TYK2 inhibitors and compositions and methods thereof

Abstract

The present invention provides a novel class of therapeutic agents which are safe and effective TYK2 inhibitors, pharmaceutical compositions of these compounds and methods of preparation thereof, and their use against various TYK2 mediated diseases and disorders.

Description

[0001] Priority and related patent applications

[0002] This application claims priority to the following PCT international applications: PCT / CN2023 / 100518, filed June 15, 2023; PCT / CN2023 / 137938, filed December 11, 2023; PCT / CN2024 / 075796, filed February 4, 2024; and PCT / CN2024 / 081039, filed March 11, 2024, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0003] This invention generally relates to novel compounds and methods for their therapeutic use. More specifically, the invention provides novel classes of tyrosine kinase 2 inhibitors, pharmaceutical compositions of these compounds, methods for their preparation, and their use in treating various diseases and disorders. Background Technology

[0004] Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that transduce cytokine signals through the Janus kinase-signal transduction activators of transcription (JAK-STAT) pathway. The human JAK enzyme family has four members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). This family is defined by the presence of two adjacent kinase domains, JH1 and JH2, where JH1 performs phosphorylation involved in pathway activation, while JH2 regulates JH1 function. (Thomas et al., 2015 British Journal of Cancer 113, 365–371.)

[0005] These cytosolic tyrosine kinases are associated with membrane cytokine receptors, such as common γ-chain receptors and the transmembrane protein glycoprotein 130 (gp130). (Murray et al., 2007 Immunol. 178(5): 2623-2629.) Approximately 40 cytokine receptors transduce signals through a combination of these four JAKs and their seven downstream substrate members of the STAT family. (Ghoreschi et al., 2009 Immunol Rev. 228(l): 273-287.)

[0006] Selective inhibition of TYK2 can be used to treat a variety of autoimmune inflammatory diseases, such as psoriasis, psoriatic arthritis, alopecia areata, eczema, ankylosing spondylitis (AS), vitiligo, atopic dermatitis, discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, inflammatory bowel disease (IBD), Crohn's disease (CD), rheumatoid arthritis (RA), diabetes, type 1 diabetes, renal fibrosis, chronic kidney diseases (such as diabetic nephropathy, polycystic kidney disease, HIV-related nephropathy), and cancers (such as T-cell acute lymphoblastic leukemia). Leukemia (T-ALL) and cutaneous T-cell lymphoma (CTCL). (Ellinghaus, D. et al., 2012 Am. J. Hum. Genet. 90:636-647; Graham, D. et al., 2007 Rheumatology (Oxford). 46:927-930; Eyre, S. et al., 2012 Nat. Genet.,44:1336-1340; Frank C. Brosius III. et al., 2015 Curr Opin Nephrol Hypertens. 24(1): 88-95; Keiichiro Mine. et al., 2024 Nature Communications. 15:1337-1350; Calliope A. Dendrou. et al., 2016 SciTransl Med. 8(363):149-180; Tao, JH et al., 2011 Mol. Biol. Rep. 38:4663-4672).

[0007] TYK2 plays a crucial role in the immune system, particularly in mediating inflammatory responses. Emerging research, primarily within the context of studies on immune-related disorders, suggests its involvement in various brain diseases. In patients with multiple sclerosis (MS), TYK2 regulates T cell activation and cytokine production, especially interleukin-12 (IL-12) and interferon-α (IFN-α), which are essential for immune responses. Th17 cells have been found in active lesions from the brains of MS patients. Dysregulation of TYK2 may exacerbate inflammation in MS, leading to central nervous system damage (Beecham et al., 2013 Nature genetics. 45(11): 1353-1360; Couturier, N. et al., 2011 Brain.134:693-703; Murphy, CA et al., 2003 Nature 421:744-748). TYK2 has been identified as a potential risk factor for AD (Alzheimer's disease), a neurodegenerative disorder characterized by cognitive decline and neuronal loss. Studies have shown that TYK2 can modulate microglial activation and neuroinflammation, processes associated with the pathological progression of AD (Shi et al., 2019 J Exp Med. 216(11):2546-2561). TYK2 is also associated with Parkinson's disease, a progressive neurodegenerative disorder that primarily affects motor function. Studies have shown that TYK2 neuroinflammation and dopaminergic neuron degeneration are key processes in PD pathology (Qin et al., 2016, Journal of Neuroscience 36(18): 5144-5159).

[0008] To increase expected pharmacological effects and reduce side effects, selectivity against other JAK family subtypes is considered crucial. Identifying kinase inhibitors with high TYK2 selectivity presents a significant challenge, partly due to the high sequence homology among active sites of JAK family kinases. TYK2 specificity plays a key role in the clinical application of TYK2 kinase inhibitors, as Tyk2 knockout mice survive with normal blood cell counts, while the lack of JAK3 leads to severe combined immunodeficiency in mice, and JAK1 or JAK2 knockout mice have shown perinatal lethality. (Ghoreschi et al., 2009 Immunol Rev. 228:273–287; Karaghiosoff et al., 2000 Immunity. 13:549–560; Shimoda et al., 2000 Immunity. 13:561–571.) Genetic evidence suggests that pharmacological inhibition of TYK2 should not lead to acute toxicity in human patients; however, careful monitoring for viral or mycobacterial infections is necessary for patients undergoing long-term treatment. (Akahane et al., 2017 Br J Haematol. 177(2): 271–282.)

[0009] The ability of drugs to cross the blood-brain barrier (BBB) ​​is crucial for treating central nervous system (CNS) diseases. The BBB is a highly selective barrier that regulates the transport of substances between the bloodstream and the brain to maintain brain homeostasis. However, this barrier also presents a significant challenge to drug delivery to the brain. To effectively treat CNS disorders such as Alzheimer's disease, Parkinson's disease, and brain tumors, drugs must be able to cross the BBB to reach their targets in the brain. Compounds with poor brain penetration may require high doses, leading to systemic side effects and reduced therapeutic efficacy. Developing drugs with enhanced brain penetration involves strategies such as optimizing molecular properties, utilizing drug delivery systems, and designing prodrugs that can be metabolically activated to increase BBB permeability. Furthermore, the discovery of transport mechanisms that facilitate the crossing of specific molecules across the BBB has opened new avenues for drug delivery. In conclusion, the ability of drugs to cross the BBB is essential for the successful treatment of CNS diseases. Improving brain penetration can enhance drug efficacy, reduce side effects, and offer hope for developing effective therapies for more challenging neurological disorders.

[0010] Gastrointestinal restrictive or enriched Janus kinase (JAK) inhibitors represent a class of drugs specifically designed to target the JAK-STAT signaling pathway within the gastrointestinal tract. These inhibitors offer several advantages in treating inflammatory bowel disease (IBD) and Crohn's disease, including: Local effects: By specifically targeting JAK inhibition within the gastrointestinal tract, these inhibitors minimize systemic exposure, potentially reducing the risk of systemic side effects associated with broader JAK inhibitors. Enhanced efficacy: By concentrating therapeutic effects within the digestive tract, gastrointestinal restrictive or enriched JAK inhibitors may provide enhanced efficacy in controlling inflammation and promoting mucosal healing in patients with IBD and Crohn's disease. Reduced systemic side effects: The local effects of these inhibitors can lead to a lower incidence of systemic adverse reactions such as infections or hematological abnormalities associated with systemic JAK inhibitors. Potential for lower doses: Targeting JAK inhibition into the gastrointestinal tract allows for lower doses of the drug to achieve therapeutic effects, further reducing the risk of systemic side effects. Combination therapy: Gastrointestinal restrictive or enriched JAK inhibitors can be used alone or in combination with other IBD management therapies, providing flexibility in treatment while potentially minimizing systemic drug exposure.

[0011] Solubility is a critical factor in small molecule drug development because it directly impacts bioavailability, efficacy, and ultimately, clinical success. Low solubility can lead to inadequate drug absorption, pharmacokinetic instability, and reduced therapeutic efficacy. Therefore, improving solubility is a major focus in drug development to ensure adequate drug delivery and optimal therapeutic outcomes. Some drug candidates have faced setbacks or failures in clinical development due to solubility issues. These cases underscore the importance of addressing solubility problems early in the drug development process to mitigate risks and optimize the clinical potential of small molecule therapeutics.

[0012] There is an urgent and unmet need for selective TYK2 inhibitors with improved efficacy and minimal side effects across various therapeutic areas, and challenges remain. Summary of the Invention

[0013] This invention provides novel, selective, and potent compounds that are orally and / or topically available and / or suitable for CNS penetration, gastrointestinal (GI) restriction, and / or topical application. These therapeutic agents are safe and effective TYK2 inhibitors and may exhibit fewer and / or milder side effects compared to currently available drugs. This invention also provides pharmaceutical compositions of these compounds, as well as methods of their preparation and use.

[0014] This document discloses a series of novel TYK2 inhibitors specifically designed to meet the characteristics suitable for (I) CNS penetration, (II) oral administration, or (III) GI and / or topical dermal application. For compounds designed for oral administration, they exhibit potent activity against TYK2 and a range of selectivity for other JAK kinases and JAK1 JH2 domains, along with generally favorable pharmaceutical properties. For compounds potentially suitable for GI-restricted use, properties such as Caco-2 data, solubility, and PK are suitable for limiting their action to the intestinal site. For compounds potentially suitable for topical application, they are designed to have good skin penetration and high retention in the epidermis and dermis. These novel inhibitors exhibit a superior potency spectrum with TYK2 IC50 values ​​in the low picomol or nanomol range. These therapeutic agents are safe and effective TYK2 inhibitors, exhibiting fewer and / or milder side effects compared to currently available drugs. The present invention also provides pharmaceutical compositions of these compounds, as well as methods of their preparation and use.

[0015] In one aspect, the present invention generally relates to compounds having structural formula (I):

[0016]

[0017] (I)

[0018] Or its pharmaceutically acceptable form or isotopic derivative.

[0019] in

[0020] Y 1 For CH, CF, or N;

[0021] Y 2 For CH or N;

[0022] Y 3 It can be NR, O, CH2, CD2, CF2 or O-NH;

[0023] t is 0 or 1;

[0024] R 1 It is H, F, CD3, or C1-C3 alkyl, provided that Y is an H, F, CD3, or C1-C3 alkyl group. 3 When R is N, O, or O-NH, 1 Not F;

[0025] R 2 for

[0026] R 2’ , where R 2’ C1-C6 alkyl, C3-C6 cycloalkyl, C 5-C7 spirocycloalkyl or C3-C6 heterocycloalkyl, each marked with 0-2 R... 2a Replace, where R 2a Choose from the group consisting of halogens, CN, OR, NRR', alkyl, cycloalkyl, and heterocycles;

[0027] aryl or heteroaryl, each surrounded by 0-2 R groups 2a replace;

[0028] (C=O)R 2b ;or

[0029] (C=O)NHR 2b ;

[0030] R 3 for

[0031]

[0032] (II)

[0033] in

[0034] X 6 For CR 6 Or N;

[0035] X 7 For CR 7 Or N;

[0036] X 8 It can be C or N;

[0037] X 9 For CR 9 , O, S, N or NR 9 ;

[0038] X 10 For CR 10 , O, S, N or NR 10 ;as well as

[0039] In this ring, ring A and ring B are each independently aryl or heteroaryl;

[0040] R 2b C 1-6 Alkyl or C 3-6 cycloalkyl, C 5-7 Spirocycloalkyl, aryl, or heteroaryl groups, each marked with 0-4 R groups. 2c replace;

[0041] R 2c Each occurrence is independently of halogen, CN, OR, NRR', OCF3, CF3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6alkenyl, C 2-6 Alkynyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, R and R' are surrounded by 0-3 Rs 2a Replace; and

[0042] R 4 C 1-3 Alkyl groups, which are 0-5 R groups 4a Replace, where R 4a Selected from D, F, and Cl;

[0043] R 5 For H, CN, halogens, OCH3, C(=O)OR, NHC(=O)R, NRR', NO2, C 1-6 Alkyl, C3-C6 cycloalkyl, or heterocyclic, wherein the alkyl, cycloalkyl, or heterocyclic is surrounded by 0-3 R... 5a Replace, where each R 5a It is independently selected from OH, D, F, Cl, CN, CH2F, CHF2, CF3, OCH3, OCD3, OCF3 and OC(=O)CH3;

[0044] R 6 R 7 R 9 and R 10 Each is independently selected from H, F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl and C3-C5 cycloalkyl, wherein the alkyl, cycloalkyl, R and R' are separated by 0-2 R's. 2a Replace; and

[0045] R and R' are each independently H or C1-C6 alkyl or acyl, or R and R' together with their bonded nitrogen atoms form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO2.

[0046] In some embodiments of (I), t is 1, and the compound has the structural formula:

[0047]

[0048] (III) a ).

[0049] In some embodiments of (I), t is 0, and the compound has the structural formula:

[0050]

[0051] (III) b ).

[0052] In another aspect, the present invention generally relates to compounds having structural formula (VIII):

[0053]

[0054] (VIII)

[0055] Or its pharmaceutically acceptable form or isotopic derivative.

[0056] in

[0057] X 6 For CR 6 Or N;

[0058] X 7 For CR 7 Or N;

[0059] X 8 It can be C or N;

[0060] X 9 For CR 9 , O, S, N or NR 9 ;

[0061] X 10 For CR 10 , O, S, N or NR 10 ;

[0062] Y 1 For CH, CF, or N;

[0063] Y 2 For CH or N;

[0064] Y 3 It can be NR, O, CH2, CD2, CF2 or O-NH;

[0065] Y 4 For NR, CH2, or CF2;

[0066] Y 5 It can be NR, CH2, O, S, SO, or SO2;

[0067] m is 0, 1, 2, and 3;

[0068] n is 0, 1, 2, or 3;

[0069] p is 0, 1, 2, and 3;

[0070] Ring A and ring B are each independently aryl or heteroaryl;

[0071] The ring C is a 5- or 6-membered aryl or heteroaryl group;

[0072] R 1For H, F, CD3, or C 1-3 Alkyl, provided that when Y 3 When R is N, O, or O-NH, 1 Not F;

[0073] R 4 C 1-3 Alkyl groups, which are 0-5 R groups 4a Replace, where R 4a Selected from D, F, and Cl;

[0074] R 5 For H, CN, halogens, OCH3, C(=O)OR, NHC(=O)R, NRR', NO2, C 1-6 Alkyl, C 3-6 cycloalkyl or heterocyclic, wherein the alkyl, cycloalkyl or heterocyclic is surrounded by 0-3 R... 5a Replace, where each R 5a It is independently selected from OH, D, F, Cl, CN, CH2F, CHF2, CF3, OCH3, OCD3, OCF3 and OC(=O)CH3;

[0075] R 6 R 7 R 9 R 10 and R 11 Each is independently selected from H, F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C 1-3 Alkyl and C 3-5 cycloalkyl, wherein the alkyl, cycloalkyl, R and R' are separated by 0-2 R 2a replace;

[0076] R 2a Selected from F, OCF3, CF3, CN, NO2, OR, NRR' and C 1-6 Alkyl groups; and

[0077] R and R' are each independently H, C1-C6 alkyl or acyl, or R and R' together with their bonded nitrogen or carbon atoms form a 3 to 6-membered ring containing 0 to 2 heteroatoms selected from O, NR, S and SO2.

[0078] In another aspect, the present invention generally relates to methods for preparing the compounds disclosed herein, as illustrated by the synthetic schemes and experimental procedures disclosed herein.

[0079] In another aspect, the present invention generally relates to a pharmaceutical composition comprising the compounds disclosed herein, which are effective in treating or alleviating one or more diseases or disorders in mammals, including humans, and pharmaceutically acceptable excipients, carriers, or diluents.

[0080] In another aspect, the present invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0081] In another aspect, the present invention generally relates to methods for treating, alleviating, or preventing diseases or disorders, comprising administering a therapeutically effective amount of the compounds disclosed herein to a subject in need, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in mammals, including humans.

[0082] In another aspect, the present invention generally relates to the use of the compounds disclosed herein, as well as pharmaceutically acceptable excipients, carriers, or diluents, in the preparation of medicaments for treating diseases or disorders. Attached Figure Description

[0083] Figure 1 Some exemplary data on mouse weight change (A) and DAI score (B) are shown. n=10 mice / group. Data are presented as mean ± SEM. * p<0.05, ** p<0.01, *** p<0.005, **** p<0.0001, compared to vehicle. Two-way ANOVA and Dunnet multiple comparison test are used.

[0084] Figure 2 Some exemplary data on mouse weight change (A) and DAI score (B) are shown. n=8 mice / group. Data are presented as mean ± SEM. * p<0.05, ** p<0.01, *** p<0.005, **** p<0.0001, compared to vector, two-way ANOVA, Dunnet multiple comparison test.

[0085] Figure 3 Some exemplary data on immune cells in whole blood are shown. n=5 mice / group. Data are presented as mean ± SEM. * p<0.05, ** p<0.01, *** p<0.005, **** p<0.0001. Compared to vector, two-way ANOVA and Dunnet multiple comparison test are used.

[0086] Figure 4 CD4 was displayed + Some exemplary data of T cell count (A) and colon histological score (B). n=8 mice / group, data are presented as mean ± SEM, * p<0.05, ** p<0.01, *** p<0.005, **** p<0.0001, compared to vector, two-way ANOVA, Dunnet multiple comparison test. Detailed Implementation

[0087] definition

[0088] 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. General principles of organic chemistry, as well as specific functional parts and reactivity, are described in *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito: 2006.

[0089] Unless otherwise stated, the following terms are intended to have the following meanings depending on the context in which they appear.

[0090] The ranges provided in this document should be understood as abbreviations for all values ​​within that range. For example, the range 1 to 16 should be understood as including any number, combination of numbers, or subrange of any group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0091] As used in this article, "at least" a specific value should be understood as this value and all values ​​greater than this value.

[0092] As used in this article, “more than one” should be understood as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 100, etc., or any value in between.

[0093] In this specification and the appended claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly specifies otherwise.

[0094] Unless otherwise specified or obvious from the context, as used herein, the term "about" should be understood as being within normal tolerances in the art, such as within two standard deviations of the mean. "About" can be understood as being within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. All numerical values ​​provided herein may be modified by the term "about" unless explicitly stated otherwise from the context.

[0095] Unless otherwise specified or obvious from the context, the term “or” as used herein should be understood as inclusive.

[0096] Any composition or method disclosed herein may be combined with one or more of any other compositions and methods disclosed herein.

[0097] The enumeration of chemical groups in any variable definition herein includes the definition of the variable as any single group or combination of the listed groups. The enumeration of embodiments of variables or aspects herein includes embodiments as any single embodiment or in combination with any other embodiment or part thereof.

[0098] The term "comprising," when used to define compositions and methods, is intended to indicate that the compositions and methods include the listed elements, but do not exclude other elements. The term "consistently composed of," when used to define compositions and methods, should indicate that the compositions and methods include the listed elements and exclude other elements that are of any substantial importance to the composition and method. For example, "consistently composed of" means the application of a explicitly listed pharmacologically active agent and excludes pharmacologically active agents that are not explicitly listed. The term "consistently composed of" does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term "composed of," when used to define compositions and methods, should indicate the exclusion of trace elements of other components and substantial method steps. Embodiments defined by each of these transitional terms are within the scope of this invention.

[0099] Certain compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention encompasses all such compounds falling within its scope, including cis and trans isomers, trans-blocking isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in this invention. In some embodiments, each asymmetric atom has an R- or S-configuration with at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess. For optically active compounds, it is generally preferred to use one enantiomer while substantially excluding the other.

[0100] According to the present invention, mixtures of isomers containing any proportion of isomers can be used. For example, when only two isomers are combined, the present invention covers mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. Those skilled in the art will readily understand that similar ratios are considered for more complex mixtures of isomers.

[0101] For example, if a specific enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization using a chiral auxiliary agent, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, it is reacted with a suitable optically active acid or base to form a diastereomeric salt, and the resulting diastereomeric isomer is then resolved by fractional crystallization or chromatographic methods well known in the art, and the pure enantiomer is subsequently recovered.

[0102] Mixtures of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, and racemates, for example, by chromatography and / or fractional crystallization, based on the physicochemical differences in their composition.

[0103] The definitions of specific functional groups and chemical terms are described in more detail below. When a range of values ​​is listed, the range is intended to cover every value within that range and its subranges. For example, “C…” 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0104] When a substituent is specified by its conventional chemical formula written from left to right, it also covers chemically identical substituents obtained by writing the structure from right to left, for example, -C(=O)-O- is equivalent to -OC(=O)-.

[0105] The structures of the compounds of the present invention are restricted by chemical bonding principles known to those skilled in the art. Thus, when a group can be substituted by one or more of a number of substituents, these substitutions are selected to conform to the chemical bonding principles, and compounds are obtained that are not inherently unstable and / or may be unstable under environmental conditions (e.g., aqueous, neutral, and various known physiological conditions) as known to those skilled in the art.

[0106] This document also covers solvates and polymorphs of the compounds of the present invention. Solvates of the compounds of the present invention include, for example, hydrates.

[0107] As used herein, the term "alkyl" refers to a straight-chain, branched, or cyclic hydrocarbon chain radical (e.g., C10) consisting only of carbon and hydrogen atoms, without unsaturation, and having one to ten carbon atoms. 1-10 Alkyl group. Whenever it appears herein, numerical ranges such as "1 to 10" refer to integers within that given range; for example, "1 to 10 carbon atoms" means that an alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, but the current definition also covers the term "alkyl" when no numerical range is specified. In some embodiments, "alkyl" may be C 1-6 Alkyl groups. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight-chain alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched 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. The alkyl group is linked to the parent molecule by a single bond. Unless otherwise stated in this specification, alkyl groups may optionally be substituted by one or more substituents that independently include: acyl, alkyl, alkenyl, alkynyl, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidine, imino, azido, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate ester, phosphonate, hypophosphonate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfonyloxy, 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(Ra )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 a Independently, it is hydrogen, alkyl, haloalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties may optionally be substituted as defined 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.

[0108] As used herein, the term "alkoxy" refers to the -O-alkyl group, which comprises 1 to 10 carbon atoms (C6H ... 1-10 Alkoxy groups are linear, branched, saturated cyclic, or combined configurations of alkoxy groups, linked to the parent molecule via oxygen atoms. Unless otherwise stated in this specification, the term is intended to include both substituted and unsubstituted alkoxy groups. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, cyclopropoxy, cyclohexyloxy, etc. "Lower alkoxy" refers to alkoxy groups containing 1 to 6 carbons. In some embodiments, C... 1-3 The alkoxy group is a straight-chain or branched alkyl group comprising 1 to 3 carbon atoms. Unless otherwise stated in this specification, the alkoxy group may optionally be substituted by one or more substituents independently comprising: acyl, alkyl, alkenyl, alkynyl, alkylaryl, cycloalkyl, aralkyl, aryl, aryl, amino, amide, amidine, imino, azido, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroaryl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate ester, phosphonate, hypophosphonate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfonyloxy, 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)ORa -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 a Independently, it is hydrogen, alkyl, haloalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties may optionally be substituted as defined herein.

[0109] As used herein, the terms "aromatic" or "aryl" refer to groups having 6 to 14 ring atoms (e.g., C14, C24, C34, C44, C54, C6 ... 6-14 Fragrance (fragrant) or C 6-14 Aryl groups (aryl groups) have at least one ring having a conjugated π-electron system, wherein the ring is a carbocyclic ring (e.g., phenyl, indenyl, and naphthyl). Unless otherwise stated in this specification, the term is intended to include both substituted and unsubstituted aryl groups. In some embodiments, the aryl group is C10. 6-10Aryl groups. For example, a divalent radical formed from a substituted benzene derivative and having a free valence at a ring atom is called a substituted phenylene group. In other embodiments, a divalent radical derived from a monovalent polycyclic hydrocarbon group whose name ends in "-" by removing a hydrogen atom from a carbon atom having a free valence is named by adding "-" 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 the individual integers within that 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 includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent ring atom pairs) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In polycyclic groups, only one ring needs to be aromatic; therefore, groups such as indaminozyl are included in the definition of aryl. Non-limiting examples of aryl groups include phenyl, phenaleny, naphthyl, tetrahydronaphthyl, phenanthryl, anthracene, indole, indanyl, and indanyl. Unless otherwise stated in this specification, the aryl moiety may optionally be substituted by one or more substituents independently comprising: acyl, alkyl, alkenyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidyl, imino, azido, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate ester, phosphonate, hypophosphonate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfonyloxy, 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 a Independently, it is hydrogen, alkyl, haloalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl, or heteroarylalkyl, and each of these moieties may optionally be substituted as defined herein.

[0110] As used herein, the terms "cycloalkyl" and "carbocyclic" refer to monocyclic or polycyclic groups containing only carbon and hydrogen and which may be saturated or partially unsaturated. A partially unsaturated cycloalkyl group may be called a "cycloalkenyl" if the carbocyclic ring contains at least one double bond, or a partially unsaturated cycloalkyl group may be called a "cycloynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups include groups having 3 to 13 ring atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-13 (Cycloalkyl). Unless otherwise stated in this specification, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Whenever it appears herein, numerical ranges such as “3 to 10” refer to each integer within that given range; for example, “3 to 13 carbon atoms” means that a cycloalkyl group can consist of 3, 4, 5, etc., up to and including 13 carbon atoms. The term “cycloalkyl” also includes bridging and spirocyclic structures that do not contain heteroatoms. The term also includes monocyclic or fused polycyclic (i.e., rings sharing adjacent ring atom pairs) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, “cycloalkyl” may be C 3-8 Cycloalkyl. In some embodiments, "cycloalkyl" may be C10. 3-5 Cycloalkyl. Exemplary examples of cycloalkyl 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 C mentioned above. 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. 3-8Carbocyclic groups and octahydro-1H-indenyl, decahydronaphthyl, spiro[4.5]decyl, etc. Unless otherwise stated in this specification, cycloalkyl groups may optionally be substituted by one or more substituents independently including: acyl, alkyl, alkenyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidyl, imino, azido, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate ester, phosphonate, hypophosphonate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfonyloxy, 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 a Independently, it can be hydrogen, alkyl, haloalkyl, carbocyclo, carbocycloalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl, and each of these moieties may optionally be substituted as defined herein. The terms “cycloalkenyl” and “cycloynyl” are borrowed from the above description of “cycloalkyl”, wherein the prefix “alkane” is replaced by “ene” or “yn” respectively, and the parent term “alkenyl” or “ynyl” is 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.

[0111] As used herein, the terms “carbocyclic,” “carbocyclic,” and “carbocyclic group” refer to monocyclic or polycyclic groups containing only carbon as ring atoms. They can be saturated or partially unsaturated. A fully saturated carbocyclic group is called a cycloalkyl group. A partially unsaturated cycloalkyl group may be called a “cycloalkenyl” if the carbocyclic ring contains at least one double bond, or a “cycloynyl” if the carbocyclic ring contains at least one triple bond. Unless otherwise stated in this specification, the term is intended to include both substituted and unsubstituted carbocyclic groups. The term “carbocyclic” also includes bridging and spirofused cyclic structures that do not contain heterocyclic atoms. The term also includes monocyclic or fused polycyclic (i.e., rings sharing adjacent ring atom pairs) groups. Polycyclic groups include bicyclic, tricyclic, tetracyclic, etc. Unless otherwise stated in this specification, a carbocyclic group may optionally be substituted with one or more substituents.

[0112] As used herein, the terms "heterocyclic," "heterocyclic," or "heterocyclic group" refer to a fully saturated or partially unsaturated cyclic group, such as a 3- to 7-membered monocyclic, a 7- to 12-membered bicyclic, or a 10- to 15-membered tricyclic system, having at least one heteroatom in at least one ring, wherein 0, 1, 2, or 3 atoms in each ring may be substituted by substituents. Each ring of a heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Heterocyclic groups may be linked at any heteroatom or carbon atom in the ring or ring system.

[0113] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). As used herein, the terms "halide" or "halogen (halogenated)" indicate a fluorinated (fluorinated), chlorolated (chlorolated), bromolated (bromolated), or iodolated (iodolated). The terms "halogenated alkyl," "halogenated alkenyl," "halogenated alkynyl," and "halogenated alkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halogens or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" respectively include alkyl and alkoxy halogroups wherein the halogen is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. Each alkyl, alkenyl, alkynyl, and alkoxy group is as defined herein and may optionally be further substituted as defined herein.

[0114] As used herein, the term “heteroatoms” refers to oxygen (O), nitrogen (N), sulfur (S), and phosphorus (P).

[0115] As used herein, the term "heteroalkyl" refers to an alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Unless otherwise stated in this specification, the term is intended to include both substituted and unsubstituted heteroalkyl groups. Numerical ranges may be given, for example, C1.1-4 A heteroalkyl group refers to a group with a total chain length of 4 atoms, as described in this example. For instance, a -CH2OCH2CH3 group is called a "C4" heteroalkyl group, which includes the heteroatom center described in the atomic chain length description. Connection to the parent molecule structure can be achieved via heteroatoms or carbon atoms in the heteroalkyl chain. For instance, an N-containing heteroalkyl moiety refers to a group whose backbone atom is at least one nitrogen atom. One or more heteroatoms in the heteroalkyl group may optionally be oxidized. One or more nitrogen atoms (if present) may also optionally be quaternized. For instance, a heteroalkyl group also includes a backbone chain substituted with one or more oxynitride (-O-) substituents. Exemplary heteroalkyl groups include, but are not limited to, ethers such as methoxyethyl (-CH2CH2OCH3), ethoxymethane (-CH2OCH2CH3), (methoxymethoxy)ethyl (-CH2CH2OCH2OCH3), (methoxymethoxy)methyl (-CH2OCH2OCH3), and (methoxyethoxy)methyl (-CH2OCH2CH2OCH3); and amines such as (-CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2NHCH2CH3, -CH2N(CH2CH3(CH3)), etc.

[0116] As used herein, the term "heterocyclic alkyl" refers to a cycloalkyl group having one or more skeletal chain atoms selected from atoms other than carbon (e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof). Unless otherwise stated in this specification, the term is intended to include both substituted and unsubstituted heterocyclic alkyl groups. Exemplary examples of heterocyclic alkyl groups include 2-hydroxy-aziridin-1-yl, 3-oxo-1-oxetane-2-yl, 2,2-dimethyl-tetrahydrofuran-3-yl, 3-carboxy-morpholin-4-yl, 1-cyclopropyl-4-methyl-piperazin-2-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydro-2H-piperanyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-[1,4]oxazine, etc.

[0117] As used herein, the term "heteroaryl" or optionally "heteroaryl" refers to a group (e.g., having 6, 10, or 14 π electrons shared in the ring array) of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring system, having a ring carbon atom 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"). Unless otherwise stated in this specification, the term is intended to include both substituted and unsubstituted heteroaryl groups. A heteroaryl polycyclic system may include one or more heteroatoms in one or two rings. Whenever it appears herein, numerical ranges such as "5 to 18" refer to individual integers within that given range; for example, "5 to 18 ring atoms" means that a heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. In some cases, a heteroaryl group may have 5 to 14 ring atoms. In some embodiments, the heteroaryl group has, for example, a divalent group derived from a monovalent heteroaryl group whose name ends with "-", and is named by removing a hydrogen atom from an atom with a free valence, by adding "-" to the name of the corresponding monovalent group, for example, a pyridyl group with two connection points is a pyridylene group.

[0118] For example, the N-containing "heteroaryl" or "heteroaryl" moiety refers to an aryl group in which at least one skeletal atom 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 include ring systems substituted with one or more oxynitride (-O-) substituents, such as pyridyl N-oxide. Heteroaryl groups are connected to the parent molecule structure through any atom of the ring.

[0119] "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the connection point with the parent molecule is on the aryl group or 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 with the parent molecule is on the heteroaryl ring. For polycyclic heteroaryl groups (e.g., indole, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom, the connection point with the parent molecule can be on either ring, i.e., on a ring containing a heteroatom (e.g., 2-indole) or on a ring without a heteroatom (e.g., 5-indole). In some embodiments, the heteroaryl is a 5-10 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic 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, the heteroaryl group is a 5-6 membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic 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, the 5-6 membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1 cyclic heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0120] Examples of heteroaryl groups include, but are not limited to, aziridine, acridine, benzimidazolyl, benzoindolyl, 1,3-benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazolyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxacyclohexyl, benzonaphthofuranyl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxacyclohexenyl, benzooxazolyl, benzopiperanyl, benzopiperanoneyl, benzofuranyl, benzofuranoneyl, benzofurandiazolyl, benzothiazolyl, benzothiaphenyl (benzothiophenyl), benzothiaphen[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1, 2-a]pyridyl, carbazole, cyclopentadien[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentadien[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cyperolinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptane[1,2-c]pyridazinyl, dibenzo[h]pyrimidinyl Furanyl, dibenzothiopheneyl, furanyl, furadiazolyl, furanoneyl, furano[3,2-c]pyridyl, 5,6,7,8,9,10-hexahydrocyclooctyl[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctyl[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctyl[d]pyridyl, isothiazolyl, imidazolyl, indazoleyl Indole, inzolyl, isoindole, dihydroindole, isodihydroindole, isoquinolinyl, indoleazinyl, isoxazolyl, 5,8-methylene-5,6,7,8-tetrahydroquinazolinyl, naphridinyl, 1,6-naphridinoneyl, oxadiazolyl, 2-oxozazolyl, oxazolyl, oxazolidinyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridinyl, purine, pyranyl, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl Pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroloyl, quinazolinyl, quinoxalinyl, 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-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridyl and thiophenyl (i.e., thiophene). Unless otherwise stated in this specification, the heteroaryl moiety may optionally be substituted by one or more substituents independently comprising: acyl, alkyl, alkenyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidine, imino, azido, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate ester, phosphonate, hypophosphonate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfonyloxy, 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 a Independently, it is hydrogen, alkyl, haloalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroaryl, and each of these moieties may optionally be substituted as defined herein.

[0121] As used herein, the term "administering" refers to oral administration, suppository administration, local contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration to a subject, or to the implantation of a sustained-release device, such as a micro-osmotic pump. The appropriate route of administration for a particular patient depends on the nature and severity of the disease or condition being treated, the nature of the therapy used, and the nature of the active compound.

[0122] Administration can be made via any suitable route, including parenteral and transmucosal administration (e.g., buccal, sublingual, palate, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery modalities include, but are not limited to, the use of liposomal formulations, intravenous infusion, and transdermal patches.

[0123] "Co-administration" means that the composition described herein is administered simultaneously with, just before, or just after one or more additional therapies.

[0124] The compounds of the present invention can be administered to a patient alone or in combination. Co-administration is intended to include the simultaneous or sequential administration of compounds (more than one compound or agent) alone or in combination. Therefore, the formulation may also be combined with other active substances when needed (e.g., to reduce metabolic degradation).

[0125] The compositions of this invention can be delivered transdermally or via a local route and can be formulated as plasters, solutions, suspensions, emulsions, gels, creams, ointments, pastes, colloids, ointments, powders, and aerosols. Oral formulations include tablets, pills, powders, sugar-coated pills, capsules, liquid formulations, lozenges, capsules, gels, syrups, pastes, suspensions, etc., suitable for patient ingestion. Solid formulations include powders, tablets, pills, capsules, capsules, suppositories, and dispersible granules. Liquid formulations include solutions, suspensions, emulsions, and gels, such as water or water / propylene glycol solutions.

[0126] The compositions of the present invention may further comprise components that provide sustained release and / or comfort. These components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in more detail in U.S. Patents 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention may also be delivered in microsphere formulations for slow release in vivo. For example, microsphere formulations can be administered as drug-containing microspheres that are slowly released subcutaneously via intradermal injection (see Rao, 1995 J. Biomater Sci. Polym. Ed. 7:623-645); as biodegradable and injectable gel formulations (see, for example, Gao 1995 Pharm.Res. 12:857-863); or as microspheres for oral administration (see, for example, Eyles 1997 J. Pharm.Pharmacol. 49:669-674).

[0127] As used herein, the terms “disease,” “symptom,” and “disorder” are used interchangeably and refer to the presence or health status of a patient or subject who can be treated with the compounds, pharmaceutical compositions, or methods disclosed herein.

[0128] As used herein, the term "effective amount" for an active agent refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the patient.

[0129] As used herein, the term "inhibition" ("inhibit / inhibiting") in relation to the interaction of a biological target (e.g., TYK2) with an inhibitor refers to a negative effect (e.g., a reduction) on the activity or function of a protein relative to the absence of an inhibitor. In embodiments, inhibition refers to a negative effect (e.g., a reduction) on the concentration or level of a protein relative to the absence of an inhibitor. In embodiments, inhibition refers to the reduction of a disease or the symptoms of a disease. In embodiments, inhibition refers to a reduction in the activity of a specific protein target. Inhibition includes at least partially or completely blocking stimulation, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signal transduction or enzyme activity or the amount of protein. In embodiments, inhibition refers to a reduction in the activity of a target protein resulting from a direct interaction (e.g., an inhibitor binding to a target protein). In embodiments, inhibition refers to a reduction in the activity of a target protein resulting from an indirect interaction (e.g., an inhibitor binding to a protein that activates the target protein, thereby preventing target protein activation).

[0130] As used herein, the terms “separation” or “purification” refer to materials that are substantially or essentially free of the components that typically accompany them in their natural state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high-performance liquid chromatography.

[0131] As used herein, the term "regulator" refers to an increase or decrease, stimulation, inhibition, interference, or blockade of the measured activity, directly or indirectly, compared to a suitable control. A "regulator" of a peptide or polynucleotide refers to a substance that affects (e.g., increases, decreases, stimulates, inhibits, interferes with, or blocks) the measured activity of the peptide or polynucleotide, compared to a suitable control. For example, a "regulator" may be a measurable affinity binding to and / or activation or inhibition of a target, or directly or indirectly affect the normal regulation of receptor activity.

[0132] As used herein, the “pharmaceutically acceptable form” of the disclosed compounds includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives thereof. In one embodiment, the “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, esters, prodrugs, and isotopically labeled derivatives thereof. In some embodiments, the “pharmaceutical acceptable form” includes, but is not limited to, pharmaceutically acceptable isomers and stereoisomers, prodrugs, and isotopically labeled derivatives thereof.

[0133] In some embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" means that, within reasonable medical judgment, it is suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic acids and bases, and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or with organic acids (such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, and gluconate. (gluconate), hemisulfate, heptanoate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, p-toluenesulfonate, undecanoate, valerate, etc. In some embodiments, the organic acids from which the salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic 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.

[0134] Salts can be prepared in situ during the isolation and purification of the disclosed compounds, or prepared separately, for example by reacting the free base or free acid of the parent compound with a suitable base or acid. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N2 salts. + (C 1-4Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Other pharmaceutically acceptable salts appropriately include non-toxic ammonium, quaternary ammonium, and amine cations formed 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 amines, secondary amines, and quaternary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and alkali ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0135] In some embodiments, the pharmaceutically acceptable form is a "solvent" (e.g., a hydrate). 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 may 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 may, for example, comprise 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.

[0136] In some embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or "pro-drug") refers to a compound that is converted in vivo to yield the disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug may be inactive when administered to a subject, but may be converted in vivo, for example, by hydrolysis (e.g., in the blood). In some cases, a prodrug has improved physical and / or delivery properties beyond those of the parent compound. Relative to the parent compound, a prodrug may increase the bioavailability of the compound when administered to a subject (e.g., by allowing enhanced absorption in the blood after oral administration) or enhance delivery to the biological metabolic region of interest (e.g., the brain or lymphatic system). Exemplary prodrugs include derivatives of the disclosed compound that, relative to the parent compound, have enhanced water solubility or active transport across the intestinal membrane.

[0137] Prodrug compounds often offer the following advantages: solubility in mammalian organisms, tissue compatibility, or delayed release (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are provided in Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14 and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

[0138] Prodrug forms often offer the advantages of solubility in mammalian organisms, tissue compatibility, or delayed release. (See Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, Calif., 1992.) Prodrugs generally known in the art include known acid derivatives, such as esters prepared by reacting a parent acid with a suitable alcohol, amides prepared by reacting a parent acid compound with an amine, basic groups reacted to form acylated base derivatives, etc. Other prodrug derivatives can be combined with other features disclosed herein to enhance bioavailability. Therefore, those skilled in the art will recognize that certain compounds having a free amino, amide, hydroxyl, or carboxyl group can be converted into prodrugs. Prodrugs also include compounds having a carbonate, carbamate, amide, or alkyl ester moiety having a covalent bond to any of the aforementioned substituents disclosed herein.

[0139] 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.

[0140] As used herein, the term "pharmaceutically acceptable" excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or packaging material, that participates in the delivery or transport of the subject pharmaceutical preparation from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with other components of the preparation and harmless to the patient. Examples of materials that can serve as pharmaceutically acceptable carriers 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; tragali gum powder; malt; gelatin; talc; suppository matrices such as 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 propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate, magnesium stearate and polyoxyethylene-polyoxypropylene copolymer), as well as colorants, releasing agents, coating agents, sweeteners, flavoring agents and aromas, preservatives and antioxidants may also be present in these compositions.

[0141] As used herein, the term “subject” means any animal (e.g., a mammal) that will be a recipient of a particular treatment, including but not limited to humans, non-human primates, rodents, etc. Subjects intended for administration include, but are not limited to, humans (e.g., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other non-human animals, such as non-human mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); economically valuable mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs), rodents (e.g., rats and / or mice), etc. In some embodiments, the non-human animal is a mammal. The non-human animal can be male or female at any developmental stage. The non-human animal can be a transgenic animal. Generally, when referring to human subjects, the terms “subject” and “patient” are used interchangeably herein.

[0142] As used herein, the term "treatment / treating" refers to any method of reducing, delaying, or improving a disease or disorder before or after its occurrence. Treatment may target one or more effects or symptoms of the disease and / or underlying condition. Treatment may be for any reduction of the disease or its symptoms and may be for, but not limited to, the complete elimination of the disease or its symptoms. Therefore, treatment ("treating / treatment") means any marker of the successful treatment or improvement of an injury, disease, lesion, or condition, including any objective or subjective parameter such as symptom relief; mitigation; reduction or making the injury, lesion, or condition more tolerable for the patient; slowing the rate of deterioration or debilitation; reducing the degree of eventual deterioration; or improving the patient's physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters such as the results of physical examinations, neuropsychiatric tests, and / or mental health assessments. A reduction of at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% compared to an untreated equivalent control group, as measured by any standard technique.

[0143] Treatment methods include administering a therapeutically effective amount of the compound described herein to a subject. Administration may be a single dose or may include a series of doses. The length of the treatment period depends on various factors, such as the severity of the condition, the patient's age, the concentration of the compound, the activity of the composition used for treatment, or combinations thereof. It should also be recognized that the effective dose of the therapeutic agent may be increased or decreased during a particular treatment regimen. It is evident that the dose may be varied according to standard diagnostic analyses known in the art. In some cases, prolonged administration may be required. For example, the composition may be administered to the subject in an amount and for a duration sufficient to treat the patient. Invention Details

[0145] This invention is based on the accidental discovery of novel, selective, and potent compounds as TYK2 inhibitors. The invention also provides pharmaceutical compositions of these compounds and methods for their preparation and use. The compounds are orally administered and exhibit fewer and / or milder side effects compared to existing drugs.

[0146] The novel class of TYK2 inhibitors disclosed herein exhibits a superior potency spectrum and is suitable for treating one or more TYK2-mediated diseases and conditions, such as allergic, autoimmune, inflammatory, metabolic, neurological, and proliferative diseases and conditions. Not wishing to be bound by theory, the compounds of this invention regulate interleukins (e.g., IL-12, IL-23) and interferons (e.g., IFN-α) by inhibiting TYK2-mediated signal transduction.

[0147] These compounds are designed to exhibit good efficacy against TYK2 with good oral absorption and good in vivo stability. This invention also provides pharmaceutical compositions of these compounds and methods of preparation and use thereof. The TYK2 inhibitors disclosed herein exhibit favorable pharmacokinetic characteristics and pharmaceutical properties suitable for the target indications.

[0148] In one aspect, the present invention generally relates to compounds having structural formula (I):

[0149]

[0150] (I)

[0151] Or its pharmaceutically acceptable form or isotopic derivative.

[0152] in

[0153] Y 1 For CH, CF, or N;

[0154] Y 2 For CH or N;

[0155] Y 3 It can be NR, O, CH2, CD2, CF2 or O-NH;

[0156] t is 0 or 1;

[0157] R 1 It is H, F, CD3, or C1-C3 alkyl, provided that Y is an H, F, CD3, or C1-C3 alkyl group. 3 When R is N, O, or O-NH, 1 Not F;

[0158] R 2 for

[0159] R 2’ , where R 2’ C1-C6 alkyl, C3-C6 cycloalkyl, C 5- C7 spirocycloalkyl or C3-C6 heterocycloalkyl, each marked with 0-2 R... 2a Replace, where R 2a Choose from the group consisting of halogens, CN, OR, NRR', alkyl, cycloalkyl, and heterocycles;

[0160] aryl or heteroaryl, each surrounded by 0-2 R groups 2a replace;

[0161] (C=O)R 2b ;or

[0162] (C=O)NHR 2b ;

[0163] R3 for

[0164]

[0165] (II)

[0166] in

[0167] X 6 For CR 6 Or N;

[0168] X 7 For CR 7 Or N;

[0169] X 8 It can be C or N;

[0170] X 9 For CR 9 , O, S, N or NR 9 ;

[0171] X 10 For CR 10 , O, S, N or NR 10 ;as well as

[0172] In this configuration, ring A and ring B are each independently aryl or heteroaryl;

[0173] R 2b C 1-6 Alkyl or C 3-6 cycloalkyl, C 5-7 Spirocycloalkyl, aryl, or heteroaryl groups, each marked with 0-4 R groups. 2c replace;

[0174] R 2c Each occurrence is independently of halogen, CN, OR, NRR', OCF3, CF3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkynyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, R and R' are surrounded by 0-3 Rs 2a Replace; and

[0175] R 4 C 1-3 Alkyl groups, which are 0-5 R groups 4a Replace, where R 4a Selected from D, F, and Cl;

[0176] R 5 For H, CN, halogens, OCH3, C(=O)OR, NHC(=O)R, NRR', NO2, C 1-6Alkyl, C3-C6 cycloalkyl, or heterocyclic, wherein the alkyl, cycloalkyl, or heterocyclic is surrounded by 0-3 R... 5a Replace, where each R 5a It is independently selected from OH, D, F, Cl, CN, CH2F, CHF2, CF3, OCH3, OCD3, OCF3 and OC(=O)CH3;

[0177] R 6 R 7 R 9 and R 10 Each is independently selected from H, F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl and C3-C5 cycloalkyl, wherein the alkyl, cycloalkyl, R and R' are separated by 0-2 R's. 2a Replace; and

[0178] R and R' are each independently H or C1-C6 alkyl or acyl, or R and R' together with their bonded nitrogen atoms form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO2.

[0179] In some embodiments of (I), t is 1, and the compound has the structural formula:

[0180]

[0181] (III) a ).

[0182] In some embodiments of (I), t is 0, and the compound has the structural formula:

[0183]

[0184] (III) b ).

[0185] In some embodiments of (II), ring A is a heteroaryl group.

[0186] In some embodiments of (II), X 6 For CH and X 7 For CH, and R 3 It has a structure:

[0187]

[0188] (II) a ).

[0189] In some embodiments of (II), X 7 For CH and X 8 Let C be the integer, and R be the integer. 3It has a structure:

[0190]

[0191] (II) b ).

[0192] In some embodiments of (II), X 6 For CH and X 8 Let C be the integer, and R be the integer. 3 It has a structure:

[0193]

[0194] (II) c ).

[0195] In some embodiments of (II), X 7 For CH and X 10 For CH, and R 3 It has a structure:

[0196]

[0197] (II) d ).

[0198] In (II)-(II) d In some implementations of ), R 4 It is CH3.

[0199] In (II)-(II) d In some implementations of ), R 4 It is CD3.

[0200] In (III) a )-(III) b In some implementations of ), R 3 Selected from:

[0201]

[0202] In some implementations, R 4 It is CD3.

[0203] In some implementations, R 4 It is CH3, and R 3 Selected from:

[0204]

[0205] In (III) a )-(III) b In some implementations of ), R 3 for:

[0206]

[0207] (II) e ).

[0208] In R 3 In some implementations, R 10 For H.

[0209] In (III) a )-(III) b In some implementations of ), R 3 for:

[0210]

[0211] (II) f ).

[0212] In R 3 In some implementations, R 9 C 1-3 Alkyl or cyclopropyl, each optionally C 1-3 Alkyl, CF3, or NRR' substitution.

[0213] In R 3 In some implementations, R 9 C 1-3 alkyl.

[0214] In R 3 In some implementations, R 9 It is CH3.

[0215] In R 3 In some implementations, R 9 It is CD3.

[0216] In R 3 In some implementations, R 5 C 1-4 Alkyl groups, which are replaced by OH.

[0217] In R 3 In some implementations, R 5 for:

[0218]

[0219] (II) g )

[0220] in

[0221] R 5’ C 1-3 Alkyl or cyclopropyl groups, substituted with 0-5 F atoms; and

[0222] R represents H and C. 1-3 Alkyl or acyl.

[0223] In R 3 In some implementations, R 5 for:

[0224]

[0225] (II) h )

[0226] in

[0227] R 5’ C 1-3 Alkyl or cyclopropyl groups, which are substituted with 0-5 F atoms; and

[0228] R represents H and C. 1-3 Alkyl or acyl.

[0229] In (II) g )-(II) h In some implementations of ), R is CH3.

[0230] In (II) g )-(II) h In some implementations of ), R is CD3.

[0231] In (II) g )-(II) h In some implementations of ), R is C(=O)CH3.

[0232] In (II) g )-(II) h In some implementations of ), R is C(=O)CD3.

[0233] In (II) g )-(II) h In some implementations of ), R 5’ It is CF3.

[0234] In (II) g )-(II) h In some implementations of ), R 5’ It is CHF2.

[0235] In (I), (III) a ) and (III) b In some implementations of ), Y 3 It is NH.

[0236] In (III) a In some implementations of ), Y 1For CH, Y 2 The compound is CH and has the following structural formula:

[0237]

[0238] (IV) a ).

[0239] In (III) a In some implementations of ), Y 1 For CH, Y 2 The N atom is present, and the compound has the following structural formula:

[0240]

[0241] (IV) b ).

[0242] In (III) a In some implementations of ), Y 1 For N, Y 2 The compound is CH and has the following structural formula:

[0243] .

[0244] (IV) c )

[0245] In (III) a In some implementations of ), Y 1 For N, Y 2 The N atom is present, and the compound has the following structural formula:

[0246]

[0247] (IV) d ).

[0248] In (I), (III) a ) and (III) b In some implementations of ), Y 3 It is O.

[0249] In (III) a In some implementations of ), Y 1 For CH, Y 2 The compound is CH and has the following structural formula:

[0250]

[0251] (V) a ).

[0252] In (III) a In some implementations of ), Y1 For CH, Y 2 The N atom is present, and the compound has the following structural formula:

[0253]

[0254] (V) b ).

[0255] In (III) a In some implementations of ), Y 1 For N, Y 2 The compound is CH and has the following structural formula:

[0256]

[0257] (V) c ).

[0258] In (III) a In some implementations of ), Y 1 For N, Y 2 The N atom is present, and the compound has the following structural formula:

[0259]

[0260] (V) d ).

[0261] In (I), (III) a ) and (III) b In some implementations of ), Y 3 It is CH2.

[0262] In (III) a In some implementations of ), Y 1 For CH, Y 2 The compound is CH and has the following structural formula:

[0263]

[0264] (VI) a ).

[0265] In (III) a In some implementations of ), Y 1 For CH, Y 2 The N atom is present, and the compound has the following structural formula:

[0266]

[0267] (VI) b ).

[0268] In (III) aIn some implementations of ), Y 1 For N, Y 2 The compound is CH and has the following structural formula:

[0269]

[0270] (VI) c ).

[0271] In (III) a In some implementations of ), Y 1 For N, Y 2 The N atom is present, and the compound has the following structural formula:

[0272]

[0273] (VI) d ).

[0274] In some embodiments of (I), where t is 0 and the compound has the structural formula (III) b ).

[0275] In (III) b In some implementations of ), Y 3 It is CD2.

[0276] In (III) b In some implementations of ), Y 3 It is CF2.

[0277] In (III) b In some implementations of ), Y 1 For CH and Y 2 The compound is CH and has the following structural formula:

[0278]

[0279] (VII) a ).

[0280] In (III) b In some implementations of ), Y 1 For CH and Y 2 The N atom is present, and the compound has the following structural formula:

[0281]

[0282] (VII) b ).

[0283] In (III) b In some implementations of ), Y 1 For N and Y 2The compound is CH and has the following structural formula:

[0284]

[0285] (VII) c ).

[0286] In (III) b In some implementations of ), Y 1 For N and Y 2 The N atom is present, and the compound has the following structural formula:

[0287]

[0288] (VII) d ).

[0289] In R 3 In some implementations, if R 6 and R 7 Existence, R 6 and R 7 Each is represented by H.

[0290] In (III) a )-(III) b In some implementations of ), R 2 For R 2’ .

[0291] In (III) a )-(III) b In some implementations of ), R 2 For (C=O)R 2b .

[0292] In some implementations, R 2b Selected from C1-C6 alkyl groups, which are marked with 0-3 R groups 2c replace.

[0293] In some implementations, R 2b C 3-6 cycloalkyl groups, which are 0-3 R groups 2c replace.

[0294] In some implementations, R 2b It is cyclopropyl.

[0295] In some implementations, R 2b It is a cyclopropyl group substituted with F.

[0296] In some implementations, R 2b C 5-7 Spirocycloalkyl groups, which are determined by 0-3 R groups 2c replace.

[0297] In some implementations, R 2b It is C5-spiro[2.2]pentyl.

[0298] In (III) a )-(III) b In some implementations of ), R 2 For (C=O)NHR 2b .

[0299] In (III) a )-(III) b In some implementations of ), R 2 It is a pyridyl group, which is surrounded by 0-2 R groups. 2c replace.

[0300] In (III) a )-(III) b In some implementations of ), R 2 It is a phenyl group, which is surrounded by 0-2 R groups. 2b replace.

[0301] In (III) a )-(III) b In some implementations of ), R 2 It is a pyrazole group, which is surrounded by 0-2 R groups. 2c replace.

[0302] In (III) a )-(III) b In some implementations of ), R 2 It is a pyrimidine group, which is surrounded by 0-2 R groups. 2c replace.

[0303] In (III) a )-(III) b In some implementations of ), R 1 It is CH3.

[0304] In (III) a )-(III) b In some implementations of ), R 1 It is CD3.

[0305] In (III) a In some embodiments, the compound has the structural formula:

[0306]

[0307] (IV) 1 )

[0308] Among them, X 6 It can be N or CH.

[0309] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0310]

[0311] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0312]

[0313] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0314]

[0315] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0316]

[0317] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0318]

[0319] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0320]

[0321] (IV) 20 )

[0322] Where R represents H, CD3, and C. 1-3 Alkyl or acyl.

[0323] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0324]

[0325] (IV) 21 )

[0326] Where R represents H, CD3, and C. 1-3 Alkyl or acyl.

[0327] In (III) aIn some embodiments, the compound has a structural formula selected from the following:

[0328]

[0329] (IV) 22 )

[0330] Where R represents H, CD3, and C. 1-3 Alkyl or acyl.

[0331] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0332]

[0333] (IV) 23 )

[0334] Where R represents H, CD3, and C. 1-3 Alkyl or acyl.

[0335] In (III) a In some embodiments, the compound has the structural formula:

[0336]

[0337] (V) 1 )

[0338] Among them, X 6 It can be N or CH.

[0339] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0340]

[0341] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0342]

[0343] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0344]

[0345] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0346]

[0347] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0348]

[0349] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0350]

[0351] (V) 20 )

[0352] Where R represents H, CD3, and C. 1-3 Alkyl or acyl.

[0353] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0354]

[0355] (V) 21 )

[0356] Where R represents H, CD3, and C. 1-3 Alkyl or acyl.

[0357] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0358]

[0359] (V) 22 )

[0360] Where R represents H, CD3, and C. 1-3 Alkyl or acyl.

[0361] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0362]

[0363] (V) 23 )

[0364] Where R represents H, CD3, and C. 1-3 Alkyl or acyl.

[0365] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0366]

[0367] (VI) 1 )

[0368] Among them, X 6 It can be N or CH.

[0369] In (III) a In some embodiments, the compound has the structural formula:

[0370]

[0371] (VI) 1 )

[0372] Among them, X 6 It can be N or CH.

[0373] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0374]

[0375] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0376]

[0377] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0378]

[0379] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0380]

[0381] In (III) a In some embodiments, the compound has a structural formula selected from the following:

[0382]

[0383] In (III) b In some embodiments, the compound has the structural formula:

[0384]

[0385] (VII) 1)

[0386] Among them, X 6 It can be N or CH.

[0387] In (III) b In some embodiments, the compound has the structural formula:

[0388]

[0389] (VII) 2 )

[0390] Among them, X 6 It can be N or CH.

[0391] In (IV) 1 In some embodiments of (VII), if R 6 and R 7 Existence, R 6 and R 7 Each is represented by H.

[0392] In (IV) 1 In some embodiments of (VII), if R 9 Existence, R 9 C 1-3 Alkyl or cyclopropyl groups, each optionally substituted with a C1-C3 alkoxy group, CF3 or NRR'.

[0393] In (IV) 1 In some embodiments of (VII), R 9 C 1-3 Alkyl or cyclopropyl.

[0394] In (IV) 1 In some embodiments of (VII), R 9 It is CH3.

[0395] In (IV) 1 In some embodiments of (VII), R 9 It is CD3.

[0396] In (IV) 1 In some embodiments of (VII), R 2b It is a C1-C6 alkyl, cyclopropyl, or cyclobutyl group, which is marked with 0-2 R groups. 2c replace.

[0397] In (IV) 1 In some embodiments of (VII), R 2b It is cyclopropyl.

[0398] In (IV) 1In some embodiments of (VII), R 5 for:

[0399]

[0400] in

[0401] R 5’ C 1-3 Alkyl or cyclopropyl groups, substituted with 0-5 F atoms; and

[0402] R represents H and C. 1-3 Alkyl or acyl.

[0403] In (IV) 1 In some embodiments of (VII), R 5 for:

[0404]

[0405] in

[0406] R 5’ C 1-3 Alkyl or cyclopropyl groups, which are substituted with 0-5 F atoms; and

[0407] R represents H and C. 1-3 Alkyl or acyl.

[0408] In some implementations, R is H.

[0409] In some implementations, R is CH3.

[0410] In some implementations, R is CD3.

[0411] In some implementations, R 5’ It is CF3.

[0412] In some implementations, R 5’ It is CHF2.

[0413] In some implementations, R 5’ C replaced by 2-5 Fs 2-3 alkyl.

[0414] In (IV) 1 In some embodiments of (VII), R 1 It is CH3.

[0415] In (IV) 1 In some embodiments of (VII), R 1 It is CD3.

[0416] In another aspect, the present invention generally relates to compounds having structural formula (VIII):

[0417]

[0418] (VIII)

[0419] Or its pharmaceutically acceptable form or isotopic derivative.

[0420] in

[0421] X 6 For CR 6 Or N;

[0422] X 7 For CR 7 Or N;

[0423] X 8 It can be C or N;

[0424] X 9 For CR 9 , O, S, N or NR 9 ;

[0425] X 10 For CR 10 , O, S, N or NR 10 ;

[0426] Y 1 For CH, CF, or N;

[0427] Y 2 For CH or N;

[0428] Y 3 It can be NR, O, CH2, CD2, CF2 or O-NH;

[0429] Y 4 For NR, CH2, or CF2;

[0430] Y 5 It can be NR, CH2, O, S, SO, or SO2;

[0431] m is 0, 1, 2, and 3;

[0432] n is 0, 1, 2, or 3;

[0433] p is 0, 1, 2, and 3;

[0434] Ring A and ring B are each independently aryl or heteroaryl;

[0435] The ring C is a 5- or 6-membered aryl or heteroaryl group;

[0436] R 1For H, F, CD3, or C 1-3 Alkyl, provided that when Y 3 When R is N, O, or O-NH, 1 Not F;

[0437] R 4 C 1-3 Alkyl groups, which are 0-5 R groups 4a Replace, where R 4a Selected from D, F, and Cl;

[0438] R 5 For H, CN, halogens, OCH3, C(=O)OR, NHC(=O)R, NRR', NO2, C 1-6 Alkyl, C 3-6 Cycloalkyl or heterocyclic, wherein the alkyl, cycloalkyl or heterocyclic compound is surrounded by 0-3 R groups. 5a Replace, where each R 5a It is independently selected from OH, D, F, Cl, CN, CH2F, CHF2, CF3, OCH3, OCD3, OCF3 and OC(=O)CH3;

[0439] R 6 R 7 R 9 R 10 and R 11 Each is independently selected from H, F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C 1-3 Alkyl and C 3-5 cycloalkyl, wherein the alkyl, cycloalkyl, R and R' are separated by 0-2 Rs. 2a replace;

[0440] R 2a Selected from F, OCF3, CF3, CN, NO2, OR, NRR' and C 1-6 Alkyl groups; and

[0441] R and R' are each independently H, C1-C6 alkyl or acyl, or R and R' together with their bonded nitrogen or carbon atoms form a 3 to 6-membered ring containing 0 to 2 heteroatoms selected from O, NR, S and SO2.

[0442] In some implementations of (VIII), Y 1 For CH and Y 2 For CH.

[0443] In some implementations of (VIII), Y 1 For N and Y 2 For CH.

[0444] In some implementations of (VIII), Y 1 For CH and Y 2 Let N be the number of elements in the array.

[0445] In some implementations of (VIII), Y 1 For N and Y 2 Let N be the number of elements in the array.

[0446] In some implementations of (VIII), Y 3 It is NH.

[0447] In some implementations of (VIII), Y 3 It is O.

[0448] In some implementations of (VIII), Y 3 It is CH2.

[0449] In some implementations of (VIII), Y 3 It is CD2.

[0450] In some implementations of (VIII), Y 4 It is NH.

[0451] In some implementations of (VIII), Y 4 It is CH2.

[0452] In some implementations of (VIII), R 1 It is CH3.

[0453] In some implementations of (VIII), R 1 It is CD3.

[0454] In some implementations of (VIII), R 4 It is CH3.

[0455] In some implementations of (VIII), R 4 It is CD3.

[0456] Non-limiting examples of the compounds of the present invention include those listed in Table 1 of the Examples section herein.

[0457] In another aspect, the present invention generally relates to methods for preparing the compounds disclosed herein, as illustrated by the synthetic schemes and experimental procedures disclosed herein.

[0458] In another aspect, the present invention generally relates to pharmaceutical compositions comprising compounds disclosed herein that are effective in treating or alleviating one or more diseases or disorders in mammals, including humans, and pharmaceutically acceptable excipients, carriers, or diluents.

[0459] In another aspect, the present invention generally relates to pharmaceutical compositions comprising a certain amount of a compound having the (I) structural formula:

[0460]

[0461] (I)

[0462] Or its pharmaceutically acceptable form or isotopic derivative.

[0463] in

[0464] Y 1 For CH, CF, or N;

[0465] Y 2 For CH or N;

[0466] Y 3 It can be NR, O, CH2, CD2, CF2 or O-NH;

[0467] R 1 It can be H, F, C1-C3 alkyl, or CD3, provided that Y is H, F, C1-C3 alkyl, or CD3. 3 When R is N, O, or O-NH, 1 Not F;

[0468] R 2 for

[0469] R 2’ , where R 2’ C1-C6 alkyl, C 3-6 cycloalkyl, C 5-7 Spirocycloalkyl or C3-C6 heterocycloalkyl, each marked with 0-2 R 2a Replace, where R 2a Choose from the group consisting of halogens, CN, OR, NRR', alkyl, cycloalkyl, and heterocycles;

[0470] aryl or heteroaryl, each surrounded by 0-2 R groups 2a replace;

[0471] (C=O)R 2b ;or

[0472] (C=O)NHR 2b ;

[0473] R 3 for

[0474]

[0475] in

[0476] X 6 For CR 6 Or N;

[0477] X 7 For CR 7 Or N;

[0478] X 8 It can be C or N;

[0479] X 9 For CR 9 , O, S, N or NR 9 ;

[0480] X 10 For CR 10 , O, S, N or NR 10 ;as well as

[0481] In this ring, ring A and ring B are each independently aryl or heteroaryl;

[0482] R 2b C 1-6 Alkyl or C 3-6 cycloalkyl, C 5-7 Spirocycloalkyl, aryl, or heteroaryl groups, each marked with 0-2 R groups. 2c replace;

[0483] R 2c Each occurrence is independently of halogen, CN, OR, NRR', OCF3, CF3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkynyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, R and R' are surrounded by 0-3 Rs. 2a Replace; and

[0484] R 4 C 1-3 Alkyl groups, which are 0-5 R groups 4a Replace, where R 4a Selected from D, F, and Cl;

[0485] R 5 For H, CN, halogens, OCH3, C(=O)OCH3, C 1-6 Alkyl, C3-C6 cycloalkyl, or heterocyclic, wherein the alkyl, cycloalkyl, or heterocyclic is surrounded by 0-3 R... 5a Replace, where each R 5a It is independently selected from OH, D, F, Cl, CN, OCH3, OCD3, OCF3 and OC(=O)CH3;

[0486] R 6 R 7 R 9 and R10 Each is independently selected from H, F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl and C3-C5 cycloalkyl, wherein the alkyl, cycloalkyl, R and R' are separated by 0-2 R's. 2a Replace; and

[0487] R and R' are each independently H or C1-C6 alkyl or acyl, or R and R' together with their bonded nitrogen atoms form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO2.

[0488] It is effective in treating or alleviating one or more diseases or disorders in mammals, including humans, and is a pharmaceutically acceptable excipient, carrier, or diluent.

[0489] In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0490] In some embodiments, the pharmaceutical composition is suitable for topical application.

[0491] In some embodiments, the pharmaceutical composition is suitable for gastrointestinal (GI) restricted administration.

[0492] In some embodiments, the pharmaceutical composition is suitable for treating or alleviating one or more of inflammatory diseases, immune-mediated diseases and cancer, or related diseases or disorders.

[0493] In some implementations, the disease or disorder is an inflammatory disease.

[0494] In some implementations, the disease or disorder is an immune-mediated disease.

[0495] In some implementations, the disease or obstacle is cancer.

[0496] In some implementations, the disease or disorder is selected from: inflammatory bowel disease, psoriasis, psoriatic arthritis, alopecia areata, eczema, ankylosing spondylitis (AS), vitiligo, atopic dermatitis, discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, Crohn's disease (CD), rheumatoid arthritis (RA), T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma (CTCL), multiple sclerosis (MS), and Alzheimer's disease. Diseases including AD, Parkinson's disease (PD), type 1 diabetes, asthma, renal fibrosis, diabetic nephropathy, polycystic kidney disease, HIV-related nephropathy, chronic myelogenous leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0497] In another aspect, the present invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0498] In some implementations, the unit dosage form is a tablet.

[0499] In some implementations, the unit dosage form is a capsule.

[0500] In some implementations, the unit dosage form is a topical formulation.

[0501] In another aspect, the present invention generally relates to methods for treating, alleviating, or preventing diseases or disorders, the methods comprising administering a therapeutically effective amount of the compounds disclosed herein to a subject in need, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in mammals including humans.

[0502] In another aspect, the present invention generally relates to methods for treating, alleviating, or preventing diseases or disorders, the method comprising administering to a subject in need a therapeutically effective amount of a compound having the (I) structural formula:

[0503]

[0504] (I)

[0505] Or its pharmaceutically acceptable form or isotopic derivative.

[0506] in

[0507] Y 1 For CH, CF, or N;

[0508] Y 2 For CH or N;

[0509] Y 3 It can be NR, O, CH2, CD2, CF2 or O-NH;

[0510] R 1 It can be H, F, C1-C3 alkyl, or CD3, provided that Y is H, F, C1-C3 alkyl, or CD3. 3 When R is N, O, or O-NH, 1 Not F;

[0511] R 2 for

[0512] R 2’ , where R 2’ C 1-6 Alkyl, C 3-6 cycloalkyl, C 5-7 Spirocycloalkyl or C3-C6 heterocycloalkyl, each marked with 0-2 R 2a Replace, where R 2a Choose from the group consisting of halogens, CN, OR, NRR', alkyl, cycloalkyl, and heterocycles;

[0513] aryl or heteroaryl, each surrounded by 0-2 R groups 2a replace;

[0514] (C=O)R 2b ;or

[0515] (C=O)NHR 2b ;

[0516] R 3 for

[0517]

[0518] in

[0519] X6 For CR 6 Or N;

[0520] X 7 For CR 7 Or N;

[0521] X 8 It can be C or N;

[0522] X 9 For CR 9 , O, S, N or NR 9 ;

[0523] X 10 For CR 10 , O, S, N or NR 10 ;as well as

[0524] In this ring, ring A and ring B are each independently aryl or heteroaryl;

[0525] R 2b C 1-6 Alkyl or C 3-6 cycloalkyl, C 5-7 Spirocycloalkyl, aryl, or heteroaryl groups, each marked with 0-2 R groups. 2c replace;

[0526] R 2c Each occurrence is independently of halogen, CN, OR, NRR', OCF3, CF3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkynyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, R and R' are surrounded by 0-3 Rs. 2a Replace; and

[0527] R 4 C 1-3 Alkyl groups, which are 0-5 R groups 4a Replace, where R 4a Selected from D, F, and Cl;

[0528] R 5 For H, CN, halogens, OCH3, C(=O)OCH3, C 1-6 Alkyl, C3-C6 cycloalkyl, or heterocyclic, wherein the alkyl, cycloalkyl, or heterocyclic is surrounded by 0-3 R... 5a Replace, where each R 5a It is independently selected from OH, D, F, Cl, CN, OCH3, OCD3, OCF3 and OC(=O)CH3;

[0529] R 6 R7 R 9 and R 10 Each is independently selected from H, F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl and C3-C5 cycloalkyl, wherein the alkyl, cycloalkyl, R and R' are separated by 0-2 R's. 2a Replace; and

[0530] R and R' are each independently H or C1-C6 alkyl or acyl, or R and R' together with their bonded nitrogen atoms form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO2.

[0531] The diseases or disorders are selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in mammals including humans.

[0532] In some implementations, the disease or disorder is an inflammatory disease.

[0533] In some implementations, the disease or disorder is an immune-mediated disease.

[0534] In some implementations, the disease or obstacle is cancer.

[0535] In some implementations, the disease or disorder is selected from: inflammatory bowel disease, psoriasis, psoriatic arthritis, alopecia areata, eczema, ankylosing spondylitis (AS), vitiligo, atopic dermatitis, discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, Crohn's disease (CD), rheumatoid arthritis (RA), T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma (CTCL), multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), type 1 diabetes, asthma, renal fibrosis, diabetic nephropathy, polycystic kidney disease, HIV-related nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0536] In some implementations, administration is via oral administration.

[0537] In some implementations, application is performed via local application.

[0538] In some implementations, application is restricted via GI.

[0539] In another aspect, the present invention generally relates to the use of the compounds disclosed herein, and pharmaceutically acceptable excipients, carriers, or diluents, in the preparation of medicaments for the treatment of diseases or disorders.

[0540] In some embodiments of the use, the disease or disorder is one or more of an inflammatory disease, an immune-mediated disease, and cancer.

[0541] In some embodiments of the application, the disease or disorder is an inflammatory disease.

[0542] In some embodiments of the application, the disease or disorder is an immune-mediated disease.

[0543] In some embodiments of the application, the disease or obstacle is cancer.

[0544] In some embodiments of the use, the drug is administered orally.

[0545] In some embodiments of the use, the drug is applied topically.

[0546] In some embodiments of the use, the drug is used for GI-restricted administration.

[0547] As discussed herein, the present invention covers isotope derivative compounds having one or more hydrogen atoms (e.g., 1, 2, 4, 5, 6, 7, 8, 9, 10, etc.) replaced by deuterium atoms.

[0548] The term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation, for example, elevated levels of inflammation compared to a control group, such as a healthy individual without the disease. Examples of inflammatory diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include autoimmune diseases, traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, and systemic lupus erythematosus. Lupus erythematosus (SLE), myasthenia gravis, juvenile diabetes mellitus, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia-reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis. These conditions are often inextricably linked with other diseases, disorders, and symptoms. A non-limiting list of inflammation-related diseases, disorders, and conditions caused by inflammatory cytokines includes arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., where inflammatory cytokines prevent healing), anemia, and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation, and multiple sclerosis. Some of the aforementioned diseases, disorders, and conditions for which the compounds of this disclosure may be particularly effective (attributable to, for example, limitations of current therapies) are described in more detail below.

[0549] The term "autoimmune disease" refers to a disease or condition in which a subject's immune system produces an abnormal immune response to substances that would not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include acne vulgaris, acute disseminated encephalomyelitis, acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, and Aicardi-Goutières syndrome. Autoimmune syndrome (AGS), alopecia areata, alopecia totalis, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic dysfunction, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathy, Balo's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Kassman's disease, celiac disease, Chagas disease, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated body temperature. Temperature, CANDLE), chronic active hepatitis, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome, cicatricial pemphigoid / benign mucosal pemphigoid, Crohn's disease, Cogans syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST disease, Cushing's disease, demyelinating neuropathy, depression, herpetiform dermatitis, dermatomyositis, Dervec disease (neuromyelitis optica), discoid lupus erythematosus, Dressler's syndrome Dry eye syndrome (DES, keratoconjunctivitis sicca), endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, primary mixed cryoglobulinemia, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrotic alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasser syndrome, granulomatous polyangiitis, graft-versus-host disease (GVDH), Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia.Henoch-Schonlein purpura, herpes gestationis, hidradenitis suppurativa, hypogammaglobulinemia, idiopathic thrombocytopenic purpura, IgA nephropathy, IgG4-related sclerosis, inflammatory bowel disease (IBD), immunomodulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile dermatomyositis (JDM), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA syndrome, lupus, Lyme disease, chronic meningitis, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, mooren's ulcer, Mucha-Habermann disease, multiple sclerosis. Sclerosis (MS), myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis, streptococcal-associated pediatric autoimmune neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemeuria, Parry-Romberg syndrome, Parsonage-Turner syndrome, pars plana plaque inflammation (peripheral uveitis), pemphigus, peripheral neuropathy, peripheral encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polycystic ovary syndrome (PCOS). Polymyalgia rheumatica syndrome (PCOS), types I, II, and III of the autoimmune polyglandular syndrome, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, plaque psoriasis, idiopathic pulmonary fibrosis, pyoderma gangrenosa, pure red cell aplasia, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy syndrome, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testis autoimmunity, stiff-person syndrome, STING-associated infantile vascular disease (SAVI), subacute bacterial endocarditis, Susac syndrome, sympathetic ophthalmia, systemic lupus erythematosus Erythematosus (SLE), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura, Tolosa-Hunt syndrome,Transplant rejection (allogeneic transplant rejection), transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, bullous dermatitis, vitiligo, or Wegener's granulomatosis.

[0550] The term "immune-mediated disease" refers to chronic inflammatory diseases maintained by antibody and cellular immunity. Immune-mediated diseases include, but are not limited to, asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis), juvenile arthritis, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), endocrine disorders (e.g., type 1 diabetes and Graves' disease), neurodegenerative diseases (e.g., multiple sclerosis (MS)), autism spectrum disorders, depression, Alzheimer's disease, Guillain-Barré syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome (DES), Sjögren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Guillain-Barré syndrome, myasthenia gravis, and chronic idiopathic demyelinating diseases. Diseases (CID), vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis), and skin diseases (e.g., acne vulgaris, dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, plaque psoriasis, vasculitis, vitiligo, and alopecia). Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS), celiac disease, pemphigus, transplant rejection (allogeneic transplant rejection), and graft-versus-host disease (GVDH).

[0551] As used herein, the term "cancer" refers to all types of cancer, tumors, or malignant tumors found in mammals such as humans, including hematologic malignancies such as leukemia and lymphoma, T-ALL, and large B-cell lymphoma, and solid cancers such as carcinoma and sarcoma. Exemplary cancers include blood cancers, brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, stomach cancer, ovarian cancer, lung cancer, and head and neck cancer. Exemplary cancers include thyroid cancer, endocrine system cancers, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, medulloblastoma, colorectal cancer, and pancreatic cancer. Other examples include penile cancer, non-melanotic skin cancer, anal cancer, hepatobiliary cancer, esophageal and gastric cancer, uterine sarcoma, gastrointestinal stromal tumors, salivary gland cancer, peripheral nervous system cancer, soft tissue sarcoma, bone cancer, kidney cancer, myeloproliferative neoplasms, thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, skin melanoma, colonic adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma, ovarian cancer, and rhabdomyosarcoma. Primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant islet cell tumors, malignant carcinoid tumors, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital tract cancers, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic tumors, medullary thyroid carcinoma, medullary thyroid adenoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, metastatic leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, round cell liposarcoma, or prostate cancer.

[0552] In some embodiments of the use, the disease or disorder is selected from: inflammatory bowel disease, psoriasis, psoriatic arthritis, alopecia areata, eczema, ankylosing spondylitis (AS), vitiligo, atopic dermatitis, discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, Crohn's disease (CD), rheumatoid arthritis (RA), T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma (CTCL), multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), type 1 diabetes, asthma, renal fibrosis, diabetic nephropathy, polycystic kidney disease, HIV-related nephropathy, chronic myeloid leukemia (CML), essential thrombocytosis (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0553] Isotope-labeled compounds are also within the scope of this disclosure. As used herein, "isotope-labeled compound" means the currently disclosed compound, including its pharmaceutical salts and prodrugs, each as described herein, wherein 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 currently disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, as appropriate. 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.

[0554] By labeling currently disclosed compounds with isotopes, these compounds can be used for the determination of drug and / or substrate tissue distribution. Tritium ( 3 H) and carbon-14 ( 14 C) labeled compounds are particularly preferred due to their ease of preparation and detection. Furthermore, heavier isotopes such as deuterium (…) are also preferred. 2 H) can be used to replace certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and is therefore preferred in some cases. Currently disclosed isotopically labeled compounds, including their pharmaceutical salts, esters, and prodrugs, can be prepared by any means known in the art.

[0555] In addition, heavier isotopes such as deuterium are used to replace hydrogen, which has a normal abundance. 1 H) can provide certain therapeutic advantages, for example, due to improved absorption, distribution, metabolism, and / or excretion (ADME) properties, resulting in drugs with improved efficacy, safety, and / or tolerability. Benefits can also be described using... 13 C is used to replace the normal abundance. 12 Obtained from C. (See WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361 and WO 2007 / 016431.)

[0556] The stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the currently disclosed compounds, as well as racemic, diastereomers and mixtures of these isomers, are all within the scope of this disclosure.

[0557] The compounds of the present invention, after their preparation, are preferably isolated and purified to obtain a composition containing an amount equal to or greater than 95% by weight (“substantially pure”), which is then used or formulated as described herein. In some embodiments, the compounds of the present invention have a purity greater than 99%.

[0558] This document also covers solvates and polymorphs of the compounds of the present invention. Solvates of the compounds of the present invention include, for example, hydrates.

[0559] It can be administered via any appropriate route of administration, such as parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intraperitoneal, rectal, or oral. The most appropriate route of administration for a particular patient depends on the nature and severity of the disease or condition being treated, or the nature of the therapy used and the active compound.

[0560] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or their derivatives are mixed with at least one inert conventional excipient (or carrier), such as sodium citrate or calcium hydrogen phosphate, or (i) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and silica; (ii) a binder, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (iii) a humectant, such as glycerin; (iv) a disintegrant, such as agar, calcium carbonate, potato or cassava starch, alginate, certain complex silicates, and sodium carbonate; (v) a dissolution inhibitor, such as paraffin; (vi) an absorption promoter, such as a quaternary ammonium compound; (vii) a wetting agent, such as cetyl alcohol and glyceryl monostearate; (viii) an adsorbent, such as kaolin and bentonite; and (ix) a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate; or mixtures thereof. For capsules, tablets, and pills, the dosage form may also include a buffer. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose (milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated pills, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the art.

[0561] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures of these substances. In addition to these inert diluents, the composition may also include additional agents such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, or aromatizers.

[0562] The materials, compositions, and components disclosed herein can be used in conjunction with the disclosed methods and compositions, to prepare products of the disclosed methods and compositions, or as products of the disclosed methods and compositions. It should be understood that when combinations, subsets, interactions, groups, etc., of these materials are disclosed, while specific references to every distinct individual and collective combination and arrangement of these compounds may not be explicitly disclosed, each is specifically covered and described herein. For example, if a method is disclosed and discussed, and various modifications that can be made to the various molecules included in the method are discussed, then every combination and arrangement of the method, and possible modifications, are specifically covered unless specifically indicated to the contrary. Similarly, any subset or combination thereof is specifically covered and disclosed. This concept applies to all aspects of this disclosure, including but not limited to method steps using the disclosed compositions. Therefore, if various additional steps can be performed, it should be understood that each of these additional steps can be performed with any particular method step or combination of method steps of the disclosed method, and each such combination or subset is specifically covered and should be considered as disclosed.

[0563] The following examples are intended to illustrate the practice of the invention and are not intended to limit it in any way.

[0564] Example

[0565] Abbreviations

[0566] Methanol: MeOH Dichloromethane: DCM Petroleum ether: PE Ethyl acetate: EtOAc or EA Acetonitrile: ACN or MeCN Isopropanol: IPA Triethylamine: TEA Sodium hydroxide: NaOH Propylphosphonic anhydride: <![CDATA[T3P]]> Nitrogen: <![CDATA[N2]]> N,N-Diisopropylethylamine: DIPEA N,N-Dimethylformamide: DMF 4-Toluenesulfonic acid: pTSA or TsOH Diphenyl azidophosphate: DPPA N-Iodosuccinimide: NIS Tetrabutylammonium fluoride: TBAF Methanesulfonyl chloride: MsCl 2,2-Difluoro-2-(fluorosulfonyl)acetic acid methyl ester: MDFA p-Toluenesulfonylmethylisocyanate: TosMIC Diethylaminosulfur trifluoride: DAST Thin-layer chromatography: TLC High performance liquid chromatography: HPLC Room temperature: r.t. Hour: h Diethylamine: DEA

[0567] Representative methods of preparative HPLC: flow rate and gradient may vary.

[0568] Exemplary methods for preparative HPLC are provided below.

[0569] Method ANH4HCO3; Column: Gilson 2-Xbridge C18 19*150 mm, 5 μm; Mobile phase: CH3CN in water (0.1% NH4HCO3), from 20% to 60%; Flow rate: 15 mL / min.

[0570] Method B TFA; Column: Waters-Xbridge C18 10*190 mm, 5 μm; Mobile phase: CH3CN in water (0.1% TFA), from 15% to 40%; Flow rate: 15 mL / min.

[0571] Method C HCOOH; Column: Waters-Xbridge C18 10*190 mm, 5 μm; Mobile phase: CH3CN in water (0.1% formic acid), from 15% to 40%; Flow rate: 15 mL / min.

[0572] Method D HCOOH; Column: Waters SunFire® Prep C18 OBD™ (5 μm, 19 x 150 mm); Mobile phase: CH3CN in water (0.1% formic acid), from 18% to 38%; Flow rate: 20 mL / min.

[0573] Method E NH4HCO3: Column: Waters Xbridge® Prep C18 OBD TM (5 μm, 19*150 mm); mobile phase: CH3CN in water (10 mM NH4HCO3), from 20% to 60%, flow rate: 20 mL / min.

[0574] Representative methods of chiral preparative HPLC:

[0575] Method F : Gilson 281, Daicel Chiralpak IE, 10 μm, 30*250 mm; Mobile phase: n-hexane / EtOH / diethylamine = 70 / 30 / 0.3, Flow rate: 25 mL / min.

[0576] Method G : Gilson 281, Daicel Chiralpak IG, 10 μm, 30*250 mm; Mobile phase: n-hexane / EtOH = 70 / 30, Flow rate: 25 mL / min.

[0577] Method H: Gilson 281, Daicel Chiralpak IB N, 10 μm, 30*250 mm; Mobile phase: n-hexane / IPA / diethylamine = 80 / 20 / 0.3, Flow rate: 30 mL / min.

[0578] Method I : Gilson 281, Daicel Chiralpak IA, 10 μm, 30*250 mm; Mobile phase: n-hexane / EtOH / diethylamine = 30 / 70 / 0.3, Flow rate: 25 mL / min.

[0579] Method J : Gilson 281, Daicel Chiralpak IB N-5, 10 μm, 30*250 mm; Mobile phase: n-hexane\IPA\diethylamine = 80\20\0.3; Flow rate: 25 mL / min.

[0580] Method K : Gilson 281, Daicel Chiralpak IE, 10 μm 50*250 mm; Mobile phase: n-hexane / EtOH = 60 / 40; Flow rate: 60 mL / min.

[0581] Method L : Gilson 281, Daicel Chiralpak IC, 10 μm 30*250 mm; Mobile phase: Hex / IPA / DEA = 60 / 40 / 0.3; Flow rate: 25 mL / min.

[0582] Method M : Gilson 281, Daicel Chiralpak IH, 10 μm 30*250 mm; Mobile phase: Hex / EtOH = 90 / 10; Flow rate: 25 mL / min

[0583] Method N : Gilson 281, Daicel Chiralpak IK, 10 μm 50*250 mm; Mobile phase: Hex / IPA = 70 / 30; Flow rate: 60 mL / min.

[0584] Method O : Gilson 281, Daicel Chiralpak ID, 10 μm 30*250 mm; Mobile phase: Hex / IPA / DEA = 80 / 20 / 0.2; Flow rate: 25 mL / min.

[0585] Representative methods of analytical HPLC

[0586] Method 1 Analysis was performed on an Agilent 1200 series HPLC-6120MS. Acetonitrile in UHPLC long-gradient equivalent water (containing 0.02% NH4OAc) ranged from 5% to 95%, with a run time of 6.5 minutes and a flow rate of 1.5 mL / min. A Waters Xbridge C18 column (18.5 μm, 4.6 x 50 mm) was used at 40 °C.

[0587] Method 2 Analysis was performed on an Agilent 1200 series HPLC-6120MS. UHPLC Long Gradient Equivalent water (containing 0.1% trifluoroacetic acid) was used with acetonitrile ranging from 5% to 95%, with a run time of 6.5 minutes and a flow rate of 1.5 mL / min. A Waters Xbridge C18 column (18.5 μm, 4.6 x 50 mm) was used at 40 °C.

[0588] Method 3 Analysis was performed on an Agilent 1260 series HPLC-6120MS. Acetonitrile in UHPLC long gradient precipitate (containing 0.02% NH4OAc) ranging from 5% to 95% was used at a run time of 2.5 min and a flow rate of 0.5 mL / min. A Diamonsil Plus C18 column (18.5 μm, 4.6 x 30 mm) was used at 40 °C.

[0589] Method 4 Analysis was performed on an Agilent 1260 series HPLC-6125C MS or an Agilent 1290 Infinity II HPLC-6125C MS. Acetonitrile in long-grained equivalent water (containing 0.1% FA) ranged from 20% to 100%, with run times of 1.3 to 4.5 minutes and flow rates of 0.7 mL / min or 1 mL / min. An Agilent ZORBAX SB-C18 column (1.8 μm, 2.1 x 50 mm) or an Agilent Poroshell 120 SB-C18 column (1.9 μm, 2.1 x 50 mm) was used at 40 °C.

[0590] Method 5Analysis was performed on a SHIMADZU 20A HPLC system. The HPLC long-gradient equivalent hexane / EtOH / DEA (70 / 30 / 0.2) was run for 20 minutes at a flow rate of 1 mL / min. A CHIRALPAK IE filter (5 μm, 4.6 x 250 mm) was used at 30 °C.

[0591] Method 6 Analysis was performed on a SHIMADZU 20A HPLC system. The HPLC long-gradient equivalent hexane / EtOH / DEA (30 / 70 / 0.2) was run for 30 minutes at a flow rate of 1 mL / min. A CHIRALPAK IA (5 μm, 4.6 x 250 mm) filter was used at 30 °C.

[0592] Method 7 Analysis was performed on a SHIMADZU 20A HPLC. HPLC long-gradient equivalent n-hexane / IPA / DEA (80 / 20 / 0.2) was run for 30 minutes at a flow rate of 1 mL / min. CHIRALPAK IB N-5 (5 μm, 4.6*250 mm) was used at 30 °C.

[0593] Method 8 Analysis was performed on a SHIMADZU 20A HPLC. The HPLC long-gradient equivalent hexane / EtOH (70 / 30) run time was 30 min at a flow rate of 1 mL / min. CHIRALPAK IG (5 μm, 4.6*250 mm) was used at 30 °C.

[0594] Method 9 Analysis was performed on a Shimadzu LC-20A HPLC system. The HPLC long gradient, equivalent Hex (EtOH) setting was 70 / 30, with a run time of 7 minutes and a flow rate of 1 mL / min. A CHIRALPAK IE filter (5 μm, 4.6 x 150 mm) was used at 35 °C.

[0595] Method 10Analysis was performed on a Shimadzu LC-20A HPLC system. The HPLC long gradient, equivalent Hex (EtOH) setting was 60 / 40, with a run time of 15 minutes and a flow rate of 1 mL / min. CHIRALPAK IG (5 μm, 4.6 x 150 mm) was used at 30 °C.

[0596] Method 11 Analysis was performed on a SHIMADZU 20A HPLC. HPLC long-gradient equivalent n-hexane / EtOH (90 / 10) was run for 30 minutes at a flow rate of 1 mL / min. CHIRALPAK IH (5 μm, 4.6*250 mm) was used at 30 °C.

[0597] Method 12 Analysis was performed on a SHIMADZU 20A HPLC. The HPLC long-gradient equivalent Hex / IPA / DEA (50 / 50 / 0.2) run time was 25 minutes and the flow rate was 1 mL / min. The CHIRALPAK ID (5 μm, 4.6*250 mm) was used at 30 °C.

[0598] Method 13 Analysis was performed on a SHIMADZU 20AT HPLC. HPLC long-gradient equivalent n-hexane / IPA (70 / 30) was run for 30 minutes at a flow rate of 1 mL / min. CHIRALPAK IK (5 μm, 4.6*250 mm) was used at 35 °C.

[0599] Method 14 Analysis was performed on a SHIMADZU 20A HPLC. The HPLC long-gradient equivalent Hex / IPA (98 / 2) run time was 25 minutes and the flow rate was 1 mL / min. The CHIRALPAK IB N (5 μm, 4.6*250 mm) was used at 30 °C.

[0600] Intermediate A

[0601]

[0602] Step 1. Methyl 4-chloro-6-(cyclopropaneformamido)nicotinic acid (A2)

[0603] A mixture of A1 (2.0 g, 9.71 mmol), cyclopropaneformamide (826 mg, 9.71 mmol), Pd(OAc)2 (109 mg, 0.49 mmol), dppf (538 mg, 0.97 mmol), and K3PO4 (4.12 g, 19.42 mmol) in dioxane (30 mL) was stirred at 90 °C under N2 for 4 h. The mixture was diluted with H2O (100 mL), extracted with EtOAc (30 mL x 3), washed with brine (30 mL), dried over Na2SO4, concentrated, and purified by rapid chromatography (PE / EA = 10 / 1 to 1 / 1) to give compound A2 (1.8 g, 73% yield) as a white solid. LC-MS (ESI, Method 4) t R = 3.33 min, m / z (M+H) + = 255.0.

[0604] Step 2. Lithium 4-chloro-6-(cyclopropaneformamido)nicotinate (A3)

[0605] LiOH·H₂O (165 mg, 3.93 mmol) was added to a solution of A2 (500 mg, 1.96 mmol) in a co-solvent of MeOH (2 mL), THF (2 mL), and water (1 mL). The mixture was then stirred overnight at rt. The mixture was concentrated to dryness to give compound A3 (480 mg, 99% yield) as a white solid. LC-MS (ESI, Method 4) R = 3.81 min, m / z(M+H) + = 241.1.

[0606] Step 3. 4-Chloro-6-(cyclopropaneformamido)-N-(methyl-d3)nicotinamide (Int. A)

[0607] At 0 °C, a solution of A3 (480 mg, 1.95 mmol) in DCM (15 mL) was successively added with methyl-d3-amine hydrochloride (275 mg, 3.89 mmol), DIPEA (1.51 g, 11.68 mmol), and T3P (1.86 g, 2.92 mmol, 50% in EtOAc). The resulting mixture was stirred overnight at rt. The mixture was diluted with H2O (30 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to dryness to give Int. A (300 mg, 60% yield) as a white solid. LC-MS (ESI, Method 4) t R= 2.25 min, m / z (M+H) + = 257.1.

[0608] Intermediate B

[0609]

[0610] Step 1. Methyl 4-chloro-6-((1S,2S)-2-fluorocyclopropane-1-carbamate)nicotinic acid (B1)

[0611] A mixture of A1 (1.0 g, 4.85 mmol), (1S,2S)-2-fluorocyclopropane-1-carboxamide (751 mg, 7.28 mmol), K3PO4 (2.04 g, 9.67 mmol), dppf (269 mg, 0.49 mmol), and Pd(OAc)2 (109 mg, 0.49 mmol) in dioxane (8 mL) was stirred at 90 °C under N2 for 12 h. After cooling to rt, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 30 / 1) to give B1 (220 mg, 17% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.16 min, m / z (M+H) + = 273.6.

[0612] Step 2. 4-Chloro-6-((1S,2S)-2-fluorocyclopropane-1-carbamate)nicotinic acid (B2)

[0613] LiOH·2H₂O (990 mg, 16.50 mmol) was added to a solution of B1 (900 mg, 3.30 mmol) in MeOH / THF / H₂O (15 mL, v / v / v = 2 / 2 / 1) and the mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to dryness and acidified to pH 2 with 1 NHCl. The resulting solid was filtered and the filter cake was dried to give B2 (700 mg, 82% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.00 min, m / z (M+H) + = 258.9.

[0614] Step 3. 4-Chloro-6-((1S,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)nicotinamide (Int.B)

[0615] A mixture of B2 (700 mg, 2.71 mmol), DIPEA (2.10 g, 16.24 mmol, 2.83 mL), T3P (1.72 g, 5.41 mmol, 3.45 mL, 50 wt.% in DMF) and methyl-d3-amine hydrochloride (379 mg, 5.41 mmol) in DMF (4 mL) was stirred at 30 °C for 48 h. The mixture was diluted with H2O (10 mL) and extracted with DCM (10 x 3 mL). The organic layer was washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give Int. B (500 mg, 67% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ11.24 (s, 1H), 8.43 (s, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 5.04-4.86 (m, 1H),2.49-2.40 (m, 1H), 1.69-1.62 (m, 1H), 1.24-1.18 (m, 1H). LC-MS (ESI, Method 3) t R = 0.91 min, m / z (M+H) + = 275.0.

[0616] Intermediate C

[0617]

[0618] Step 1. 4-Chloro-6-(cyclopropaneformamido)-N-methylnicotinamide (Int. C)

[0619] A mixture of A3 (338 mg, 1.37 mmol), DIPEA (1.06 g, 8.23 ​​mmol), methylamine hydrochloride (184 mg, 2.75 mmol), and T3P (1.75 g, 2.74 mmol, 50 wt.% in DMF) in DMF (2 mL) was stirred at 50 °C for 24 h. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (20 mL x 3). The organic layer was separated, washed with water (5 mL), and concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 10 / 1) to give Int. C (120 mg, 34% yield) as a white solid. 1¹H NMR (400 MHz, DMSO-d⁶) δ 11.19 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 2.75 (d, J = 5.2 Hz, 3H), 2.02–1.99 (m, 1H), 0.85–0.82 (m, 4H). LC-MS (ESI, Method 3) t R = 0.94 min, m / z (M+H) + = 254.2.

[0620] Intermediate D

[0621]

[0622] Step 1. Methyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinic acid (D1)

[0623] (4-Methoxyphenyl)methylamine (3.33 g, 24.27 mmol, 3.2 mL) and TEA (4.91 g, 48.54 mmol, 6.8 mL) were added to a solution of A1 (5 g, 24.27 mmol) in ACN (8 mL). The mixture was then stirred at rt for 24 h. The mixture was diluted with H2O (100 mL), extracted with EA (50 mL x 3), washed with brine, dried over Na2SO4, concentrated, and purified by rapid chromatography (PE / EA = 20 / 1 to 5 / 1) to give compound D1 (6.5 g, 87% yield) as a grayish-white solid. LC-MS (ESI, Method 4) t R = 4.18 min, m / z (M+H) + = 307.1.

[0624] Step 2. Methyl 6-(cyclopropaneformamido)-4-((4-methoxybenzyl)amino)nicotinic acid (D2)

[0625] A mixture of D1 (2 g, 6.52 mmol), cyclopropaneformamide (1.11 g, 13.04 mmol), XantPhos (754 mg, 1.30 mmol), Pd2(dba)3 (597 mg, 0.65 mmol), and Cs2CO3 (5.31 g, 16.30 mmol) in 1,4-dioxane (30 mL) was stirred at 110 °C for 2 h. The mixture was then diluted with H2O (100 mL), extracted with EA (60 mL x 3), washed with brine, dried over Na2SO4, and concentrated to obtain compound D2 (2.3 g, 99% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.91 min, m / z (M+H) + = 356.2.

[0626] Step 3. 4-Amino-6-(cyclopropaneformamido)nicotinic acid methyl ester 2,2,2-trifluoroacetate (Int. D)

[0627] A solution of D2 (2.1 g, 5.91 mmol) in TFA (10 mL) was stirred at 80 °C for 16 h. The mixture was then concentrated and diluted with EA (10 mL), filtered, and washed with EA (5 mL x 2). The solid was then dried to give compound Int. D (1.8 g, 87% yield, TFA salt) as a grayish-white solid. LC-MS (ESI, Method 4) R = 1.28 min, m / z(M+H) + = 236.2.

[0628] Intermediate E

[0629]

[0630] Step 1. 2,4-Dichloro-N-(methyl-d3)pyrimidine-5-carboxamide (Int. E)

[0631] At -78 °C, E1 (3.5 g, 16.55 mmol) was slowly added to a mixture of methyl-d3-amine hydrochloride (1.40 g, 19.86 mmol) in DCM (200 mL), followed by the addition of TEA (1.68 g, 16.55 mmol, 2.31 mL). After stirring at this temperature for 1 h, the reaction was quenched with water (30 mL). The organic layer was separated and concentrated. The residue was purified by silica gel rapid chromatography (PE / EA = 5 / 1) to give Int. E (1.38 g, 35% yield) as a white solid. 1¹H NMR (400 MHz, DMSO-d⁶) δ 8.88 (s, ¹H), 8.85 (s, ¹H). LC-MS (ESI, Method 3) t R = 0.80 min, m / z (M+H) + = 208.9.

[0632] intermediate F

[0633]

[0634] Step 1. Methyl 4-chloro-6-((5-fluoropyridin-2-yl)amino)nicotinic acid (F1)

[0635] A mixture of A1 (2.0 g, 9.71 mmol), 5-fluoropyridin-2-amine (1.31 g, 11.65 mmol), K3PO4 (4.12 g, 19.42 mmol), DPPF (807 mg, 1.46 mmol), and Pd(OAc)2 (327 mg, 1.46 mmol) in anhydrous dioxane (20 mL) was stirred at 90 °C for 12 h. After cooling to rt, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel rapid chromatography (PE / EA = 7 / 1) to give F1 (2.0 g, 73% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.11 min, m / z (M+H) + = 282.4.

[0636] Step 2. 4-Chloro-6-((5-Fluoropyridin-2-yl)amino)nicotinic acid (F2)

[0637] LiOH·H2O (1.49 g, 35.50 mmol) was added to a solution of F1 (2.0 g, 7.10 mmol) in MeOH / THF / H2O (20 mL, v / v / v = 2 / 2 / 1). After stirring at rt for 12 h, the reaction mixture was concentrated to dryness and acidified to pH 2 with 1 NHCl. The solid formed was collected by filtration and the filter cake was dried to give compound F2 (1.8 g, 95% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 0.88 min, m / z (M+H) + = 268.2.

[0638] Step 3. 4-Chloro-6-((5-fluoropyridin-2-yl)amino)-N-(methyl-d3)nicotinamide (Int. F)

[0639] A mixture of F2 (400 mg, 1.50 mmol), methyl-d3-amine hydrochloride (529 mg, 7.50 mmol), and DIPEA (1.16 g, 9.00 mmol) in T3P (2 mL, 50 wt% in DMF) was stirred at 50 °C for 16 h. After cooling to rt, the reaction mixture was poured into water (10 mL), and the solid formed was collected by filtration. The filter cake was slurried with MeOH (5 mL) for 30 min. The solid was filtered and dried to give Int. F (380 mg, 90% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.10 min, m / z (M+H) + = 284.1.

[0640] intermediate G

[0641]

[0642] Step 1. Methyl-d3 4,6-dichloronicotinate (G2)

[0643] At 0 °C, (COCl)₂ (3.96 g, 31 mmol) and DMF (0.08 g, 1 mmol, 0.08 mL) were added to a solution of G1 (2.00 g, 11 mmol) in DCM (20 mL). The mixture was then stirred at 25 °C for 2 h and concentrated to obtain a residue. At 0 °C, CD₃OD (0.38 g, 0.011 mol, 0.43 mL) and TEA (2.10 g, 0.021 mol, 2.9 mL) were added to a DCM (20 mL) solution of the residue. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (20 mL) and then extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc in PE: 2-20%) to give G2 as a white solid (1.5 g, 68% yield). LC-MS (ESI, Method 4) R = 0.25 min, m / z [M+H] + = 208.9.

[0644] Step 2. Methyl-d3-4-chloro-6-(cyclopropanecarbamate)nicotinate (Int. G)

[0645] Under a nitrogen atmosphere, a solution of G2 (1.5 g, 7 mmol) in dioxane (20 mL) was added with cyclopropaneformamide (0.61 g, 7 mmol), Pd(OAc)2 (0.16 g, 0.7 mmol), dppf (1.20 g, 1.4 mmol), and K3PO4 (3.06 g, 14 mmol). The mixture was stirred at 75 °C for 16 h. The reaction mixture was diluted with water (30 mL) and then extracted with EA (30 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (PE / EA = 5 / 1) to give Int. G (0.80 g, 44% yield) as a white solid. LC-MS (ESI, Method 3) R = 1.92 min, m / z [M+H] + = 257.7.

[0646] Example 1

[0647]

[0648] Step 1. 3-Iodo-4-methoxy-1-methyl-1H-indole (1b)

[0649] At 0 °C, KOH (2.28 g, 40.72 mmol) and CH3I (4.34 g, 30.54 mmol) were added to a solution of 1a (2.78 g, 10.18 mmol) in DMF (15 mL). The mixture was stirred at rt for 1 h. The reaction mixture was poured into ice water (50 mL) and the resulting solid was filtered. The solid was dried to give compound 1b (2.8 g, 96% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.37 (s, 1H), 7.11-7.05 (m, 2H), 6.55 (dd, J =7.6, 1.2 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 3H).

[0650] Step 2. (4-Methoxy-1-methyl-1H-indole-3-yl)tert-butyl carbamate (1c)

[0651] A mixture of 1b (500 mg, 1.74 mmol), K3PO4 (738 mg, 3.48 mmol), BocNH2 (612 mg, 5.22 mmol), CuI (100 mg, 0.52 mmol), and N,N-dimethylethane-1,2-diamine (46 mg, 0.52 mmol) in toluene (5 mL) was stirred overnight at 110 °C. The mixture was concentrated, and the residue was purified by silica gel rapid chromatography (PE / EA = 4 / 1) to give compound 1c (240 mg, 50% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ7.76 (s, 1H), 7.34 (s, 1H), 7.10-6.97 (m, 2H), 6.52 (d, J = 10.4 Hz, 1H), 3.90 (s, 3H), 3.71 (s, 3H), 1.50 (s, 9H).

[0652] Step 3. 4-Methoxy-1-methyl-1H-indole-3-amine hydrochloride (1d)

[0653] At rest, HCl / EA (2 mL, 6 M) was added to a solution of 1c (300 mg, 1.09 mmol) in EtOAc (2 mL). The mixture was stirred at rest overnight. The resulting solid was filtered and the filter cake was dried to give compound 1d (158 mg, 68% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (brs, 3H), 7.37 (s, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 3.94 (s, 3H), 3.76 (s, 3H).

[0654] Step 4. Methyl 6-chloro-4-((4-methoxy-1-methyl-1H-indol-3-yl)amino)pyridazine-3-carboxylate (1e)

[0655] A mixture of 1d (90 mg, 0.42 mmol), methyl 4,6-dichloropyridazine-3-carboxylate (88 mg, 0.42 mmol), and DIPEA (273 mg, 2.12 mmol) in DMF (1 mL) was stirred at 80 °C for 10 h. The reaction was concentrated, and the residue was purified by silica gel rapid chromatography (PE / EA = 4 / 1) to give compound 1e (80 mg, 55% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.45 min, m / z (M+H) + = 347.1.

[0656] Step 5. Methyl 6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-1H-indol-3-yl)amino)pyridazine-3-carboxylate (1f)

[0657] A mixture of 1e (98 mg, 0.28 mmol), cyclopropaneformamide (48 mg, 0.57 mmol), Cs₂CO₃ (276 mg, 0.85 mmol), BrettPhos (26 mg, 0.028 mmol), and BrettPhos Pd G₃ (15 mg, 28 mmol) in anhydrous 1,4-dioxane (1 mL) was stirred at 80 °C for 6 h. The mixture was concentrated, and the residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give compound 1f (65 mg, 58% yield) as a yellow solid. LC-MS (ESI, Method 3) R = 0.49 min, m / z (M+H) + = 396.2.

[0658] Step 6. 6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-1H-indole-3-yl)amino)-N-methylpyridazine-3-carboxamide (1)

[0659] The mixture of 1f (50 mg, 0.13 mmol) in methylamine (1.5 mL, 30% alcohol solution) was stirred at 80 °C for 48 h. The mixture was concentrated. The residue was purified by preparative HPLC (method C) to give compound 1 (4 mg, 8% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 11.02 (s, 1H), 9.02-8.99(m, 1H), 7.98 (s, 1H), 7.23 (s, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.04 (d, J =8.0 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 2.86 (d, J= 4.8 Hz, 3H), 2.10-2.06 (m, 1H), 0.83-0.81 (m, 4H). LC-MS (ESI, method 2) t R =2.43 min, m / z (M+H) + = 395.2.

[0660] Example 2

[0661]

[0662] Step 1. 5-Bromo-4-methoxy-1-methyl-1H-indole-3-carboxaldehyde (2b)

[0663] 2a (1.5 g, 6.3 mmol) and t The mixture of BuOK (1.7 g, 15.6 mmol) in DMF (15 mL) was stirred at 0 °C for 10 min. Iodimethane (3.5 g, 24.9 mmol) was then added to the reaction mixture. After stirring at rt for 18 h, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (40 mL), concentrated, and the residue was purified by silica gel rapid chromatography (PE / DCM = 1 / 1) to give 2b (1.6 g, 96% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.25 (s, 1H), 7.48 (d, J =8.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H).

[0664] Step 2. 5-Bromo-4-methoxy-1-methyl-1H-indole-3-carboxylic acid (2c)

[0665] A mixture of 2b (1.2 g, 4.5 mmol) and KMnO4 (1.4 g, 8.9 mmol) in acetone / H2O (80 mL, v / v = 1 / 1) was stirred at rt for 10 h. The mixture was filtered and the organic solvent was removed under reduced pressure. The aqueous layer was alkalized with 1 M NaOH to pH > 10 and washed with EtOAc (20 mL). The separated aqueous layer was acidified with 2 M HCl to pH = 5 and extracted with DCM / MeOH (40 mL * 3, v / v = 10 / 1). The combined organic phases were washed with brine (40 mL) and concentrated to give crude product 2c (0.60 g, 50% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.11 min, m / z ( 79 Br, M+H) + = 284.0.

[0666] Step 3. (5-Bromo-4-methoxy-1-methyl-1H-indole-3-yl)tert-butyl carbamate (2d)

[0667] The mixture of 2c (417 mg, 1.5 mmol), DPPA (444 mg, 1.6 mmol), and Et3N (444 mg, 4.40 mmol) in toluene (4 mL) was stirred at 110 °C for 1 h. Then t BuOH (217 mg, 2.9 mmol) was added to the mixture. After stirring at 110 °C for 12 h, the reaction mixture was cooled, concentrated, and the residue was purified by silica gel rapid chromatography (PE / EA = 20 / 1) to give 2d (60 mg, 12% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.47min, m / z ( 79 Br, M+H) + = 355.2.

[0668] Step 4. 4-((5-bromo-4-methoxy-1-methyl-1H-indol-3-yl)amino)-6-(cyclopropaneformamido)-N-(methyl-d3)nicotinamide hydrochloride (2e)

[0669] A mixture of 2d (55 mg, 0.15 mmol), Int. A (40 mg, 0.14 mmol), catalyst (cat.), concentrated HCl, and EtOH (1 mL) was stirred at 90 °C for 18 h. The reaction mixture was cooled, concentrated, and purified by preparative TLC (DCM / MeOH = 30 / 1) to give 2e (46 mg, 60% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.30min, m / z ( 79 Br, M+H) + = 475.3.

[0670] Step 5. 6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-vinyl-1H-indole-3-yl)amino)-N-(methyl-d3)nicotinamide (2f)

[0671] A mixture of 2e (56 mg, 0.11 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (19 mg, 0.13 mmol), CsF (48 mg, 0.315 mmol), and Pd(dppf)Cl2 (8 mg, 0.01 mmol) in dioxane / H2O (1.2 mL, v / v = 3 / 1) was stirred in N2 at 150 °C for 5 h under microwave. After cooling to rt, the mixture was filtered and the residue was concentrated to give crude 2f (40 mg, 90% yield) as a black solid. LC-MS (ESI, Method 3) t R = 1.26 min, m / z (M+H) + = 423.4.

[0672] Step 6. 6-(cyclopropaneformamido)-4-((5-ethyl-4-methoxy-1-methyl-1H-indol-3-yl)amino)-N-(methyl-d3)nicotinamide (2)

[0673] A mixture of 2f (40 mg, 0.095 mmol) and Pd / C (4 mg, 0.036 mmol, moistened with about 50% water) in MeOH was stirred at rt under H2 (0.1 MPa) for 5 h. The mixture was filtered and purified by preparative HPLC (Method A) to give 2 (11.4 mg, 28% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s,1H), 10.33 (s, 1H), 8.44-8.46 (m, 2H), 7.74 (s, 1H), 7.27 (s, 1H), 7.16 (d, J= 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 3.74 (s, 3H), 3.61 (s, 3H), 2.63 (q,J = 7.6 Hz, 2H), 1.97-1.91 (m, 1H), 1.16 (t, J = 7.6 Hz, 3H), 0.73-0.69 (m,4H). LC-MS (ESI, method 2) t R = 2.58 min, m / z (M+H) + = 425.2.

[0674] Example 3

[0675]

[0676] Step 1. (3-Methoxypyridin-4-yl)tert-butyl carbamate (3b)

[0677] A solution of 3a (800 mg, 6.44 mmol), Boc₂O (1.83 g, 8.38 mmol, 1.9 mL), and DIPEA (1.67 g, 12.89 mmol, 2.24 mL) in DCM (15 mL) was stirred at 20 °C for 12 h. A yellow solution was formed. The reaction mixture was concentrated and purified by rapid chromatography (EA in PE: 10-50%) to give compound 3b (1.45 g, yield given) as a white solid. LC-MS (ESI, Method 4) t R = 1.92 min, m / z (M+H) + = 225.1.

[0678] Step 2. 1-Amino-4-((tert-butoxycarbonyl)amino)-3-methoxypyridine-1-onium 2,4-dinitrophenolate (3c)

[0679] A mixture of 3b (1.45 g, 6.47 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (1.42 g, 7.11 mmol) in MeCN (50 mL) was stirred at 50 °C for 16 h. A yellow solution was formed. The reaction was concentrated to give 3c (2.73 g, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) R = 1.66 min, m / z M + = 240.1.

[0680] Step 3. Ethyl 5-((tert-butoxycarbonyl)amino)-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (3d)

[0681] A mixture of ethyl propargyl ester (685 mg, 6.98 mmol, 0.71 mL), 3c (1.29 g, 5.37 mmol), and K₂CO₃ (1.48 g, 10.74 mmol) in DMF (15 mL) was stirred at 20 °C for 2 h. A black suspension was formed. The reaction mixture was concentrated under vacuum and diluted with water (50 mL), then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE: 10-30%) to give 3d (428 mg, 22% yield) as a yellow solid. LC-MS (ESI, Method 4) R = 4.16 min, m / z (M+H) + = 336.1.

[0682] Step 4. Ethyl 5-chloro-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (3e)

[0683] At 20°C, HCl / dioxane (4M, 2 mL) was added to a mixture of 3d (330 mg, 0.98 mmol) in DCM (2 mL). The resulting mixture was stirred at 20°C for 1 h. A yellow solution was formed. The reaction mixture was concentrated to give ethyl 5-amino-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (231 mg, HCl salt, crude) as a yellow solid. LC-MS (ESI, Method 4) t R = 0.48 min, m / z (M+H) + = 236.1.

[0684] At 0 °C, tert-butyl nitrite (152 mg, 1.47 mmol, 0.18 mL) was added to a mixture of ethyl 5-amino-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (231 mg, HCl salt, crude) in MeCN (5 mL) and stirred for 10 min. Then, CuCl (145.8 mg, 1.47 mmol) was added to the mixture. The resulting mixture was stirred at 80 °C for 12 h. A yellow solution was formed. The reaction mixture was concentrated and purified by rapid chromatography (EA in PE was 10-30%) to give 3e as a yellow solid (100 mg, 40% yield). LC-MS (ESI, Method 4) R = 2.44 min, m / z (M+H) + =255.2.

[0685] Step 5. 5-Chloro-4-methoxy-pyrazolo[1,5-a]pyridine (3f)

[0686] A solution of 3e (100 mg, 0.39 mmol) in 2 mL of 50% H₂SO₄, stirred thoroughly, was heated at 110 °C for 3 h. A yellow solution was formed. The solution was cooled to room temperature. The solution was neutralized with an aqueous NaOH solution (1.0 M). 40 mL of water was added to the above solution. The solution was extracted with EtOAc (30 mL x 3). The organic layers were combined. The organic layers were dried over anhydrous Na₂SO₄. The organic layers were filtered through a diatomaceous earth mat. The organic layers were vacuum evaporated to give 3f (33 mg, 46% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.63 (dd, J = 2.4 Hz, 1.2 Hz, 1H),4.06 (s,3H). LC-MS (ESI, Method 4) t R = 2.46 min, m / z (M+H) + = 183.1.

[0687] Step 6. 5-Chloro-3-iodo-4-methoxy-pyrazolo[1,5-a]pyridine (3g)

[0688] A mixture of 3f (31 mg, 0.17 mmol) and NIS (38.2 mg, 0.17 mmol) in DMF (2 mL) was stirred at 20 °C for 12 h. A yellow suspension was formed. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE: 10-30%) to give 3 g (50 mg, 95% yield) of a yellow solid. LC-MS (ESI, Method 4) R = 3.12 min, m / z (M+H) + = 308.9.

[0689] Step 7. Methyl 4-((5-chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-6-(cyclopropanecarbamate)nicotinic acid (3h)

[0690] A mixture of 3 g (50 mg, 0.16 mmol), Int. D (68 mg, 0.19 mmol, TFA salt), BrettPhos (17.4 mg, 0.032 mmol), Cs₂CO₃ (132 mg, 0.41 mmol), and BrettPhos Pd G₃ (14.7 mg, 0.016 mmol) in dioxane (1 mL) was degassed and purged three times with nitrogen. The resulting mixture was stirred at 100 °C under a N₂ atmosphere for 24 h, forming a yellow suspension. The reaction mixture was concentrated and purified by preparative TLC (PE / EA = 1 / 2) to give a yellow solid (60 mg, 89% yield) for 3 h. 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.58 (s,1H), 8.67 (s, 1H), 8.54 (d, J = 7.2 Hz, 1 H), 8.15 (s, 1H), 7.64 (s, 1H), 6.98 (d, J = 7.2 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 1.98-1.90 (m, 1H), 0.78-0.70 (m, 4H). LC-MS (ESI, Method 4) t R = 2.42 min, m / z (M+H) + = 416.2.

[0691] Step 8. 4-((5-chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-6-(cyclopropanecarbamate)nicotinic acid (3i)

[0692] A mixture of 3h (60 mg, 0.144 mmol) and LiOH·H₂O (18 mg, 0.433 mmol) in a co-solvent of THF (3 mL) and water (1 mL) was stirred at 40 °C for 12 h. A yellow solution was formed. The reaction mixture was concentrated and dried under vacuum to give 3i (58 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) R = 1.01 min, m / z (M+H) + = 402.2.

[0693] Step 9 4-((5-chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-6-(cyclopropaneformamido)-N-(methyl-d3)nicotinamide (3)

[0694] A mixture of CD3NH2.HCl (30.5 mg, 0.433 mmol), 3i (58 mg, crude), DIPEA (93.3 mg, 0.721 mmol, 0.13 mL), and T3P (275.6 mg, 0.433 mmol, 50% purity in EtOAc) in DMF (2 mL) was stirred at 20 °C for 12 h. A yellow solution was formed. The reaction mixture was filtered and purified by preparative HPLC (Method E) to give 3 (3.6 mg, 6% yield) as a white solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 10.69 (s, 1H), 10.35 (s, 1H), 8.55 (s, 1H), 8.51–8.43 (m, 2H), 8.11 (s, 1H), 7.65 (s, 1H), 6.94 (d, J = 7.2 Hz, 1H), 3.79 (s, 3H), 1.98–1.90 (m, 1H), 0.76–0.71 (m, 4H). LC-MS (ESI, Method 4) t R = 1.97 min, m / z (M+H) + = 418.2.

[0695] Example 4

[0696]

[0697] Step 1. Methyl 5-((tert-butoxycarbonyl)amino)-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (4a)

[0698] A mixture of methyl propargylate (749 mg, 8.91 mmol, 7.93 mL), 3c (1.89 g, 4.45 mmol), and K₂CO₃ (1.23 g, 8.91 mmol) in DMF (5 mL) was stirred at 20 °C for 2 h. A black suspension was formed. The reaction mixture was concentrated and diluted with water (50 mL), then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE: 10-30%) to give 4a (350 mg, 24% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.35(s, 1H), 8.28 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.32 (brs, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 1.55 (s, 9H). LC-MS (ESI, Method 4) t R = 4.13 min, m / z(M+H) + = 322.1.

[0699] Step 2. Methyl 5-chloro-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (4b)

[0700] At 20°C, TFA (2 mL) was added to a mixture of 4a (1.25 g, 3.89 mmol) in DCM (5 mL). The resulting mixture was stirred at 20°C for 1 h. A yellow solution was formed. The reaction mixture was concentrated to give methyl 5-amino-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (800 mg, TFA salt, crude) as a yellow solid. LC-MS (ESI, Method 4) R = 0.46 min, m / z (M+H) + = 222.1.

[0701] At 0 °C, tert-butyl nitrite (559 mg, 5.42 mmol, 0.65 mL) was added to a mixture of methyl 5-amino-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (800 mg, TFA salt, crude) in MeCN (10 mL) and stirred for 10 min. Then, CuCl (716 mg, 7.23 mmol) was added to the mixture, and the resulting mixture was stirred at 80 °C for 2 h. A yellow solution was formed. The reaction mixture was concentrated and purified by rapid chromatography (EA in PE: 10-30%) to give 4b (600 mg, 69% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.31 min, m / z (M+H) + =241.2.

[0702] Step 3. 5-Chloro-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (4c)

[0703] A mixture of 4b (300 mg, 1.25 mmol) and LiOH·H₂O (157 mg, 3.74 mmol) in a co-solvent of THF (6 mL) and water (2 mL) was stirred at 70 °C for 12 h. A yellow solution was formed. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL). The aqueous layer was adjusted to pH = 3 with aqueous HCl solution (2 M) and extracted with EtOAc (20 mL * 3). The organic layer was concentrated and dried under vacuum to give 4c (180 mg, 64% yield) as a white solid. LC-MS (ESI, Method 4) t R = 1.79 min, m / z (M+H) + = 227.0.

[0704] Step 4. (5-Chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)tert-butyl carbamate (4d)

[0705] A mixture of 4c (180 mg, 0.79 mmol), N,N-diethylethylamine (161 mg, 1.59 mmol, 0.22 mL), and DPPA (284 mg, 1.03 mmol, 0.22 mL) in tBuOH (3 mL) was stirred at 110 °C for 6 h. A yellow suspension was formed. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (100 mL x 3) and brine (100 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE: 5-30%) to give 4d (100 mg, 42% yield) as a yellow solid. LC-MS (ESI, Method 4) R =2.31 min, m / z (M+H) + = 298.1.

[0706] Step 5. 5-Chloro-4-methoxypyrazolo[1,5-a]pyridine-3-amine (4e)

[0707] TFA (1 mL) was added to a mixture of 4d (100 mg, 0.34 mmol) in DCM (3 mL) at 20 °C. The resulting mixture was stirred at 20 °C for 1 h. A yellow solution was formed. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (60 mL x 3) and brine (60 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE was 10-60%) to give 4e (40 mg, 60% yield) as a yellow solid. LC-MS (ESI, Method 4) R = 0.65 min, m / z (M+H) + = 198.1.

[0708] Step 6. 2-Chloro-4-((5-chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide (4f)

[0709] DIPEA (52 mg, 0.40 mmol, 0.07 mL) was added to a mixture of 4e (40 mg, 0.20 mmol) and Int. E (42 mg, 0.20 mmol) in DCM (5 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 12 h. A yellow solution was formed. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (60 mL x 3) and brine (60 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to give 4f (74 mg, 98% yield) as a white solid. LC-MS (ESI, Method 4) t R = 2.88 min, m / z (M+H) + = 370.1.

[0710] Step 7. 2-Amino-4-((5-chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide (4g)

[0711] A mixture of 4f (20 mg, 0.054 mmol) and TsOH (19 mg, 0.11 mmol) in NH3 / dioxane solution (3 mL, 0.4 M) was stirred at 80 °C for 72 h. A white suspension was formed. The reaction mixture was diluted with water (40 mL) and extracted with DCM (40 mL x 3). The combined organic layers were washed with water (40 mL x 3) and brine (40 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give 4 g (12 mg, 63% yield) of a yellow solid. LC-MS (ESI, Method 4) t R = 1.87 min, m / z (M+H) + = 351.2.

[0712] Step 8. 4-(N-(5-chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)cyclopropanecarbamate)-2-(cyclopropanecarbamate)-N-(methyl-d3)pyrimidine-5-carbamate (4h)

[0713] A mixture of 4 g (12 mg, 0.034 mmol), cyclopropanecarbamate (11 mg, 0.103 mmol), and DIPEA (17 mg, 0.171 mmol, 0.024 mL) in DCM (2 mL) was stirred at 20 °C for 12 h. A yellow solution was formed. The reaction mixture was concentrated and dried under vacuum to give a yellow solid of 4 h (16 mg, crude product), which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 2.94 min, m / z (M+H) + = 487.3.

[0714] Step 9. 4-((5-chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-2-(cyclopropanecarbamate)-N-(methyl-d3)pyrimidine-5-carboxamide (4)

[0715] The mixture of 4h (16 mg, crude) and K2CO3 (9 mg, 0.066 mmol) in MeOH (3 mL) was stirred at 20 °C for 12 h. A yellow solution was formed. The reaction mixture was filtered and purified by preparative HPLC (Method D) and further lyophilized to give 4 (2.3 mg, 16.7% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H),10.98 (s, 1H), 9.62 (s, 1H), 8.72 (s, 1H), 8.62 (s, 1H), 8.39 (d, J = 7.2 Hz,1H), 6.83 (d, J = 7.2 Hz, 1H), 4.09 (s, 3H), 2.15-2.06 (m, 1H), 0.93-0.80 (m, 4H). LC-MS (ESI, Method 4) t R = 2.17 min, m / z (M+H) + = 419.2.

[0716] Example 5

[0717]

[0718] Step 1. 3-Methoxy-4-methylpyridine (5b)

[0719] At 0 °C, NaH (1.37 g, 34.36 mmol, 60% in mineral oil) and CH3I (3.58 g, 25.20 mmol, 1.57 mL) were added to a mixture of 5a (2.50 g, 22.91 mmol) in DMF (20 mL). The resulting mixture was stirred at 20 °C for 2 h. A black suspension was formed. The reaction mixture was diluted with water (100 mL) and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE was 10-30%) to give 5b (230 mg, 8% yield) as a yellow solid. 1 ¹H NMR (400MHz, CDCl₃) δ 8.15 (s, 1H), 8.10 (d, J = 4.8 Hz, 1H), 6.72 (m, 1H), 3.90 (s, 3H), 2.21 (s, 3H). LC-MS (ESI, Method 4) t R = 0.56 min, m / z (M+H) + = 124.0.

[0720] Step 2. 1-Amino-3-methoxy-4-methylpyridine-1-onium 2,4-dinitrophenol (5c)

[0721] A mixture of 5b (230 mg, 1.87 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (409 mg, 2.05 mmol) in MeCN (3 mL) was stirred at 50 °C for 16 h. A yellow solution was formed. The reaction was concentrated to give 5c (260 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 1.16 min, m / z M + = 140.1.

[0722] Step 3. Methyl 4-methoxy-5-methylpyrazolo[1,5-a]pyridine-3-carboxylate (5d)

[0723] A mixture of methyl propargyl ester (236 mg, 2.80 mmol, 0.25 mL), 5c (260 mg, 1.87 mmol), and K₂CO₃ (516 mg, 3.74 mmol) in DMF (3 mL) was stirred at 20 °C for 2 h. A black suspension was formed. The reaction mixture was concentrated under vacuum and diluted with water (50 mL), then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE: 10-30%) to give 5d (140 mg, 34% yield) as a yellow solid. LC-MS (ESI, Method 4) R = 2.60min, m / z (M+H) + = 221.0.

[0724] Step 4. 4-Methoxy-5-methylpyrazolo[1,5-a]pyridine (5e)

[0725] A solution of 5d (140 mg, 0.636 mmol) in 2 mL of 50% H₂SO₄, stirred thoroughly, was heated at 110 °C for 3 h. A yellow solution was formed. The solution was cooled to room temperature. The solution was neutralized with an aqueous solution of NaOH (1.0 M) using litmus paper as an indicator. 40 mL of water was added to the above solution. The solution was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered through a diatomaceous earth mat, and evaporated to give 5e (50 mg, 48% yield) as a light-yellow solid. 1 ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 6.54 (d, J = 7.2 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 3.95 (s, 3H), 2.28 (s, 3H). LC-MS (ESI, Method 4) t R = 2.29 min, m / z (M+H) + = 163.1.

[0726] Step 5. 3-Iodo-4-methoxy-5-methylpyrazolo[1,5-a]pyridine (5f)

[0727] A mixture of 5e (50 mg, 0.308 mmol) and NIS (73 mg, 0.324 mmol) in DMF (1 mL) was stirred at 20 °C for 24 h. A yellow suspension was formed. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE: 10-30%) to give 5f (70 mg, 79% yield) as a yellow solid. LCMS (ESI, Method 4) t R = 2.93 min, m / z (M+H) + = 289.0. 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J =6.8 Hz, 1H), 7.85 (s, 1H), 6.59 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 2.32 (s,3H).

[0728] Step 6. Methyl 6-(cyclopropaneformamido)-4-((4-methoxy-5-methylpyrazolo[1,5-a]pyridin-3-yl)amino)nicotinic acid (5g)

[0729] A mixture of 5f (70 mg, 0.243 mmol), Int. D (102 mg, 0.29 mmol, TFA salt), BrettPhos (26 mg, 0.049 mmol), Cs₂CO₃ (198 mg, 0.607 mmol), and BrettPhos Pd G₃ (22 mg, 0.024 mmol) in dioxane (3 mL) was degassed and purged three times with nitrogen. The resulting mixture was stirred at 100 °C under a N₂ atmosphere for 72 h, forming a yellow suspension. The reaction mixture was concentrated and purified by preparative TLC (DCM / MeOH = 10 / 1) to give 5 g (60 mg, 62% yield) of a yellow solid. LC-MS (ESI, Method 4) t R = 2.18 min, m / z (M+H) + =396.3.

[0730] Step 7. 6-(cyclopropaneformamido)-4-((4-methoxy-5-methylpyrazolo[1,5-a]pyridin-3-yl)amino)nicotinic acid (5h)

[0731] A mixture of 5 g (60 mg, 0.152 mmol) and LiOH·H₂O (19 mg, 0.455 mmol) in THF (3 mL) and water (1 mL) was stirred at 40 °C for 12 h. A yellow solution was formed. The reaction mixture was concentrated and dried under vacuum to give a yellow solid, 5 h (58 mg, crude product), which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 1.78 min, m / z (M+H) + = 382.2.

[0732] Step 8. 6-(cyclopropaneformamido)-4-((4-methoxy-5-methylpyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (5)

[0733] A mixture of CD3NH2.HCl (32 mg, 0.456 mmol), 5h (58 mg, crude), DIPEA (118 mg, 0.912 mmol, 0.158 mL), and T3P (290 mg, 0.456 mmol, 50% purity in EtOAc) in DMF (2 mL) was stirred at 20 °C for 12 h. A yellow solution was formed. The reaction mixture was filtered and purified by preparative HPLC (Method D) to give 5h (5.2 mg, 9% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 10.28 (s,1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.35 (d, J = 6.8 Hz, 1H), 7.99 (s, 1H), 7.64(s, 1H), 6.73 (d, J = 6.8 Hz, 1H), 3.66 (s, 3H), 2.22 (s, 3H), 1.98-1.90 (m,1H), 0.74-0.70 (m, 4H). LC-MS (ESI, Method 4) t R = 1.82 min, m / z (M+H) + = 398.3.

[0734] Example 6

[0735]

[0736] Step 1. 1-Amino-3-methoxy-4-(methoxycarbonyl)pyridine-1-onium 2,4-dinitrophenolate (6b)

[0737] A mixture of 6a (6.8 g, 40.68 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (9.72 g, 48.82 mmol) in ACN (60 mL) was stirred overnight at 50 °C. The mixture was concentrated to give 6b (14.9 g, crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) R = 0.46min, m / z M + = 183.0.

[0738] Step 2. Dimethyl 4-methoxypyrazolo[1,5-a]pyridine-3,5-dicarboxylate (6c)

[0739] A mixture of 6b (14.9 g, 40.68 mmol), methyl propargyl 2-propynate (3.53 g, 42.03 mmol), and K₂CO₃ (10.56 g, 76.43 mmol) in DMF (60 mL) was stirred at 30 °C for 2 h. The reaction mixture was poured into ice water (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic phases were washed with brine (100 mL x 2) and concentrated. The residue was purified by silica gel rapid chromatography (PE / EtOAc = 5 / 1) to give 6c (6.62 g, 62% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.10 min, m / z (M+H) + = 265.2.

[0740] Step 3. 4-Methoxypyrazolo[1,5-a]pyridine-5-carboxylic acid (6d)

[0741] A mixture of 6c (7 g, 26.49 mmol) in an aqueous H₂SO₄ solution (130 mL, 50 wt% in water) was stirred at 85 °C for 4 h. After cooling to rt, the mixture was diluted with water (200 mL) and neutralized to pH 3 with an aqueous NaOH solution (1 N). The mixture was extracted with EtOAc (200 mL * 3). The organic layer of the compound was washed with brine (100 mL) and concentrated to give 6d (4.4 g, 86% yield) as a brown solid. LC-MS (ESI, Method 3) t R = 0.94 min, m / z (M+H) + = 193.1.

[0742] Step 4. Methyl 4-methoxypyrazolo[1,5-a]pyridine-5-carboxylate (6e)

[0743] Concentrated HCl (3.75 mL, 46 mmol) was added to a solution of 6e (4.4 g, 22.90 mmol) in MeOH (250 mL). After stirring at 80 °C for 18 h, the mixture was concentrated and the residue was diluted with DCM (20 mL). The solution was washed with saturated NaHCO3 (20 mL) and the aqueous layer was extracted with DCM (20 mL x 2). The combined organic layers were concentrated and the residue was purified by silica gel rapid chromatography (PE / EA = 4 / 1) to give 6e (2.76 g, 58% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.14 min, m / z (M+H) + = 207.1.

[0744] Step 5. Methyl 4-methoxy-3-nitropyrazolo[1,5-a]pyridine-5-carboxylate (6f)

[0745] At rt, KNO3 (245 mg, 2.42 mmol) was added to a solution of 6e (500 mg, 2.42 mmol) in TFA (5 mL), and the mixture was stirred at 35 °C for 3 h. The solvent was removed by purging with N2. The mixture was alkalized with saturated Na2CO3 to pH > 8 and extracted with EtOAc (5 mL * 3). The organic layer was concentrated and purified by rapid chromatography (PE / EA = 3 / 1) to give the crude product. The crude product was ground with EtOAc (3 mL). The resulting solid was filtered and dried to give 6f (300 mg, 49% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.06 min, m / z (M+H) + = 252.2.

[0746] Step 6. Methyl 3-amino-4-methoxypyrazolo[1,5-a]pyridine-5-carboxylate hydrochloride (6g)

[0747] SnCl₂·2H₂O (359 mg, 1.59 mmol) was added to a solution of 6g (200 mg, 0.79 mmol) in concentrated HCl (4 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The resulting solid was filtered and dried to give 6g (150 mg, 73% yield) of a yellow solid. LC-MS (ESI, Method 3) t R = 0.53 min, m / z (M+H) + = 222.0.

[0748] Step 7. Methyl 3-((2-(cyclopropanecarbamoyl)-5-((methyl-d3)carbamoyl)pyridin-4-yl)amino)-4-methoxypyrazolo[1,5-a]pyridine-5-carboxylate (6)

[0749] A solution of 6 g (150 mg, 0.58 mmol) and Int. A (149 mg, 0.58 mmol) in dioxane (2 mL) was added with TsOH·H₂O (22 mg, 0.12 mmol) and stirred at 100 °C for 12 h. The reaction mixture was concentrated and purified by silica gel rapid chromatography (DCM / MeOH = 10 / 1) to give 6 (110 mg, 43% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 10.76 (s, 1H), 10.68 (s, 1H), 8.56 (s, 1H), 8.51 (s, 1H), 8.44 (d, J = 7.2 Hz, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.07 (d, J = 7.2 Hz,1H), 3.87 (s, 3H), 3.87 (s, 3H), 2.03-1.92 (m, 1H), 0.80-0.70 (m, 4H). LC-MS(ESI, method 3) t R = 1.05 min, m / z (M+H) + = 442.1.

[0750] Example 7

[0751]

[0752] Step 1. (4-Methoxypyrazolo[1,5-a]pyridin-5-yl)methanol (7a)

[0753] At 0 °C, LiAlH4 (455 mg, 11.98 mmol) was added to a solution of 6e (1.3 g, 6.30 mmol) in THF (15 mL). After stirring at 0 °C for 1 h, the reaction was quenched with Rochelle salt aqueous solution (10 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were concentrated, and the residue was purified by silica gel rapid chromatography (PE / EA = 2 / 1) to give 7a (1.07 g, 95% yield) as a white solid. LC-MS (ESI, Method 3) R = 0.94 min, m / z (M+H) + =179.0.

[0754] Step 2. 4-Methoxypyrazolo[1,5-a]pyridine-5-carboxaldehyde (7b)

[0755] At rt, MnO2 (2.92 g, 33.68 mmol) was added to a solution of 7a (1.0 g, 5.62 mmol) in EtOAc (10 mL). After stirring at 80 °C for 4 h, the mixture was filtered, and the filtrate was concentrated to give 7b (800 mg, 81% yield) as a yellow solid. LC-MS (ESI, Method 3) R = 1.02 min, m / z (M+H) + = 177.3.

[0756] Step 3. 2,2,2-Trifluoro-1-(4-methoxypyrazolo[1,5-a]pyridin-5-yl)ethanol (7c)

[0757] At 0 °C, TBAF (0.2 mL, 0.2 mmol, 1.0 M in THF) was added to a solution of 7b (620 mg, 3.52 mmol) and trimethyl(trifluoromethyl)silane (1.10 g, 7.74 mmol) in THF (10 mL). The mixture was stirred at 0 °C for 1 h and then at 25 °C for 16 h. Then, 1 M HCl solution was added, and the reaction was stirred at 25 °C for 2 h. The mixture was adjusted to pH 8 with an aqueous solution of NaOH (1 M). The mixture was extracted with EtOAc (5 mL x 3). The organic layer was concentrated, and the residue was purified by rapid chromatography (PE / EA = 3 / 1) to give 7c (834 mg, 96% yield) as a yellow oil. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.52 (d, J = 6.8 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 6.97–6.88 (m, 3H), 5.48–5.45 (m, 1H), 4.03 (s, 3H). LC-MS (ESI, Method 3) t R = 1.09 min, m / z(M+H) + = 247.2.

[0758] Step 4. 2,2,2-Trifluoro-1-(4-methoxy-3-nitropyrazolo[1,5-a]pyridin-5-yl)ethanol (7d)

[0759] A mixture of 7c (210 mg, 0.85 mmol) and KNO3 (95 mg, 0.94 mmol) in TFA (3 mL) was stirred at 30 °C for 2 h. The solvent was removed by purging with N2. The residue was dissolved in EtOAc (5 mL) and alkalized to pH 9 with saturated Na2CO3 solution (10 mL). The mixture was extracted with EtOAc (10 mL x 2). The organic phases were combined and concentrated, and the residue was purified by silica gel rapid chromatography (DCM / MeOH = 19 / 1) to give 7d (150 mg, 60% yield) as a brown solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 8.96 (s, 1H), 8.86 (d, J = 6.8 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 6.0 Hz, 1H), 5.62–5.55 (m, 1H), 3.80 (s, 3H). LC-MS (ESI, Method 3) t R = 1.12 min, m / z (M+H) + = 292.1.

[0760] Step 5. 1-(3-amino-4-methoxypyrazolo[1,5-a]pyridin-5-yl)-2,2,2-trifluoroethane-1-ol hydrochloride (7e)

[0761] SnCl₂·2H₂O (620 mg, 2.75 mmol) was added to a mixture of 7d (200 mg, 0.69 mmol) and concentrated HCl (4 mL) at 0 °C. After stirring at 10 °C for 1 h, the reaction mixture was filtered. The filter cake was dried under vacuum to give 7e (150 mg, 66% yield) as a yellow solid. LC-MS (ESI, Method 3) R = 0.85 min, m / z (M+H) + =262.0.

[0762] Step 6. 6-(cyclopropaneformamido)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (7)

[0763] A mixture of 7e (193 mg, 0.59 mmol), Int. A (151 mg, 0.59 mmol), and TsOH·H₂O (45 mg, 0.24 mmol) in 1,4-dioxane (3 mL) was stirred at 100 °C in a sealed tube for 16 h. The reaction mixture was concentrated, and the residue was purified by silica gel rapid chromatography (DCM / MeOH = 9 / 1) to give a crude product. The crude product was purified by preparative HPLC (Method A) to give 7e as a white solid (250 mg, 88% yield). 1 H NMR (400 MHz, DMSO-d6) δ10.68 (s, 1H), 10.36 (s, 1H), 8.55 (s, 1H), 8.51-8.49 (m, 2H), 8.11 (s, 1H),7.68 (s, 1H), 7.02 (d, J = 5.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 5.43-5.36(m, 1H), 3.72 (s, 3H), 1.99-1.90 (m, 1H), 0.76-0.67 (m, 4H). LC-MS (ESI, Method 2)t R = 3.15 min, m / z (M+H) + = 482.0.

[0764] Step 7. (S)-6-(cyclopropaneformamido)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (7A) and (R)-6-(cyclopropaneformamido)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (7B)

[0765] Compound 7 (520 mg, 1.08 mmol) was separated by chiral preparative HPLC (method F) to obtain 7A (204.2 mg, 39% yield) and 7B (206.1 mg, 40% yield) as white solids.

[0766] 7A: 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 10.36 (s, 1H), 8.54 (s,1H), 8.51-8.49 (m, 2H), 8.11 (s, 1H), 7.68 (s, 1H), 7.01 (d, J = 5.6 Hz, 1H), 6.90 (d, J = 7.2 Hz, 1H), 5.45-5.32 (m, 1H), 3.72 (s, 3H), 1.97-1.90 (m, 1H), 0.74-0.71 (m, 4H). LC-MS (ESI, method 2) t R = 2.39 min, m / z (M+H) + = 482.1. HPLC (Method 5) t R = 10.03 min.

[0767] 7B: 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 10.36 (s, 1H), 8.54 (s,1H), 8.51-8.49 (m, 2H), 8.11 (s, 1H), 7.68 (s, 1H), 7.01 (d, J = 6.0 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 5.41-5.30 (m, 1H), 3.72 (s, 3H), 1.97-1.90 (m, 1H), 0.74-0.71 (m, 4H). LC-MS (ESI, method 2) t R = 2.40 min, m / z (M+H) + = 482.1. HPLC (Method 5) t R = 12.27 min.

[0768] Example 8

[0769]

[0770] Step 1. 1-(3-((2-(cyclopropanecarbamoyl)-5-((methyl-d3)carbamoyl)pyridin-4-yl)amino)-4-methoxypyrazolo[1,5-a]pyridin-5-yl)-2,2,2-trifluoroethyl methanesulfonate (8a)

[0771] MsCl (29 mg, 0.50 mmol) was added to a solution of 7 (80 mg, 0.17 mmol) and TEA (100 mg, 1.00 mmol, 0.14 mL) in DCM (1 mL) at 0 °C. The mixture was then stirred at 14 °C for 30 min. The reaction was quenched with ice water (3 mL) and extracted with DCM (5 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated to give 8a (90 mg, crude) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 1.12 min, m / z (M+H) + = 560.2.

[0772] Step 2. 6-(cyclopropaneformamido)-4-((4-methoxy-5-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (8)

[0773] At 0 °C, NaBH4 (9 mg, 0.24 mmol) was added to a solution of 8a (90 mg, 0.16 mmol) in EtOH (1 mL), and the mixture was stirred at 15 °C for 18 h. The reaction mixture was quenched with ice water (3 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were concentrated, and the residue was purified by preparative HPLC (Method A) to give 8 (3.5 mg, 5% yield) as a white solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 10.68 (s, 1H), 10.35 (s, 1H), 8.55 (s, 1H), 8.51–8.48 (m, 2H), 8.10 (s, 1H), 7.69 (s, 1H), 6.83 (d, J = 6.8 Hz, 1H), 3.71 (s, 3H), 3.74–3.65 (m, 2H), 1.96–1.93 (m, 1H), 0.75–0.72 (m, 4H). LC-MS (ESI, Method 2) t R = 2.91 min, m / z (M+H) + = 466.1.

[0774] Example 9

[0775]

[0776] Step 1. Methyl 5-bromo-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (9a)

[0777] At 20°C, TFA (10 mL) was added to a mixture of 4a (2.20 g, 6.85 mmol) in DCM (10 mL). The resulting mixture was stirred at 20°C for 1 h. A yellow solution was formed. The reaction mixture was concentrated to give methyl 5-amino-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (1.51 g, TFA salt, crude) as a yellow solid. LC-MS (ESI, Method 4) R = 1.38 min, m / z (M+H) + = 222.1.

[0778] At 0 °C, tert-butyl nitrite (1.06 g, 10.24 mmol, 1.22 mL) was added to a mixture of methyl 5-amino-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (1.51 mg, TFA salt, crude) in MeCN (10 mL), and the mixture was stirred for 10 min. Then, CuBr (1.96 g, 13.65 mmol) was added to the mixture, and the resulting mixture was stirred at 80 °C for 2 h. A yellow solution was formed. The reaction mixture was concentrated and purified by rapid chromatography (EA in PE: 10-30%) to give 9a as a yellow solid (300 mg, 15% yield). LC-MS (ESI, Method 4) t R = 2.53 min, m / z ( 79 Br, M+H) + = 285.0.

[0779] Step 2. Methyl 4-methoxy-5-(3,3,3-trifluoroprop-1-en-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (9b)

[0780] A mixture of 9a (80 mg, 0.281 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaboranecyclohexane (86 mg, 0.365 mmol), Na₂CO₃ (89 mg, 0.842 mmol), and Pd(dppf)Cl₂ (46 mg, 0.056 mmol) in dioxane (2 mL) and water (0.2 mL) was degassed and purged three times with nitrogen. The resulting mixture was stirred at 100 °C under a N₂ atmosphere for 1 h, forming a yellow suspension. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 mL x 3) and brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE: 0-20%) to give 9b as a white solid (84 mg, 99% yield). LC-MS (ESI, Method 4) R = 2.91 min, m / z (M+H) + = 301.1.

[0781] Step 3. Methyl 4-methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (9c)

[0782] Pd / C (8 mg, 10% wt%, 10% Pd (dry basis), wetted with 55% H2O) was added to a solution of 9b (84 mg, 0.28 mmol) in MeOH (5 mL). The reaction mixture was degassed and purged three times with hydrogen. The resulting mixture was stirred at 40 °C under H2 atmosphere for 24 h. A black suspension was formed. The reaction mixture was filtered and concentrated to give 9c (80 mg, 99% yield) as a white solid. LC-MS (ESI, Method 4) t R = 2.93 min, m / z (M+H) + = 303.2.

[0783] Step 4. 4-Methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (9d)

[0784] A mixture of 9c (80 mg, 0.26 mmol) and LiOH·H₂O (89 mg, 2.12 mmol) in a co-solvent of THF (3 mL) and water (1 mL) was stirred at 70 °C for 24 h. A yellow solution was formed. The reaction mixture was diluted with water (30 mL), extracted with EtOAc (20 mL), and the organic layer was discarded. The aqueous layer was adjusted to pH 3 with an aqueous solution of HCl (2 M) and then extracted with EtOAc (20 mL * 3). The organic layer was concentrated and dried under vacuum to give 9d (76 mg, 99% yield) as a white solid. LC-MS (ESI, Method 4) t R = 2.35 min, m / z (M+H) + = 289.1.

[0785] Step 5. (4-Methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-a]pyridin-3-yl)tert-butyl carbamate (9e)

[0786] A mixture of 9d (80 mg, 0.28 mmol), N,N-diethylethylamine (56 mg, 0.56 mmol, 0.08 mL), and DPPA (99 mg, 0.36 mmol, 0.08 mL) in tBuOH (1 mL) was stirred at 110 °C for 6 h. A yellow suspension was formed. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 mL x 3) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE: 5-30%) to give 9e as a yellow solid (20 mg, 20% yield). LC-MS (ESI, Method 4) t R = 3.20min, m / z (M+H) + = 360.2.

[0787] Step 6. 4-Methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-a]pyridine-3-amine (9f)

[0788] At 20°C, TFA (1 mL) was added to a mixture of 9e (20 mg, 0.056 mmol) and DCM (3 mL). The resulting mixture was stirred at 20°C for 1 h. A yellow solution was formed. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (60 mL x 3) and brine (60 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE was 10-60%) to give 9f (12 mg, 83% yield) as a yellow solid. LC-MS (ESI, Method 4) R = 1.87 min, m / z (M+H) + = 260.2.

[0789] Step 7. 6-(cyclopropaneformamido)-4-((4-methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (9)

[0790] A mixture of 9f (10 mg, 0.039 mmol), Int. A (10 mg, 0.039 mmol), and TsOH (7 mg, 0.041 mmol) in dioxane (1 mL) was stirred at 100 °C for 2 h. A yellow solution was formed. The reaction mixture was filtered and purified by preparative HPLC (Method E) to give 9 as a grayish-white solid (3.7 mg, 20% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 10.36 (s, 1H), 8.55 (s, 1H), 8.52-8.49 (m, 2H), 8.10 (s, 1H), 7.69 (s, 1H), 6.86 (d, J = 7.2 Hz, 1H), 4.16-4.07 (m, 1H), 3.68(s, 3H), 1.98-1.90 (m, 1H), 1.44 (d, J = 7.2 Hz, 3H), 0.74-0.70 (m, 4H). LC-MS(ESI, method 4) t R = 2.27 min, m / z (M+H) + = 480.3.

[0791] Step 8. (R*)-6-(cyclopropaneformamido)-4-((4-methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (9A) and (S*)-6-(cyclopropaneformamido)-4-((4-methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (9B)

[0792] Compound 9 (24 mg, 0.05 mmol) was separated by chiral preparative HPLC (Method I) to obtain 9A (9.5 mg, 40% yield) and 9B (9.1 mg, 38% yield) as white solids.

[0793] 9A: LC-MS (ESI, Method 4) t R = 2.26 min, m / z (M+H) + = 480.2. HPLC (Method 6) t R = 6.42 min.

[0794] 9B: LC-MS (ESI, Method 4) t R = 2.27 min, m / z (M+H) + = 480.3. HPLC (Method 6) t R = 11.56 min.

[0795] Example 10

[0796]

[0797] Step 1. 5-Bromo-4-methoxy-pyrazolo[1,5-a]pyridine (10a)

[0798] A well-stirred solution of 9a (285 mg, 1.00 mmol) in 5 mL of 50% H₂SO₄ was heated at 110 °C for 3 h. A yellow solution was formed. The solution was cooled to room temperature. The solution was neutralized with an aqueous solution of NaOH (1.0 M) using litmus paper as an indicator. 40 mL of water was added to the above solution. The solution was extracted with EtOAc (30 mL x 3). The organic layers were combined. The organic layers were dried over anhydrous Na₂SO₄. The organic layers were filtered through a diatomaceous earth mat. The solvent was evaporated under vacuum to give 10a (220 mg, 97% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.15 (dd, J = 7.2 Hz, 1.2 Hz, 1H), 7.91 (d,J = 2.4 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.63 (dd, J = 2.4 Hz, 0.8 Hz, 1H), 4.05 (s, 3H). LC-MS (ESI, Method 4) t R = 2.54 min, m / z ( 79 Br, M+H) + = 227.0.

[0799] Step 2. 5-Bromo-4-methoxy-3-nitro-pyrazolo[1,5-a]pyridine (10b)

[0800] A mixture of 10a (100 mg, 0.44 mmol) and KNO3 (40 mg, 0.40 mmol) in TFA (3 mL) was stirred at 30 °C for 2 h. A yellow solution was formed. The reaction mixture was diluted with EtOAc (30 mL), quenched with NaHCO3 aqueous solution (50 mL), separated, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 mL x 3) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE was 5-30%) to give 10b (100 mg, 83% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.53 min, m / z ( 79 Br, M+H) + = 272.0.

[0801] Step 3. 4-Methoxy-3-nitro-5-(trifluoromethyl)pyrazolo[1,5-a]pyridine (10c)

[0802] A mixture of 10b (80 mg, 0.29 mmol), CuI (67 mg, 0.35 mmol), and MDFA (85 mg, 0.44 mmol) in DMF (1 mL) was stirred at 100 °C for 12 h. A yellow suspension was formed. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 mL x 3) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE was 5-30%) to give 10c (60 mg, 78% yield) as a yellow solid.1 ¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 8.47 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 4.01 (s, 3H). LC-MS (ESI, Method 4) t R =2.75 min, m / z (M+H) + = 262.1.

[0803] Step 4. 4-Methoxy-5-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-amine (10d)

[0804] Pd / C (6 mg, 10% wt%, 10% Pd (dry basis), wetted with 55% H2O) was added to a solution of 10c (60 mg, 0.23 mmol) in MeOH (5 mL). The apparatus was degassed and purged three times with hydrogen. The resulting mixture was stirred at 40 °C under H2 atmosphere for 24 h. A black suspension was formed. The reaction mixture was filtered and concentrated to give 10d (27 mg, 51% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 1.92 min, m / z (M+H) + = 232.1.

[0805] Step 5. 6-(cyclopropaneformamido)-4-((4-methoxy-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (10)

[0806] A mixture of 10d (27 mg, 0.12 mmol), Int. A (29 mg, 0.12 mmol), and TsOH (24 mg, 0.14 mmol) in dioxane (1 mL) was stirred at 100 °C for 2 h. A yellow solution was formed. The reaction mixture was filtered and purified by rapid chromatography (MeOH in DCM: 0–10%) and further ground with MeCN to give 10 (9.7 mg, 18% yield) as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 10.48 (s, 1H), 8.63-8.59 (m, 2H), 8.52 (s, 1H), 8.25 (s, 1H), 7.73 (s, 1H), 7.01 (d, J = 7.6Hz, 1H), 3.81 (s, 3H), 1.98-1.90 (m, 1H), 0.76-0.71 (m, 4H). LC-MS (ESI, Method 4)t R = 2.15 min, m / z (M+H) + = 452.3.

[0807] Example 11

[0808]

[0809] Step 1. 6-((1S,2S)-2-fluorocyclopropane-1-carbamate)-4-((4-methoxy-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (11)

[0810] A mixture of 10d (16 mg, 0.068 mmol), Int. B (15 mg, 0.055 mmol), and TsOH (14 mg, 0.082 mmol) in dioxane (1 mL) was stirred at 100 °C for 6 h. A yellow suspension was formed. The reaction mixture was diluted with an aqueous solution of NaHCO3 (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (60 mL x 2) and brine (60 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (MeOH in DCM 0-10%) and ground in MeCN to give 11 (17.4 mg, 66% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 10.74 (s, 1H), 10.46 (s, 1H), 8.59-8.55 (m, 2H), 8.49 (s,1H), 8.23 ​​(s, 1H), 7.69 (s, 1H), 6.97 (d, J = 7.2 Hz, 1H), 4.93-4.72 (m, 1H), 3.78 (s, 3H), 2.14-2.06 (m, 1H), 1.56-1.43 (m, 1H), 1.11-1.02 (m, 1H). LC-MS(ESI, method 4) tR = 2.22 min, m / z (M+H) + = 470.2.

[0811] Example 12

[0812]

[0813] Step 1. 1-Amino-4-cyano-3-methoxypyridine-1-onium 2,4-dinitrophenol (12b)

[0814] A mixture of 12a (500 mg, 3.73 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (816 mg, 4.10 mmol) in MeCN (10 mL) was stirred at 50 °C for 16 h. A yellow solution was formed. The reaction was concentrated to give 12b (559 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 0.64 min, m / z M + = 150.1.

[0815] Step 2. Methyl 5-cyano-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (12c)

[0816] A mixture of methyl propargylate (626 mg, 7.45 mmol, 0.66 mL), 12b (559 mg, 3.72 mmol), and K₂CO₃ (1.03 g, 7.45 mmol) in DMF (10 mL) was stirred at 20 °C for 2 h. A black suspension was formed. The reaction mixture was concentrated under vacuum and diluted with water (50 mL), then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE: 10-30%) to give 12c (400 mg, 46% yield) as a yellow solid. 1 ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 8.32 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 4.29 (s, 3H), 3.92 (s, 3H). LC-MS (ESI, Method 4) t R = 2.18 min, m / z (M+H) + =232.1.

[0817] Step 3. 4-Methoxypyrazolo[1,5-a]pyridine-5-nitrile (12d)

[0818] A well-stirred solution of 12c (50 mg, 0.216 mmol) in 1 mL of 50% H₂SO₄ was heated at 100 °C for 1 h. A brown solution was formed. The solution was cooled to room temperature. The solution was neutralized with 1.0 M NaOH aqueous solution using litmus paper as an indicator. 40 mL of water was added to the above solution. The solution was extracted with EtOAc (30 mL x 3). The organic layers were combined. The organic layers were dried over anhydrous Na₂SO₄. The organic layers were filtered through a diatomaceous earth mat. The organic layers were evaporated under vacuum to give 12d (20 mg, 53% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 7.2 Hz, 0.8 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 2.4 Hz, 0.8 Hz, 1H), 6.72 (d, J = 7.2 Hz, 1H), 4.40 (s, 3H). LC-MS (ESI, Method 4) t R = 2.07 min, m / z (M+H) + = 174.2.

[0819] Step 4. 4-Methoxy-3-nitro-pyrazolo[1,5-a]pyridine-5-nitrile (12e)

[0820] At 20 °C, a mixture of 12d (20 mg, 0.115 mmol) in TFA (1 mL) was added to KNO3 (11 mg, 0.11 mmol). The resulting mixture was stirred at 30 °C for 2 h. A yellow solution was formed. The reaction mixture was quenched with an aqueous solution of NaHCO3 (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE was 10-30%) to give 12e as a yellow solid (20 mg, 79% yield). LC-MS (ESI, Method 4) R = 2.19 min, m / z (M+H) + = 219.1.

[0821] Step 5. 3-Amino-4-methoxy-pyrazolo[1,5-a]pyridine-5-nitrile (12f)

[0822] A mixture of 12e (20 mg, 0.092 mmol) and Pd / C (5 mg, 10% Pd (dry basis), moistened with 55% H2O) in MeOH (3 mL) was degassed and purged three times with hydrogen. The resulting mixture was stirred at 40 °C under H2 atmosphere for 12 h. A black suspension was formed. The reaction mixture was filtered and concentrated to give 12f (12 mg, 70% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 0.62 min, m / z (M+H) + = 189.1. 1 H NMR (400 MHz, CDCl3) δ7.83 (d, J = 7.2 Hz, 1H), 7.50 (s, 1H), 6.40 (d, J = 7.2 Hz, 1H), 4.41 (s,3H).

[0823] Step 6. 4-((5-cyano-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-6-(cyclopropaneformamido)-N-(methyl-d3)nicotinamide (12)

[0824] A mixture of 12f (12 mg, 0.064 mmol), Int. A (13 mg, 0.051 mmol), and TsOH (13 mg, 0.076 mmol) in dioxane (2 mL) was stirred at 100 °C for 6 h. A yellow suspension was formed. The reaction mixture was diluted with an aqueous solution of NaHCO3 (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (60 mL x 2) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (MeOH in DCM 0-10%) and ground in MeOH to give 12 as a yellow solid (9.0 mg, 34% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 10.81 (s, 1H), 8.58 (s, 1H), 8.52 (s, 1H), 8.41 (d,J = 7.2 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 6.94 (d, J = 7.2 Hz, 1H), 4.25(s, 3H), 2.01-1.94 (m, 1H), 0.80-0.77 (m, 4H). LC-MS (ESI, Method 4) t R = 1.87min, m / z (M+H)+ = 409.3.

[0825] Example 13

[0826]

[0827] Step 1. 4-((5-cyano-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-6-((1S,2S)-2-fluorocyclopropane-1-carbamate)-N-(methyl-d3)nicotinamide (13)

[0828] A mixture of 12f (18 mg, 0.096 mmol), Int. B (21 mg, 0.076 mmol), and TsOH (20 mg, 0.115 mmol) in dioxane (2 mL) was stirred at 100 °C for 6 h. A yellow suspension was formed. The reaction mixture was diluted with an aqueous solution of NaHCO3 (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (60 mL x 2) and brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (MeOH in DCM 0-10%) and ground in MeCN to give 13 (23.4 mg, 72% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 10.90 (s, 1H), 10.85 (s, 1H), 8.60 (s, 1H), 8.53 (s, 1H), 8.42 (d, J = 7.2 Hz, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 6.95 (d, J = 7.2 Hz,1H), 5.00-4.79 (m, 1H), 4.25 (s, 3H), 2.22-2.14 (m, 1H), 1.66-1.55 (m, 1H), 1.18-1.09 (m, 1H). LC-MS (ESI, Method 4) t R = 1.85 min, m / z (M+H) + = 427.2.

[0829] Example 14

[0830]

[0831] Step 1. 6-(cyclopropaneformamido)-4-((4-methoxy-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-5-yl)amino)-N-methylnicotinamide (14)

[0832] A solution of 7e (150 mg, 0.46 mmol), Int. C (116 mg, 0.46 mmol), and TsOH.H2O (38 mg, 0.20 mmol) in dioxane (3 mL) was stirred at 100 °C for 16 h. After cooling to rt, the mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 14 (136 mg, 62% yield) as a white solid. LC-MS (ESI, Method 3) t R = 1.08 min, m / z (M+H) + = 479.2.

[0833] Step 2. (S)-6-(cyclopropanecarbamate)-4-((4-methoxy-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-5-yl)amino)-N-methylnicotinamide (14A) and (R)-6-(cyclopropanecarbamate)-4-((4-methoxy-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-5-yl)amino)-N-methylnicotinamide (14B)

[0834] Compound 14 (136 mg, 0.28 mmol) was separated by chiral preparative HPLC (method F) to give 14A (43 mg, 32% yield) and 14B (39 mg, 29% yield) as white solids.

[0835] 14A: 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.34 (s, 1H), 7.56 (d, J = 4.4 Hz, 1H), 8.51-8.49 (m, 2H), 8.11 (s, 1H), 7.68 (s, 1H), 7.02 (d, J = 5.6 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 5.41-5.37 (m, 1H), 3.72 (s, 3H), 2.80 (d, J = 4.4 Hz, 3H), 1.94-1.92 (m, 1H), 0.73-0.71 (m, 4H). LC-MS (ESI, method 2) t R = 2.39 min, m / z (M+H) + = 479.2. HPLC (Method 5) t R = 8.98 min.

[0836] 14B: 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.35 (s, 1H), 7.56 (d, J = 4.4 Hz, 1H), 8.51-8.49 (m, 2H), 8.11 (s, 1H), 7.68 (s, 1H), 7.03 (d,J = 5.6 Hz, 1H), 6.90 (d, J = 7.2 Hz, 1H), 5.41-5.38 (m, 1H), 3.72 (s, 3H),2.80 (d, J = 4.4 Hz, 3H), 1.95-1.92 (m, 1H), 0.74-0.72 (m, 4H). LC-MS (ESI, method 2) t R = 2.39 min, m / z (M+H) + = 479.2. HPLC (Method 5) t R = 10.89 min.

[0837] Example 15

[0838]

[0839] Step 1. 6-((1S,2S)-2-fluorocyclopropane-1-carbamate)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (15)

[0840] A mixture of 7e (252 mg, 0.77 mmol), Int. B (210 mg, 0.77 mmol), and TsOH.H2O (58 mg, 0.31 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 12 h. After cooling to rt, the mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to give 15 (170 mg, 45% yield) as a white solid. LC-MS (ESI, Method 3) t R = 1.06 min, m / z (M+H) + = 500.2.

[0841] Step 2. 6-((1S,2S)-2-fluorocyclopropane-1-carboxamido)-4-((4-methoxy-5-((S*)-2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (15A) and 6-((1S,2S)-2-fluorocyclopropane-1-carboxamido)-4-((4-methoxy-5-((R*)-2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (15B)

[0842] Compound 15 (170 mg, 0.34 mmol) was separated by chiral preparative HPLC (method F) to give 15A (66 mg, 17% yield) and 15B (73 mg, 19% yield) as white solids.

[0843] 15A: 1 H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 10.37 (s, 1H), 8.55(s, 1H), 8.52-8.50 (m, 2H), 8.13 (s, 1H), 7.68 (s, 1H), 7.04 (d, J = 5.6 Hz,1H), 6.91 (d, J = 7.2 Hz, 1H), 5.42-5.38 (m, 1H), 4.96-4.75 (m, 1H), 3.73 (s,3H), 2.16-2.12 (m, 1H), 1.58-1.51 (m, 1H), 1.12-1.06 (m, 1H). LC-MS (ESI, Method 2) t R = 2.36 min, m / z (M+H) + = 500.2. HPLC (Method 5) t R = 9.59 min.

[0844] 15B: 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 10.38 (s, 1H), 8.55(s, 1H), 8.52-8.50 (m, 2H), 8.12 (s, 1H), 7.69 (s, 1H), 7.01 (d, J = 5.6 Hz,1H), 6.90 (d, J = 7.2 Hz, 1H), 5.42-5.38 (m, 1H), 4.96-4.76 (m, 1H), 3.72 (s,3H), 2.17-2.10 (m, 1H), 1.57-1.49 (m, 1H), 1.13-1.05 (m, 1H). LC-MS (ESI, Method 2) t R = 2.34 min, m / z (M+H) + = 500.2. HPLC (Method 5) t R = 11.56 min.

[0845] Example 16

[0846]

[0847] Step 1. 4-Methoxy-5-(methoxymethyl)pyrazolo[1,5-a]pyridine (16a)

[0848] At 0 °C, a solution of 7a (200 mg, 1.12 mmol) in THF (2 mL) was added with NaH (67 mg, 1.68 mmol, 60% purity in mineral oil), and the mixture was stirred at 0 °C for 30 min. Iodimethane (191 mg, 1.35 mmol) was added to the mixture and stirred at rt for 5 h. The mixture was diluted with H₂O (30 mL), extracted with EtOAc (15 mL x 3), washed with brine (20 mL), dried over Na₂SO₄, and concentrated to give compound 16a (181 mg, 84% yield) as a yellow oil. LC-MS (ESI, Method 4) t R = 2.08 min, m / z (M+H) + = 193.1.

[0849] Step 2. 4-Methoxy-5-(methoxymethyl)-3-nitropyrazolo[1,5-a]pyridine (16b)

[0850] At 0 °C, KNO3 (95 mg, 0.94 mmol) was added to a solution of 16a (180 mg, 0.94 mmol) in TFA (2 mL), and the mixture was stirred at rt for 4 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with aqueous Na2CO3 solution and brine, dried over Na2SO4, and concentrated to obtain compound 16b (150 mg, 67% yield) as a yellow oil. LC-MS (ESI, Method 4) R = 2.16 min, m / z (M+H) + = 238.1.

[0851] Step 3. 4-Methoxy-5-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-amine (16c)

[0852] Fe powder (177 mg, 3.16 mmol) and NH4Cl (169 mg, 3.16 mmol) were added to a solution of 16b (150 mg, 0.63 mmol) in EtOH (3 mL) and H2O (1 mL). The mixture was then stirred at 80 °C for 2 h. The mixture was filtered and the filter cake was washed with EtOAc (10 mL). The filtrate was concentrated and diluted with H2O (10 mL), extracted with EtOAc (10 mL x 3), washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by rapid chromatography (DCM / MeOH = 50 / 1 to 5 / 1) to give compound 16c (75 mg, 57% yield) as a yellow oil. LC-MS (ESI, Method 4) R = 0.44 min, m / z(M+H) + = 208.1.

[0853] Step 4. 6-(cyclopropanecarbamate)-4-((4-methoxy-5-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (16)

[0854] A mixture of 16c (20 mg, 0.96 mmol), Int. A (25 mg, 0.096 mmol), and PTSA (17 mg, 0.096 mmol) in dioxane (1 mL) was stirred at 100 °C for 2 h. The mixture was then concentrated and purified by preparative HPLC (Method E) to give compound 16 (11.4 mg, 28% yield) as a pale yellow solid. 1HNMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.16 (d, J= 6.8 Hz, 1H), 8.05 (s, 1H), 7.87 (s, 1H), 6.77 (d, J = 7.2 Hz, 1H), 6.39 (s,1H), 4.51 (s, 2H), 3.80 (s, 3H), 3.39 (s, 3H), 1.52-1.47 (m, 1H), 1.05-1.01(m, 2H), 0.89-82 (m, 2H). LC-MS (ESI, Method 4) t R = 1.72 min, m / z (M+H) + = 428.4.

[0855] Example 17

[0856]

[0857] Step 1. 6-((1S,2S)-2-fluorocyclopropane-1-carbamate)-4-((4-methoxy-5-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (17)

[0858] A mixture of 16c (15 mg, 0.72 mmol), Int. B (16 mg, 0.058 mmol), and PTSA (12 mg, 0.072 mmol) in dioxane (1 mL) was stirred at 100 °C for 2 h. The mixture was then concentrated and purified by preparative HPLC (Method E) to give compound 17 (10.7 mg, 33% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 10.33 (s, 1H), 8.51 (s, 1H), 8.46 (s, 1H), 8.39 (d,J = 6.8 Hz, 1H), 8.03 (s, 1H), 7.64 (s, 1H), 6.79 (d, J = 7.2 Hz, 1H), 4.92-4.72 (m, 1H), 4.41 (s, 2H), 3.67 (s, 3H), 3.26 (s, 3H), 2.11-2.08 (m, 1H),1.55-1.45 (m, 1H), 1.08-1.03 (m, 1H). LC-MS (ESI, Method 4) tR = 1.68 min, m / z (M+H) + = 446.3.

[0859] Example 18

[0860]

[0861] Step 1. 2-(4-methoxypyrazolo[1,5-a]pyridin-5-yl)acetonitrile (18a)

[0862] At -60 °C, a suspension of t-BuOK (127 mg, 1.14 mmol) in THF (2 mL) was added to a solution of TosMIC (111 mg, 0.57 mmol) in THF (2 mL), and the mixture was stirred at -60 °C for 15 min. A solution of 7b (50 mg, 0.28 mmol) in THF (1 mL) was added dropwise to the mixture at -60 °C, and the mixture was stirred at -60 °C for another 1.5 h. MeOH (5 mL) was added to the mixture, and the mixture was stirred at 70 °C for 20 min. The mixture was then concentrated and diluted with H₂O (20 mL), extracted with EtOAc (10 mL x 3), washed with brine (15 mL), dried over Na₂SO₄, concentrated, and purified by rapid chromatography (PE / EA = 10 / 1 to 1 / 2) to give compound 18a (10 mg, 19% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 1.82 min, m / z (M+H) + = 188.1.

[0863] Step 2. 2-(4-methoxy-3-nitropyrazolo[1,5-a]pyridin-5-yl)acetonitrile (18b)

[0864] At 0 °C, KNO3 (5 mg, 0.053 mmol) was added to a solution of 18a (10 mg, 0.053 mmol) in TFA (1 mL), and the mixture was stirred at rt for 4 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with aqueous Na2CO3 solution and brine, dried over Na2SO4, and concentrated to obtain compound 18b (10 mg, 81% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 1.94 min, m / z (M+H) + = 233.1.

[0865] Step 3. 2-(3-amino-4-methoxypyrazolo[1,5-a]pyridin-5-yl)acetonitrile (18c)

[0866] Fe powder (12 mg, 0.22 mmol) and NH4Cl (12 mg, 0.22 mmol) were added to a solution of 18b (10 mg, 0.043 mmol) in EtOH (1 mL) and H2O (0.2 mL). The mixture was then stirred at 80 °C for 2 h. The mixture was filtered and the filter cake was washed with EtOAc (10 mL). The filtrate was concentrated and diluted with H2O (10 mL), extracted with EtOAc (10 mL x 3), washed with brine (10 mL), dried over Na2SO4, and concentrated to obtain compound 18c (5 mg, 57% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 0.45 min, m / z (M+H) + = 203.2.

[0867] Step 4. 4-((5-(cyanomethyl)-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-6-(cyclopropanecarbamoyl)-N-(methyl-d3)nicotinamide (18)

[0868] A solution of 18c (5 mg, 0.025 mmol), Int. A (6 mg, 0.025 mmol), and PTSA (4 mg, 0.025 mmol) in dioxane (0.5 mL) was stirred at 100 °C for 2 h. The mixture was then concentrated and purified by preparative HPLC (Method E) to give compound 18 (2 mg, 19% yield) as a pale yellow solid. 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.64 (s, 1H), 10.31 (s, 1H), 8.51 (s, 1H), 8.48–8.46 (m, 2H), 8.06 (s, 1H), 7.62 (s, 1H), 6.83 (d, J = 7.2 Hz, 1H), 3.98 (s, 2H), 3.70 (s, 3H), 1.93–1.87 (m, 1H), 0.70–0.68 (m, 4H). LC-MS (ESI, Method 4): t R = 1.48 min, m / z (M+H) + = 423.3.

[0869] Example 19

[0870]

[0871] Step 1. (S)-2,2,2-trifluoro-1-(4-methoxy-3-nitropyrazolo[1,5-a]pyridin-5-yl)ethanol (7d-A)

[0872] 7d (5.9 g, 20 mmol) was separated into 7d-A (2.6 g, 44% yield) as a green solid by chiral preparative HPLC (method G).

[0873] 1 ¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 8.42 (d, J = 6.8 Hz, 1H), 7.33 (d, J = 6.8 Hz, 1H), 5.70–7.67 (m, 1H), 3.92 (s, 3H). HPLC (Method 8) t R = 6.06min.

[0874] Step 2. (S)-1-(3-amino-4-methoxypyrazolo[1,5-a]pyridin-5-yl)-2,2,2-trifluoroethane-1-ol hydrochloride (7e-A)

[0875] SnCl₂·2H₂O (1.7 g, 7.56 mmol) was added to a mixture of 7d-A (1.1 g, 3.78 mmol) and concentrated HCl (15 mL) at 0 °C. After stirring at 10 °C for 1 h, the reaction mixture was filtered. The filter cake was dried under vacuum to give 7e-A (1 g, 89% yield) as a yellow solid. LC-MS (ESI, Method 3) R = 0.81 min, m / z (M+H) + =262.0.

[0876] Step 3. (S)-6-chloro-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (19a)

[0877] A mixture of 7e-A (55 mg, 0.21 mmol), 4,6-dichloro-N-(methyl-d3)nicotinamide (48 mg, 0.23 mmol), and TsOH·H2O (16 mg, 0.084 mmol) in 1,4-dioxane (0.3 mL) was stirred at 100 °C for 18 h. After cooling to rt, the mixture was concentrated. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 19 / 1) to give 19a (50 mg, 55% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.16 min, m / z (M+H) + =433.0.

[0878] Step 4. (S)-6-(1-fluorocyclopropane-1-carbamate)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (19)

[0879] A mixture of 19a (50.0 mg, 0.12 mmol), 1-fluorocyclopropane-1-carboxamide (60.0 mg, 0.58 mmol), Cs₂CO₃ (113 mg, 0.35 mmol), and Brettphos Pd G₃ (21 mg, 0.023 mmol) in 1,4-dioxane (0.5 mL) was incubated at 90 °C under a N₂ atmosphere for 12 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to give 19a (5.2 mg, 9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s,1H), 9.97 (s, 1H), 8.63 (s, 1H), 8.61-8.51 (m, 2H), 8.15 (s, 1H), 7.61 (s,1H), 7.03 (d, J = 4.4 Hz, 1H), 6.91 (d, J = 6.4 Hz, 1H), 5.43-5.38 (m, 1H), 3.73 (s, 3H), 1.47-1.35 (m, 4H). LC-MS (ESI, method 2) t R = 2.48 min, m / z (M+H) + =500.1.

[0880] Example 20

[0881]

[0882] Step 1. Methyl 4-methoxy-5-(2-oxopropyl)pyrazolo[1,5-a]pyridine-3-carboxylate (20a)

[0883] A mixture of 9a (500 mg, 1.7 mmol), propen-1-en-2-yl acetate (263 mg, 2.6 mmol), tri-o-tolylphosphine (32 mg, 0.105 mmol), and tributylmethoxystannane (844 mg, 2.6 mmol) in toluene (5 mL) was stirred at 100 °C for 15 min. PdCl₂ (9 mg, 0.052 mmol) was added to the mixture, and the mixture was stirred at 100 °C for 3 h. The mixture was concentrated. The residue was purified by silica gel rapid chromatography (PE / EA = 3 / 1) to give compound 20a (130 mg, 28% yield) as a yellow solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 8.60 (d, J = 7.2 Hz, 1H), 8.42 (s, 1H), 6.96 (d, J = 7.2 Hz, 1H), 3.96 (s, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 2.24 (s, 3H). LC-MS (ESI, Method 3) t R = 1.36 min, m / z (M+H) + =263.1.

[0884] Step 2. 1-(4-methoxypyrazolo[1,5-a]pyridin-5-yl)prop-2-one (20b)

[0885] The mixture of 20a (270 mg, 1 mmol) in 50% H₂SO₄ (3 mL) was stirred at 85 °C for 4 h. After cooling, the reaction mixture was diluted with ice water (5 mL) and alkalized to pH 3 with 1 N NaOH. The mixture was extracted with EtOAc (5 mL * 3). The organic layer was washed with brine (5 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated. The residue was purified by silica gel rapid chromatography (PE / EA = 3 / 1) to give 20b (200 mg, 95% yield) as a yellow oil. LC-MS (ESI, Method 3) R =1.29 min, m / z (M+H) + =205.2.

[0886] Step 3. 1-(4-methoxy-3-nitropyrazolo[1,5-a]pyridin-5-yl)prop-2-one (20c)

[0887] At 0 °C, KNO3 (99 mg, 0.98 mmol) was added to a solution of 20b (200 mg, 0.98 mmol) in TFA (2 mL). The mixture was stirred at 30 °C for 2 h. The solvent was removed by pumping through N2. The residue was dissolved in EtOAc (15 mL) and alkalized to pH 9 with saturated Na2CO3. The mixture was extracted with EtOAc (20 mL x 2). The combined organic phases were concentrated and the residue was purified by silica gel rapid chromatography (PE / EA = 3 / 1) to give 20c (153 mg, 62% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.34 min, m / z (M+H) + =250.1.

[0888] Step 4. 5-(2,2-difluoropropyl)-4-methoxy-3-nitropyrazolo[1,5-a]pyridine (20d)

[0889] DAST (355 mg, 2 mmol) was added to a solution of 20d (110 mg, 0.44 mmol) in DCM (2 mL) at 0 °C. The mixture was then stirred at 25 °C for 10 h. The mixture was diluted with DCM (5 mL) and washed with saturated NaHCO3 (5 mL). The organic layer was concentrated and the residue was purified by silica gel rapid chromatography (PE / EA = 3 / 1) to give 20d (84 mg, 70% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.55 min, m / z (M+H) + =272.2.

[0890] Step 5. 5-(2,2-difluoropropyl)-4-methoxypyrazolo[1,5-a]pyridine-3-amine (20e)

[0891] At 0 °C, tetrahydroxydiboron (73 mg, 0.82 mmol) was added to a solution of 20d (74 mg, 0.27 mmol) and 4,4'-bipyridine (2 mg, 0.013 mmol) in DMF (1 mL). After stirring at 10 °C for 10 min, the mixture was concentrated and the residue was purified by preparative HPLC (Method A) to give 20e (50 mg, 75% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.42 min, m / z (M+H) + =242.2.

[0892] Step 6. 6-(cyclopropaneformamido)-4-((5-(2,2-difluoropropyl)-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (20)

[0893] A mixture of 20e (40 mg, 0.16 mmol), Int. A (46 mg, 0.18 mmol), and TsOH.H2O (15 mg, 0.08 mmol) in 1,4-dioxane (1 mL) was stirred at 90 °C for 7 h. The mixture was concentrated and the residue was purified by preparative HPLC (Method A) to give 20e as a white solid (63 mg, 82% yield). 1 H NMR (400 MHz, DMSO-d6) δ10.67 (s, 1H), 10.31 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.43 (d, J = 7.2Hz, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 6.76 (d, J = 7.2 Hz, 1H), 3.66 (s, 3H), 3.26 (t, J = 16.4 Hz, 2H), 1.94-1.91 (m, 1H), 1.61 (t, J = 18.8 Hz, 3H), 0.73-0.70 (m, 4H). LC-MS (ESI, method 2) t R = 2.94 min, m / z (M+H) + = 462.1.

[0894] Example 21

[0895]

[0896] Step 1. (S)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)-6-((1-methyl-1H-pyrazol-3-yl)amino)nicotinamide (21)

[0897] A mixture of 19a (44 mg, 0.10 mmol), 1-methyl-1H-pyrazole-3-amine (49 mg, 0.51 mmol), Cs₂CO₃ (66 mg, 0.20 mmol), and Brettphos Pd G₃ (18 mg, 0.02 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90 °C under a N₂ atmosphere for 12 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to give 21 (23 mg, 47% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s,1H), 9.14 (s, 1H), 8.51 (d, J = 7.2 Hz, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.22(s, 1H), 7.45 (s, 1H), 7.03-7.01 (m, 2H), 6.89 (d, J = 6.8 Hz, 1H), 6.08 (s,1H), 5.44-5.39 (m, 1H), 3.77 (s, 3H), 3.63 (s, 3H). LC-MS (ESI, method 2) t R = 0.94min, m / z (M+H) + = 494.1.

[0898] Example 22

[0899]

[0900] Step 1. 6-(cyclopropanecarbamate)-4-((5-(hydroxymethyl)-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (22)

[0901] At 0 °C, LiAlH4 (51 mg, 1.50 mmol) was slowly added to a solution of 6 (110 mg, 0.25 mmol) in THF (5 mL), and the mixture was stirred at 0 °C for 2 h. The mixture was then quenched sequentially at 0 °C with H2O (0.05 mL), 15% NaOH aqueous solution (0.05 mL), and H2O (0.1 mL). The mixture was then stirred at rt for 15 min, dried over Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel rapid chromatography (DCM / MeOH = 8 / 1) to give 22 (70 mg, 68% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 11.31 (s, 1H), 8.50 (s,1H), 8.48 (s, 1H), 8.42 (d, J = 7.2 Hz, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 6.91(d, J = 7.2 Hz, 1H), 5.29-5.26 (m, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.69 (s,3H), 1.97-1.91 (m, 1H), 0.73-0.72 (m, 4H). LC-MS (ESI, method 2) t R = 2.73 min, m / z(M+H) + = 414.0.

[0902] Example 23

[0903]

[0904] Step 1. 1-(4-methoxypyrazolo[1,5-a]pyridin-5-yl)ethanol-1-ol (23a)

[0905] At 0 °C, methyl magnesium bromide (2.89 mL, 8.67 mmol, 3 M in Et₂O) was added dropwise to a stirred solution of 7b (755 mg, 4.29 mmol) in anhydrous DCM (10 mL). The reaction mixture was then stirred at 0 °C for 0.5 h. It was then quenched with saturated NH₄Cl (5 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with water (15 mL) and brine (10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum, and the residue was purified by rapid chromatography (MeOH / DCM = 3 / 100) to give compound 23a (787 mg, 96% yield) as a pale yellow oil. LC-MS (ESI, Method 4) R = 1.49 min, m / z (M+H) + = 193.1.

[0906] Step 2. 1-(4-methoxy-3-nitropyrazolo[1,5-a]pyridin-5-yl)ethanol-1-ol (23b)

[0907] At 0 °C, KNO3 (385 mg, 3.77 mmol) was added to a stirred solution of 23a (740 mg, 3.85 mmol) in TFA (7 mL). The solution was then stirred at 25 °C for 0.5 h. The solvent was evaporated under reduced pressure to give a residue, which was purified by rapid chromatography (PE / EA = 2 / 1) to give compound 23b (830 mg, 91% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 1.75 min, m / z (M+H) + = 238.0.

[0908] Step 3. 1-(3-amino-4-methoxypyrazolo[1,5-a]pyridin-5-yl) ethanol-1-ol hydrochloride (23c)

[0909] SnCl₂·H₂O (3.28 g, 12.83 mmol) was added to a suspension of 23b (830 mg, 3.50 mmol) in concentrated HCl (10 mL) at 0 °C. The mixture was then stirred at 25 °C for 0.5 h. After filtration, the solid was dried under vacuum to give 23c (802 mg, 94% yield) as a yellow solid. LC-MS (ESI, Method 4) R = 0.34 min, m / z (M+H) + =208.2.

[0910] Step 4. 5-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methoxypyrazolo[1,5-a]pyridine-3-amine (23d)

[0911] A solution of 23c (710 mg, 2.91 mmol), imidazole (992 mg, 14.57 mmol), and DMAP (36 mg, 0.29 mmol) in THF (10 mL) was added with tert-butylchlorodiphenylsilane (1.04 g, 3.79 mmol). The mixture was then stirred at 50 °C for 2 h. The mixture was diluted with H₂O (20 mL), extracted with EtOAc (15 mL x 3), washed with brine (20 mL), dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to give compound 23d (70 mg, 5.4% yield) as a yellow oil. LC-MS (ESI, Method 4) R = 4.10 min, m / z (M+H) + =446.3.

[0912] Step 5. 4-((5-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-6-(cyclopropanecarbamoyl)-N-(methyl-d3)nicotinamide (23e)

[0913] A mixture of 23d (60 mg, 0.13 mmol), Int. A (21 mg, 0.081 mmol), and pTSA (23 mg, 0.13 mmol) in dioxane (1 mL) was stirred at 70 °C for 6 h. The mixture was diluted with H2O (10 mL), extracted with EtOAc (10 mL x 3), washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give compound 23e (20 mg, 22% yield) as a yellow oil. LC-MS (ESI, Method 4) R = 3.87 min, m / z (M+H) + = 666.5.

[0914] Step 6. 6-(cyclopropanecarbamate)-4-((5-(1-hydroxyethyl)-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (23)

[0915] Compound 23e (20 mg, 0.03 mmol) was dissolved in TBAF solution (1 M, 0.5 mL in THF), and the mixture was stirred at rt for 2 h. The mixture was diluted with H2O (10 mL), extracted with EtOAc (10 mL x 3), washed with NH4Cl aqueous solution (10 mL) and brine (10 mL), dried over Na2SO4, concentrated, and purified by rapid chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to give a crude product. The crude product was then purified by preparative HPLC (Method E) to give compound 23 (4.0 mg, 35% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.29 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 8.43 (d, J = 7.2 Hz, 1H), 8.02 (s, 1H), 7.66 (s,1H), 6.93 (d, J = 7.2 Hz, 1H), 5.26 (d, J = 4.4 Hz, 1H), 5.10-5.04 (m, 1H), 3.68 (s, 3H), 1.96-1.90 (m, 1H), 1.31 (d, J = 6.4 Hz, 3H), 0.74-0.71 (m, 4H). LC-MS (ESI, Method 4) t R = 1.00 min, m / z (M+H) + = 428.3.

[0916] Example 24

[0917]

[0918] Step 1. (S)-6-((5-fluoropyridin-2-yl)amino)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (24)

[0919] A mixture of 7e-A (35 mg, 0.12 mmol), Int. F (33 mg, 0.12 mmol), and TsOH.H2O (2 mg, 0.012 mmol) in NMP (0.1 mL) and 1,4-dioxane (0.3 mL) was stirred at 100 °C for 12 h. After cooling to rt, the mixture was concentrated. The residue was purified by preparative HPLC (Method A) to give 24 (14 mg, 23% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.64 (s, 1H), 8.52 (d, J =7.2 Hz, 1H), 8.47-8.44 (m, 2H), 8.20 (s, 1H), 8.00 (s, 1H), 7.82-7.79 (m,1H), 7.62-7.58 (m, 1H), 7.17 (s, 1H), 7.04 (d, J = 5.2 Hz, 1H), 6.91 (d, J =7.2 Hz, 1H), 5.43-5.39 (m, 1H), 3.77 (s, 3H). LC-MS (ESI, method 2) t R = 2.87 min,m / z (M+H) + = 509.0.

[0920] Example 25

[0921]

[0922] Step 1. (S)-6-((2,6-dimethylpyrimidin-4-yl)amino)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (25)

[0923] A mixture of 19a (50 mg, 0.11 mmol) and 2,6-dimethylpyrimidin-4-amine (28 mg, 0.23 mmol) in dioxane (2 mL) was added with BrettPhos Pd G3 (41 mg, 0.05 mmol) and Cs2CO3 (75 mg, 0.23 mmol). The mixture was stirred at 100 °C under a N2 atmosphere for 3 h. The mixture was concentrated and the residue was purified by preparative HPLC (Method A) to give 25 (7.3 mg, 12% yield) as a yellow solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 10.36 (s, 1H), 9.90 (s, 1H), 8.54–8.49 (m, 3H), 8.24 (s, 1H), 7.73 (s, 1H), 7.06–7.02 (m, 2H), 6.90 (d, J = 6.8 Hz, 1H), 5.42–5.39 (m, 1H), 3.76 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H). LC-MS (ESI, Method 2) t R= 0.88 min, m / z (M+H) + = 520.2.

[0924] Example 26

[0925]

[0926] Step 1. (S)-6-(cyclopropaneformamido)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)nicotinic acid methyl ester (26)

[0927] A mixture of 7e-A (30 mg, 0.10 mmol), A2 (23 mg, 0.090 mmol), and TsOH·H2O (7.0 mg, 0.036 mmol) in dioxane (0.5 mL) was stirred at 100 °C for 18 h. The mixture was concentrated and the residue was purified by preparative HPLC (Method A) to give 26 (12.2 mg, 25% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), δ 9.57 (s, 1H), 8.67 (s, 1H), 8.54 (d, J = 6.8 Hz, 1H), 8.15 (s, 1H), 7.66 (s, 1H), 7.04 (d, J = 4.4 Hz, 1H), 6.93 (d, J = 6.8 Hz,1H), 5.46-5.33 (m, 1H), 3.89 (s, 3H), 3.70 (s, 3H), 2.03-1.86 (m, 1H), 0.79-0.65 (m, 4H). LC-MS (ESI, method 2) t R = 2.64 min, m / z (M+H) + = 480.1.

[0928] Example 27

[0929]

[0930] Step 1. (S)-4-methoxy-3-nitro-5-(2,2,2-trifluoro-1-methoxyethyl)pyrazolo[1,5-a]pyridine (27a)

[0931] At 0 °C, NaH (21 mg, 0.52 mmol, 60% in mineral oil) was added to a solution of 7d-A (100 mg, 0.34 mmol) in THF (5 mL). The mixture was stirred for 20 min, and then CH3I (73 mg, 0.52 mmol, 0.032 mL) was slowly added. The mixture was transferred to room temperature and stirred for 4 h. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by rapid chromatography (EA 25% in PE) to give 27a (52 mg, 49% yield) as a yellow solid. 1 ¹H NMR (400 MHz, CDCl₃) δ 8.69 (s, 1H), 8.42 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 5.23 (q, J = 6.4 Hz, 1H), 3.92 (s, 3H), 3.45 (s, 3H). LC-MS (ESI, Method 4) t R = 2.94 min, m / z (M+H) + = 306.1.

[0932] Step 2. (S)-4-methoxy-5-(2,2,2-trifluoro-1-methoxyethyl)pyrazolo[1,5-a]pyridine-3-amine (27b)

[0933] Under a H2 atmosphere, Pd / C (5 mg, 0.05 mmol, 10% on charcoal) was added to a solution of 27a (52 mg, 0.17 mmol) in MeOH (2 mL), and the mixture was stirred at 25 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated to give 27b (45 mg, 96% yield) as a brown solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) R = 1.92 min, m / z (M+H) + = 276.1.

[0934] Step 3. (S)-6-(cyclopropanecarbamate)-4-((4-methoxy-5-(2,2,2-trifluoro-1-methoxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (27)

[0935] TsOH (31 mg, 0.18 mmol) was added to a solution of 27b (45 mg, 0.16 mmol) and Int. A (34 mg, 0.13 mmol) in dioxane (2 mL). The mixture was stirred at 85 °C for 3 h. The mixture was concentrated under vacuum and the residue was purified by preparative HPLC (Method E) to give 27b (18 mg, 22% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.37 (s, 1H), 8.53 (s, 1H), 8.49 (d, J = 7.2 Hz,1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.68 (s, 1H), 6.73 (d, J = 7.2 Hz, 1H), 5.24(q, J = 6.8 Hz, 1H), 3.69 (s, 3H), 3.30 (s, 3H), 1.97-1.82 (m, 1H), 0.73-0.61(m, 4H). LC-MS (ESI, Method 4) t R = 2.29 min, m / z (M+H) + = 496.4.

[0936] Example 28

[0937]

[0938] Step 1. (S)-4-methoxy-3-nitro-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)pyrazolo[1,5-a]pyridine (28a)

[0939] At 0 °C, NaH (21 mg, 0.52 mmol, 60% in mineral oil) was added to a solution of 7d-A (100 mg, 0.34 mmol) in THF (5 mL). The mixture was stirred for 20 min, and then CD3I (75 mg, 0.52 mmol, 0.032 mL) was slowly added. The mixture was transferred to room temperature and stirred for 4 h. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by rapid chromatography (EA 25% in PE) to give 28a (55 mg, 52% yield) as a yellow solid. LC-MS (ESI, Method 4) R = 2.91 min, m / z (M+H) += 309.1.

[0940] Step 2. (S)-4-methoxy-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)pyrazolo[1,5-a]pyridine-3-amine (28b)

[0941] Under a H2 atmosphere, Pd / C (5 mg, 0.05 mmol, 10% on charcoal) was added to a solution of 28a (55 mg, 0.17 mmol) in MeOH (2 mL). The mixture was stirred at 25 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated to give 28b (45 mg, 91% yield) as a brown solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) R = 1.89 min, m / z (M+H) + = 279.1.

[0942] Step 3. (S)-6-(cyclopropanecarbamate)-4-((4-methoxy-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (28)

[0943] TsOH (31 mg, 0.18 mmol) was added to a solution of 28b (45 mg, 0.16 mmol) and Int. A (34 mg, 0.13 mmol) in dioxane (2 mL), and the mixture was stirred at 85 °C for 3 h. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (Method E) to give 28b as a white solid (23 mg, 28% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.37 (s, 1H), 8.53 (s, 1H), 8.49 (d, J = 7.2 Hz,1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.68 (s, 1H), 6.73 (d, J = 7.2 Hz, 1H), 5.24 (q, J = 6.8 Hz, 1H), 3.69 (s, 3H), 1.95-1.85 (m, 1H), 0.74-0.61 (m, 4H). LC-MS(ESI, method 4) t R = 2.27 min, m / z (M+H) + = 499.4.

[0944] Example 29

[0945]

[0946] Step 1. 4-Methoxy-5-((methoxy-d3)methyl)pyrazolo[1,5-a]pyridine (29a)

[0947] At 0 °C, a solution of 7a (80 mg, 0.45 mmol) in THF (1 mL) was added to NaH (23 mg, 0.58 mmol, 60% purity in mineral oil), and the mixture was stirred at 0 °C for 30 min. Iodomethane-d3 (78 mg, 0.54 mmol) was added to the mixture, and the mixture was stirred at rt for 1 h. The mixture was diluted with H2O (30 mL), extracted with EtOAc (15 mL x 3), washed with brine (20 mL), dried over Na2SO4, and concentrated to obtain compound 29a (80 mg, 91% yield) as a yellow oil. LC-MS (ESI, Method 4) t R = 2.05 min, m / z (M+H) + = 196.1.

[0948] Step 2. 4-Methoxy-5-((methoxy-d3)methyl)-3-nitropyrazolo[1,5-a]pyridine (29b)

[0949] At 0 °C, KNO3 (41 mg, 0.41 mmol) was added to a solution of 29a (80 mg, 0.41 mmol) in TFA (1 mL), and the mixture was stirred at rt for 4 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with aqueous Na2CO3 solution and saturated brine, dried over Na2SO4, and concentrated to obtain compound 29b (90 mg, 91% yield) as a yellow oil. LC-MS (ESI, Method 4) R = 2.16 min, m / z (M+H) + = 241.1.

[0950] Step 3. 4-Methoxy-5-((methoxy-d3)methyl)pyrazolo[1,5-a]pyridine-3-amine (29c)

[0951] Fe powder (105 mg, 1.87 mmol) and NH4Cl (100 mg, 1.87 mmol) were added to a solution of 29b (90 mg, 0.37 mmol) in MeOH (2 mL) and H2O (0.5 mL). The mixture was then stirred at 70 °C for 2 h. The mixture was filtered and washed with EtOAc (10 mL). The filtrate was concentrated and diluted with H2O (10 mL), extracted with EtOAc (10 mL x 3), washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by rapid chromatography (DCM / MeOH = 50 / 1 to 5 / 1) to give compound 29c (70 mg, 89% yield) as a yellow oil. LC-MS (ESI, Method 4) R = 0.45 min, m / z (M+H) + = 211.3.

[0952] Step 4. 6-(cyclopropaneformamido)-4-((4-methoxy-5-((methoxy-d3)methyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (29)

[0953] A mixture of 29c (33 mg, 0.16 mmol), Int. A (40 mg, 0.16 mmol), and PTSA (27 mg, 0.16 mmol) in dioxane (1 mL) was stirred at 100 °C for 2 h. The mixture was then concentrated and purified by preparative HPLC (Method E) to give compound 29 (18.4 mg, 27% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6)δ 10.67 (s, 1H), 10.34 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 8.42 (d, J = 7.2Hz, 1H), 8.05 (s, 1H), 7.68 (s, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.44 (s, 2H), 3.70 (s, 3H), 1.96-1.90 (m, 1H), 0.74-0.71 (m, 4H). LC-MS (ESI, Method 4) t R = 1.68min, m / z (M+H) + = 431.4.

[0954] Example 30

[0955]

[0956] Step 1. (S)-1-(3-amino-4-methoxypyrazolo[1,5-a]pyridin-5-yl)-2,2,2-trifluoroethane-1-ol (30a)

[0957] At 0 °C, tetrahydroxydiboron (92 mg, 1.032 mmol) was added to a solution of 7d-A (100 mg, 0.34 mmol) and 4,4'-bipyridine (2 mg, 0.013 mmol) in DMF (1 mL). After stirring at 10 °C for 10 min, the mixture was concentrated and the residue was purified by preparative HPLC (Method A) to give 30a (45 mg, 50% yield) as a green solid. 1 H NMR(400 MHz, DMSO-d6) δ 8.16 (d, J = 7.2 Hz, 1H), 7.49 (s, 1H), 6.83 (d, J = 6.0Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.36-5.29 (m, 1H), 4.31 (s, 2H), 3.87 (3,3H).

[0958] Step 2. (S)-6-chloro-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (30b)

[0959] Concentrated HCl (7 mg, 0.17 mmol) was added to a solution of 30a (45 mg, 0.17 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (47 mg, 0.22 mmol) in EtOH (0.5 mL), and the mixture was stirred at 80 °C for 12 h. The reaction mixture was purified by preparative HPLC (Method A) to give 30b (60 mg, 80% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.14 min, m / z (M+H) + = 434.1.

[0960] Step 3. (S)-6-(cyclopropanecarbamate)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (30)

[0961] A mixture of 30b (60 mg, 0.14 mmol), cyclopropaneformamide (35 mg, 0.41 mmol), BrettPhos (15 mg, 0.03 mmol), and BrettPhos Pd G3 (25.08 mg, 0.03 mmol) in dioxane (0.5 mL) was stirred at 100 °C under N2 for 12 h. The reaction mixture was concentrated to dryness and purified by silica gel rapid chromatography (DCM / MeOH = 10 / 1) to give compound 30 (15 mg, 22% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ11.24 (s, 1H), 10.55 (s, 1H), 9.09 (s, 1H), 8.54 (d, J = 7.2 Hz, 1H), 8.12(s, 1H), 7.79 (s, 1H), 7.04 (d, J = 5.6Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 5.40-5.37 (m, 1H), 3.72 (s, 3H), 2.01-1.99 (m, 1H), 0.79-0.75 (m, 4H). LC-MS(ESI, method 2) t R = 0.98 min, m / z (M+H) + = 483.1.

[0962] Example 31

[0963]

[0964] 6-(cyclopropaneformamido)-4-((4-methoxy-5-(2,2,2-trifluoroacetyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide and 6-(cyclopropaneformamido)-4-((4-methoxy-5-(2,2,2-trifluoro-1,1-dihydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (31)

[0965] 2-Iodobenzoic acid (116 mg, 0.40 mmol) was added to a solution of 7 (50 mg, 0.10 mmol) in EtOAc (0.5 mL). After stirring at 95 °C for 12 h, the reaction mixture was concentrated to dryness and purified by rapid chromatography (DCM / MeOH = 10 / 1) to give a mixture 31 as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 0.2H), 10.79 (s, 0.2H), 10.69 (s, 0.8H), 10.37 (s, 0.8H), 8.62 (s, 0.2H), 8.56 (s, 0.2H), 8.55 (s, 0.8H), 8.54 (d, J = 8.0 Hz, 0.2H), 8.53 (s, 0.8H), 8.42 (d, J = 7.6 Hz, 0.8H), 8.28 (s, 0.2H), 8.10 (s, 0.8H), 7.93 (s, 0.2H),7.75 (s, 0.8H), 7.71 (s, 1.6H), 7.04 (d, J = 7.2 Hz, 0.2H), 6.98 (d, J = 7.6Hz, 0.8H), 3.90 (s, 0.6H), 3.70 (s, 2.4H), 1.97-1.93 (m, 7H), 0.77-0.73 (m,4H). LC-MS (ESI, method 2) t R = 1.99 min, m / z (M+H) + = 480.2, 498.2.

[0966] Example 32

[0967]

[0968] Step 1. 4-((4-methoxy-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)-6-(spiro[2,2]pentane-1-carbamoyl)nicotinamide (32)

[0969] A mixture of 19a (30.0 mg, 0.07 mmol) and spiro[2.2]pentane-1-carboxamide (39.0 mg, 0.35 mmol), Xantphos (8 mg, 0.014 mmol), XPhos Pd G2 (11 mg, 0.014 mmol) and Cs2CO3 (45 mg, 0.14 mmol) in 1,4-dioxane (0.4 mL) was stirred at 100 °C under a N2 atmosphere for 12 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (Method A) to give 32 (7 mg, 20% yield) as a white solid. 1H NMR(400 MHz, DMSO-d6) δ 10.49 (s, 1H), 10.40 (d, J = 6.4 Hz, 1H), 8.56-8.49 (m,3H), 8.14 (s, 1H), 7.74-7.71 (m, 1H), 7.04 (d, J = 5.6 Hz, 1H), 6.90 (d, J =7.2 Hz, 1H), 5.42-5.39 (m, 1H), 3.72 (s, 3H), 2.31-2.28 (m, 1H), 1.35-1.30(m, 1H), 1.26-1.23 (m, 1H), 0.85-0.79 (m, 3H), 0.68–0.67 (m, 1H). LC-MS (ESI, Method 2) t R = 1.11 min, m / z (M+H) + = 508.0.

[0970] Step 2. 4-((4-methoxy-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)-6-((S*)-spiro[2.2]pentane-1-carboxamido)nicotinamide (32A) and 4-((4-methoxy-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)-6-((R*)-spiro[2.2]pentane-1-carboxamido)nicotinamide (32B)

[0971] Compound 32 (23 mg, 0.05 mmol) was separated by chiral preparative HPLC (method H) to obtain 32A (5 mg, 22% yield) and 32B (6.5 mg, 28% yield) as white solids.

[0972] 32A: 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.40 (s, 1H), 8.54-8.49 (m, 3H), 8.14 (s, 1H), 7.74 (s, 1H), 7.04 (d, J = 4.4 Hz, 1H), 6.91 (d,J = 6.8 Hz, 1H), 5.42-5.38 (m, 1H), 3.73 (s, 3H), 2.31-2.28 (m, 1H), 1.30-1.26 (m, 2H), 0.83-0.82 (m, 3H), 0.68-0.65 (m, 1H). LC-MS (ESI, method 2) t R = 1.11min, m / z (M+H) + = 508.0. HPLC (Method 7) t R = 8.14 min.

[0973] 32B: 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.38 (s, 1H), 8.56-8.49 (m, 3H), 8.14 (s, 1H), 7.71 (s, 1H), 7.04 (d, J = 5.2 Hz, 1H), 6.91 (d,J = 7.2 Hz, 1H), 5.42-5.39 (m, 1H), 3.73 (s, 3H), 2.31-2.28 (m, 1H), 1.30-1.25 (m, 2H), 0.84-0.81 (m, 3H), 0.69-0.66 (m, 1H). LC-MS (ESI, method 2) t R = 1.11min, m / z (M+H) + = 508.0. HPLC (Method 7) t R = 10.48 min.

[0974] Example 33

[0975]

[0976] Step 1. (S)-2-chloro-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide (33a)

[0977] At -40 °C, LiHMDS (1.2 mL, 1.2 mmol, 1 M in THF) was added to a solution of 30a (80 mg, 0.31 mmol) and Int. E (77 mg, 0.37 mmol) in THF (0.8 mL). The reaction was stirred at -40 °C to rt for 1 h and quenched with H2O (2 mL). The organic solvent was removed under reduced pressure. The resulting solid was collected by filtration and purified by rapid chromatography (DCM / MeOH = 20 / 1) to give 33a (32 mg, 24% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.18 min, m / z (M+H) + = 434.2.

[0978] Step 2. (S)-2-(cyclopropanecarbamate)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide (33)

[0979] A mixture of 33a (60 mg, 0.07 mmol), cyclopropaneformamide (31 mg, 0.37 mmol), BrettPhos Pd G3 (13 mg, 0.015 mmol), and Cs2CO3 (48 mg, 0.15 mmol) in dioxane (0.4 mL) was stirred at 90 °C under a N2 atmosphere for 12 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to give 33a (8 mg, 22% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 10.96 (s,1H), 9.61 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H), 8.43 (d, J = 7.2 Hz, 1H), 7.04(d, J = 5.6 Hz, 1H), 6.84 (d, J = 7.2 Hz, 1H), 5.47-5.44 (m, 1H), 3.95 (s,3H), 2.14-2.11 (m, 1H), 0.93-0.86 (m, 4H). LC-MS (ESI, method 2) t R = 1.11 min, m / z(M+H) + = 483.0.

[0980] Example 34

[0981]

[0982] Step 1. 6-(cyclopropanecarbamate)-4-((5-(2-hydroxypropyl-2-yl)-4-methylpyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (34)

[0983] At 0 °C and under a N2 atmosphere, CH3MgBr (0.041 mL, 0.12 mmol, 3 M in Et2O) was slowly added to a solution of 6 (5 mg, 0.01 mmol) in THF (1 mL). The mixture was stirred for 10 min, then heated to 50 °C and stirred for 12 h. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried, and concentrated under vacuum. The residue was purified by preparative HPLC (Method A) to give 34 (1.8 mg, 37% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.96 (s, 1H), 8.48(s, 1H), 8.44 (s, 1H), 8.37 (d, J = 7.2 Hz, 1H), 7.87 (s, 1H), 7.24 (s, 1H), 6.99 (d, J= 7.6 Hz, 1H), 5.14 (s, 1H), 2.55 (s, 3H), 1.91-1.82 (m, 1H), 1.47 (s, 6H), 0.69-0.59 (m, 4H). LC-MS (ESI, Method 4) t R = 1.46 min, m / z (M+H) + =426.3.

[0984] Example 35

[0985]

[0986] Step 1. Dimethyl 2-(6-chloro-5-methoxypyrimidin-4-yl)malonate (35b)

[0987] Cs₂CO₃ (36.40 g, 111.73 mmol) and 4,6-dichloro-5-methoxypyrimidine (10 g, 55.86 mmol) were added to a solution of dimethyl malonate (7.38 g, 55.86 mmol, 6.36 mL) in DMF (100 mL), and the mixture was stirred at 100 °C for 2 h. The mixture was concentrated under vacuum, diluted with H₂O (100 mL), adjusted to pH 2 with 2 N HCl, extracted with EtOAc (100 mL * 3), washed with brine (100 mL * 2), dried over Na₂SO₄, and concentrated to give crude compound 35b (15 g, 98% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.23 min, m / z (M+H) + =275.1.

[0988] Step 2. Methyl 2-(5,6-dimethoxypyrimidin-4-yl)acetate (35c)

[0989] A solution of 35b (12 g, 43.69 mmol) in MeOH (50 mL) was added with NaOMe (16.2 mL, 87.38 mmol, 5.4 M in MeOH), and the mixture was stirred at 60 °C for 2 h. The mixture was concentrated and diluted with H₂O (100 mL), the pH was adjusted to 2 with 2 N HCl, extracted with EtOAc (100 mL * 3), washed with brine (100 mL), dried over Na₂SO₄, concentrated, and purified by rapid chromatography (PE / EA = 20 / 1 to 1 / 1) to give compound 35c (9 g, 97% yield) as a white solid. LC-MS (ESI, Method 4) t R = 1.79 min, m / z (M+H) + = 213.1.

[0990] Step 3. Methyl 2-(5,6-dimethoxypyrimidin-4-yl)-3-(dimethylamino)acrylate (35d)

[0991] A solution of 35c (1 g, 4.71 mmol) in DMF-DMA (1 mL) was stirred at 120 °C for 6 h. The mixture was concentrated to obtain compound 35d (1.26 g, crude product), which was a yellow oil. LC-MS (ESI, Method 4) R = 1.23 min,m / z (M+H) + = 268.1.

[0992] Step 4. Methyl 4,5-dimethoxypyrazolo[1,5-c]pyrimidine-3-carboxylate (35e)

[0993] At 0 °C, O-(trisylbenzenesulfonyl)hydroxylamine (2.90 g, 9.43 mmol) was added to a solution of 35d (1.26 g, 4.71 mmol) in DCM (10 mL), and the mixture was stirred at rt for 2 h. The mixture was then concentrated, and the solid was ground with H2O (10 mL), filtered, and the filter cake was washed with DCM (2 mL x 2). The solid was dried under vacuum to give compound 35e (600 mg, 54% yield) as a white solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 9.42 (s, 1H), 8.45 (s, 1H), 3.99 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H). LC-MS (ESI, Method 4) t R = 2.04min, m / z (M+H) + = 238.1.

[0994] Step 5. 4,5-Dimethoxypyrazolo[1,5-c]pyrimidine-3-carboxylic acid (35f)

[0995] A solution of NaOH (4.64 mL, 4.64 mmol, 1 M in H₂O) was slowly added to a suspension of 35e (550 mg, 2.32 mmol) in MeOH (11 mL), and the mixture was stirred at 40 °C for 16 h. The mixture was concentrated and then treated with H₂O (5 mL), and the pH was adjusted to 1 with 2 N HCl. The mixture was then filtered, and the filter cake was washed with Et₂O (2 mL). The solid was dried under vacuum to give compound 35f (90 mg, 17% yield) as a white solid. LC-MS (ESI, Method 4) t R = 1.20 min, m / z (M+H) + = 224.1.

[0996] Step 6. (4,5-Dimethoxypyrazolo[1,5-c]pyrimidin-3-yl)tert-butyl carbamate (35g)

[0997] DPPA (74 mg, 0.27 mmol) and TEA (54 mg, 0.54 mmol) were added to a solution of 35f (30 mg, 0.134 mmol) in toluene (1 mL), and the mixture was stirred at 80 °C for 1 h and cooled to rt. tBuOH (0.5 mL) was added to the mixture. The mixture was stirred at 110 °C for 4 h, concentrated, and purified by rapid chromatography (DCM / MeOH = 50 / 1 to 15 / 1) to give 35 g (25 mg, 63% yield) of the compound as a yellow solid. LC-MS (ESI, Method 4) t R = 2.64min, m / z (M+H) + = 295.2.

[0998] Step 7. 6-(cyclopropaneformamido)-4-((4,5-dimethoxypyrazolo[1,5-c]pyrimidin-3-yl)amino)-N-(methyl-d3)nicotinamide (35)

[0999] A mixture of 35 g (25 mg, 0.085 mmol), Int. A (22 mg, 0.085 mmol), and PTSA (15 mg, 0.085 mmol) in dioxane (1 mL) was stirred at 100 °C for 2 h. The mixture was then concentrated and purified by preparative HPLC (Method E) to give compound 35 (10.7 mg, 30% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 10.13 (s, 1H), 9.22 (s, 1H), 8.48 (s, 1H), 8.44 (s,1H), 8.13 (s, 1H), 7.49 (s, 1H), 3.92 (s, 3H), 3.67 (s, 3H), 1.92-1.86 (m, 1H), 0.70-0.67 (m, 4H). LC-MS (ESI, Method 4) t R = 1.71 min, m / z (M+H) + = 415.3.

[1000] Example 36

[1001]

[1002] Step 1. 4-((4,5-dimethoxypyrazolo[1,5-c]pyrimidin-3-yl)amino)-6-((1S,2S)-2-fluorocyclopropane-1-carbamate)-N-(methyl-d3)nicotinamide (36)

[1003] A mixture of 35 g (18 mg, 0.061 mmol), Int. B (17 mg, 0.061 mmol), and PTSA (11 mg, 0.061 mmol) in dioxane (1 mL) was stirred at 100 °C for 2 h. The mixture was then concentrated and purified by preparative HPLC (Method E) to give compound 36 (6.5 mg, 24% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.79 (s, 1H), 8.25 (s, 1H), 8.23 ​​(s, 1H), 8.04 (s,1H), 7.64 (s, 1H), 6.22 (s, 1H), 4.86-4.65 (m, 1H), 4.02 (s, 3H), 3.84 (s, 3H), 1.85-1.82 (m, 1H), 1.64-1.60 (m, 1H), 1.21-1.13 (m, 1H). LC-MS (ESI, Method 4) t R = 1.65 min, m / z (M+H) + = 433.3.

[1004] Example 37

[1005]

[1006] Step 1. 1-tert-butyl 3-methyl-2-(6-chloro-5-methoxypyrimidin-4-yl)malonic acid (37a)

[1007] At 0 °C, a solution of tert-butyl methylmalonate (13.08 g, 75.08 mmol) in THF (200 mL) was added to a solution of NaH (6.01 g, 150.16 mmol, 60% in mineral oil). The mixture was stirred at 0 °C for 30 min. Then, a solution of 35a (11.2 g, 62.57 mmol) in THF (20 mL) was added to the mixture at 0 °C. The mixture was stirred at 80 °C for 3 h and then poured into ice water (150 mL). The mixture was acidified to pH 2 with 2 N HCl and extracted with EtOAc (300 mL * 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to give 37a (19.8 g, crude product) as a yellow oil. LC-MS (ESI, Method 3) R = 1.26 min, m / z (M+H-56) + = 261.2.

[1008] Step 2. Methyl 2-(6-chloro-5-methoxypyrimidin-4-yl)acetate (37b)

[1009] At 0 °C, TFA (75 mL) was added to a mixture of 37a (18.0 g, 56.83 mmol) and DCM (150 mL). After stirring at rt for 4 h, the reaction mixture was concentrated. The residue was diluted with EtOAc (500 mL) and washed with saturated NaHCO3 (150 mL) and brine (100 mL). The organic layer was concentrated. The residue was purified by silica gel rapid chromatography (PE / EA = 10 / 1) to give 37b (10.5 g, 85% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 3.95 (s, 3H), 3.91 (s, 2H), 3.75 (s, 3H).

[1010] Step 3. Methyl 2-(6-((2,4-dimethoxybenzyl)amino)-5-methoxypyrimidin-4-yl)acetate (37c)

[1011] A mixture of 37b (1.0 g, 4.62 mmol), TEA (934 mg, 9.23 mmol), and DMBNH2 (1.00 g, 6.00 mmol) in EtOH (10 mL) was stirred at 80 °C for 5 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (40 mL x 2). The organic layer was concentrated, and the residue was purified by silica gel rapid chromatography (PE / EA = 1 / 1) to give 37c (1.33 g, 83% yield) as a white solid. LC-MS (ESI, Method 3) t R = 1.07 min, m / z (M+H) + = 348.2.

[1012] Step 4. (Z)-Methyl 2-(6-((2,4-dimethoxybenzyl)amino)-5-methoxypyrimidin-4-yl)-3-(dimethylamino)acrylate (37d)

[1013] The mixture of 37c (1.33 g, 3.83 mmol) in DMF-DMA (10 mL) was stirred at 120 °C for 18 h. The mixture was concentrated to give 37d (1.54 g, crude product) as a brown oil. LC-MS (ESI, Method 3) R = 1.07 min, m / z(M+H) + = 403.3.

[1014] Step 5. Methyl 5-((2,4-dimethoxybenzyl)amino)-4-methoxypyrazolo[1,5-c]pyrimidine-3-carboxylate (37e)

[1015] At 0 °C, a solution of O-(trisylbenzenesulfonyl)hydroxylamine (1.03 g, 4.80 mmol) in DCM (30 mL) was added dropwise to a mixture of 37d (1.61 g, 4.00 mmol) in DCM (5 mL). The mixture was stirred at 0 °C for 2 h. At 0 °C, another batch of a solution of O-(trisylbenzenesulfonyl)hydroxylamine (515 mg, 2.40 mmol) in DCM (5 mL) was added to the mixture. The mixture was stirred at 0 °C for 1 h. The mixture was concentrated and purified by silica gel rapid chromatography (DCM / MeOH = 50 / 1) to give 37e (788 mg, 53% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.84 (s,1H), 8.27 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.41(dd, J = 8.0 Hz, 2.4 Hz, 1H), 5.64 (t, J = 6.0 Hz, 1H), 4.64 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H).

[1016] Step 6. Methyl 5-amino-4-methoxypyrazolo[1,5-c]pyrimidine-3-carboxylate (37f)

[1017] Under rt, TFA (15 mL) was added dropwise to a mixture of 37e (4.26 g, 11.44 mmol) and DCM (15 mL). The reaction mixture was stirred under rt for 1 h and concentrated under vacuum at 30 °C. The residue was dissolved in DCM (80 mL) and the solution was alkalized to pH 12 with 1 M NaOH. The mixture was extracted with DCM (80 mL). The organic layer was concentrated and the residue was purified by silica gel rapid chromatography (DCM / MeOH = 10 / 1) to give 37f (1.94 g, 76% yield) as a yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.27 (s, 1H), 6.68 (brs, 2H), 3.77 (s,3H), 3.71 (s, 3H).

[1018] Step 7. Methyl 5-iodo-4-methoxypyrazolo[1,5-c]pyrimidine-3-carboxylate (37g)

[1019] At 0 °C, tert-butyl nitrite (766 mg, 7.43 mmol, 0.88 mL) was added to a mixture of 37f (1.1 g, 4.95 mmol) and ACN (12 mL). The mixture was stirred at 15 °C for 10 min. CuI (1.41 g, 7.43 mmol) was added to the mixture and stirred at 70 °C for 2 h. After cooling to rt, the reaction was quenched with 40 mL of 25% NH3·H2O aqueous solution and extracted with EtOAc (60 mL*2). The combined organic layers were concentrated and the residue was purified by rapid chromatography (PE / EA=2 / 1) to give 37 g (410 mg, 25% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.24 min, m / z (M+H) + = 333.9.

[1020] Step 8. Methyl 4-methoxy-5-(3,3,3-trifluoroprop-1-en-2-yl)pyrazolo[1,5-c]pyrimidine-3-carboxylate (37h)

[1021] A mixture of 37 g (450 mg, 1.35 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborane (600 mg, 2.70 mmol), Na₂CO₃ (287 mg, 2.70 mmol), and Pd(dppf)Cl₂ (99 mg, 0.14 mmol) in 1,4-dioxane / H₂O (4.5 mL / 1.5 mL) was stirred at 90 °C for 3 h. After cooling to rt, the reaction mixture was diluted with EtOAc (15 mL) and washed with water (7 mL) and brine (7 mL). The organic layer was concentrated to give a yellow oily 37 h (400 mg, crude product), which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 1.25 min, m / z (M+H) + = 302.0.

[1022] Step 9. Methyl 4-methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-c]pyrimidine-3-carboxylate (37i)

[1023] A mixture of 37i (400 mg, 1.33 mmol), Pd(OH)₂ / C (200 mg, 20% Pd on carbon, moistened with water) and Pd / C (200 mg, 10 wt.% moistened with water) in MeOH (4 mL) was stirred at 50 °C under a H₂ (50 psi) atmosphere for 18 h. The reaction mixture was filtered and the filtrate was concentrated to give 37i (400 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 1.27 min, m / z (M+H) + = 304.2.

[1024] Step 10. 4-Methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-c]pyrimidine-3-carboxylic acid (37j)

[1025] A mixture of 37i (400 mg, 1.32 mmol) and NaOH (106 mg, 2.64 mmol) in MeOH (8 mL) and H₂O (4 mL) was stirred at 40 °C for 10 h. The reaction mixture was concentrated and added to water (8 mL). The aqueous solution was acidified to pH 1 with 2 NHCl. The resulting mixture was extracted with EtOAc (20 mL x 2) and the combined organic phases were concentrated. The residue was purified by preparative HPLC (Method A) to give 37j (180 mg, 51% yield) as a white solid. LC-MS (ESI, Method 3) R =0.47 min, m / z (M+H) + = 290.1.

[1026] Step 11. 3-Iodo-4-methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-c]pyrimidine (37k)

[1027] At 0 °C, NIS (215 mg, 0.95 mmol) was added to a mixture of 37k (92 mg, 0.32 mmol) and NaHCO3 (80 mg, 0.95 mmol) in DMF (2 mL). The mixture was stirred at 40 °C for 10 h. After cooling to rt, the reaction mixture was diluted with saturated Na2S2O3 (5 mL) at 0 °C. The mixture was then extracted with EtOAc (8 mL x 2). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated to give 37k (115 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) tR = 1.38min, m / z (M+H) + = 371.9.

[1028] Step 12. N-(4-methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-c]pyrimidin-3-yl)-1,1-benzophenone imine (37l)

[1029] A mixture of 37k (115 mg, 0.31 mmol), benzophenone imine (112 mg, 0.62 mmol, 0.1 mL), Xantphos (18 mg, 0.031 mmol), Pd2(dba)3 (28 mg, 0.031 mmol), and Cs2CO3 (202 mg, 0.62 mmol) in 1,4-dioxane (1 mL) was stirred at 90 °C under N2 for 16 h. After cooling to rt, the mixture was diluted with water (5 mL) and extracted with EtOAc (8 mL x 3). The combined organic layers were concentrated, and the residue was purified by rapid chromatography (PE / EA = 5 / 1) to give 37k (20 mg, 15% yield) as a yellow oil. LC-MS (ESI, Method 3) t R = 1.62min, m / z (M+H) + = 425.2.

[1030] Step 13. 6-(cyclopropaneformamido)-4-((4-methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-c]pyrimidin-3-yl)amino)-N-(methyl-d3)nicotinamide (37)

[1031] A mixture of 37 L (20 mg, 0.047 mmol), Int. A (12 mg, 0.047 mmol), and TsOH·H2O (2 mg, 0.01 mmol) in 1,4-dioxane (0.5 mL) was stirred at 60 °C for 16 h. The mixture was concentrated and the residue was purified by preparative HPLC (Method A) to give 37 L (7.2 mg, 32% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 10.36 (s, 1H), 9.37 (s, 1H), 8.56 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 7.63 (s, 1H), 4.20-4.03 (m, 1H), 3.74 (s, 3H), 2.02-1.87 (m, 1H), 1.45 (d, J = 7.2 Hz, 3H), 0.80-0.66 (m, 4H). LC-MS (ESI, method 2) t R =2.75 min, m / z (M+H) + = 481.2.

[1032] Example 38

[1033]

[1034] Step 1. 6-((1S,2S)-2-fluorocyclopropane-1-carbamate)-4-((4-methoxy-5-(1,1,1-trifluoroprop-2-yl)pyrazolo[1,5-c]pyrimidin-3-yl)amino)-N-(methyl-d3)nicotinamide (38)

[1035] A mixture of 37 L (20 mg, 0.047 mmol), Int. B (13 mg, 0.047 mmol), and TsOH.H2O (3 mg, 0.016 mmol) in 1,4-dioxane (0.5 mL) was stirred at 80 °C for 8 h. After cooling to rt, the mixture was diluted with EtOAc (6 mL) and washed with water (2 mL) and brine (2 mL). The organic layer was concentrated and the residue was purified by preparative HPLC (Method A) to give 38 (10.2 mg, 43% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ10.76 (s, 1H), 10.40-10.38 (m, 1H), 9.38 (s, 1H), 8.59 (s, 1H), 8.53 (s, 1H),8.35 (s, 1H), 7.64-7.63 (m, 1H), 4.94-4.77 (m, 1H), 4.13-4.11 (m, 1H), 3.75-3.74 (m, 3H), 2.14-2.12 (m, 1H), 1.56-1.44 (m, 4H), 1.13-1.10 (m, 1H). LC-MS(ESI, method 2) tR = 2.73 min, m / z (M+H) + = 499.2.

[1036] Example 39

[1037]

[1038] Step 1. Methyl 2-(5-methoxy-6-vinylpyrimidin-4-yl)acetate (39a)

[1039] Pd(dppf)Cl2 (2.0 g, 2.79 mmol), XPhos Pd G3 (472 mg, 0.56 mmol), and Na2CO3 (11.8 g, 111.72 mmol) were added to a mixture of 37b (12.1 g, 55.86 mmol) in dioxane (64 mL) and water (16 mL). The reaction mixture was stirred at 90 °C under a N2 atmosphere for 28 h. After cooling to rt, the mixture was diluted with water (20 mL) and extracted with EtOAc (70 mL x 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (PE / EA = 3 / 1) to give 39a (7 g, 60% yield) as a yellow oil. LC-MS (ESI, Method 3) t R = 1.02 min, m / z (M+H) + = 209.3.

[1040] Step 2. Methyl 3-(dimethylamino)-2-(5-methoxy-6-vinylpyrimidin-4-yl)acrylate (39b)

[1041] The mixture of 39a (7 g, 33.61 mmol) and DMF-DMA (13.4 mL, 100.83 mmol) was stirred at 60 °C for 4 h. The mixture was concentrated to give 39b (8.7 g, crude product) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 0.94 min, m / z (M+H) + = 264.3.

[1042] Step 3. Methyl 4-methoxy-5-vinylpyrazolo[1,5-c]pyrimidine-3-carboxylate (39c)

[1043] At 0 °C, a solution of 2,4,6-trisylbenzenesulfonate amino ester (14.23 g, 66.09 mmol) in DCM (30 mL) was added dropwise to a mixture of 39b (8.7 g, 33.04 mmol) in DCM (30 mL). The reaction was stirred at 0 °C for 1 h. The mixture was alkalized to pH 9 with saturated Na₂CO₃. The aqueous layer was separated and extracted with DCM (200 mL x 3). The combined organic layers were concentrated, and the residue was purified by silica gel rapid chromatography (PE / EA = 1 / 1) to give 39c (2.1 g, 27% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.17 min, m / z (M+H) + = 234.2.

[1044] Step 4. Methyl 5-formyl-4-methoxypyrazolo[1,5-c]pyrimidine-3-carboxylate (39d)

[1045] Add K₂O₅ to a mixture of 39c (2.0 g, 8.58 mmol) in acetone (10 mL). 4. 2H₂O (158 mg, 0.43 mmol). A solution of NaIO₄ (3.67 g, 17.15 mmol) in water (10 mL) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 1 h and then filtered. The filtrate was concentrated and purified by silica gel rapid chromatography (PE / EA = 1 / 1) to give 39d (1.2 g, 59% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 0.94 min, m / z (M+H) + = 236.0.

[1046] Step 5. Methyl 4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-c]pyrimidine-3-carboxylate (39e)

[1047] TMSCF3 (1.60 g, 11.22 mmol) was added dropwise to a mixture of 39d (1.20 g, 5.10 mmol) and THF (10 mL), followed by TBAF (1.0 M, 0.25 mL in THF). After stirring at 0 °C for 10 min, the reaction mixture was diluted with THF (10 mL) and an aqueous HCl solution (10 mL, 1 M). The mixture was stirred at 25 °C for 1 h. The mixture was alkalized to pH 8 with an aqueous NaOH solution (1 M) and extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated to give 39e (1 g, 64% yield) as a brown oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) R = 1.12 min, m / z (M+H) + = 306.0.

[1048] Step 6. 4-Methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-c]pyrimidine-3-carboxylic acid (39f)

[1049] To a mixture of 39e (600 mg, 1.97 mmol) in methanol (4 mL) and water (2 mL), NaOH (157.3 mg, 3.93 mmol) was added, and the mixture was stirred at 45 °C for 8 h. The mixture was adjusted to pH 1 with aqueous HCl (2 M) and extracted with EtOAc (20 mL x 3). The organic layer was concentrated, and the residue was purified by preparative HPLC (Method A) to give 39f (130 mg, 23% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 0.92 min, m / z (M+H) + = 292.0.

[1050] Step 7. 2,2,2-Trifluoro-1-(3-iodo-4-methoxypyrazolo[1,5-c]pyrimidin-5-yl)ethanol (39g)

[1051] NIS (255 mg, 1.13 mmol) was added to a solution of 39 f (110 mg, 0.38 mmol) and NaHCO3 (95 mg, 1.13 mmol) in DMF (1.2 mL) at 0 °C. The mixture was stirred at 15 °C for 18 h. The reaction was quenched with saturated Na2S2O3 (10 mL) in an ice-water bath and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method A) to give 39 g (16 mg, 11% yield) of a yellow solid. LC-MS (ESI, Method 3) t R = 1.19 min, m / z (M+H) + = 373.9.

[1052] Step 8. 1-(3-((diphenylmethylene)amino)-4-methoxypyrazolo[1,5-c]pyrimidin-5-yl)-2,2,2-trifluoroethane-1-ol (39h)

[1053] A mixture of 39 g (17 mg, 0.045 mmol), benzophenone imine (17 mg, 0.091 mmol), Xantphos (3 mg, 0.0046 mmol), Pd2(dba)3 (4 mg, 0.0046 mmol), and Cs2CO3 (30 mg, 0.091 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90 °C under a N2 atmosphere for 8 h. The mixture was diluted with water (3 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were concentrated, and the residue was purified by preparative TLC (PE / EA = 5 / 1) to give a yellow solid of 39 h (8 mg, 41% yield). LC-MS (ESI, Method 3) t R = 1.44 min, m / z (M+H) + = 427.2.

[1054] Step 9. 6-((1S,2S)-2-fluorocyclopropane-1-carbamate)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-c]pyrimidin-3-yl)amino)-N-(methyl-d3)nicotinamide (39)

[1055] A mixture of 39h (16 mg, 0.038 mmol), Int. B (12 mg, 0.045 mmol), and TsOH·H2O (3 mg, 0.015 mmol) in 1,4-dioxane (0.5 mL) was stirred at 80 °C for 8 h. The mixture was filtered and washed with DCM (2 mL). The filter cake was purified by preparative TLC (DCM / MeOH = 10 / 1) to give 39h (5.8 mg, 31% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.43 (s, 1H), 9.38 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.38 (s, 1H), 7.64 (s, 1H), 5.39-5.27 (m, 1H), 4.95-4.74 (m, 1H), 3.78 (s, 3H), 2.20-2.07 (m, 1H), 2.05-1.94 (m, 1H), 1.59-1.41(m, 1H), 1.15-1.03 (m, 1H). LC-MS (ESI, method 2) t R = 2.45 min, m / z (M+H) + =501.0.

[1056] Example 40

[1057]

[1058] Step 1. 6-(cyclopropanecarbamoyl)-N-(methyl-d3)-4-(pyrazolo[1,5-a]pyridin-3-ylamino)nicotinamide (40)

[1059] At rt, 40a (21 mg, 0.16 mmol) was added to a solution of Int. A (20 mg, 0.078 mmol) and pTSA (13 mg, 0.078 mmol) in dioxane (7 mL). The mixture was stirred at 100 °C for 3 h. It was then added to H2O (10 mL) and extracted by EA (20 mL). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (Method E) to give 40a (16.5 mg, 60% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 10.06 (s, 1H), 8.68-8.65 (m,1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.04 (s, 1H), 7.42-7.39 (m, 1H), 7.38 (s,1H), 7.23-7.18 (m, 1H), 6.95-6.90 (m, 1H), 1.95-1.86 (m, 1H), 0.72-0.63 (m,4H). LC-MS (ESI, Method 4) t R = 4.44 min, m / z (M+H) + = 354.3.

[1060] Example 41

[1061]

[1062] Step 1. (Isobutyl carbonate)pyrazolo[1,5-a]pyridine-5-carboxylic anhydride (41b)

[1063] NMM (749 mg, 7.40 mmol) was added to a solution of 41a (1 g, 6.17 mmol) in THF (20 mL) at 0 °C under nitrogen atmosphere. Isobutyl chloroformate (1.01 g, 7.40 mmol) was added dropwise after 5 minutes. The reaction was stirred at 0 °C to rt for 2 h. The resulting solution was added to H2O (30 mL) and extracted by EA (50 mL). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to give 41b (1.8 g, crude) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) R = 3.14 min, m / z (M+H) + = 263.1.

[1064] Step 2. Pyrazolo[1,5-a]pyridin-5-ylmethanol (41c)

[1065] NaBH4 (662 mg, 17.5 mmol) was added to a solution of 41b (1.8 g, crude) in methanol (20 mL) at 0 °C. The reaction was stirred at 0 °C for 2 h. The resulting solution was added to NH4Cl solution (30 mL) and extracted by EA (40 mL). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to obtain 41c (1 g, crude) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 0.72 min, m / z (M+H) + = 149.1.

[1066] Step 3. Pyrazolo[1,5-a]pyridine-5-carboxaldehyde (41d)

[1067] At rt, Dess-Martin periodane (3.44 g, 8.10 mmol) was added to a solution of 41c (1 g, 5.40 mmol) in DCM (15 mL). The reaction was stirred at 25 °C for 1 h. The resulting solution was filtered and the combined organic layers were concentrated under vacuum. The crude product was purified by rapid chromatography (EA 10-40% in PE) to give 41d (600 mg, 76% yield) as a white solid. LC-MS (ESI, Method 4) R = 1.34 min, m / z (M+H) + = 147.1.

[1068] Step 4. 2,2,2-Trifluoro-1-(pyrazolo[1,5-a]pyridin-5-yl)ethanol (41e)

[1069] At 0 °C, TBAF (1.0 M, 107 mg, 0.41 mmol in THF) was added to a solution of 41d (300 mg, 2.05 mmol) and TMSCF3 (409 mg, 2.87 mmol) in 15 mL of THF. The mixture was stirred at 0 °C for 1 h and then at 25 °C for 12 h. Then, 1 M HCl solution was added, and the reaction was stirred at 25 °C for 2 h. The mixture was adjusted to pH 8 with 1 M NaOH aqueous solution. The mixture was extracted with EA (15 mL x 3). The organic layer was concentrated, and the residue was purified by rapid chromatography (PE / EA = 2 / 1) to give 41e (238 mg, 54% yield) as a white solid. LC-MS (ESI, Method 4) t R = 2.00 min, m / z (M+H) + = 217.1.

[1070] Step 5. 2,2,2-Trifluoro-1-(3-nitropyrazolo[1,5-a]pyridin-5-yl)ethanol (41f)

[1071] At rt, KNO3 (56 mg, 0.56 mmol) was added to a solution of 41e (100 mg, 0.46 mmol) in TFA (5 mL). The reaction was stirred at 25 °C for 2 h. The resulting solution was added to H2O (10 mL) and the pH was adjusted to 8–9 with saturated Na2CO3 solution. The mixture was extracted with EA (20 mL x 2). The organic phases were combined and concentrated, and the residue was purified by rapid chromatography (PE / EA = 1 / 1) to give 41f (100 mg, 83% yield) as a yellow oil. LC-MS (ESI, Method 4) t R =2.33 min, m / z (M+H) + = 262.0.

[1072] Step 6. 1-(3-aminopyrazolo[1,5-a]pyridin-5-yl)-2,2,2-trifluoroethane-1-ol (41g)

[1073] Under a H2 atmosphere, Pd / C (10% on carbon, wetted with approximately 55% water) (8 mg) was added to a solution of 41f (100 mg, 0.38 mmol) in methanol (10 mL). The mixture was stirred at 25 °C for 3 h. The catalyst was filtered off and the filtrate was concentrated under vacuum to give 41 g (100 mg, crude product) as a brown solid, which was used in the next step without further purification. LC-MS (ESI, Method 4) t R = 0.38 min, m / z (M+H) + = 232.0.

[1074] Step 7. 6-(cyclopropanecarbamate)-N-(methyl-d3)-4-((5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)nicotinamide (41)

[1075] At rt, 41 g (27 mg, 0.12 mmol) was added to a solution of Int. A (15 mg, 0.058 mmol), 4-toluenesulfonic acid (10 mg, 0.058 mmol), and dioxane (4 mL). The mixture was stirred at 100 °C for 3 h. The resulting solution was added to H2O (20 mL) and extracted by EA (30 mL). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by rapid chromatography and then by preparative HPLC (Method E) to give 41 g (6.4 mg, 24% yield) as a light pink solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H),10.09 (s, 1H), 8.71 (d, J = 7.2 Hz, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 8.09 (s,1H), 7.56 (d, J = 1.6 Hz, 1H), 7.43 (s, 1H), 7.06 (d, J = 6.0 Hz, 1H), 6.99(d, J = 7.2 Hz, 1H), 5.36-5.27 (m, 1H), 1.94-1.85 (m, 1H), 0.73-0.62 (m, 4H). LC-MS (ESI, Method 4) t R = 1.47 min, m / z (M+H) + = 452.2.

[1076] Example 42

[1077]

[1078] Step 1. (S)-6-(cyclopropaneformamido)-4-((4-methoxy-5-(2,2,2-trifluoro-1-methoxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)nicotinic acid methyl ester (42)

[1079] TsOH (48 mg, 0.28 mmol) was added to a solution of 27b (70 mg, 0.25 mmol) and A2 (45 mg, 0.18 mmol) in dioxane (2 mL), and the mixture was stirred at 85 °C for 3 h. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (Method E) to give 42 (30 mg, 24% yield) as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6)δ 10.81 (s, 1H), 9.57 (s, 1H), 8.64 (s, 1H), 8.53 (d, J = 7.2 Hz, 1H), 8.14(s, 1H), 7.64 (s, 1H), 6.76 (d, J = 7.2 Hz, 1H), 5.25 (q, J = 6.8 Hz, 1H), 3.85 (s, 3H), 3.67 (s, 3H), 3.30 (s, 3H), 1.95-1.84 (m, 1H), 0.75-0.57 (m, 4H). LC-MS (ESI, Method 4) t R = 2.82 min, m / z (M+H) + = 494.3.

[1080] Example 43

[1081]

[1082] Step 1. Ethyl (S)-2,2,2-trifluoro-1-(4-methoxy-3-nitropyrazolo[1,5-a]pyridin-5-yl)acetate (43a)

[1083] Ac₂O (526 mg, 5.15 mmol, 0.49 mL) was added to a solution of 7d-A (150 mg, 0.52 mmol), TEA (261 mg, 2.58 mmol, 0.36 mL), and DMAP (6 mg, 0.052 mmol) in THF (5 mL). The mixture was stirred at 55 °C for 2 h. The mixture was quenched with saturated NaHCO₃ (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried, and concentrated under vacuum. The residue was purified by rapid chromatography (20% EtOAc in PE) to give 43a (149 mg, 87% yield) as a yellow solid. LC-MS (ESI, Method 4) R = 2.95 min, m / z (M+H) + = 334.1.

[1084] Step 2. (S)-1-(3-amino-4-methoxypyrazolo[1,5-a]pyridin-5-yl)-2,2,2-trifluoroethyl acetate (43b)

[1085] Under a H2 atmosphere, Pd / C (9 mg, 0.081 mmol, 10% on carbon, wetted with approximately 55% water) was added to a solution of 43a (90 mg, 0.27 mmol) in MeOH (4 mL). The mixture was stirred at 25 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated to give 43b (70 mg, 85% yield) as a brown oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 2.18 min, m / z (M+H) + = 304.1.

[1086] Step 3. (S)-1-(3-((2-(cyclopropanecarbamoyl)-5-((methyl-d3)carbamoyl)pyridin-4-yl)amino)-4-methoxypyrazolo[1,5-a]pyridin-5-yl)-2,2,2-trifluoroethyl acetate (43)

[1087] TsOH (44 mg, 0.25 mmol) was added to a solution of 43b (70 mg, 0.23 mmol) and Int. A (41 mg, 0.16 mmol) in dioxane (4 mL). The mixture was stirred at 85 °C for 3 h. The mixture was concentrated under vacuum and the residue was purified by preparative HPLC (Method E) to give 43b (45 mg, 37% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 10.41 (s, 1H), 8.58 (s, 1H), 8.55 (d, J = 7.2 Hz,1H), 8.52 (s, 1H), 8.17 (s, 1H), 7.71 (s, 1H), 6.83 (d, J = 7.2 Hz, 1H), 6.59(q, J = 7.2 Hz, 1H), 3.78 (s, 3H), 2.20 (s, 3H), 1.97-1.89 (m, 1H), 0.78-0.66(m, 4H). LC-MS (ESI, Method 4) t R = 2.34 min, m / z (M+H) + = 524.4.

[1088] Example 44

[1089]

[1090] Step 1. 4-Methoxypyrazolo[1,5-a]pyridine (44b)

[1091] A well-stirred solution of 44a (200 mg, 1.04 mmol) in 1 mL of 50% H₂SO₄ was heated at 100 °C for 1 h. A brown solution was formed. The solution was cooled to room temperature. The solution was neutralized with an aqueous solution of NaOH (1.0 M) using litmus paper as an indicator. 40 mL of water was added to the above solution. The solution was extracted with EtOAc (30 mL x 3). The organic layers were combined. The organic layers were dried over anhydrous Na₂SO₄. The organic layers were filtered through a diatomaceous earth mat. The organic layers were evaporated under vacuum to give 44b (45 mg, 94% yield) as a colorless oil. LC-MS (ESI, Method 4) t R = 2.01 min, m / z (M+H) + = 149.1.

[1092] Step 2. 4-Methoxy-3-nitro-pyrazolo[1,5-a]pyridine (44c)

[1093] At 20 °C, a mixture of 44b (145 mg, 0.98 mmol) in TFA (2 mL) was added to KNO3 (89 mg, 0.88 mmol). The resulting mixture was stirred at 30 °C for 1 h, forming a yellow solution. The reaction mixture was quenched with an aqueous solution of NaHCO3 (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (EA in PE: 20-60%) to give 44c (80 mg, 42% yield) as a yellow solid. LC-MS (ESI, Method 4) R = 1.78 min, m / z (M+H) + = 194.1.

[1094] Step 3. 4-Methoxypyrazolo[1,5-a]pyridine-3-amine (44d)

[1095] A mixture of 44c (50 mg, 0.26 mmol) and Pd / C (5 mg, 10% Pd (dry basis), moistened with 55% H2O) in MeOH (3 mL) was degassed and purged three times with hydrogen. The resulting mixture was stirred at 40 °C under H2 atmosphere for 12 h, forming a black suspension. The reaction mixture was filtered and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give 44d (20 mg, 47% yield) as a red solid. 1¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 7.2 Hz, 1H), 7.46 (s, 1H), 6.43 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 3.92 (s, 3H), 3.56 (brs, 2H). LC-MS (ESI, Method 4) t R = 0.43 min, m / z (M+H) + =164.1.

[1096] Step 4. 6-(cyclopropanecarbamate)-4-((4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (44)

[1097] A mixture of 44d (20 mg, 0.12 mmol), Int. A (31 mg, 0.12 mmol), and PTSA (42 mg, 0.24 mmol) in dioxane (2 mL) was stirred at 100 °C for 12 h. A yellow suspension was formed. The reaction mixture was diluted with an aqueous solution of NaHCO3 (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (60 mL x 2) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (MeOH in DCM 0-10%) and ground in MeCN to give 44 (26.5 mg, 56% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 10.58 (s, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.19 (d,J = 6.8 Hz, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 6.78 (t, J = 7.2 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 3.86 (s, 3H), 2.00-1.93 (m, 1H), 0.78-0.73 (m, 4H). LC-MS(ESI, method 4) t R = 4.92 min, m / z (M+H) + = 384.3.

[1098] Example 45

[1099]

[1100] Step 1. 2,2,2-Trifluoro-1-(4-fluoro-2-methoxyphenyl)ethanol-1-ol (45b)

[1101] At 0 °C, TMSCF3 (9.23 g, 64.88 mmol) was slowly added to a solution of 45a (5 g, 32.44 mmol) and CsF (98 mg, 0.65 mmol) in THF (50 mL). After stirring at 30 °C for 3 h, the reaction was quenched with an aqueous HCl solution (1 mL, 2 M) and stirred at 20 °C for 1 h. The mixture was diluted with saturated NaHCO3 (10 mL) and extracted with EtOAc (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by silica gel rapid chromatography (PE / EtOAc = 20 / 1) to give 45b (7.2 g, 99% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (t, J = 8.0 Hz, 1H), 6.97 (dd, J = 11.6, 2.8 Hz, 1H), 6.87-6.82 (m, 1H), 6.72 (d, J = 6.0 Hz, 1H), 5.37-5.32 (m, 1H), 3.82 (s, 3H).

[1102] Step 2. 4-Fluoro-2-methoxy-1-(2,2,2-trifluoro-1-methoxyethyl)benzene (45c)

[1103] At 0 °C, a solution of 45b (4.8 g, 21.41 mmol) in THF (48 mL) was added with NaH (1.03 g, 25.70 mmol, 60% in mineral oil). After stirring at 0 °C for 30 min, CH3I (9.12 g, 64.24 mmol) was added and the reaction was stirred at 0 °C for 1 h, then at 30 °C for 3 h. The solution was poured into ice water (30 mL) and extracted with EtOAc (40 mL x 2). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel rapid chromatography (PE / EtOAc = 30 / 1) to give 45c (4.5 g, 88% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (t, J = 7.6 Hz, 1H), 6.97 (dd, J = 11.6, 2.4 Hz, 1H), 6.91-6.85 (m, 1H), 5.18-5.15 (m, 1H), 3.85 (s, 3H), 3.31 (s, 3H).

[1104] Step 3. 6-Fluoro-2-methoxy-3-(2,2,2-trifluoro-1-methoxyethyl)benzaldehyde (45d)

[1105] At -50°C, LDA (4.03 mL, 2 M in THF) was added dropwise to a solution of 45c (1.28 g, 5.37 mmol) in 13 mL of THF. The mixture was stirred at -50°C for 1 h. Then, DMF (8.06 mmol, 0.62 mL) was added to the mixture at -50°C and the reaction was stirred at -50°C for 1 h. The reaction was quenched with saturated NH4Cl (25 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 45d (1.43 g, crude) as a yellow oil, which was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.77-7.73 (m, 1H), 7.31-7.26 (m, 1H), 5.26-5.23(m, 1H), 3.85 (s, 3H), 3.31 (s, 3H).

[1106] Step 4. 6-Fluoro-2-methoxy-3-(2,2,2-trifluoro-1-methoxyethyl)benzyl nitrile (45e)

[1107] At 0 °C, a solution of 45d (1.43 g, 5.37 mmol) in NH3·H2O (7 mL) and 1,4-dioxane (7 mL) was added to a solution of 2,3-diiodo-5,5-dimethylimidazolidine-2,4-dione (2.04 g, 5.37 mmol). The mixture was then stirred at 33 °C for 16 h. TLC showed the disappearance of the starting material. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 2). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 45e (1.4 g, crude) as a yellow solid, which was used directly in the next step without further purification.

[1108] Step 5. 4-Methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-amine (45f)

[1109] A mixture of 45e (1.2 g, 4.56 mmol) and 40% aqueous methylhydrazine (7 mL) in EtOH (5 mL) was stirred at 90 °C for 4 h. After cooling to rt, the mixture was diluted with water (25 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel rapid chromatography (PE / EtOAc = 5 / 1) to give 45f (390 mg, 36% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.19 min, m / z (M+H) + = 290.4.

[1110] Step 6. Methyl 6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazol-3-yl)amino)nicotinic acid ester (45)

[1111] A mixture of 45f (200 mg, 0.69 mmol), A2 (194 mg, 0.76 mmol), Pd2(dba)3 (127 mg, 0.14 mmol), Xantphos (80 mg, 0.14 mmol), and Cs2CO3 (451 mg, 1.38 mmol) in 1,4-dioxane (2 mL) was stirred at 90 °C under N2 for 5 h. The reaction mixture was concentrated, and the residue was purified by silica gel rapid chromatography (DCM / MeOH = 49 / 1) to give 45f (298 mg, 85% yield) as a yellow solid. LC-MS (ESI, Method 3) t R =1.29 min, m / z (M+H) + = 508.5.

[1112] Step 7. (R)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)methyl nicotinate (45A) and (S)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)methyl nicotinate (45B)

[1113] Compound 45 (290 mg, 0.57 mmol) was separated by chiral preparative HPLC (Method J) to give 45A (77.5 mg, 27% yield) and 45B (77.5 mg, 27% yield) as white solids.

[1114] 45A: LC-MS (ESI, Method 2) t R = 0.98 min, m / z (M+H) + = 508.1. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.90 (s, 1H), 10.89 (s, 1H), 9.17 (s, 1H), 8.77 (s, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.29 (q, J = 6.8 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.32 (s, 3H), 2.06–2.01 (m, 1H), 0.84–0.80 (m, 4H). Chiral-HPLC (Method 7) t R = 13.97 min.

[1115] 45B: LC-MS (ESI, Method 2) t R = 0.98 min, m / z (M+H) + = 508.1. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.90 (s, 1H), 10.89 (s, 1H), 9.17 (s, 1H), 8.77 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 5.29 (q, J = 7.2 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.31 (s, 3H), 2.07–2.01 (m, 1H), 0.86–0.79 (m, 4H). Chiral-HPLC (Method 7) t R = 17.26 min.

[1116] Step 8: (S)-4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-amine (45f-A) and (R)-4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-amine (45f-B)

[1117] 45f (5.8 g, 20.05 mmol) was separated into a white solid, 45f-A (1.84 g, 32% yield), by chiral preparative HPLC (Method G, Hex / EtOH = 90 / 10) and chiral HPLC (Method 8, Hex / EtOH = 90 / 10). R =8.64 min and 45f-B (2.23 g, 38% yield) as a white solid, chiral HPLC (Method 8, Hex / EtOH = 90 / 10) t R =10.30min.

[1118] Example 46

[1119]

[1120] Step 1. 6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazol-3-yl)amino)nicotinic acid (46a)

[1121] At 10°C, a solution of 45 (80 mg, 0.16 mmol) in THF (6 mL) and MeOH (2 mL) was added to a solution of 46a (0.5 mL, 2 M in water). The mixture was then stirred at 30°C for 3 h. The mixture was adjusted to pH < 7 with 2 N HCl and extracted with EtOAc (8 mL * 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to give 46a (77 mg, crude) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 1.21 min, m / z (M+H) + = 494.4.

[1122] Step 2. 6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazol-3-yl)amino)-N-(methyl-d3)nicotinamide (46)

[1123] BOP (125 mg, 0.28 mmol) was added to a solution of 46a (70 mg, 0.14 mmol), methyl-d3-amine hydrochloride (20 mg, 0.28 mmol), and DIPEA (73 mg, 0.57 mmol) in DMF (0.5 mL) at 0 °C. The mixture was then stirred at 0 °C for 2 h. The mixture was quenched with ice water (3 mL) and extracted with EtOAc (6 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method C) to give 46a (8.8 mg, 12% yield) as a white solid. LC-MS (ESI, Method 2) t R = 0.93 min, m / z (M+H) + = 510.2. 1 H NMR(400 MHz, DMSO-d6) δ 11.60 (s, 1H), 10.70 (s, 1H), 9.12 (s, 1H), 8.62 (s,1H), 8.57 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 5.32-5.24 (m, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 3.31 (s, 3H), 2.08-2.00 (m, 1H), 0.85-0.77 (m, 4H).

[1124] Step 3. (S)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazol-3-yl)amino)-N-(methyl-d3)nicotinamide (46A) and (R)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazol-3-yl)amino)-N-(methyl-d3)nicotinamide (46B)

[1125] 46 (220 mg, 0.41 mmol) was separated by chiral preparative HPLC (method K) to obtain 46A (102 mg, 46% yield) and 46B (102 mg, 46% yield) as white solids.

[1126] 46A: LC-MS (ESI, Method 2) t R = 1.09 min, m / z (M+H) + = 510.0. 1¹H NMR (400MHz, DMSO-d6) δ 11.62 (s, 1H), 10.73 (s, 1H), 9.14 (s, 1H), 8.65 (s, 1H), 8.58 (s, 1H), 7.45–7.38 (m, 2H), 5.32–5.26 (m, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 3.32 (s, 3H), 2.05–2.00 (m, 1H), 0.85–0.78 (m, 4H). Chiral HPLC (Method 9) t R =5.39 min.

[1127] 46B: LC-MS (ESI, Method 2) t R = 1.09 min, m / z (M+H) + = 510.0. 1 ¹H NMR (400MHz, DMSO-d6) δ 11.62 (s, 1H), 10.72 (s, 1H), 9.14 (s, 1H), 8.64 (s, 1H), 8.58 (s, 1H), 7.45–7.38 (m, 2H), 5.31–5.26 (m, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.31 (s, 3H), 2.04–1.99 (m, 1H), 0.87–0.79 (m, 4H). Chiral HPLC (Method 9) t R =5.94 min.

[1128] Example 47

[1129]

[1130] Step 1. (S)-4-methoxy-3-nitro-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)pyrazolo[1,5-a]pyridine (47a)

[1131] At 0 °C, NaH (33 mg, 0.82 mmol, 60% in mineral oil) was slowly added to a solution of 7d-A (200 mg, 0.69 mmol) and CD3I (498 mg, 3.43 mmol) in anhydrous DMF (2 mL), and the mixture was stirred at 0 °C for 30 min. The solution was poured into ice water (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (PE / EtOAc = 20 / 1) to give 47a (200 mg, 94% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.27 min, m / z (M+H) + = 309.3.

[1132] Step 2. (S)-4-methoxy-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)pyrazolo[1,5-a]pyridine-3-amine (47b)

[1133] At 0 °C, B2(OH)4 (175 mg, 1.95 mmol) was slowly added to a solution of 47a (200 mg, 0.65 mmol) and 4,4'-bipyridine (4.05 mg, 0.026 mmol) in DMF (2 mL), and the reaction was stirred at 0 °C for 30 min. The reaction mixture was directly purified by preparative HPLC (Method A) to give 47b (130 mg, 72% yield) as a brown solid. LC-MS (ESI, Method 3) t R = 1.01 min, m / z (M+H) + = 279.2.

[1134] Step 3. (S)-6-(cyclopropaneformamido)-4-((4-methoxy-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)nicotinic acid methyl ester (47)

[1135] A mixture of 47b (30 mg, 0.11 mmol), A2 (33 mg, 0.13 mmol), Cs2CO3 (70 mg, 0.22 mmol), Xantphos (12 mg, 0.022 mmol), and Pd2(dba)3 (20 mg, 0.022 mmol) in dioxane (0.4 mL) was stirred at 100 °C under N2 for 5 h. The reaction mixture was cooled, concentrated, and purified by silica gel rapid chromatography (PE / EtOAc = 3 / 1) to give 47b as a yellow solid (21.5 mg, 40% yield). LC-MS (ESI, Method 2) t R = 0.90min, m / z (M+H) + = 497.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.61 (s,1H), 8.68 (s, 1H), 8.56 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 7.67(s, 1H), 6.81(d, J = 7.2 Hz, 1H), 5.29-5.26 (m, 1H), 3.89 (s, 3H), 3.71 (s, 3H), 1.95-1.92 (m, 1H), 0.75-0.67 (m, 4H).

[1136] Example 48

[1137]

[1138] Step 1. Tert-butyldimethyl(2,2,2-trifluoro-1-(4-fluoro-2-methoxyphenyl)ethoxy)silane (48a)

[1139] Under rt, TBSCl (3.03 g, 20.08 mmol) was added to a solution of 45b (3 g, 13.38 mmol) and imidazole (1.37 g, 20.08 mmol) in DMF (3 mL). After stirring at 30 °C for 3 h, the reaction was diluted with 0.2 M HCl (20 mL) and extracted with EtOAc (20 mL x 2). The organic layer was washed with brine (5 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel rapid chromatography (PE / EtOAc = 50 / 1) to give 48a (3.5 g, 77% yield) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 11.2,2.4 Hz, 1H), 7.08 (td, J = 8.4, 2.4 Hz, 1H), 5.53 (q, J = 6.8 Hz, 1H), 3.91 (s, 3H), 0.91 (s, 9H), 0.14 (s, 3H), 0.07 (s, 3H).

[1140] Step 2. 3-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-6-fluoro-2-methoxybenzaldehyde (48b)

[1141] At -60 °C, LDA (6 mL, 12 mmol, 2 M in THF) was added dropwise to a solution of 48a (1 g, 2.95 mmol) in 10 mL of THF over 30 min. The reaction mixture was stirred at the same temperature for 1 h. Then, DMF (0.65 g, 8.86 mmol) was added dropwise to the solution at -60 °C. The reaction was stirred again at -60 °C for 2 h and quenched with an aqueous HCl solution (10 mL, 2 M). The mixture was extracted with EtOAc (10 mL x 2) and the combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 48b (1 g, 92% yield) as a yellow oil, which was used directly in the next step without further purification.

[1142] Step 3. 3-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-6-fluoro-2-methoxybenzyl nitrile (48c)

[1143] In an ice bath, 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione (207 mg, 0.55 mmol) was added to a solution of 48b (200 mg, 0.55 mol) in 1,4-dioxane (1 mL) and NH3·H2O (1 mL). The mixture was then stirred at rt for 16 h. The mixture was diluted with water (4 mL) and extracted with EtOAc (8 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35 °C to give 48c (198 mg, crude) as a yellow oil, which was used directly in the next step without further purification.

[1144] Step 4. 5-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-4-methoxy-1-methyl-1H-indazole-3-amine (48d)

[1145] A mixture of 48c (198 mg, 0.55 mmol), 40% methylhydrazine aqueous solution (2 mL), and EtOH (2 mL) was stirred at 90 °C for 5 h. After cooling to rt, the reaction mixture was diluted with water (8 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (PE / EtOAc = 5 / 1 to 2 / 1) to give 48d (70 mg, 33% yield) as a yellow oil. LC-MS (ESI, Method 3) t R = 1.57 min, m / z (M+H) + = 390.5.

[1146] Step 5. 4-((5-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-4-methoxy-1-methyl-1H-indazol-3-yl)amino)-6-(cyclopropaneformamido)methyl nicotinate (48e)

[1147] A mixture of 48d (75 mg, 0.19 mmol), A2 (54 mg, 0.21 mmol), Pd2(dba)3 (35 mg, 0.039 mmol), Xantphos (22 mg, 0.039 mol), and Cs2CO3 (125 mg, 0.39 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90 °C under N2 for 3 h. The reaction mixture was concentrated, and the residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give 48e (85 mg, 73% yield) as a yellow solid. LC-MS (ESI, Method 3) t R =1.56 min, m / z (M+H) + = 608.7.

[1148] Step 6. Methyl 6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-3-yl)amino)nicotinic acid ester (48)

[1149] At 0 °C, TBAF (1 mL, 1 M in THF) was added to a solution of 48e (70 mg, 0.12 mmol) in THF (1 mL). The mixture was then stirred at 30 °C for 1 h. The reaction mixture was diluted with water (3 mL) and extracted with EtOAc (6 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 97 / 3) to give 48e (40 mg, 70% yield) as a yellow solid. LC-MS (ESI, Method 3) R = 1.17 min,m / z (M+H) + = 494.4. 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.88 (s, 1H), 9.20 (s, 1H), 8.77 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 6.87 (brs, 1H), 5.48-5.42 (m, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.87 (s,3H), 2.10-1.96 (m, 1H), 0.93-0.76 (m, 4H).

[1150] Step 7. (S)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-3-yl)amino)methyl nicotinate (48A) and (R)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-3-yl)amino)methyl nicotinate (48B)

[1151] 48 (15 mg, 0.03 mmol) was separated by chiral preparative HPLC (method G, Hex / EtOH=60 / 40) to obtain 48A (5.3 mg, 36% yield) and 48B (5.6 mg, 38% yield) as white solids.

[1152] 48A: LC-MS (ESI, Method 2) t R = 0.89 min, m / z (M+H) + = 494.1. 1¹H NMR (400MHz, DMSO-d⁶) δ 10.91 (s, 1H), 10.88 (s, 1H), 9.20 (s, 1H), 8.77 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 5.2 Hz, 1H), 5.52–5.39 (m, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 2.07–2.01 (m, 1H), 0.87–0.79 (m, 4H). Chiral HPLC (Method 8, Hex\EtOH = 60\40) t R = 5.08 min.

[1153] 48B: LC-MS (ESI, Method 2) t R = 0.88 min, m / z (M+H) + = 494.1. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.91 (s, 1H), 10.88 (s, 1H), 9.20 (s, 1H), 8.77 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 5.6 Hz, 1H), 5.51–5.38 (m, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 2.07–2.01 (m, 1H), 0.87–0.79 (m, 4H). Chiral HPLC (Method 8, Hex\EtOH = 60\40) t R = 6.87 min.

[1154] Example 49

[1155]

[1156] Step 1. 6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazol-3-yl)amino)nicotinic acid (49a)

[1157] Under ice bath conditions, LiOH (0.25 mL, 2 M) in water was added to a solution of 48 (38 mg, 0.077 mmol) in THF (0.5 mL) and MeOH (0.5 mL). The mixture was then stirred at 30 °C for 2 h. The mixture was adjusted to pH < 7 with 2 N HCl and extracted with EtOAc (8 mL * 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to give 49a (36 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 1.12 min, m / z (M+H) + = 480.4.

[1158] Step 2. 6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazol-3-yl)amino)-N-(methyl-d3)nicotinamide (49)

[1159] BOP (65 mg, 0.15 mmol) was added to a solution of 49a (35 mg, 0.073 mmol), trideuterated methylamine hydrochloride (10 mg, 0.15 mmol), and DIPEA (38 mg, 0.29 mmol) in DMF (0.5 mL) at 0 °C. The mixture was then stirred at 0 °C for 2 h. The mixture was quenched with ice water (4 mL) and extracted with EtOAc (7 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC (Method A) to give 49a (7.3 mg, 20% yield) as a white solid. LC-MS (ESI, Method 2) t R = 0.84 min, m / z (M+H) + = 496.1. 1 H NMR(400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.69 (s, 1H), 9.14 (s, 1H), 8.61 (s,1H), 8.56 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.81(d, J = 6.0 Hz, 1H), 5.46-5.41 (m, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 2.06-1.95(m, 1H), 0.92-0.69 (m, 4H).

[1160] Step 3. (S)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazol-3-yl)amino)-N-(methyl-d3)nicotinamide (49A) and (R)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazol-3-yl)amino)-N-(methyl-d3)nicotinamide (49B)

[1161] 49 (135 mg, 0.27 mol) was separated into white solid 49A (40 mg, 30% yield) and white solid 49B (45.4 mg, 34% yield) by chiral preparative HPLC (Method I, Hex / IPA / DEA=60 / 40 / 0.3).

[1162] 49A: LC-MS (Method 2) t R = 0.83 min, m / z (M+H) + = 496.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.69 (s, 1H), 9.14 (s, 1H), 8.61 (s, 1H), 8.56 (s,1H), 7.51 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 5.2 Hz,1H), 5.46-5.41 (m, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 2.07-1.97 (m, 1H), 0.89-0.75 (m, 4H). Chiral HPLC (Method 6, Hex / IPA / DEA = 60 / 40 / 0.2) t R = 9.08 min.

[1163] 49B: LC-MS (Method 2) t R = 0.84 min, m / z (M+H) + = 496.1. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.69 (s, 1H), 9.14 (s, 1H), 8.61 (s, 1H), 8.56 (s,1H), 7.52 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 5.2 Hz,1H), 5.57-5.31 (m, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 2.12-1.91 (m, 1H), 0.99-0.72 (m, 4H). Chiral HPLC (Method 6, Hex / IPA / DEA = 60 / 40 / 0.2) t R = 12.84 min.

[1164] Example 50

[1165]

[1166] Step 1. 4-Fluoro-2-methoxy-1-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)benzene (50a)

[1167] At 0 °C, a solution of 45b (5 g, 22.31 mmol) in THF (50 mL) was added with NaH (1.07 g, 26.77 mmol, 60% in mineral oil). After stirring at 0 °C for 30 min, CD3I (9.70 g, 66.92 mmol) was added. The reaction was stirred at 0 °C for 1 h and then at 30 °C for 3 h. The solution was poured into ice water (30 mL) and extracted with EtOAc (40 mL x 2). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (PE / EtOAc = 30 / 1) to give 50a (5 g, 93% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 1H), 6.7-6.73 (m, 1H), 6.69-6.65 (m, 1H), 5.12-5.07(m, 1H), 3.86 (s, 3H).

[1168] Step 2. 4-Fluoro-2-methoxy-1-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)benzene (50b)

[1169] At -50°C, LDA (15 mL, 30 mmol, 2 M in THF) was added dropwise to a solution of 50a (2.5 g, 10.36 mmol) in 20 mL of THF. The mixture was stirred at -50°C for 1 h. Then, DMF (2.41 mL, 31.09 mmol) was added to the mixture at -50°C and stirred at -50°C for 1 h. The reaction was quenched with saturated NH4Cl (25 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35°C to give 50b (2 g, crude) as a yellow oil, which was used directly in the next step without further purification.

[1170] Step 3. 6-Fluoro-2-methoxy-3-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)benzylnitrile (50c)

[1171] In an ice bath, 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione (567 mg, 1.49 mmol) was added to a solution of 50b (400 mg, 1.49 mmol) in NH3·H2O (2 mL) and 1,4-dioxane (2 mL). The mixture was then stirred at 30 °C for 12 h. TLC showed the disappearance of the starting material. The mixture was diluted with water (3 mL) and extracted with EtOAc (10 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35 °C to give 50c (1.6 g, crude) as a yellow liquid, which was used directly in the next step without further purification.

[1172] Step 4. 4-Methoxy-1-methyl-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazole-3-amine (50d)

[1173] A mixture of 50d (300 mg, 1.13 mmol) and 40% methylhydrazine aqueous solution (1.5 mL) in EtOH (1.5 mL) was stirred at 90 °C for 12 h. After cooling to rt, the mixture was diluted with water (3 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (PE / EtOAc = 5 / 1) to give 50d (150 mg, 46% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.20 min, m / z (M+H) + = 293.4.

[1174] Step 5. Methyl 6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazol-3-yl)amino)nicotinic acid ester (50)

[1175] A mixture of 50d (150 mg, 0.51 mmol), A2 (131 mg, 0.51 mmol), Pd2(dba)3 (94 mg, 0.10 mmol), Xantphos (60 mg, 0.10 mmol), and Cs2CO3 (335 mg, 1.03 mmol) in 1,4-dioxane (2 mL) was stirred at 90 °C under N2 for 12 h. The reaction mixture was concentrated, and the residue was purified by silica gel rapid chromatography (PE / EtOAc = 2 / 1) to give 50 (70 mg, 27% yield) as a yellow solid. LC-MS (ESI, Method 3) t R =1.28 min, m / z (M+H) + = 511.5.

[1176] Step 6. (R)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazole-3-yl)amino)methyl nicotinic acid (50A) and (S)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazole-3-yl)amino)methyl nicotinic acid (50B)

[1177] 50 (70 mg, 0.14 mmol) was separated into 50A (26 mg, 37% yield) and 50B (25 mg, 36% yield) as white solids by chiral preparative HPLC (Method G, Hex\EtOH=80\20).

[1178] 50A: LC-MS (ESI, Method 2) t R = 1.13 min, m / z (M+H) + = 511.0. 1¹H NMR (400MHz, DMSO-d⁶) δ 10.92 (s, 1H), 10.91 (s, 1H), 9.18 (s, 1H), 8.77 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.30–5.27 (m, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 2.05–1.98 (m, 1H), 0.84–0.80 (m, 4H). Chiral HPLC (Method 8, Hex / IPA = 80 / 20) t R = 12.51 min.

[1179] 50B: LC-MS (ESI, Method 2) t R = 1.13 min, m / z (M+H) + = 511.0. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.92 (s, 1H), 10.91 (s, 1H), 9.18 (s, 1H), 8.77 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.30–5.27 (m, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.88 (s, 3H), 2.05–2.02 (m, 1H), 0.84–0.80 (m, 4H). Chiral HPLC (Method 8, Hex / IPA = 80 / 20) t R = 16.16 min.

[1180] Example 51

[1181]

[1182] Step 1. 6-Chloro-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazol-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (51a)

[1183] At -40 °C, LiHMDS (1.4 mL, 1.40 mmol, 1 M in THF) was added to a solution of 45f (100 mg, 0.35 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (87 mg, 0.41 mmol) in THF (0.8 mL). The reaction was stirred for 2 h at -40 °C to 25 °C. The mixture was quenched with H2O (2 mL) and the organic solvent was evaporated. The resulting solid was filtered and the filter cake was dried to give 51a (100 mg, 63% yield) as a white solid. LC-MS (ESI, Method 3) t R =1.48 min, m / z (M+H) + = 462.3.

[1184] Step 2. 6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazol-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (51)

[1185] A mixture of 51a (100 mg, 0.22 mmol), cyclopropaneformamide (91 mg, 1.08 mmol), BrettPhos Pd G3 (39 mg, 0.043 mmol), and Cs₂CO₃ (141 mg, 0.43 mol) in 1,4-dioxane (1.2 mL) was stirred at 90 °C under a N₂ atmosphere for 5 h. The reaction mixture was concentrated, and the residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give 51a (80 mg, 72% yield) as a white solid. LC-MS (ESI, Method 3) t R = 1.31 min,m / z (M+H) + = 511.5.

[1186] Step 3. (R)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazol-3-yl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (51A) and (S)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazol-3-yl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (51B)

[1187] 51 (80 mg, 0.16 mmol) was separated by chiral preparative HPLC (Method L) to obtain 51A (20 mg, 25% yield) and 51B (12 mg, 15% yield) as white solids.

[1188] 51A: LC-MS (ESI, Method 2) t R = 1.16 min, m / z (M+H) + = 511.0. 1 ¹H NMR (400MHz, DMSO-d6) δ 12.04 (s, 1H), 11.30 (s, 1H), 9.44 (s, 1H), 9.20 (s, 1H), 7.48–7.41 (m, 2H), 5.32–5.29 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.32 (s, 3H), 2.14–2.10 (m, 1H), 0.90–0.87 (m, 4H). Chiral HPLC (Method 8, Hex\EtOH = 90\10) R = 8.65 min.

[1189] 51B: LC-MS (ESI, Method 2) t R = 1.00 min, m / z (M+H) + = 511.2. 1 ¹H NMR (400MHz, DMSO-d6) δ 12.04 (s, 1H), 11.30 (s, 1H), 9.44 (s, 1H), 9.21 (s, 1H), 7.48–7.41 (m, 2H), 5.33–5.27 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.34 (s, 3H), 2.17–2.11 (m, 1H), 0.92–0.84 (m, 4H). Chiral HPLC (Method 8, Hex\EtOH = 90\10) R = 10.33 min.

[1190] Example 52

[1191]

[1192] Step 1. 4-Methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-amine (52a)

[1193] In an ice bath, KOH (1.34 g, 23.94 mmol) was added to a mixture of methyl-d3-hydrazine hydrochloride (1:2) (1.50 g, 12.30 mmol) in EtOH / H2O (0.5 mL / 0.1 mL). The reaction was stirred at 30 °C for 30 min. The solid was filtered off. The filtrate was added to 45 °C (175 mg, 0.66 mmol) and stirred at 90 °C in a sealed tube for 2 h. After cooling to rt, the mixture was purified by preparative HPLC (Method C, HCOOH) to give compound 52a (58 mg, 29.8% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.8Hz, 1H), 5.22 (s, 2H), 5.21-5.15 (m, 1H), 3.87 (s, 3H), 3.28 (s, 3H).

[1194] Step 2. (S)-4-methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-amine (52a-A) and (R)-4-methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-amine (52a-B)

[1195] 52a (150 mg, 0.51 mmol) was separated by chiral preparative HPLC (Method G, Hex / EtOH = 90 / 10, 20 mL / min) to obtain 52a-A (64 mg, 43% yield) and 52a-B (65 mg, 43% yield) as white solids.

[1196] 52a-A: Chiral HPLC (Method 8, Hex\EtOH = 90\10) t R = 8.63 min.

[1197] 52a-B: Chiral HPLC (Method 8, Hex\EtOH = 90\10) t R = 10.32 min.

[1198] Step 3. (S)-6-(cyclopropaneformamido)-4-((4-methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)methyl nicotinic acid (52A) and (R)-6-(cyclopropaneformamido)-4-((4-methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)methyl nicotinic acid (52B)

[1199] A mixture of 52a-A (30 mg, 0.10 mmol), A2 (26 mg, 0.10 mmol), Pd2(dba)3 (19 mg, 0.021 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (67 mg, 0.21 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90 °C under N2 for 4 h. The reaction mixture was concentrated, and the residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give a crude product. The crude compound was then further purified by preparative HPLC (Method A) to give 52A as a white solid (24.2 mg, 46% yield). LC-MS (ESI, Method 2) t R = 0.97 min, m / z (M+H) + =511.1. 1 ¹H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.89 (s, 1H), 9.17 (s, 1H), 8.78 (s, 1H), 7.49–7.40 (m, 2H), 5.32–5.27 (m, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.31 (s, 3H), 2.09–1.99 (m, 1H), 0.88–0.76 (m, 4H). Chiral HPLC (Method 7, Hex\IPA = 85\15, run time 40 min) t R = 21.74 min.

[1200] A mixture of 52a-B (30 mg, 0.10 mmol), A2 (29 mg, 0.11 mmol), Pd2(dba)3 (19 mg, 0.021 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (67 mg, 0.21 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90 °C under N2 for 4 h. The reaction mixture was concentrated, and the residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give a crude product. The crude compound was then further purified by preparative HPLC (Method A) to give 52B as a white solid (13.5 mg, 26% yield). LC-MS (ESI, Method 2) t R = 0.97 min, m / z (M+H) + =511.1. 1 ¹H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.90 (s, 1H), 9.18 (s, 1H), 8.78 (s, 1H), 7.49–7.40 (m, 2H), 5.33–5.27 (m, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.33 (s, 3H), 2.04–1.98 (m, 1H), 0.83–0.76 (m, 4H). Chiral HPLC (Method 7, Hex\IPA = 85\15, run time 40 min) t R = 16.91 min.

[1201] Example 53

[1202]

[1203] Step 1. 4-(methoxy-d3)-1-methyl-5-(2,2,2-trifluoro-1-(methoxy-d3))-1H-indazole-3-amine 4-fluoro-2-methoxy-1-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)benzene (53a)

[1204] KOH (600 mg, 10.69 mmol) was added to a solution of CD3NHNH2.HCl (700 mg, 5.74 mmol) in EtOH / H2O (0.5 mL / 0.1 mL) under ice bath conditions, and the solution was stirred at 30 °C for 30 min. The solid formed was filtered off. The filtrate was added to 50b (500 mg, 1.88 mmol). The reaction mixture was stirred at 90 °C for 6 h in a sealed tube. The mixture was concentrated, and the residue was purified by silica gel rapid chromatography (PE / EtOAc = 2 / 1) to give the crude compound. The crude compound was further purified by preparative HPLC (Method C) to give 53a (80 mg, 15% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 5.13-5.08 (m,1H), 3.99 (s, 3H).

[1205] Step 2. Methyl 6-(cyclopropaneformamido)-4-((4-(methoxy-d3)-1-methyl-5-(2,2,2-trifluoro-1-(methoxy-d3))-1H-indazol-3-yl)amino)nicotinic acid ester (53)

[1206] A mixture of 53a (35 mg, 0.12 mmol), A2 (36 mg, 0.14 mmol), Pd2(dba)3 (22 mg, 0.02 mmol), Xantphos (14 mg, 0.02 mmol), and Cs2CO3 (77 mg, 0.23 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90 °C under N2 for 4 h. The reaction mixture was concentrated, and the residue was purified by silica gel rapid chromatography (DCM / MeOH = 19 / 1) to give a crude product. The crude product was further purified by preparative HPLC (Method C) to give 53a (39 mg, 57% yield) as a white solid. LC-MS (ESI, Method 3) t R = 1.30 min, m / z (M+H) + = 514.4.

[1207] Step 3. (R)-6-(cyclopropaneformamido)-4-((4-methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazole-3-yl)amino)methyl nicotinate (53A) and (S)-6-(cyclopropaneformamido)-4-((4-methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazole-3-yl)amino)methyl nicotinate (53B)

[1208] 53 (39 mg, 0.07 mmol) was separated by chiral preparative HPLC (method G, Hex / IPA=80 / 20) to obtain 53A (13.2 mg, 34% yield) and 53B (11.6 mg, 30% yield) as white solids.

[1209] 53A: LC-MS (ESI, Method 2) t R = 0.96 min, m / z (M+H) + = 514.2. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.90 (s, 1H), 10.89 (s, 1H), 9.17 (s, 1H), 8.77 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.31–5.26 (m, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.08–1.99 (m, 1H), 0.87–0.79 (m, 4H). Chiral HPLC (Method 8, Hex / IPA = 80 / 20) t R = 12.46 min.

[1210] 53B: LC-MS (ESI, Method 2) t R = 0.96 min, m / z (M+H) + = 514.2. 1¹H NMR (400MHz, DMSO-d⁶) δ 10.99 (s, 1H), 10.94 (s, 1H), 9.12 (s, 1H), 8.77 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 5.31–5.26 (m, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.05–1.99 (m, 1H), 0.84–0.78 (m, 4H). Chiral HPLC (Method 8, Hex / IPA = 80 / 20) t R = 16.09 min.

[1211] Example 54

[1212]

[1213] Step 1. N-(4-((5-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-4-methoxy-1-methyl-1H-indazol-3-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (54b)

[1214] A mixture of 54a (60 mg, 0.235 mmol, WO2020086616, P246), 48d (110 mg, 0.281 mmol), Cs2CO3 (153 mg, 0.469 mmol), Pd2(dba)3.CHCl3 (24 mg, 0.023 mmol), and BINAP (15 mg, 0.0241 mmol) in 1,4-dioxane (1 mL) was stirred at 110 °C under N2 for 4 h. The mixture was concentrated, and the crude product was purified by silica gel rapid chromatography (PE / EtOAc = 3 / 1) to give 54b (80 mg, 56% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.66 min, m / z (M+H) + = 609.6.

[1215] Step 2. N-(4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazol-3-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropaneformamide (54)

[1216] At 0 °C, TBAF (0.1 mL, 1.0 M in THF) was added to a solution of 54b (80 mg, 0.13 mmol) in 1 mL THF. After stirring at 25 °C for 1 h, the reaction mixture was concentrated and the residue was purified by preparative HPLC (Method C) to give 54b as a green solid (30 mg, 46% yield). LC-MS (ESI, Method 2) t R = 0.90 min, m / z (M+H) + = 495.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.87 (s,1H), 9.21 (s,1H), 8.92 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.83(brs, 1H), 5.49-5.43 (m, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.13 (s, 2H), 2.09-2.03 (m, 1H), 0.87-0.79 (m, 4H).

[1217] Step 3. (S)-N-(4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-3-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (54A) and (R)-N-(4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-3-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (54B)

[1218] 54 (28 mg, 0.05 mmol) was separated by chiral preparative HPLC (Method G) to obtain 54A (12.0 mg, 43% yield) and 54B (12.0 mg, 43% yield) as green solids.

[1219] 54A: LC-MS (ESI, Method 2) t R = 0.91 min, m / z (M+H) + = 495.1. 1¹H NMR (400MHz, DMSO-d6) δ 11.98 (s, 1H), 10.87 (s, 1H), 9.21 (s, 1H), 8.92 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 6.0 Hz, 1H), 5.48–5.44 (m, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.13 (s, 2H), 2.08–2.04 (m, 1H), 0.85–0.81 (m, 4H). Chiral HPLC (Method 8) t R = 8.35 min.

[1220] 54B: LC-MS (ESI, Method 2) t R = 0.90 min, m / z (M+H) + = 495.1. 1 ¹H NMR (400MHz, DMSO-d6) δ 11.99 (s, 1H), 10.87 (s, 1H), 9.21 (s, 1H), 8.92 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 6.0 Hz, 1H), 5.48–5.44 (m, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.13 (s, 2H), 2.08–2.04 (m, 1H), 0.85–0.81 (m, 4H). Chiral HPLC (Method 8) t R = 12.07 min.

[1221] Example 55

[1222]

[1223] Step 1. (S)-4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-(methyl-d3))-1H-indazole-3-amine (50d-A) and (R)-4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-(methyl-d3))-1H-indazole-3-amine (50d-B)

[1224] 50d (320 mg, 1.09 mmol) was separated into a white solid, 50d-A (130 mg, 41% yield), by chiral preparative HPLC (Method G, Hex / EtOH = 90 / 10) and chiral HPLC (Method 8, Hex / EtOH = 90 / 10). R =8.69 min; and 50 d-B (130 mg, 41% yield) as a white solid, chiral HPLC (Method 8, Hex\EtOH=90\10) t R =10.39min.

[1225] Step 2. (S)-6-(cyclopropaneformamido)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazol-3-yl)amino)-N-(methyl-d3)nicotinamide (55A)

[1226] A mixture of 50d-A (120 mg, 0.41 mmol), Int. A (137 mg, 0.53 mmol), and TsOH.H2O (8 mg, 0.041 mmol) in 1,4-dioxane (1.5 mL) was stirred in N2 at 100 °C for 72 h. The reaction mixture was concentrated, and the residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give 55A (24.2 mg, 11.5% yield) as a yellow solid. LC-MS (ESI, Method 1) t R = 1.29 min, m / z (M+H) + = 513.1. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 11.69 (s, 1H), 10.97 (s, 1H), 9.02 (s, 1H), 8.75 (s, 1H), 8.56 ...

Claims

1. A compound having the structural formula (I): ###0001### or a pharmaceutically acceptable form or isotopic derivative thereof, wherein t is 0 or 1; ###0002### (II) wherein ring A and ring B are each independently aryl or heteroaryl; R and R' are each independently H or Ci-C6 alkyl or acyl, or R and R' together with the nitrogen atom to which they are bonded form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2. （I） 2. The compound of claim 1, wherein t is 1, having the structural formula: ###0003### 3. The compound of claim 1, wherein t is 0, having the structural formula: ###0004### Y 1 is CH, CF or N; Y 2 is CH or N; Y 3 is NR, O, CH2, CD2, CF2or O-NH; 4. The compound of any one of claims 1 to 3, wherein ring A is heteroaryl. ###0005### R 1 is H, F, CD3, or C 1-3 alkyl, provided that when Y 3 is N, O or O-NH, R 1 is not F; R 2 To R 2’ wherein, R 2’ C1-C6alkyl, C 3-6 cycloalkyl, C 5-7 spirocycloalkyl, or C 3-6 heterocycloalkyl, each substituted with 0-2 R 2a wherein R 2a is selected from the group consisting of halogen, CN, OR, NRR’, alkyl, cycloalkyl, and heterocycle; aryl or heteroaryl, each substituted with 0-2 R 2a substituents; (C=0)R 2b ; or (C=0)NHR 2b ; R 3 To wherein R is CH3. R is CD3. X 6 CR 6 or N; X 7 CR 7 or N; X 8 is C or N; X 9 CR 9 , O, S, N or NR 9 ; X 10 is CR 10 , O, S, N or NR 10 ; and wherein R is CH3. R 2b is C 1-6 alkyl, C 3-6 cycloalkyl, C 5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-4 R 2c substituents; R 2c independently at each occurrence is halogen, CN, OR, NRR', OCF3, CF3, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, R and R' are substituted with 0-3 R 2a ; and R 4 is C 1-3 alkyl, which is substituted with 0-5 R 4a , wherein R 4a is selected from D, F and Cl; R 5 is H, CN, halogen, OCH3, C(=0)OR, NHC(=0)R, NRR', NO2, C 1-6 alkyl, C 3-6 cycloalkyl or heterocycle, wherein the alkyl, cycloalkyl or heterocycle is substituted with 0-3 R 5a , wherein each R 5a is independently selected from OH, D, F, Cl, CN, CH2F, CHF2, CF3, OCH3, OCD3, OCF3, and OC(=0)CH3; R 6 , R 7 , R 9 , and R 10 are each independently selected from H, F, CI, CN, CD3, CH2CF3, CF3, OR, NRR', C 1-3 alkyl, and C 3-5 cycloalkyl, wherein said alkyl, cycloalkyl, R, and R' are substituted with 0-2 R 2a ; and R is CD3. R is C(=O)CH3 or C(=O)CD3. (III a ).

66. The compound of claim 1, having the structural formula: ###0006### (III b ).

67. The compound of claim 1, having the structural formula selected from the group consisting of: ###0007### 5. The compound of any one of claims 1 to 3, wherein, X 6 CH and X 7 CH, and R 3 has the structure: (I a ).

6. The compound of any one of claims 1 to 3, wherein, X 7 is CH and X 8 is C, and R 3 has the structure: (I b ).

7. The compound of any one of claims 1 to 3, wherein, X 6 is CH and X 8 is C, and R 3 has the structure: (I c ).

8. The compound of any one of claims 1 to 3, wherein, X 7 CH and X 10 CH, and R 3 having the structure: (I d ).

9. The compound of any one of claims 1 to 8, wherein, R 3 selected from the group consisting of:

10. The compound of claim 9, wherein, R 4 is CH3.

11. The compound of claim 9, wherein, R 4 CD3.

12. The compound of claim 9, wherein, R 3 is: (I e ).

13. The compound of any one of claims 1 to 12, wherein, R 10 is present, R 10 is H.

14. The compound of claim 9, wherein, R 3 is: (I f ).

15. The compound of any one of claims 1 to 14, wherein, R 9 is present, R 9 is C 1-3 alkyl or cyclopropyl, each of which is optionally substituted with C 1-3 alkoxy, CF3, or NRR'.

16. The compound of claim 15, wherein, R 9 is C 1-3 alkyl.

17. The compound of claim 16, wherein, R 9 is CH3.

18. The compound of claim 16, wherein, R 9 CD3.

19. The compound of any one of claims 1 to 18, wherein, R 5 is C 1-4 alkyl, which is substituted by OH.

20. The compound of any one of claims 1 to 18, wherein, R 5 is:

68. The compound of claim 1, having the structural formula selected from the group consisting of: ###0008### R 5’ is C 1-3 alkyl or cyclopropyl, which is substituted with 0 to 5 F; and R is H, C 1-3 alkyl or acyl.

21. The compound of claim 20, wherein, 69. The compound of claim 1, having the structural formula selected from the group consisting of: ###0009### 22. The compound of claim 20, wherein, 70. The compound of claim 1, having the structural formula selected from the group consisting of: ###0010### 23. The compound of any one of claims 1 to 18, wherein, R 5 is:

71. The compound of claim 1, having the structural formula selected from the group consisting of: ###0011### R 5’ is C 1-3 alkyl or cyclopropyl, which is substituted with 0 to 5 F; and R is H, C 1-3 alkyl or acyl.

24. The compound of claim 23, wherein, 72. The compound of claim 1, having the structural formula: ###0012### 25. The compound of claim 23, wherein, 73. The compound of claim 1, having the structural formula: ###0013### 26. The compound of claim 20 or 23, wherein, 74. The compound of claim 1, having the structural formula: ###0014### 27. The compound of any one of claims 20 to 26, wherein, R 5’ is CF3.

28. The compound of any one of claims 20 to 26, wherein, R 5’ is CHF2.

29. The compound of any one of claims 1 to 28, wherein Y 3 is NH.

30. The compound of claim 29, wherein Y is CH and Y is CH. 1 2 CH.​ (IV a ).

31. The compound of claim 29, wherein Y is CH and Y is N. 1 2 N.​ (IV b ).

32. The compound of claim 29, wherein Y 1 is N and Y 2 is CH. (IV c ).

33. The compound of claim 29, wherein Y 1 is N and Y 2 is N: (IV d ).

34. The compound of any one of claims 1 to 28, wherein Y 3 is O.

35. The compound of claim 34, wherein Y 1 is CH and Y 2 is CH. （V a ）。 36. The compound of claim 34, wherein Y 1 is CH and Y 2 is N: （V b ）。 37. The compound of claim 34, wherein Y 1 is N and Y 2 is CH. （V c ）。 38. The compound of claim 34, wherein Y 1 is N and Y 2 is N: （V d ）。 39. The compound of any one of claims 1 to 28, wherein Y 3 is CH2.

40. The compound of claim 39, wherein Y 1 is CH and Y 2 is CH. (VI a ).

41. The compound of claim 39, wherein Y 1 is CH and Y 2 is N: (VI b ).

42. The compound of claim 39, wherein Y 1 is N and Y 2 is CH: (VI c ).

43. The compound of claim 39, wherein Y 1 is N and Y 2 is N: (VI d ).

44. The compound of any one of claims 1 to 28, wherein Y 3 is CD2.

45. The compound of any one of claims 1 to 28, wherein Y 3 is CF2and t is 0.

46. The compound of claim 45, wherein Y 1 is CH and Y 2 is CH: (VII a ).

47. The compound of claim 45, wherein Y 1 is CH and Y 2 is N: (VII b ).

48. The compound of claim 45, wherein Y 1 is N and Y 2 is CH: (VII c ).

49. The compound of claim 45, wherein Y 1 is N and Y 2 is N: (VII d ).

50. The compound of any one of claims 1 to 49, wherein if R 6 and R 7 are present, R 6 and R 7 are H.

51. The compound of any one of claims 1 to 50, wherein, R 2 For R 2’ .

52. The compound of any one of claims 1 to 50, wherein, R 2 R is (C=O)R 2b .

53. The compound of claim 52, wherein, R 2b selected from C1-C6alkyl, which is substituted with 0 to 3 R 2c substituents.

54. The compound of claim 52, wherein, R 2b is C 3-6 cycloalkyl, which is substituted with 0 to 3 R 2c substituents.

55. The compound of claim 54, wherein, R 2b is cyclopropyl.

56. The compound of claim 54, wherein, R 2b is cyclopropyl, which is substituted by F.

57. The compound of claim 52, wherein, R 2b is C 5-7 spiro cycloalkyl, substituted with 0 to 3 R 2c substituents.

58. The compound of claim 57, wherein, R 2b is C5spiro[2.2]pentyl.

59. The compound of any one of claims 1 to 49, wherein, R 2 R2is H, (C=O)NHR, or (C=O)OR; 2b .

60. The compound of any one of claims 1 to 49, wherein, R 2 is pyridyl, which is substituted by 0 to 2 R 2c substituents.

61. The compound of any one of claims 1 to 49, wherein, R 2 is phenyl, which is substituted by 0 to 2 R 2c substituents.

62. The compound of any one of claims 1 to 49, wherein, R 2 is pyrazolyl, which is substituted with 0 to 2 R 2c substituents.

63. The compound of any one of claims 1 to 49, wherein, R 2 is pyrimidinyl, which is substituted with 0 to 2 R 2c substituents.

64. The compound of any one of claims 1 to 63, wherein, R 1 is CH3.

65. The compound of any one of claims 1 to 63, wherein, R 1 CD3.

75. The compound of claim 1, having the structural formula: ###0015### (IV 1 ) wherein X 6 is N or CH.

76. The compound of claim 1, having the structural formula: ###0016### 。 77. The compound of claim 1, having the structural formula selected from the group consisting of: ###0017### 。 78. The compound of claim 1, having the structural formula selected from the group consisting of: ###0018### 。 79. The compound of claim 1, having the structural formula selected from the group consisting of: ###0019### 。 80. The compound of claim 1, having the structural formula selected from the group consisting of: ###0020### 。 81. The compound of claim 1, having the structural formula selected from the group consisting of: ###0021### (IV 20 ) wherein R is H, CD3, C 1-3 alkyl or acyl.

82. The compound of claim 1, having the structural formula: ###0022### (IV 21 ) wherein R is H, CD3, C 1-3 alkyl or acyl.

83. The compound of claim 1, having the structural formula: ###0023### (IV 22 ) wherein R is H, CD3, C 1-3 alkyl or acyl.

84. The compound of claim 1, having the structural formula: ###0024### (IV 23 ) wherein R is H, CD3, C 1-3 alkyl or acyl.

85. The compound of claim 1, having the structural formula: ###0025### （V 1 ） wherein X 6 is N or CH.

86. The compound of claim 1, having the structural formula: ###0026### 。 87. The compound of claim 1, having the structural formula selected from the group consisting of: ###0027### 。 88. The compound of claim 1, having the structural formula selected from the group consisting of: ###0028### 。 89. The compound of claim 1, having the structural formula selected from the group consisting of: ###0029### 。 ​ 。 ​ （V 20 ） wherein, R is H, CD3, C 1-3 alkyl or acyl. ​ （V 21 ） wherein, R is H, CD3, C 1-3 alkyl or acyl. ​ （V 22 ） wherein, R is H, CD3, C 1-3 alkyl or acyl. ​ （V 23 ） wherein R is H, CD3, C 1-3 alkyl or acyl. ​ (VI 1 ) wherein X 6 is N or CH. ​ 。 ​ 。 ​ 。 90. The compound of claim 1 having a structural formula selected from the group consisting of: 。 91. The compound of claim 1 having a structural formula selected from the group consisting of: 。 92. The compound of claim 1 having a structural formula: (VII 1 ) wherein, X 6 is N or CH.

93. The compound of claim 1 having a structural formula: (VII 2 ) wherein X 6 is N or CH.

94. The compound of any one of claims 66-93, wherein, R 6 and R 7 are present, R 6 and R 7 are H.

95. The compound of any one of claims 1 to 94, wherein, R 9 is present, R 9 is C 1-3 alkyl or cyclopropyl, each of which is optionally substituted with C 1-3 alkoxy, CF3, or NRR'.

96. The compound of claim 95, wherein, R 9 is C 1-3 alkyl or cyclopropyl.

97. The compound of claim 96, wherein, R 9 is CH3.

98. The compound of claim 96, wherein, R 9 CD3.

99. The compound of any one of claims 66-98, wherein, R 2b is Ci-C6alkyl, cyclopropyl or cyclobutyl, which is substituted with 0 to 2 R 2c substituents.

100. The compound of claim 99, wherein, R 2b is cyclopropyl.

101. The compound of any one of claims 66-100, wherein, R 5 is: wherein R 5’ is C 1-3 alkyl or cyclopropyl, which is substituted with 0 to 5 F; and R is H, C 1-3 alkyl or acyl.

102. The compound of claim 101, wherein, R is H.

103. The compound of claim 101, wherein, R is CH3.

104. The compound of claim 101, wherein, R is CD3.

105. The compound of any one of claims 66-100, wherein, R 5 is: wherein R 5’ is C 1-3 alkyl or cyclopropyl, which is substituted with 0 to 5 F; and R is H, C 1-3 alkyl or acyl.

106. The compound of claim 105, wherein, R is H.

107. The compound of claim 105, wherein, R is CH3.

108. The compound of claim 105, wherein, R is CD3.

109. The compound of any one of claims 101 to 108, wherein, R 5’ is CF3.

110. The compound of any one of claims 101 to 108, wherein, R 5’ is CHF2.

111. The compound of any one of claims 101 to 108, wherein, R 5’ is C 2-3 alkyl, which is substituted with 2 to 5 F.

112. The compound of any one of claims 66-111, wherein, R 1 is CH3.

113. The compound of any one of claims 66 to 111, wherein, R 1 CD3.

114. A compound having a structural formula (VIII): (VIII) or a pharmaceutically acceptable form or isotopic derivative thereof, wherein X 6 CR 6 or N; X 7 CR 7 or N; X 8 is C or N; X 9 CR 9 , O, S, N or NR 9 ; X 10 CR 10 , O, S, N or NR 10 ; Y 1 is CH, CF or N; Y 2 is CH or N; Y 3 is NR, O, CH2, CD2, CF2or O-NH; Y 4 is NR, CH2or CF2; Y 5 NR, CH2, O, S, SO, or SO2; m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, and 3; ring A and ring B are each independently aryl or heteroaryl; ring C is a 5- or 6-membered aryl or heteroaryl; R 1 is H, F, CD3, or C 1-3 alkyl, provided that when Y 3 is N, O or O-NH, R 1 is not F; R 4 is C 1-3 alkyl, which is substituted with 0 to 5 R 4a wherein, R 4a selected from D, F and CI; R 5 is H, CN, halogen, OCH3, C(=0)OR, NHC(=0)R, NRR', NO2, C 1-6 alkyl, C 3-6 cycloalkyl or heterocycle, wherein the alkyl, cycloalkyl or heterocycle is substituted with 0 to 3 R 5a , wherein each R 5a is independently selected from OH, D, F, Cl, CN, CH2F, CHF2, CF3, OCH3, OCD3, OCF3, and OC(=0)CH3; R 6 , R 7 , R 9 , R 10 and R 11 are each independently selected from H, F, CI, CN, CD3, CH2CF3, CF3, OR, NRR', C 1-3 alkyl and C 3-5 cycloalkyl, wherein said alkyl, cycloalkyl, R and R' are substituted with 0 to 2 R 2a groups; R 2a selected from F, OCF3, CF3, CN, NO2, OR, NRR', and C 1-6 alkyl; and R and R' are each independently H, C1-C6 alkyl, or acyl, or R and R' together with the nitrogen or carbon atom to which they are bonded form a 3- to 6-membered ring containing 0 to 2 heteroatoms selected from O, NR, S, and SO2.

115. The compound of claim 114, wherein Y 1 is CH and Y 2 is CH.

116. The compound of claim 114, wherein Y 1 is N and Y 2 is CH.

117. The compound of claim 114, wherein Y 1 is CH and Y 2 is N.

118. The compound of claim 114, wherein Y 1 is N and Y 2 is N.

119. The compound of any one of claims 114 to 118, wherein Y 3 is NH.

120. The compound of any one of claims 114 to 118, wherein Y 3 is O.

121. The compound of any one of claims 114 to 118, wherein Y 3 is CH2.

122. The compound of any one of claims 114 to 118, wherein Y 3 is CD2.

123. The compound of any one of claims 114 to 122, wherein Y 4 is NH.

124. The compound of any one of claims 114 to 122, wherein Y 4 is CH2.

125. The compound of any one of claims 114 to 122, wherein, R 1 is CH3.

126. The compound of any one of claims 114 to 122, wherein, R 1 CD3.

127. The compound of any one of claims 114 to 126, wherein, R 4 is CH3.

128. The compound of any one of claims 114 to 126, wherein, R 4 CD3.

129. A compound selected from Table 1 or a pharmaceutically acceptable form or isotopic derivative thereof.

130. A pharmaceutical composition comprising a compound of any one of claims 1 to 129 effective to treat or reduce one or more diseases or disorders in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

131. The pharmaceutical composition of claim 130, which is suitable for oral administration.

132. The pharmaceutical composition of claim 130, which is suitable for topical administration.

133. The pharmaceutical composition of claim 130, which is suitable for GI-restricted administration.

134. The pharmaceutical composition of any one of claims 130 to 133, which is useful for treating or reducing one or more of an inflammatory disease, an immune-mediated disease, and a cancer, or a related disease or disorder.

135. The pharmaceutical composition of claim 134, wherein the disease or disorder is an inflammatory disease.

136. The pharmaceutical composition of claim 134, wherein the disease or disorder is an immune-mediated disease.

137. The pharmaceutical composition of claim 134, wherein the disease or disorder is a neuroinflammatory disease.

138. The pharmaceutical composition of claim 134, wherein the disease or disorder is a cancer.

139. The pharmaceutical composition of claim 134, wherein the disease or disorder is selected from the group consisting of inflammatory bowel disease, psoriasis, psoriatic arthritis, alopecia areata, eczema, ankylosing spondylitis (AS), vitiligo, atopic dermatitis, discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), systemic lupus erythematosus (SLE), Sjogren's syndrome, scleroderma, Crohn's disease (CD), rheumatoid arthritis (RA), T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma (CTCL), multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), type I diabetes, asthma, renal fibrosis, diabetic nephropathy, polycystic kidney disease, HIV-associated nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

140. A unit dosage form comprising the pharmaceutical composition of any one of claims 130-139.

141. The unit dosage form of claim 140, which is a tablet.

142. The unit dosage form of claim 140, which is a capsule.

143. The unit dosage form of claim 140, which is a topical formulation.

144. A method for treating, ameliorating, or preventing a disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-129, wherein the disease or disorder is selected from an inflammatory disease, an immune-mediated disease, a cancer, or a related disease or disorder thereof in a mammal, including a human.

145. The method of claim 144, wherein the disease or disorder is an inflammatory disease.

146. The method of claim 144, wherein the disease or disorder is an immune-mediated disease.

147. The method of claim 144, wherein the disease or disorder is a neuroinflammatory disease.

148. The method of claim 144, wherein the disease or disorder is a cancer.

149. The method of claim 144, wherein the disease or disorder is selected from the group consisting of inflammatory bowel disease, psoriasis, psoriatic arthritis, alopecia areata, eczema, ankylosing spondylitis (AS), vitiligo, atopic dermatitis, discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), systemic lupus erythematosus (SLE), Sjogren's syndrome, scleroderma, Crohn's disease (CD), rheumatoid arthritis (RA), T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma (CTCL), multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), type I diabetes, asthma, renal fibrosis, diabetic nephropathy, polycystic kidney disease, HIV-associated nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

150. The method of any one of claims 144 to 149, wherein administration is via oral administration.

151. The method of any one of claims 144 to 149, wherein administration is via topical administration.

152. The method of any one of claims 144 to 149, wherein administration is via Gl restricted administration.

153. Use of a compound of any one of claims 1 to 129, and a pharmaceutically acceptable excipient, carrier, or diluent, in the manufacture of a medicament for the treatment of a disease or disorder.

154. The use of claim 153, wherein the disease or disorder is one or more of an inflammatory disease, an immune-mediated disease, and a cancer.

155. The use of claim 154, wherein the disease or disorder is an inflammatory disease.

156. The use of claim 154, wherein the disease or disorder is an immune-mediated disease.

157. The use of claim 154, wherein the disease or disorder is a cancer.

158. The use of any one of claims 153 to 157, wherein the medicament is for oral administration.

159. The use of any one of claims 153 to 157, wherein the medicament is for topical administration.

160. The use of any one of claims 153 to 157, wherein the medicament is for Gl restricted administration.

161. A method of making a compound of any one of claims 1 to 129.

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