mmol), Xant-phos (1.76 g, 3.16 mmol), and Cs₂CO₃ (12.8 g, 39.5 mmol) were added. The reaction mixture was stirred at 95 °C for 5 h and then cooled to room temperature. HCl (2 M, 20 mL) was added and the mixture was stirred for 0.5 h. The pH of the reaction mixture was adjusted to 8–9 by adding saturated sodium bicarbonate, and the mixture was extracted with DCM. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (silica gel, 24 g, 0–10% MeOH / DCM) to give methyl 4-amino-1-(oxan-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (2.2 g, 8.72 mmol, 55.14%) as a pale yellow solid. LCMS: m / z 253 (M+H) + .

[0609] Step E. Methyl 4-amino-5-iodo-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate

[0610] A stirred solution of methyl 4-amino-1-(oxan-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (2.2 g, 8.72 mmol) in MeCN (20 mL) and DCM (10 mL) was added to a (thionyl)amine (1.66 g, 9.59 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with NaHCO3, dried over Na2SO4, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (silica gel, 24 g, 0–100% EtOAc / PE) to give methyl 4-amino-5-iodo-1-(oxan-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1.9 g, 5.02 mmol, 57.6%) as a white solid. LCMS: m / z 379 (M+H) + .

[0611] Step F.(E)-4-amino-5-(2-ethoxyvinyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylic acid methyl ester

[0612] To a stirred solution of methyl 4-amino-5-iodo-1-(oxan-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1.9 g, 5.02 mmol) in dioxane (30 mL) and H₂O (5 mL), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (1.17 mL, 5.52 mmol), Pd(dppf)Cl₂ (0.37 g, 0.50 mmol), and K₂CO₃ (1.39 g, 10.04 mmol) were added. The reaction mixture was stirred at 95 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (silica gel, 24 g, 0–100% EtOAc / PE) to give methyl 4-amino-1-(oxan-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (2.20 g, 8.72 mmol, 55.1%) as a pale yellow solid. LCMS: m / z 323 (M+H) + .

[0613] Step G. Methyl 4-oxo-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate: A mixture of methyl 4-amino-5-[(E)-2-ethoxyvinyl]-1-(oxan-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (380 mg, 1.179 mmol) in AcOH (5 mL) was stirred at 100 °C for 2 hours. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (silica gel, 24 g, 0–60% EtOAc / PE) to give methyl 5-(oxan-4-yl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylate (120 undefined, 0.43 mmol, 36.3%) as a pale yellow solid. LCMS: m / z 277(M+H) + .

[0614] Step H.4-oxo-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid

[0615] A solution of methyl 5-(oxapan-4-yl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (120 mg, 0.43 mmol) in MeOH (3 mL) was added to a stirred solution of H₂O (2 mL) containing LiOH (173 mg, 4.34 mmol). The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 3–4 and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give crude 5-(oxapan-4-yl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (90 mg, 0.34 mmol, 79.0%) as a pale yellow solid. LCMS: m / z 263 (M+H) + .

[0616] Step I. (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-4-oxo-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide

[0617] To a stirred solution of 5-(oxan-4-yl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (30 mg, 0.114 mmol) in DMF (3 mL), (1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethane-1-amine (26.98 mg, 0.14 mmol), DIPEA (74.10 mg, 0.57 mmol), and HATU (65.2 mg, 0.17 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a residue. The residue was purified by TLC (100% EtOAc) to obtain a crude product, which was then purified by preparative HPLC to obtain N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-5-(oxan-4-yl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxamide (3.0 mg, 0.007 mmol, 5.94%) as a white solid. LCMS: m / z 408 (M+H) + . 1H NMR (400MHz, DMSO) δ11.35(s,1H),8.82(d,J=7.0Hz,1H),8.25(d,J=15.4Hz,1H),7.66– 7.50(m,1H),7.47–7.39(m,2H),7.06–6.88(m,1H),6.51(dd,J=2.9,2.3Hz,1H),5.33–5 .06(m,2H),4.06(dd,J=11.2,3.9Hz,2H),3.53(dd,J=24.2,12.9Hz,2H),3.19–3.05(m, 2H), 2.73–2.56 (m, 2H), 2.20–2.03 (m, 2H), 1.71 (d, J = 9.6Hz, 2H), 1.53 (d, J = 7.1Hz, 3H).

[0618] Example 39: Synthesis of (R)-N-(1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-4-oxo-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide. (The subject compound was synthesized from compound 9 in Example 38.)

[0619]

[0620] Step A of (R)-N-(1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-4-oxo-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide

[0621] To a stirred solution of 5-(oxapan-4-yl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (30 mg, 0.11 mmol) in DMF (3 mL), 2-{3-[(1R)-1-aminoethyl]phenyl}-2,2-difluoroethane-1-ol (27.53 mg, 0.14 mmol), DIEA (0.09 mL, 0.57 mmol), and HATU ≥ 98.0% (CHN) (86.7 mg, 0.23 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative TLC (100% EtOAc) to obtain a crude product, which was then purified by preparative HPLC to obtain N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-5-(oxan-4-yl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxamide (2.1 mg, 0.005 mmol, 4.14%) as a white solid. 1 H NMR (400MHz, DMSO) δ11.35(s,1H),8.82(d,J=7.0Hz,1H),8.25(d,J=15.4Hz,1H),7.66–7. 50(m,1H),7.47–7.39(m,2H),7.06–6.88(m,1H),6.51(dd,J=2.9,2.3Hz,1H),5.33–5.06( m,2H),4.06(dd,J=11.2,3.9Hz,2H),3.53(dd,J=24.2,12.9Hz,2H),3.19–3.05(m,2H),2. 73–2.56(m,2H),2.20–2.03(m,2H),1.71(d,J=9.6Hz,2H),1.53(d,J=7.1Hz,3H).LCMS:m / z 446(M+H) + .

[0622] Example 40: Synthesis of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-oxo-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide. (The subject compound was synthesized from compound 9 in Example 38.)

[0623]

[0624] Step A of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-oxo-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide

[0625] To a stirred solution of 5-(oxacarbamate-4-yl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (30 mg, 0.11 mmol) in DMF (3 mL), (1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethane-1-amine (21.6 mg, 0.11 mmol), DIEA (0.10 mL, 0.57 mmol), and HATU ≥ 98.0% (CHN) (65.0 mg, 0.171 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by TLC (100% EtOAc) to obtain a crude product, which was then purified by preparative HPLC to obtain N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-5-(oxan-4-yl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxamide (16.8 mg, 0.04 mmol, 34.0%) as a white solid. 1 H NMR (400MHz, DMSO) δ11.37(s,1H),8.88(d,J=6.8Hz,1H),8.26(s,1H),7.66(t,J=7.1Hz,1H),7 .52(t,J=6.9Hz,1H),7.36(d,J=8.0Hz,1H),7.23(t,J=45.7Hz,1H),7.01–6.96(m,1H),6.54–6 .48(m,1H),5.47–5.35(m,1H),5.26–5.05(m,1H),4.07(dd,J=11.1,3.7Hz,2H),3.55(t,J=11. 3Hz,2H),2.13(tt,J=16.6,8.3Hz,2H),1.72(d,J=10.4Hz,2H),1.55(d,J=7.1Hz,3H).LCMS:m / z 434(M+H) + .

[0626] Example 41: Synthesis of (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide

[0627]

[0628] Step A. Dimethyl 2-formyl-3-oxoglutarate

[0629] DMF-DMA (13.9 mL, 103 mmol) was added dropwise to a stirred solution of 1,5-dimethyl 3-oxoglutaric acid (7.63 mL, 51.7 mmol) in THF (50 mL) over 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 3–4 by adding HCl (5 mL, 4 M). The reaction mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (silica gel, 40 g, 0–2% MeOH / DCM) to give 1,5-dimethyl 2-formyl-3-oxoglutaric acid (10 g, 49.46 mmol, 95.7%) as a yellow oil. LCMS: m / z 203 (M+H) + .

[0630] Step B. Methyl 4-hydroxy-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

[0631] 1-Methylcyclopropane-1-amine (1.58 g, 22.26 mmol) was added to a stirred solution of 1,5-dimethyl 2-formyl-3-oxoglutaric acid (3 g, 14.8 mmol) in MeOH (20 mL). The reaction mixture was stirred at room temperature for 16 hours. Then, MeONa (7.4 mL, 29.6 mmol) was added. The reaction mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (silica gel, 40 g, 0–5% MeOH / DCM) to give methyl 4-hydroxy-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (800 undefined) as a yellow solid. LCMS: m / z 224 (M+H) + .

[0632] Step C. Methyl 4-bromo-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

[0633] POBr3 (2.73 mL, 26.8 mmol) was added to a solution of methyl 4-hydroxy-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (3 g, 13.4 mmol) in DMF (50 mL). The reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was poured into NaHCO3 (aqueous solution) and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by column chromatography (silica gel, 40 g, 0–50% EtOAc / PE) to give methyl 4-bromo-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (3.1 g, 10.8 mmol, 80.6%) as a yellow oil. LCMS: m / z 286 (M+H) + .

[0634] Step D. Methyl 4-amino-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

[0635] To a stirred solution of methyl 4-bromo-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (3.1 g, 10.8 mmol) in dioxane (30 mL), diphenylmethyleneimine (2.0 mL, 11.9 mmol), Pd₂(dba)₃ (1.02 g, 1.08 mmol), Xant-Phos (1.20 g, 2.17 mmol), and Cs₂CO₃ (8.8 g, 27.1 mmol) were added. The reaction mixture was stirred at 95 °C for 5 hours. Then, HCl (2 M, 20 mL) was added and the mixture was stirred for 0.5 hours. The pH of the reaction mixture was adjusted to 8–9 by adding saturated sodium bicarbonate, and the mixture was extracted with DCM. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain a residue. This residue was purified by silica gel (20 g, 0–5% MeOH / DCM) to give methyl 4-amino-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (2 g, 8.99 mmol, 83.1%) as a pale yellow solid. LCMS: m / z 223 (M+H) + .

[0636] Step E. Methyl 4-amino-5-iodo-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

[0637] To a stirred solution of methyl 4-amino-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1.8 g, 8.10 mmol) in AcOH (5 mL) and DCM (10 mL), iodo(thionyl)amine (1.5 g, 8.90 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EtOAc, washed with NaHCO3, dried over Na2SO4, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (silica gel, 24 g, 0–100% EtOAc / PE) to give methyl 4-amino-5-iodo-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1.2 g, 3.45 mmol, 42.5%) as a colorless solid. LCMS: m / z 349 (M+H) + .

[0638] Step F.(E)-4-amino-5-(2-ethoxyvinyl)-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester

[0639] To a stirred solution of methyl 4-amino-5-iodo-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (700 mg, 2.01 mmol) in dioxane (10 mL) and H₂O (2 mL), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (0.47 mL, 2.21 mmol), Pd(dppf)Cl₂ (147.1 mg, 0.20 mmol), and K₂CO₃ (555.8 mg, 4.02 mmol) were added. The reaction mixture was stirred at 95 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue, which was then purified by column chromatography (silica gel, 24 g, 0–100% EtOAc / PE) to give methyl 4-amino-5-[(E)-2-ethoxyvinyl]-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (500 mg, 1.71 mmol, 85.0%) as a pale yellow solid. LCMS: m / z 292 (M+H) + .

[0640] Step G. methyl 5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate

[0641] The reaction mixture of methyl 4-amino-5-[(E)-2-ethoxyvinyl]-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (500 mg, 1.71 mmol) in AcOH (10 mL) was stirred at 100 °C for 2 hours. The reaction mixture was concentrated under vacuum to obtain a residue, which was purified by column chromatography (silica gel, 24 g, 0–60% EtOAc / PE) to give methyl 5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylate (150 mg, 0.61 mmol, 35.6%) as a pale yellow solid. LCMS: m / z 247 (M+H) + .

[0642] Step H.5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid

[0643] To a stirred solution of methyl 5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (90 mg, 0.36 mmol) in MeOH (3 mL), 2 mL of H₂O containing LiOH (174 mg, 4.3 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 3–4 and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give crude 5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (70 mg, 0.301 mmol, 82.5%) as a pale yellow solid. LCMS: m / z 233 (M+H) + .

[0644] Step I. (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide

[0645] To a stirred solution of 5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (35 mg, 0.151 mmol) in DMF (3 mL), (1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethane-1-amine (35.6 mg, 0.18 mmol), DIPEA (97.9 mg, 0.75 mmol), and HATU (114 mg, 0.30 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a residue. The residue was purified by TLC (100% EtOAc) to obtain a crude product, which was then purified by preparative HPLC to obtain N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxamide (15 mg, 0.036 mmol, 24.2%) as a white solid. 1 H NMR (400MHz, DMSO) δ11.20(s,1H),8.72(d,J=7.1Hz,1H),8.15(s,1H),7.51(dd,J=8.1,5.1Hz,1H),7.39–7.31(m,2H),6.89(t,J=2.6Hz,1H),6.4 4–6.36(m,1H),5.15(p,J=6.9Hz,1H),3.15–2.98(m,2H),2.63–2.47(m,2 H),1.44(t,J=6.0Hz,3H),1.42(s,3H),1.00(t,J=8.2Hz,2H),0.91(s,2H LCMS:m / z412(M+H) + .

[0646] Example 42: Synthesis of (R)-N-(1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide. (The title compound was synthesized from compound 10 in the same order as used in the synthesis of Example 41.)

[0647]

[0648] Step A. (R)-N-(1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide

[0649] To a stirred solution of 5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (35 mg, 0.151 mmol) in DMF (3 mL), 2-{3-[(1R)-1-aminoethyl]phenyl}-2,2-difluoroethane-1-ol (36.4 mg, 0.181 mmol), DIEA (0.125 mL, 0.754 mmol), and HATU ≥ 98.0% (CHN) (114 mg, 0.30 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a residue. The residue was purified by preparative TLC (100% EtOAc) to obtain a crude product, which was then purified by preparative HPLC to obtain N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxamide (12 mg, 0.029 mmol, 19.17%) as a white solid. 1 H NMR (400MHz, DMSO) δ11.21(s,1H),8.71(d,J=7.6Hz,1H),8.12(s,1H),7.47(d,J=8 .9Hz,2H),7.39(t,J=7.6Hz,1H),7.32(d,J=7.7Hz,1H),6.97–6.85(m,1H),6.45–6 .34(m,1H),5.57(t,J=6.3Hz,1H),5.16(p,J=7.0Hz,1H),3.78(td,J=14.2,6.3Hz, 2H),1.46(d,J=7.1Hz,3H),1.41(s,3H),1.05–0.96(m,2H),0.91(s,2H).LCMS:m / z 416(M+H) + .

[0650] Example 43: Synthesis of (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-3-methyl-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide. (The subject compound was synthesized from compound 9 in Example 41.)

[0651]

[0652] Step A. Methyl 3-bromo-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate

[0653] NBS (47.7 mg, 0.27 mmol) was added to a stirred solution of methyl 5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylate (60 mg, 0.24 mmol) in AcOH (1 mL) and DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with aqueous NaHCO3 solution, dried over Na2SO4, and concentrated under vacuum to obtain a residue, which was purified by column chromatography (silica gel, 24 g, 0–100% EtOAc / PE) to give methyl 3-bromo-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylate (60 mg, 0.19 mmol, 75.7%) as a colorless solid. LCMS: m / z 326(M+H) + .

[0654] Step B. Methyl 3-methyl-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate

[0655] To a stirred solution of methyl 3-bromo-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylate (60 mg, 0.185 mmol) in dioxane (3 mL) and H₂O (1 mL), trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (0.08 mL, 0.55 mmol), Pd(dppf)Cl₂ (13.5 mg, 0.02 mmol), and K₂CO₃ (76.5 mg, 0.55 mmol) were added. The reaction mixture was stirred at 70 °C for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue, which was then purified by column chromatography (silica gel, 24 g, 0–80% EtOAc / PE) to give methyl 3-methyl-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylate (10 mg, 0.04 mmol, 20.8%) as a pale yellow solid. LCMS: m / z 261 (M+H) + .

[0656] Step C. 3-Methyl-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid

[0657] To a stirred solution of methyl 3-methyl-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (10 mg, 0.04 mmol) in MeOH (3 mL), 2 mL of H₂O containing LiOH (15.37 mg, 0.38 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 3–4 and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give crude 3-methyl-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (6 mg, 0.02 mmol, 63.4%) as a pale yellow solid. LCMS: m / z 247 (M+H) + .

[0658] Step D.(R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-3-methyl-5-(1-methylcyclopropyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide

[0659] To a stirred solution of 3-methyl-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (6 mg, 0.024 mmol) in DMF (3 mL), (1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethane-1-amine (5.77 mg, 0.03 mmol), DIPEA (15.84 mg, 0.12 mmol), and HATU (13.9 mg, 0.037 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a residue. The residue was purified by TLC (100% EtOAc) to obtain a crude product, which was then purified by preparative HPLC to give N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-3-methyl-5-(1-methylcyclopropyl)-4-oxo-1H,4H,5H-pyrrolo[3,2-c]pyridine-7-carboxamide (5 mg, undefined, 0.01 mmol, 48.2%) as a white solid. LCMS: m / z 426 (M+H) + . 1H NMR (400MHz, MeOD) δ8.08(s,1H),7.62–7.51(m,1H),7.48–7.31(m,2H),6.35(d,J=0.9Hz,1H),5.40–5.14(m,1H),3.10(ddd,J=16.9,9.3,5.3 Hz,1H),2.60(tt,J=14.4,7.2Hz,2H),2.33(d,J=0.7Hz,3H),1.58(d,J=7.1Hz,3H),1.55(s,3H),1.18(d,J=6.8Hz,2H),1.04(t,J=5.9Hz,2H).

[0660] Example 44: Synthesis of (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-4-methoxy-5-morpholino-2H-pyrazolo[3,4-c]pyridine-7-carboxamide

[0661]

[0662] Step A: 6-Chloro-5-fluoro-2-iodopyridin-3-ol

[0663] Iodine (4.30 g, 16.9 mmol) was slowly added to a stirred solution of 6-chloro-5-fluoropyridin-3-ol (2.5 g, 16.9 mmol) and Na₂CO₃ (3.6 g, 33.9 mmol) in H₂O (30 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ice water (50 mL), and the pH was adjusted to 5–6 with 1 N HCl. The mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude 6-chloro-5-fluoro-2-iodopyridin-3-ol (3.7 g, 13.5 mmol, 79.8%) as a brown solid. The crude product was used directly in the next step without purification. LC / MS (ESI) m / z: 274 (M+H) + .

[0664] Step B: 2-Chloro-3-fluoro-6-iodo-5-methoxypyridine

[0665] Iodomethane (1.2 g, 8.4 mmol) was slowly added to a stirred mixture of 6-chloro-5-fluoro-2-iodopyridin-3-ol (2.1 g, 7.7 mmol) and K₂CO₃ (1.6 g, 11.5 mmol) in DMF (30 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ice water (50 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product purified by silica gel column chromatography (EtOAc / PE: 0–30%) to obtain 2-chloro-3-fluoro-6-iodo-5-methoxypyridine (1.8 g, 6.3 mmol, 81.5%) as a white solid. LC / MS (ESI) m / z: 287 (M+H) + .

[0666] Step C: 4-(6-chloro-5-fluoro-3-methoxypyridin-2-yl)morpholine

[0667] CuI (370 mg, 1.9 mmol) and L-proline (220 mg, 1.9 mmol) were slowly added to a stirred mixture of 2-chloro-3-fluoro-6-iodo-5-methoxypyridine (2.8 g, 9.7 mmol), morpholine (2.6 g, 29.2 mmol), and Cs₂CO₃ (9.5 g, 29.2 mmol) in DMSO (30 mL). The reaction mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The following mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product purified by silica gel column chromatography (EtOAc / PE: 0–30%) to obtain 4-(6-chloro-5-fluoro-3-methoxypyridin-2-yl)morpholine (1.3 g, 5.3 mmol, 54.1%) as a white solid. LC / MS (ESI) m / z: 247 (M+H) + .

[0668] Step D: 2-Chloro-3-fluoro-5-methoxy-6-(morpholin-4-yl)pyridine-4-carboxaldehyde

[0669] Diisopropylaminolithium (3.4 mL, 2.0 M solution in THF) was slowly added to a stirred solution of 1.3 g (5.3 mmol) of 4-(6-chloro-5-fluoro-3-methoxypyridin-2-yl)morpholine in 20 mL of anhydrous THF at -78 °C. The reaction mixture was stirred at -70 °C for 30 min under a nitrogen atmosphere before adding DMF (1.9 g, 26 mmol). The resulting solution was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated NH4Cl (50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product purified by silica gel column chromatography (EtOAc / PE: 0–40%) to yield 2-chloro-3-fluoro-5-methoxy-6-(morpholin-4-yl)pyridine-4-carboxaldehyde (1.1 g, 4 mmol, 76%) as a yellow solid. LC / MS (ESI) m / z: 275 (M+H) + .

[0670] Step E: (E)-{[2-chloro-3-fluoro-5-methoxy-6-(morpholin-4-yl)pyridin-4-yl]methylene}(methoxy)amine

[0671] Under a nitrogen atmosphere, a mixture of 2-chloro-3-fluoro-5-methoxy-6-(morpholin-4-yl)pyridin-4-carboxaldehyde (1.1 g, 4.0 mmol), methoxyammonium chloride (350 mg, 4.2 mmol), and K₂CO₃ (1.4 g, 10.0 mmol) in 1,2-dimethoxyethane (20 mL) was stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to give a crude product (E)-{[2-chloro-3-fluoro-5-methoxy-6-(morpholin-4-yl)pyridin-4-yl]methylene}(methoxy)amine (1.1 g, 3.6 mmol, 90.5%) as a yellow solid, which was used directly in the next step. LC / MS (ESI) m / z: 304 (M+H) + .

[0672] Step F: 4-{7-chloro-4-methoxy-1H-pyrazolo[3,4-c]pyridin-5-yl}morpholine

[0673] Hydrazine hydrate (214 mg, 3.4 mmol) was added to a stirred solution of (E)-{[2-chloro-3-fluoro-5-methoxy-6-(morpholin-4-yl)pyridin-4-yl]methylene}(methoxy)amine (130 mg, 0.43 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at 120 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (20 mL). The mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product purified by silica gel column chromatography (EtOAc / PE: 0–40%) to obtain 4-{7-chloro-4-methoxy-1H-pyrazolo[3,4-c]pyridin-5-yl}morpholine (35 mg, 0.13 mmol, 30.4%) as a yellow solid (40 mg of (E)-{[2-chloro-3-fluoro-5-methoxy-6-(morpholin-4-yl)pyridin-4-yl]methylene}(methoxy)amine was recovered). LC / MS (ESI) m / z: 269 (M+H) + .

[0674] Step G: Methyl 4-methoxy-5-morpholino-2H-pyrazolo[3,4-c]pyridine-7-carboxylate

[0675] Pd(dppf)Cl2 (9 mg, 0.013 mmol) was added to a stirred solution of 4-{7-chloro-4-methoxy-1H-pyrazolo[3,4-c]pyridin-5-yl}morpholine (35 mg, 0.13 mmol), triethylamine (39 mg, 0.4 mmol), and MeOH (5 mL). The reaction mixture was stirred at 80 °C for 3 hours under a carbon monoxide atmosphere. The reaction mixture was filtered and concentrated to obtain a crude product purified by silica gel column chromatography (EtOAc / PE: 0–60%) to obtain methyl 4-methoxy-5-(morpholin-4-yl)-1H-pyrazolo[3,4-c]pyridin-7-carboxylate (30 mg, 0.1 mmol, 78.8%) as a yellow solid. LC / MS (ESI) m / z: 293 (M+H) + .

[0676] Step G: Lithium 4-methoxy-5-morpholino-2H-pyrazolo[3,4-c]pyridine-7-carboxylate

[0677] LiOH (13 mg, 0.3 mmol) was added to a stirred solution of methyl 4-methoxy-5-(morpholino-4-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (30 mg, 0.1 mmol) in MeOH (4 mL) and H₂O (4 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to obtain crude lithium 4-methoxy-5-morpholino-2H-pyrazolo[3,4-c]pyridine-7-carboxylate (30 mg, 0.1 mmol, 105%) as a yellow solid, which was used directly in the next step. LC / MS (ESI) m / z: 279 (M+H) + .

[0678] Step H: (R)-N-(1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)-4-methoxy-5-morpholino-2H-pyrazolo[3,4-c]pyridine-7-carboxamide

[0679] N,N-diisopropylethylamine (28 mg, 0.2 mmol) was slowly added to a stirred solution of 4-methoxy-5-morpholino-2H-pyrazolo[3,4-c]pyridine-7-carboxylate (30 mg, 0.1 mmol), (1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethane-1-amine (42 mg, 0.2 mmol), (30 mg, 0.1 mmol), and HATU (61 mg, 0.16 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL). The following mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product purified by silica gel column chromatography (MeOH / DCM: 0–8%) and further purified by preparative TLC (DCM:MeOH = 25:1) to obtain N-[(1R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl]-4-methoxy-5-(morpholin-4-yl)-2H-pyrazolo[3,4-c]pyridine-7-carboxamide (13 mg, 0.03 mmol, 26%) as a yellow solid. LC / MS (ESI) m / z: 458 (M+H) + . 1H NMR (400MHz, DMSO) δ13.37(s,1H),8.57(s,1H),8.51(d,J=7.9Hz,1H),7.75(d,J=6.9Hz,1H),7.51(d,J=7.2Hz,2H),5.42–5 .30(m,1H),4.37(s,3H),3.92–3.85(m,4H),3.37–3.33(m,4H),3.30–3.25(m,2H),2.77–2.67(m,2H),1.68(d,J=7.0Hz,3H).

[0680] Bioassay

[0681] KRAS-WT (or G12C / G12D / G12V) / SOS1 binding assay

[0682] The KRAS-WT (or G12C / G12D / G12V) / SOS1 binding assay was designed to measure the potency of compounds in inhibiting protein-protein interactions between KRAS-WT (or G12C / G12D / G12V) and SOS1 proteins using HTRF (homogeneous time-resolved fluorescence) methods. Low IC50 values ​​indicate high potency of SOS1 inhibitor compounds in this assay setting.

[0683] The KRAS-WT (or G12C / G12D / G12V) / SOS1 combination assay is performed using the assay kit (Cisbio, catalog number 63ADK000CB15PEG or 63ADK000CB16PEG / 63ADK000CB17PEG / 63ADK000CB18PEG) according to the manufacturer's recommended procedure.

[0684] 1) Thaw and prepare working solutions of Tag1-SOS1 and Tag2-KRAS-WT (or G12C / G12D / G12V) proteins with a final concentration of 10 μM GTP (Sigma, catalog number V900868).

[0685] 2) Thaw and prepare anti-Tag1-Tb 3+ Working solution against Tag2-XL665.

[0686] 3) Dispense 2 μL of serially diluted compound, 4 μL of Tag1-SOS1 protein and 4 μL of Tag2-KRAS-WT (or G12C / G12D / G12V) protein with GTP into ProxiPlate-384 Plus, white 384-shallow-well microplates (PerkinElmer, catalog number 6008280).

[0687] 4) Incubate the plate at room temperature for 15 minutes.

[0688] 5) Add 10 μL of premixed anti-Tag1-Tb 3+ The anti-Tag2-XL665 was distributed into the board.

[0689] 6) Seal the plate and incubate at room temperature for 2 hours.

[0690] 7) Remove the plate sealer and read the PHERAstar FS (BMG Laboratory Technology Ltd. (BMGLABTECH), PHERAstar FS).

[0691] 8) Use the following equation to calculate the ratio of the receptor and donor emitted signals for each individual pore.

[0692]

[0693] 9) Using GraphPad Prism 8.0, the IC50 value was fitted and calculated by the logarithm of the nonlinear regression of HTRF signal value and compound concentration [logarithm (inhibitor) versus response-variable slope (four parameters)].

[0694] Table 3. Kras: SOS1 activity data in assays*

[0695] *A: <100nM; B: 100~500nM; C: 500~5μM; D: >5μM

[0696]

[0697]

Claims

1. A compound of formulas (I), (II) and (III): (I), (II)or (III), Or its pharmaceutically acceptable salts, tautomers, or stereoisomers. in: Q is independently selected from phenyl or 5- or 6-membered heteroaryl rings each time it appears, wherein the heteroaryl ring comprises at least one carbon atom and 1 to 4 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; X is CH or N; R 1 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl, -NR a R b OH, C 1-6 Alkyl-OH, Halogenated C 1-6 Alkyl-OH, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, C 3-7 cycloalkyl, C 3-7 cycloalkyl-OH, C 3-7 Cycloalkoxy groups, -S(O) t -C 1-6 Alkyl group, -S(O) t -NR a R b , phenyl or 3-7-membered heterocyclic group, wherein the phenyl and 3-7-membered heterocyclic group are optionally substituted by 1-4 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl groups -OH, OH, halogens, CN, -S(O) t -C 1-6 Alkyl group, -S(O) t -NR a R b -NR a R b and C 1-4 Alkyl-NR a R b ; or two adjacent R 1 The groups, together with the carbon atoms they are attached to, form a 5-7 membered carbon ring or heterocycle, optionally substituted by 1-3 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b C 1-4 Alkyl-NR a R b And oxy groups (=O); R 2 Each time it appears, it is independently hydrogen, halogen, CN, or -OR. a -NR a R b C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Each of the following groups is optionally surrounded by 1-5 R groups: cycloalkyl, 3-7-membered heterocyclic, phenyl, and 5-6-membered heteroaryl. 8 replace; R 3 Each time it appears, it is independently halogen, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-OH, CN, C 3-7 cycloalkyl, C 3-7 cycloalkyl-OH, C 3-7 Cycloalkoxy, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl) 2- or 3-7 membered cyclic amines; R 4 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, NH2, C 3-7 cycloalkyl or C 3-7 Cycloalkoxy; R 8 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-7 cycloalkyl, C 3-7 Cycloalkoxy, 3-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -OR a -SR a S(O) t R a -S(O) t NR a R b -OC(O)-R a -NR a R b -C(O)R a -C(O)OR a -OC(O)NR a R b 2. -C(O)NR a R b -N(R) a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)NR a R b -N(R) a )C(NR a )NR a R b -N(R) a S(O) t NR a R b -P(=O)(R a (R) b -OP(=O)(OR) a (OR) b ) or oxo group (=O); R a and R b Each time it appears, it is independently hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 Alkyl-NH2, C 1-6 Alkyl-NHC 1-4 Alkyl, C 1-6 Alkyl-N(C) 1-4 Alkyl)2 or C 1-6 Alkyl-(3-7 membered cyclic amine); wherein each of the aforementioned groups may optionally be substituted by one to three independent substituents selected from the group consisting of: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, halogen, OH, NH2, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, CN and -C(O)C 1-4 Alkyl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a saturated or unsaturated heterocycle containing three to seven ring atoms. This ring may optionally contain one or two additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and may optionally be composed of one to three independently selected C1-4 alkyl groups, -C(O)C groups, etc. 1-4 Substituents in the group consisting of alkyl, phenyl, and benzyl groups; n is independently 1, 2, or 3 each time it appears, and t is 1 or 2 independently each time it appears.

2. The compound according to claim 1, having the structure of formula (I): （I）。 3. The compound according to claim 1, having the structure of formula (II): (II)。 4. The compound according to claim 1, having the structure of formula (III): (III)。 5. The compound according to any one of claims 1 to 4, wherein Q is phenyl each time it appears.

6. The compound according to any one of claims 1 to 4, wherein Q is independently a 5-membered heteroaryl group each time it appears.

7. The compound according to any one of claims 1 to 4, wherein Q is independently a 6-membered heteroaryl group each time it appears.

8. The compound according to any one of claims 1 to 4, wherein Q is thienyl in each occurrence.

9. The compound according to any one of claims 1 to 4, wherein Q is pyridyl in each occurrence.

10. The compound according to any one of claims 1 to 4, wherein R 1 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NR a R b OH, C 1-6 Alkyl-OH, Halogenated C 1-6 Alkyl-OH, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, C 3-7 cycloalkyl, C 3-7 cycloalkyl-OH, C 3-7 Cycloalkoxy or -S(O) t -C 1-6 alkyl.

11. The compound according to any one of claims 1 to 4, wherein R 1 Each time it appears, it is independently a phenyl or a 3-7 membered heterocyclic group, wherein the phenyl and the 3-7 membered heterocyclic group are optionally substituted by 1-4 substituents independently selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl groups -OH, OH, halogens, CN, -S(O) t -C 1-6 Alkyl group, -S(O) t -NR a R b -NR a R b and C 1-4 Alkyl-NR a R b .

12. The compound according to any one of claims 1 to 4, wherein two adjacent R 1 Each time the group appears, it forms a 5-7 membered carbon ring or heterocycle with the carbon atom it is attached to, optionally substituted by 1-3 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b C 1-4 Alkyl-NR a R b And oxy groups (=O).

13. The compound according to any one of claims 1 to 4, wherein two adjacent R 1 Each time the group appears, it forms a 5-6 membered carbon ring together with the carbon atom to which it is attached, optionally substituted by 1-3 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b C 1-4 Alkyl-NR a R b And oxy groups (=O).

14. The compound according to any one of claims 1 to 4, wherein two adjacent R 1 Each time the group appears, it forms a 5-6 membered heterocycle together with the carbon atom to which it is attached, optionally substituted by 1-3 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b C 1-4 Alkyl-NR a R b And oxy groups (=O).

15. The compound according to claim 1, wherein Q and its substituent (R) 1 ) n Together, It has independent characteristics each time it appears. The structure, in: R 1a Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, OH, C 1-6 Alkyl-OH, Halogenated C 1-6 Alkyl-OH, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, C 3-7 cycloalkyl, C 3-7 cycloalkyl-OH, C 3-7 Cycloalkoxy groups, -S(O) t -C 1-6 Alkyl group, -S(O) t -NR a R b Or a 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is optionally substituted by 1-4 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl groups -OH, OH, halogens, CN, -S(O) t -C 1-6 Alkyl group, -S(O) t -NR a R b -NR a R b and C 1-4 Alkyl-NR a R b ; R 1b Each time it appears, it is independently hydrogen, halogen, or carbon. 1-4 Alkyl or C 3-6 cycloalkyl; Or R 1a and R 1b Each time they appear, they form, together with the carbon atoms to which they are attached, a 5-7 membered carbon ring or heterocycle, optionally substituted by 1-3 independent substituents selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b C 1-4 Alkyl-NR a R b and oxo groups (=O); and R 1c Each time it appears, it is independently hydrogen, halogen, NH2, or C. 1-4 alkyl.

16. The compound according to claim 15, having the structure of formula (Ia), (It).

17. The compound according to claim 15, having the structure of formula (IIa), (IIa)。 18. The compound according to claim 15, having the structure of formula (IIIa), (IIIa)。 19. The compound according to any one of claims 15 to 18, wherein R 1a Each time it appears, it is independently hydrogen, halogen, or carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, OH, C 1-6 Alkyl-OH, Halogenated C 1-6 Alkyl-OH, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, C 3-7 cycloalkyl, C 3-7 cycloalkyl-OH, C 3-7 Cycloalkoxy or -S(O) t -C 1-6 alkyl.

20. The compound according to any one of claims 15 to 18, wherein R 1a Each time it appears, it is independently and optionally substituted by 1-4 substituents selected independently from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl groups -OH, OH, halogens, CN, -S(O) t -C 1-6 Alkyl group, -S(O) t -NR a R b -NR a R b and C 1-4 Alkyl-NR a R b .

21. The compound according to any one of claims 15 to 18, wherein R 1a Each time it appears, it is independently CHF2, CH2F, CF3, CF2CH3, or CF2CH2OH.

22. The compound according to any one of claims 15 to 18, wherein R 1a and R 1b Each time they appear, they form a 5- or 6-membered carbon ring together with the carbon atoms to which they are attached, which may be substituted by 1-3 halogens.

23. The compound according to any one of claims 15 to 18, wherein R 1a and R 1b Each time it appears, it forms a structure together with the carbon atoms to which they are attached. The structure of carbon rings.

24. The compound according to any one of claims 15 to 18, wherein R 1b It is hydrogen each time it appears.

25. The compound according to any one of claims 15 to 18, wherein R 1b It is a halogen, which appears independently each time.

26. The compound according to any one of claims 15 to 18, wherein R 1b It is C independently each time it appears. 1-4 alkyl.

27. The compound according to any one of claims 15 to 18, wherein R 1b Each time it appears, it is independently either F or methyl.

28. The compound according to any one of claims 15 to 18, wherein R 1c It is hydrogen each time it appears.

29. The compound according to any one of claims 15 to 18, wherein R 1c It is a halogen, which appears independently each time.

30. The compound according to any one of claims 15 to 18, wherein R 1c It appears as NH2 each time.

31. The compound according to any one of claims 15 to 18, wherein R 1c It is C independently each time it appears. 1-4 alkyl.

32. The compound according to claim 1, wherein Q and its substituent (R) 1 ) n Together, It has independent characteristics each time it appears. The structure, in: R 1d and R 1e Each time it appears, it is independently hydrogen, halogen, or carbon. 1-4 Alkyl or halogenated C 1-4 Alkyl; and R 1f Each time it appears, it is independently a phenyl, a 5-6-membered heteroaryl, or a 3-7-membered heterocyclic group, wherein the phenyl, the 5-6-membered heteroaryl, and the 3-7-membered heterocyclic group are optionally substituted by 1-4 substituents independently selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b and C 1-4 Alkyl-NR a R b .

33. The compound according to claim 32, having the structure of formula (Ib), (One).

34. The compound according to claim 32, having the structure of formula (IIb), (IIb)。 35. The compound according to claim 32, having the structure of formula (IIIb), (IIIb)。 36. The compound according to any one of claims 32 to 35, wherein R 1d and R 1e Each time it appears, it is independently hydrogen and methyl.

37. The compound according to any one of claims 32 to 35, wherein R 1d and R 1e It is hydrogen each time it appears.

38. The compound according to any one of claims 34 to 35, wherein R 1f Each time it appears, it is independently, optionally, a phenyl group substituted with 1 to 4 substituents independently selected from the following: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-OH, Halogenated C 1-4 Alkyl group -OH, OH, halogen, CN, -NR a R b and C 1-4 Alkyl-NR a R b .

39. The compound according to any one of claims 1 to 4, 15 to 18 and 32 to 35, wherein R 2 Each time it appears, it is independently hydrogen, halogen, CN, or -OR. a -NR a R b C 1-6 Alkyl or halogenated C 1-6 Alkyl, wherein the C 1-6 Alkyl groups and the halo-C 1-6 Each of the alkyl groups is optionally surrounded by 1-5 R groups. 8 replace.

40. The compound according to any one of claims 1 to 4, 15 to 18, and 32 to 35, wherein R 2 Each time it appears, it is independently and optionally assigned 1-5 R's. 8 Replacement C 3-7 Cycloalkyl.

41. The compound according to any one of claims 1 to 4, 15 to 18, and 32 to 35, wherein R 2 Each time it appears, it is independently and optionally assigned 1-5 R's. 8 Substituted 3-7 membered heterocyclic groups.

42. The compound according to any one of claims 1 to 4, 15 to 18 and 32 to 35, wherein R 2 Each time it appears, it is independently and optionally assigned 1-5 R's. 8 Substituted phenyl groups.

43. The compound according to any one of claims 1 to 4, 15 to 18, and 32 to 35, wherein R 2 Each time it appears, it is independently and optionally assigned 1-5 R's. 8 Substituted 5-membered heteroaryl group.

44. The compound according to any one of claims 1 to 4, 15 to 18, and 32 to 35, wherein R 2 Each time it appears, it is independently and optionally assigned 1-5 R's. 8 Substituted 6-membered heteroaryl group.

45. The compound according to any one of claims 1, 4, 18 and 35, wherein R 3 Each time it appears, it is independently halogen, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl or CN.

46. ​​The compound according to any one of claims 1, 4, 18 and 35, wherein R 3 It is C independently each time it appears. 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 1-6 Alkyl-OH.

47. The compound according to any one of claims 1, 4, 18 and 35, wherein R 3 It is C independently each time it appears. 3-7 cycloalkyl or C 3-7 Cycloalkyl-OH.

48. The compound according to any one of claims 1, 4, 18 and 35, wherein R 3 Each time it appears, it is independently -NH2 or -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl) 2 or 3-7 membered cyclic amines.

49. The compound according to any one of claims 1, 4, 18 and 35, wherein X is CH.

50. The compound according to any one of claims 1, 4, 18 and 35, wherein X is N.

51. The compound according to any one of claims 1 to 4, 15 to 18, and 32 to 35, wherein R 4 It is hydrogen each time it appears.

52. The compound according to any one of claims 1 to 4, 15 to 18 and 32 to 35, wherein R 4 Each time it appears, it is independently either halogen or C. 1-6 alkyl.

53. The compound according to any one of claims 1 to 4, 15 to 18, and 32 to 35, wherein R 8 Each time it appears, it is independently hydrogen, halogen, or carbon. 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 1-4 Alkyl group.

54. The compound according to any one of claims 1 to 4, 15 to 18, and 32 to 35, wherein R 8 It is C independently each time it appears. 3-7 Cycloalkyl or 3-7 membered heterocyclic groups.

55. The compound according to any one of claims 1 to 4, 15 to 18, and 32 to 35, wherein R 8 Each time it appears, it is independently either phenyl or a 5-6 membered heteroaryl group.

56. The compound according to any one of claims 1 to 4, 15 to 18, and 32 to 35, wherein R 8 It is -OR independently each time it appears. a -SR a -S(O) t R a -S(O) t -NR a R b -OC(O)-R a -NR a R b -C(O)R a -C(O)OR a -OC(O)NR a R b -C(O)NR a R b -N(R) a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)NR a R b -N(R) a )C(NR a )NR a R b -N(R) a S(O) t NR a R b -P(=O)(R a (R) b -OP(=O)(OR) a (OR) b ) or oxo group (=O).

57. The compound according to any one of claims 1 to 4, 15 to 18, and 32 to 35, wherein R 8 It appears as an oxo group (=O) each time.

58. The compound according to any one of claims 1 to 4, 15 to 18 and 32 to 35, wherein R 8 It is -NR independently each time it appears. a R b .

59. The compound of claim 58, wherein the -NR a R b Independently, they are NH2 and -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl) 2 or 3-7 membered cyclic amines.

60. The compound according to any one of claims 1 to 4, 15 to 18, and 32 to 35, wherein R 8 It is -S(O) independently each time it appears. t -C 1-4 alkyl.

61. A compound selected from: , , , and .

62. A compound selected from: , , , and .

63. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, 15 to 18, 32 to 35, 61 and 62, and a pharmaceutically acceptable carrier.

64. Use of the compound of any one of claims 1 to 4, 15 to 18, 32 to 35, 61 and 62 in the preparation of a medicament for treating or preventing diseases or symptoms mediated by mammalian Ras family proteins.

65. Use of the compound of any one of claims 1 to 4, 15 to 18, 32 to 35, 61 and 62 in the preparation of a medicament for treating or preventing cancer.

66. The use according to claim 65, wherein the cancer is breast cancer, leukemia, prostate cancer, ovarian cancer, pancreatic cancer, colon cancer, lung cancer, endometrial cancer, thyroid cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, hepatocellular carcinoma, glioblastoma, kidney cancer, sarcoma, bladder cancer, urothelial carcinoma, gastric cancer, or cervical cancer.

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