1H-pyrrolo[2,3-b]pyridine-4-yl]-2-oxopyrrolidine-3-carbonitrile derivatives as tyrosine kinase 2 (TYK2) inhibitors for the treatment of inflammatory diseases

Abstract

This disclosure relates to compounds of formula (I-1) or (I-2): This relates to TIFF2026513962000575.tif74102. The compounds of this disclosure can inhibit the activity of tyrosine kinase 2 (TYK2), for example, in inflammation, autoimmune diseases, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, head trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retina It is useful in treating diseases or disorders such as inflammation, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, autoimmune diseases, osteoporosis, multiple sclerosis, endometriosis, menstrual pain, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis, and sunburn. This disclosure further provides a method for preparing the compound.

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 457,857, filed Apr. 7, 2023. The entire contents of the foregoing application are hereby expressly incorporated herein by reference.

[0002] The present disclosure relates to inhibitors of tyrosine kinase 2 (TYK2) and pharmaceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, their use in the treatment of diseases, their use for the manufacture of pharmaceutical preparations, optionally in combination with a pharmaceutically acceptable carrier, the use of pharmaceutical preparations in the treatment of diseases, and methods of treating diseases, including administering a TYK2 inhibitor to a warm-blooded animal, particularly a human.

Background Art

[0003] Cytokines are small secreted proteins released by cells and have specific effects on cell-cell interactions and signal transduction. Cytokine pathways mediate a wide range of biological functions, mainly through extracellular signaling, including many aspects of inflammation and immunity.

[0004] Cytokine kinase 2 (TYK2) is a cytoplasmic protein kinase that associates with cytokine receptors and is a member of the Janus kinase (JAK) family, playing a central role in mediating cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1, and Yamaoka et al., Genome Biology 2004, 5, 253). The JAK family also includes JAK1, JAK2, and JAK3. More specifically, when cytokines engage with their homologous receptors, the activation of the JAK-associated receptor is induced, which leads to JAK-mediated tyrosine phosphorylation of signaling and transcriptional activator (STAT) proteins, and ultimately to transcriptional activation of specific gene sets (Schindler et al, 2007, J. Biol. Chem. 282:20059-63). Numerous cytokines known to activate the JAK family include the interferon (IFN) family (IFN-alpha, IFN-beta, IFN-omega, limtin, IFN-gamma, IL-10, IL-19, IL-20, IL-22), the glycoprotein (gp) 130 family (IL-6, IL-11, OSM, LlF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, leptin, IL-12, IL-23), the gamma C family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), the IL-3 family (IL-3, IL-5, GM-CSF), the single-strand family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and G protein-coupled receptors (AT1).

[0005] TYK2 is important in the signaling of type I interferons (e.g., IFN-alpha), IL-6, IL-10, IL-12, and IL-23 (Liang, Y. et al., Expert Opinion on Therapeutic Targets, 2014, 18, 5, 571-580; Kisseleva et al., 2002, Gene 285:1-24; and Watford, WT & O'Shea, JJ, 2006, Immunity 25:695-697). Consistent with this, primary cells derived from TYK2-deficient humans lack signaling for type I interferons, IL-6, IL-10, IL-12, and IL-23. TYK2 signals with other members of the JAK family in the following combinations: TYK2 / JAK1, TYK2 / JAK2, and TYK2 / JAK1 / JAK2.

[0006] Studies have shown that inappropriate JAK activity can result from mutations, overexpression, or improper regulation, dysregulation, or deregulation, as well as overproduction or underproduction of growth factors or cytokines, which can trigger a variety of biological cellular responses related to cell growth, differentiation, function, survival, apoptosis, and cell migration. Inappropriate JAK activity has been suggested to be associated with many diseases, including but not limited to cancer, cardiovascular disease, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease.

[0007] Small molecule JAK inhibitors have emerged as a major therapeutic advance in the treatment of autoimmune diseases. To date, all known small molecule JAK inhibitors that have progressed to development are active site-specific inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain of the JAK protein (also known as the JH1 or "Janus homology 1" domain). These inhibitors disrupt the catalytic activity of the kinase by blocking ATP, thereby interfering with downstream phosphorylation and the resulting pathway signaling (Bryan et al., J.Med.Chem. 2018, 61, 9030-9058).

[0008] Achieving high selectivity for specific JAK family members while maintaining intra-quinom selectivity is a significant challenge due to the high homology of ATP active sites across the entire quinom, and particularly within the JAK family. Consequently, many developed JAK inhibitors are either pan-JAK inhibitors or only slightly selective for one or more JAK family members. While these inhibitors have shown promising results in treating autoimmune diseases, undesirable side effects leading to narrow therapeutic indices have been observed, suggesting the need for improved treatment.

[0009] TYK2 has been shown to be important in the differentiation and function of several cell types crucial in inflammatory and autoimmune diseases, such as natural killer cells, B cells, and helper T cells. Abnormal TYK2 expression is associated with several autoimmune or inflammatory conditions.

[0010] There is still a need for potent compounds that exhibit high selectivity for TYK2 compared to other members of the JAK family. [Overview of the project]

[0011] One aspect of this disclosure relates to a compound of formula (I-1) or (I-2): [ka] or a pharmaceutically acceptable salt thereof, in the formula, Q1 and Q2 each independently represent either C or N. X1 is N, NR X1 , or CR X1 And, X2 is S, NR X2 , or CR X2 And, X3 is N, O, S, or CR X3 However, if X2 is S, then X3 cannot be S or O. X4 is N or CR X4and X5 is C-R X5 and X6 is N or C-R X6 and Y1 is N or C-R Y1 and Y2 is N-R Y2 or C-R Y2 and Y3 is N or C-R Y3 and Y4 is N or C-R Y4 and Y5 is C-R Y5 and Y6 is C-R Y6 and R X1 R X3 R X4 and R X6 are each independently H, halo, -CN, -NR 1a R 1b -OR 1c C 1-4 alkyl, and C 1-4 haloalkyl, and are selected from R X2 and R X5 are each independently H, halo, CN, -NR 1a R 1b -OR 1c C 1-6 alkyl, C 3-8 cycloalkyl, and R S and where C alkyl and C X2 R X5 represented by 1-6 alkyl and C 3-8 cycloalkyl are each optionally substituted with one or more R 8 and R Y1 R Y3 R Y4 and R Y6 are each independently H, halo, -CN, -NR 1a R 1b -OR 1c C 1-4 alkyl, and C 1-4Selected from haloalkyls, R Y2 and R Y5 These are H, Hal, -CN, and -NR, respectively, and are independent of each other. 1a R 1b , -OR 1c , C 1-6 Alkyl, C 3-8 Cycloalkyl, and R S Selected from, where R Y2 and R Y5 C represented by 1-6 Alkyl and C 3-8 Each cycloalkyl group contains one or more R 8 Replaced by optional selection, R S Independently, C 6-10 Selected from aryls, 4-7 membered monocyclic heterocyclines, and 5-10 membered heteroaryls, where R S C represented by 6-10 Aryls, 4- to 7-membered monocyclic heterocyclines, and 5- to 10-membered heteroaryls each contain one or more R 7 Replaced by optional selection, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 These are H, Hal, -CN, and -NR, respectively, and are independent of each other. 1a R 1b , -OR 1c , C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Selected from aryls, 4-10 membered heterocycloalkyls, and 5-10 membered heteroaryls, where R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 C represented by 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryls, 4-10 membered heterocycloalkyls, and 5-10 membered heteroaryls are classified as halo, -CN, and -NR, respectively.1a R 1b 、 -OR 1c 、 C 1-6 alkyl, and C 3-8 is optionally substituted with one or more substituents independently selected from cycloalkyl, and is R 7 is independently halo, -CN, -NR 1a R 1b 、 -NR 1a C(O)R 1d 、 -OR 1c 、 -C(O)OR 1c 、 -C(O)NR 1a R 1b 、 -SO2R 1e 、 C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 4- to 7-membered monocyclic heterocycloalkyl, 7- to 10-membered bicyclic heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein C 7 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 4- to 7-membered monocyclic heterocycloalkyl, 7- to 10-membered bicyclic heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with one or more R 7a ; Alternatively, two of R 7 together with their intervening atoms form a 3- to 7-membered monocyclic heterocyclyl optionally substituted with one or two substituents independently selected from C 1-6 alkyl and oxo(=O), R 7a is independently, each time it appears, halo, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, -NR 1a R 1b 、 -OR 1c 、 and 4- to 6-membered monocyclic heterocycloalkyl, wherein C 1-4Alkyl, C 3-6 Cycloalkyls and 4-6 membered monocyclic heterocycloalkyls are, respectively, C 1-3 Alkyl, -OR 1c , CN, and halo are optionally substituted with one or more substituents independently selected from the above. R 8 Each instance independently produces Halo, -CN, and -NR. 1a R 1b , -OR 1c , -C(O)OR 1c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 The aryl group is a 4-7 member monocyclic heterocycloalkyl group, or a 5-6 member heteroaryl group, where R 8 C represented by 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryls, 4-7 membered monocyclic heterocycloalkyls, and 5-6 membered heteroaryls are, respectively, halos and C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, -NR 1a R 1b , -OR 1c , and optionally substituted with one or more substituents independently selected from 4-6 membered monocyclic heterocycloalkyl groups, R 1a and R 1b These are, independently, H or C 1-4 It is alkyl, R 1c H, C 1-4 Alkyl or C 1-4 It is a haloalkyl, R 1d C 1-4 Alkyl or -OR 1e And, R 1e C 1-4 It is alkyl, Here, R X1 , R X2 , RX3 , R X4 , R X5 , and R X6 At least one of them is R, not H. Y1 , R Y2 , R Y3 , R Y4 , R Y5 , and R Y6 At least one of them is not H.

[0012] In one embodiment, the present disclosure is a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0013] Another aspect of the present disclosure is a method for inhibiting TYK2 activity in a subject in which TYK2 activity needs to be inhibited, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0014] In some embodiments, the present disclosure is a method for treating a disease or disorder in which inhibition of TYK2 is effective, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0015] This disclosure also includes the use of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the manufacture of agents for inhibiting TYK2 activity. It also includes the use of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the manufacture of agents for treating diseases or disorders that respond to inhibition of TYK2.

[0016] This disclosure also provides compounds described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described herein, used for inhibiting TYK2 activity. It also provides compounds described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described herein, used for treating diseases or disorders that respond to inhibition of TYK2.

[0017] Other features or advantages will become apparent from the following detailed description of some embodiments and, further, from the appended claims. [Modes for carrying out the invention]

[0018] The compounds or pharmaceutically acceptable salts described herein exhibit high efficacy against TYK2. In addition, the compounds or pharmaceutically acceptable salts of the compounds disclosed herein have higher selectivity for TYK2 inhibition compared to other members of the JAK family, such as JAK1, JAK2, and JAK3.

[0019] Compounds and compositions In the first embodiment, the present disclosure relates to a compound of formula (I-1) or (I-2): [ka] The present invention provides a pharmaceutically acceptable salt thereof, wherein the variables in formula (I-1) or (I-2) are as described in the first embodiment.

[0020] In the second embodiment, with respect to a compound of formula (I-1) or (I-2), or a pharmaceutically acceptable salt thereof, (i) Is Q1 C and Q2 C? (ii) Q1 is N and Q2 is C, or (iii) Q1 is C, Q2 is N, and the remaining variables are as described in the first embodiment.

[0021] In the third embodiment, with respect to the compound of formula (I-1) or a pharmaceutically acceptable salt thereof, (i)X1 is CR X1 And X2 is CR X2 Therefore, X4 is N or CR X4 And X5 is CR X5 X6 is N, and X3 is N, S, O, and CR. X3 Selected from, or (ii) X1 is N and X2 is CR X2 Therefore, X4 is N or CR X4 And X5 is CR X5 X6 is CR Y6 X3 is N, S, and CR X3 The variables are selected from the above, and the remaining variables are as described in the first or second embodiment.

[0022] In the fourth embodiment, for the compound of formula (I-1) or a pharmaceutically acceptable salt thereof, R X2 and R X5 One of them is R S The other is H, and the remaining variables are as described in the third embodiment.

[0023] In the fifth embodiment, with respect to the compound of formula (I-2) or a pharmaceutically acceptable salt thereof, (i) Y1 is N and Y2 is NR Y2 Y3 is N, and Y4 is CR. Y4 And Y5 is CR Y5 Therefore, Y6 is CR Y6 Is it, (ii) Y1 is CR Y1 And Y2 is NR Y2 Y3 is N, and Y4 is CR. Y4 And Y5 is CR Y5 Therefore, Y6 is CR Y6 Is it, (iii) Y1 is CR Y1 And Y2 is CR Y2 Y3 is N, and Y4 is CR. Y4 And Y5 is CR Y5 Therefore, Y6 is CR Y6is, or (iv) Y1 is N and Y2 is NR Y2 And Y3 is CR Y3 Y4 is N, and Y5 is CR. Y5 Therefore, Y6 is CR Y6 The remaining variables are as described in the first or second embodiment.

[0024] In the sixth embodiment, for the compound of formula (I-2) or a pharmaceutically acceptable salt thereof, R Y2 and R Y5 One of them is R S The other is H, and the remaining variables are as described in the fifth embodiment.

[0025] In the seventh embodiment, the compound of the present disclosure has the following formula: [ka] [ka] It is represented by one of the following, or a pharmaceutically acceptable salt thereof, where the variables in formulas (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), and (II-17) are as described in the first embodiment.

[0026] In the eighth embodiment, for a compound of formula (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), or (II-17), or a pharmaceutically acceptable salt thereof, R X2 R is a 4-7 member monocyclic heterocyclyl or a 5-10 member heteroaryl, where R X2A 4-7 member monocyclic heterocyclyl or a 5-10 member heteroaryl represented by is each one or two R 7 Replaced by any choice, R X5 If present, it is H, and the remaining variables are as described in the first, second, third, fourth, or seventh embodiment.

[0027] In the ninth embodiment, for a compound of formula (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), or (II-17), or a pharmaceutically acceptable salt thereof, R X5 R is a 4-7 member monocyclic heterocyclyl or a 5-10 member heteroaryl, where R X5 A 4-7 member monocyclic heterocyclyl or a 5-10 member heteroaryl represented by is each one or two R 7 Replaced by any choice, R X2 If present, it is H, and the remaining variables are as described in the first, second, third, fourth, or seventh embodiment above.

[0028] In the tenth embodiment, the compound of the present disclosure is given by the following formula: [ka] It is represented by one of the following, or a pharmaceutically acceptable salt thereof, where the variables in formulas (II-1), (II-2), (II-3), (II-4), and (II-5) are as described in the first embodiment.

[0029] In the eleventh embodiment, for a compound of formula (I-1), (I-2), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R Y2 R S And R SR is a 4-7 member monocyclic heterocyclyl or a 5-10 member heteroaryl, where R S A 4-7 member monocyclic heterocyclyl or a 5-10 member heteroaryl represented by is each one or two R 7 Replaced by any choice, R Y5 is H, and the remaining variables are as described in the first, second, fifth, sixth, or tenth embodiment.

[0030] In the twelfth embodiment, for a compound of formula (I-1), (I-2), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R Y5 R S And R S R is a 4-7 member monocyclic heterocyclyl or a 5-10 member heteroaryl, where R S A 4-7 member monocyclic heterocyclyl or a 5-10 member heteroaryl represented by is each one or two R 7 Replaced by any choice, R Y2 is H, and the remaining variables are as described in the first, second, fifth, sixth, or tenth embodiment.

[0031] In the 13th embodiment, for a compound of formula (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R S The following are selected from pyrazine, pyridazine, pyridine, pyridine-2(1H)-one, pyrazole, pyrazolopyridine, pyrimidine, pyrrolopyridine, isoxazole, imidazole, imidazopyridine, indazole, thiazole, triazole, thiazolopyridine, and triazolopyridine, each of which is R7 One or two of these are optionally substituted, and the remaining variables are as described in the 8th, 9th, 11th, or 12th embodiment.

[0032] In the 14th embodiment, for a compound of formula (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R S teeth, [ka] [ka] [ka] Selected from, in the formula, [ka] This represents a combination to X2, X5, Y2, or Y5. n represents 0, 1, or 2. m represents 0 or 1, and the remaining variables are as described in the 8th, 9th, 11th, or 12th embodiment.

[0033] In the 15th embodiment, for compounds of formula (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or pharmaceutically acceptable salts thereof, R 7 These are independently: Halo, -CN, -NR 1a R 1b , -NR 1a C(=O)R 1d , -OR 1c -C(O)NR 1a R 1b , -SO2R 1e , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyls, 4-7 membered monocyclic heterocycloalkyls, 7-8 membered bicyclic heterocycloalkyls, and 5-6 membered heteroaryls, where R 7 C represented by 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyls, 4-7 membered monocyclic heterocycloalkyls, 7-8 membered bicyclic heterocycloalkyls, and 5-6 membered heteroaryls each have 1-3 R groups. 7a Replaced by optional selection, Alternatively, R 7 Two of them, together with those intervening atoms, C 1-6 It forms a 3- to 7-membered monocyclic heterocycline which is optionally substituted with one or two substituents independently selected from alkyl and =O, R 7a Each instance, independently, C 1-3 Alkyl, Halo, -CN, -OR 1c , C 3-6 Selected from cycloalkyls and 4-6 membered monocyclic heterocycloalkyls, where R 7aC represented by 1-3 Alkyl, C 3-6 Cycloalkyls and 4-6 membered monocyclic heterocycloalkyls are, respectively, C 1-3 Optionally substituted with one or two substituents independently selected from alkyl, -OH, and CN, R 1a and R 1b These are, independently, H or C 1-4 It is alkyl, R 1c is H or C 1-4 Alkyl or C 1-4 It is a haloalkyl, R 1d C 1-4 Alkyl or -OR 1e And, R 1e C 1-4 It is alkyl, and the remaining variables are as described in the 8th, 9th, 11th, 12th, 13th, or 14th embodiment. In some embodiments, R 7 C 1-6 It is an alkyl group, where one or more hydrogen atoms are replaced by deuterium.

[0034] In the sixteenth embodiment, for a compound of (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R 7are independently Cl, F, -CN, -OH, -OCH3, -O-CHF2, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CHF2, -CH2CHF2, -CF3, -CH2-OH, -CH(OH)-CH3, -CH2O CH3, -CH2CH2OCH2CH3, -CH2-CN, -N(CH3)2, -C(O)-NH-CH3, -C(O)-N(CH3)2, -NH-C(O)-CH3, -N(CH3)-C(O)-OC(CH3)3, -SO2-CH3, [ka] Selected from, in the formula, [ka] R S This represents a coupling to , and the remaining variables are as described in the eighth, ninth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

[0035] In the 17th embodiment, for a compound of formula (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R 7 Two of them, together with those intervening atoms, C 1-6 The molecules form a 3- to 7-membered monocyclic heterocycline which is optionally substituted with one or two substituents independently selected from alkyl and =O, the remaining variables as described in the 8th, 9th, 11th, 12th, 13th, or 14th embodiment.

[0036] In the 18th embodiment, for a compound of formula (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R S teeth, [ka] Selected from, in the formula, [ka] represents a coupling to X2, X5, Y2, or Y5, and the remaining variables are as described in the 17th embodiment.

[0037] In the 19th embodiment, for a compound of formula (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 These are H, -CN, and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyls and 4-6 member heterocycloalkyls, C 1-6 Alkyl is -CN or -OR 1f Replaced by any choice, R 1f C 1-4It is alkyl, and the remaining variables are as described in the embodiments of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

[0038] In the 20th embodiment, for a compound of formula (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 These are, independently, H, CN, -CH3, -CH2CH3, cyclopropyl, cyclobutyl, -CHF2, -CH2-O-CH3, CH2-CN, and [ka] The variables are selected from the above, and the remaining variables are as described in the 19th embodiment.

[0039] In the 21st embodiment, for a compound of formula (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R 1 and R 2 These are H, CN, and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl, C3-6 Selected from cycloalkyls and 4-10 member heterocycloalkyls, where C 1-6 Alkyl is -CN or -OR 1f Replaced by any choice, R 3 and R 4 These are H and C, respectively, independently. 1-6 Alkyl and C 1-6 Selected from haloalkyl, R 5 and R 6 These are, independently, H or C 1-6 It is alkyl, R 1f C 1-4 It is alkyl, and the remaining variables are as described in the embodiments of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

[0040] In the 22nd embodiment, for a compound of formula (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R 1 and R 2 These are, independently, H, CN, -CH3, -CH2CH3, -CHF2, cyclopropyl, cyclobutyl, -CH2-O-CH3, -CH2-CN, and [ka] Selected from, R 3 and R 4 Each is independently selected from H, -CH3, -CH2CH3, and -CHF2, and R 5 and R 6 These are independently selected from H, -CH3, and -CH2CH3, and the remaining variables are as described in the 21st embodiment.

[0041] In the 23rd embodiment, for a compound of formula (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R X1 , R X3 , R X4 , and R X6 These are H, Halo, and C, respectively, independently. 1-4 Selected from alkyl, R Y1 , R Y3 , R Y4 , and R Y6 These are H, Halo, and C, respectively, independently. 1-4 Selected from alkyl, the remaining variables are as described in the embodiments of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, or 22nd embodiment.

[0042] In the 24th embodiment, for a compound of formula (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R X1 , R X3 , R X4 , and R X6 Each is independently selected from H, Cl, F, and CH3, and R Y1 , R Y3 , R Y4 , and RY6 Each of these is independently selected from H, Cl, F, and CH3, and the remaining variables are as described in the 23rd embodiment.

[0043] In the 24th embodiment, for a compound of formula (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (III-3), (III-4), or (III-5), or a pharmaceutically acceptable salt thereof, R X1 , R X3 , R X4 , and R X6 H is R Y1 , R Y3 , R Y4 , and R Y6 H is the remaining variable, as described in the 23rd embodiment.

[0044] In the 26th embodiment, the compound of the present disclosure is of the following formula: [ka] It is represented by one of the following, or a pharmaceutically acceptable salt thereof, in the formula, R X1 H or halo, R X2 is one or two R 7 It is a 5-member heteroaryl that is optionally substituted, R X3 H or halo, R X5 is one or two R 7 A 5-membered or 6-membered heteroaryl that is optionally substituted, R Y2 is one or two R 7 It is a 5-member heteroaryl that is optionally substituted, R1 and R 2 These are, independently, -CN or C 3-6 It is a cycloalkyl, R 3 and R 4 These are, independently, H or C 1-3 It is alkyl, and the remaining variables are as described in the first embodiment.

[0045] In the 27th embodiment, for a compound of formula (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), or a pharmaceutically acceptable salt thereof, R X2 , R X5 , or R Y2 A 5-membered or 6-membered heteroaryl represented by is a pyrazole or pyridine, each of which is one R 7 The variables are optionally replaced, and the remaining variables are as described in the 26th embodiment.

[0046] In the 28th embodiment, for a compound of formula (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), or a pharmaceutically acceptable salt thereof, R X2 , R X5 , or R Y2 A 5-membered or 6-membered heteroaryl represented by the following: The formula: [ka] It is represented by one of the following variables, and the remaining variables are as described in the 26th embodiment.

[0047] In the 29th embodiment, for a compound of formula (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), or a pharmaceutically acceptable salt thereof, R 7 Hello, C 1-4 Alkyl, C 1-4A haloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from oxygen and nitrogen, the remaining variables being as described in the 27th or 28th embodiment.

[0048] In the 30th embodiment, for a compound of formula (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), or a pharmaceutically acceptable salt thereof, R 7 These are F, -CH3, -CHF2, -CH2CH3, or [ka] The remaining variables are as described in the 29th embodiment.

[0049] In the 31st embodiment, for a compound of formula (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), or a pharmaceutically acceptable salt thereof, R 1 is CN, and R 2 C 3-6 It is cycloalkyl, R 3 H is R 4 C 1-3 It is alkyl, and the remaining variables are as described in the 26th, 27th, 28th, 29th, or 30th embodiment.

[0050] In the 32nd embodiment, for a compound of formula (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), or a pharmaceutically acceptable salt thereof, R 1 is CN, and R 2 It is cyclopropyl, and R 3 H is R 4 is -CH3, and the remaining variables are as described in the 21st embodiment.

[0051] In the 33rd embodiment, the disclosure provides compounds described herein (for example, compounds described in any one of Examples 1 to 358) or pharmaceutically acceptable salts thereof.

[0052] In the 34th embodiment, this disclosure is as follows: (3R,4S)-3-cyclopropyl-4-methyl-1-[2-(1-methylpyrazole-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-2-oxopyrrolidine-3-carbonitrile, (3R)-3-cyclopropyl-1-[2-(1-methylpyrazole-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3S)-3-cyclopropyl-1-[2-(2-methoxypyridine-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3S)-3-cyclopropyl-1-[2-(1-methylpyrazole-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R)-3-cyclopropyl-1-[2-(2-methoxypyridine-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-2-oxopyrrolidine-3-carbonilicate, rac-(3R)-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazine-4-yl]-2-oxopyrrolidine-3-carbonitrile, (3S)-3-cyclopropyl-1-[6-(2-methoxypyridine-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3S)-3-cyclopropyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3S)-3-cyclopropyl-1-[6-[1-(difluoromethyl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3S)-3-cyclopropyl-1-[6-(3-methyl-1,2-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile, (3S)-3-cyclopropyl-1-[6-(3-fluoro-1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R)-3-cyclopropyl-1-[6-(2-methoxypyridine-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R)-3-cyclopropyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R)-3-cyclopropyl-3-(difluoromethyl)-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrroridine-2-one, (3R,5R)-3-cyclopropyl-5-methyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3S,5R)-3-cyclopropyl-5-methyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3S,5R)-3-cyclopropyl-5-ethyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3S,5S)-3-cyclopropyl-5-ethyl-1-[6-(2-methyl-2H-imidazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile, (3S,4S)-4-methyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-3-(oxetan-3-yl)-2-oxopyrrolidine-3-carbonitrile, (3S,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4R)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-ethyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4R)-3-cyclopropyl-4-ethyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile, (3S,4R)-3-cyclopropyl-4-ethyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3S,4S)-3-cyclopropyl-4-ethyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, 2-[(3R)-3-cyclopropyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazine-4-yl]-2-oxopyrrolidine-3-yl]acetonitrile, (3R,4S)-3-cyclopropyl-1-[7-fluoro-6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3S,4R)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,5S)-3-cyclopropyl-5-methyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3S,5S)-3-cyclopropyl-5-methyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,5S)-3-cyclopropyl-5-ethyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,5R)-3-cyclopropyl-5-ethyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-(difluoromethyl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, rel-(3R)-3-cyclopropyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrroridine-2-one, rel-(3R)-3-cyclopropyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrroridine-2-one, (3S)-3-methyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R)-3-methyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile, rel-(3R)-3-(methoxymethyl)-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazine-4-yl]-2-oxopyrrolidine-3-carbonitrile, rel-(3R)-3-(methoxymethyl)-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazine-4-yl]-2-oxopyrrolidine-3-carbonitrile, rel-(3R)-3-ethyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile, rel-(3R)-3-ethyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile, rel-(3R)-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazine-4-yl]-3-(oxetan-3-yl)-2-oxopyrrolidine-3-carbonitrile, rel-(3R)-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazine-4-yl]-3-(oxetan-3-yl)-2-oxopyrrolidine-3-carbonitrile, rel-(3R)-3-cyclobutyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazine-4-yl]-2-oxopyrrolidine-3-carbonitrile, rel-(3R)-3-cyclobutyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazine-4-yl]-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-1-[6-(6-methoxypyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(2-methylpyrazole-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[2-(difluoromethoxy)pyridine-3-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-(6-imidazo[1,5-a]pyridine-6-ylpyrrolo[1,2-b]pyridazine-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(6-methylsulfonylpyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(5-hydroxypyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylindazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylindazole-5-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(2-fluoropyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-([1,2,4]triazolo[1,5-a]pyridine-6-yl)pyrrolo[1,2-b]pyridazine-4-yl]pyrrolidine-3-carbonilicate, 5-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazine-6-yl]-N-methylpyridine-2-carboxamide, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1H-pyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(6-pyridine-3-ylpyrrolo[1,2-b]pyridazin-4-yl)pyrrolidine-3-carbonitrile, N-[4-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazine-6-yl]pyridin-2-yl]acetamide, (3R,4S)-3-cyclopropyl-1-[6-[6-(dimethylamino)pyridine-3-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrroridine-3-carbonitrile, (3R,4S)-3-cyclopropyl-1-[6-(2-methoxypyridine-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1H-pyrazole-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(6-methylpyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylindazole-6-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-[2-(trifluoromethyl)pyridine-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-[5-(trifluoromethyl)pyridine-3-yl]pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(5-methylpyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonitrile (3R,4S)-3-cyclopropyl-1-[6-(2-fluoropyridine-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-[6-(trifluoromethyl)pyridine-3-yl]pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1H-pyrazolo[3,4-b]pyridine-5-yl)pyrrolo[1,2-b]pyridazine-4-yl]pyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(2-methoxypyrimidine-5-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(2-methylpyridine-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylindazole-7-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methyl-2-oxopyrridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(2-methylpyrimidine-5-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(6-fluoropyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(5-methoxypyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methyl-6-oxopyrridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(5-fluoropyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, 5-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazin-6-yl]-2-methoxypyridine-3-carbonitrile, 5-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazin-6-yl]pyridin-2-carbonitrile;2,2,2-trifluoroacetic acid, (3R,4S)-1-[6-(5-chloropyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (3R,4S)-3-cyclopropyl-1-(6-imidazo[1,2-a]pyridine-6-ylpyrrolo[1,2-b]pyridazine-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(3-methylimidazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, N-[5-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazine-6-yl]pyridin-3-yl]acetamide, (3R,4S)-3-cyclopropyl-1-[6-[2-(dimethylamino)pyrimidine-5-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(6-pyrimidine-5-ylpyrrolo[1,2-b]pyridazin-4-yl)pyrrolidine-3-carbonilicate, 4-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazine-6-yl]pyridine-2-carbonitrile, (3R,4S)-3-cyclopropyl-1-[6-(5-fluoro-2-methoxypyridine-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, tert-butyl N-[5-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazin-6-yl]pyridin-2-yl]-N-methylcarbamate, (3R,4S)-3-cyclopropyl-1-[6-(2-methoxypyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-(oxetan-3-yl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(3,6-dimethoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(2-methyltriazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-[2-(difluoromethyl)-1,3-thiazole-5-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-([1,3]thiazolo[4,5-c]pyridine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, 3-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazine-6-yl]imidazo[1,2-a]pyridine-7-carbonitride; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(6-pyrazolo[1,5-a]pyridine-2-ylpyrrolo[1,2-b]pyridazin-4-yl)pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonitriel; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[2-methyl-5-(trifluoromethyl)pyrazole-3-yl]pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-([1,2,4]triazolo[1,5-a]pyridine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(2,3-dihydropyrazolo[5,1-b][1,3]oxazole-6-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylimidazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methyltriazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(4-methyl-1,3-thiazole-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, 2-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazin-6-yl]-1,3-thiazole-4-carbonitrile;2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methyl-1,2,4-triazole-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-(6-imidazo[1,2-a]pyrazine-3-ylpyrrolo[1,2-b]pyridazin-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, 2-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazin-6-yl]-1,3-thiazole-5-carbonitride; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(5-methyl-1,3-thiazole-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, 6-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazin-6-yl]-2-methylpyridine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-[4-(trifluoromethyl)pyrimidine-2-yl]pyrrolo[1,2-b]pyridazin-4-yl]pyrroridine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-[6-(trifluoromethyl)pyrimidine-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(4-methoxypyrimidine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-(6-imidazo[1,2-a]pyrazine-8-ylpyrrolo[1,2-b]pyridazin-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, 6-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazin-6-yl]-N,N-dimethylpyridine-3-carboxamide; 2,2,2-trifluoroacetic acid, (3R,4S)-1-[6-[6-(cyanomethyl)pyridine-2-yl]pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(6-methoxypyrazine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-1-[6-[5-(cyanomethyl)pyridine-2-yl]pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-(6-imidazo[1,5-a]pyridine-5-ylpyrrolo[1,2-b]pyridazin-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, 2-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazin-6-yl]-4-hydroxypyridine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-[5-(1-hydroxyethyl)pyridine-2-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, N-[6-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazin-6-yl]pyridin-2-yl]acetamide; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(5-methoxypyrazine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, 6-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazin-6-yl]pyrazine-2-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-[5-(dimethylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-[6-(difluoromethyl)pyridine-2-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(5-methoxypyrimidine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(6-methylpyridazin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(3-fluoropyridine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(6-pyrimidine-2-ylpyrrolo[1,2-b]pyridazin-4-yl)pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(3-hydroxy-6-methylpyridine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-(6-imidazo[1,2-a]pyridine-5-ylpyrrolo[1,2-b]pyridazin-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(5-fluoro-4-methylpyridine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(6-methoxypyridine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, 6-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrrolo[1,2-b]pyridazin-6-yl]-4-methylpyridine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(5-methoxypyridine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(3-methoxypyridine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(5-fluoro-6-methylpyridine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-[4-(hydroxymethyl)pyridine-2-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(3-hydroxypyridine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-[5-(hydroxymethyl)pyridine-2-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(6-pyrazine-2-ylpyrrolo[1,2-b]pyridazin-4-yl)pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, rac-(3R,4R)-3-cyclopropyl-4-(difluoromethyl)-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, rac-(3R,4S)-3-cyclopropyl-4-(difluoromethyl)-1-[6-(1-methylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-[(1RS)-2,2-difluorocyclopropyl]pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-[(1R*)-2,2-difluorocyclopropyl]pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-[(1R*)-2,2-difluorocyclopropyl]pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-(3,3-difluorocyclobutyl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1-pyridine-2-ylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonitol, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1-pyridine-3-ylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonitol, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1-pyridine-4-ylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonitol, (3R,4S)-3-cyclopropyl-1-[6-(1-cyclopropylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-[1-[(3RS)-oxolan-3-yl]pyrazole-4-yl]pyrrolo[1,2-b]pyridazine-4-yl]pyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylsulfonylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-[1-(triduteriomethyl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]pyrroridine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(1,3-dimethylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-1-[6-(1,5-dimethylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1-propan-2-ylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrroridine-3-carbonitrile (3R,4S)-1-[6-[1-(cyanomethyl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-1-[6-(1-cyclohexylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-1-[6-(1-cyclopentylpyrazole-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-1-[6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-(2-ethoxyethyl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(6-ethylpyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(4-ethylpyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-[6-(difluoromethoxy)pyridine-3-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[5-(difluoromethoxy)pyridine-3-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(2-ethylpyridine-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-[4-(trifluoromethyl)pyridine-3-yl]pyrrolo[1,2-b]pyridazin-4-yl]pyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-yl]-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-4-methyl-1-[2-(1-methylpyrazole-4-yl)-3H-imidazo[4,5-b]pyridine-7-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[2-(1-methylpyrazole-4-yl)imidazo[1,2-b]pyridazine-8-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-2-(1-methylpyrazole-4-yl)imidazo[1,2-b]pyridazin-8-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-(difluoromethyl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[3-methyl-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(1-ethylpyrazole-4-yl)-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-(difluoromethyl)pyrazole-4-yl]-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-(1-propan-2-ylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-[(3RS)-oxolan-3-yl]pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(6-methoxypyridine-2-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(6-pyridine-3-ylpyrazolo[1,5-a]pyrazine-4-yl)pyrrolidine-3-carbonitol, 5-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrazolo[1,5-a]pyrazine-6-yl]pyridine-2-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(5-fluoro-2-methoxypyridine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, 4-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrazolo[1,5-a]pyrazine-6-yl]pyridine-2-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-[(1RS)-2,2-difluorocyclopropyl]pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(1,5-dimethylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1,3,5-trimethylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]pyrrolidine-3-carbonitol, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-[1-(triduteriomethyl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]pyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(1-ethylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-(oxan-4-yl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]pyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyrazine-4-yl]pyrrolidine-3-carbonitol, (3R,4S)-1-[3-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-(1-bicyclo[1.1.1]pentanyl)pyrazole-4-yl]-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(1,3-dimethylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(2,4-dimethyl-1,3-thiazole-5-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-(difluoromethyl)-6-oxopyrridin-3-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-(triduteriomethyl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(3-fluoropyridine-2-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(5-methoxypyridine-2-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(2-methyl-1,3-thiazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[2-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-(1-cyclopentylpyrazole-4-yl)-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-(oxan-4-yl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-(1-cyclohexylpyrazole-4-yl)-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-1-[6-[1-(cyanomethyl)pyrazole-4-yl]-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(1,5-dimethylpyrazole-4-yl)-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-(3-fluoro-6-pyridine-3-ylpyrazolo[1,5-a]pyrazine-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-(5-methoxypyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(6-methoxypyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylindazole-5-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(2-fluoropyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, 5-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrazolo[1,5-a]pyrazine-6-yl]-N-methylpyridine-2-carboxamide; 2,2,2-trifluoroacetic acid, N-[4-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrazolo[1,5-a]pyrazine-6-yl]pyridine-2-yl]acetamide, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyrazine-4-yl]pyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(2-methoxypyridine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1H-pyrazole-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(6-methylpyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-[2-(trifluoromethyl)pyridine-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(4-methyl-3-oxopyrido[3,2-b][1,4]oxazin-7-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(5-methylpyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(2-fluoropyridine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-[6-(trifluoromethyl)pyridine-3-yl]pyrazolo[1,5-a]pyrazine-4-yl]pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(2-methyl-1,3-thiazole-5-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(2-methoxypyrimidine-5-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(2-methylpyridine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylindazole-7-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(6-fluoropyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(5-methoxypyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methyl-6-oxopyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(5-fluoropyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(1H-imidazole-2-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-1-[6-(5-chloropyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, N-[5-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrazolo[1,5-a]pyrazine-6-yl]pyridine-3-yl]acetamide; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(2-methoxypyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-(oxetan-3-yl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, 4-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrazolo[1,5-a]pyrazine-6-yl]-N-methylpyridine-2-carboxamide; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(3,6-dimethoxypyridazin-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(2-methylpyrazole-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(6-fluoropyridine-2-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-[2-(difluoromethoxy)pyridine-3-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(6-methylsulfonylpyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(5-hydroxypyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylindazole-6-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-[5-(trifluoromethyl)pyridine-3-yl]pyrazolo[1,5-a]pyrazine-4-yl]pyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methyl-2-oxopyridine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, 5-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrazolo[1,5-a]pyrazine-6-yl]-2-methoxypyridine-3-carbonitrile;2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-(6-imidazo[1,2-a]pyridine-6-ylpyrazolo[1,5-a]pyrazine-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-[2-(dimethylamino)pyrimidine-5-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(6-pyrimidine-5-ylpyrazolo[1,5-a]pyrazine-4-yl)pyrrolidine-3-carbonnitrile; 2,2,2-trifluoroacetic acid, tert-butyl N-[5-[4-[(3R,4S)-3-cyano-3-cyclopropyl-4-methyl-2-oxopyrrolidine-1-yl]pyrazolo[1,5-a]pyrazine-6-yl]pyridine-2-yl]-N-methylcarbamate; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-1-[6-(6-hydroxypyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid, (3R,4S)-3-cyclopropyl-4-methyl-1-[2-(1-methylpyrazole-4-yl)flo[3,2-b]pyridine-7-yl]-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-4-methyl-1-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-(difluoromethyl)pyrazole-4-yl]-3-fluoropyrazolo[1,5-a]pyridine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[2-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl]-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-4-methyl-1-[2-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-7-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[5-(1-methylpyrazole-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[1-(1-methylpyrazole-4-yl)pyrazolo[3,4-c]pyridine-3-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[1-[1-(difluoromethyl)pyrazole-4-yl]pyrazolo[3,4-c]pyridine-3-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[1-(1-ethylpyrazole-4-yl)pyrazolo[3,4-c]pyridine-3-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[1-[1-(oxetan-3-yl)pyrazole-4-yl]pyrazolo[3,4-c]pyridine-3-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[1-(1-methyl-6-oxopyrridin-2-yl)pyrazolo[3,4-c]pyridine-3-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[1-(1-propan-2-ylpyrazole-4-yl)pyrazolo[3,4-c]pyridine-3-yl]pyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[1-(2-methylpyridine-4-yl)pyrazolo[3,4-c]pyridine-3-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[1-(6-methylpyridine-3-yl)pyrazolo[3,4-c]pyridine-3-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[3-(1-methylpyrazole-4-yl)pyrrolo[1,2-a]pyrimidine-6-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-4-yl)-[1,3]thiazolo[5,4-c]pyridine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[7-(1-methylpyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-4-yl)thieno[3,2-d]pyrimidine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[7-(1-methylpyrazole-4-yl)imidazo[1,2-a]pyridine-5-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[5-(1-methylpyrazole-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-2-oxopyrrolidine-3-carbonil, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-(2-oxaspiro[3,3]heptan-6-yl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-(3,3-difluorocyclobutyl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-(oxetan-3-yl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-(3-cyanocyclobutyl)pyrazole-4-yl]-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-(3-cyanocyclobutyl)pyrazole-4-yl]-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1-pyridine-3-ylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]pyrrolidine-3-carbonitol, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1-pyridine-4-ylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]pyrrolidine-3-carbonitol, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(1-pyridine-2-ylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]pyrrolidine-3-carbonitol, (3R,4S)-1-[6-[1-(3-cyano-1-bicyclo[1.1.1]pentanyl)pyrazole-4-yl]-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-(2-oxaspiro[3,3]heptan-6-yl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-(3-methoxycyclobutyl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-(3-methyloxetan-3-yl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-(3-hydroxy-3-methylcyclobutyl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-[(1-cyanocyclopropyl)methyl]pyrazole-4-yl]-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-[(3-methyloxetan-3-yl)methyl]pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-(oxetan-3-ylmethyl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-[(2RS,3RS)-2-methyloxetane-3-yl]pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-[(2RS,3SR)-2-methyloxetane-3-yl]pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-(3-cyano-3-methylcyclobutyl)pyrazole-4-yl]-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-(3-cyano-3-methylcyclobutyl)pyrazole-4-yl]-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-(3-cyano-3-fluorocyclobutyl)pyrazole-4-yl]-3-fluoropyrazolo[1,5-a]pyrazine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[3-fluoro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxo-3-propane-2-ylpyrrolidine-3-carbonil, (3R,4S)-3-cyclopropyl-1-[3-fluoro-6-[1-(1-methylazetidine-3-yl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-(1-methylpiperidine-4-yl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-[(3RS)-1-methylpyrrolidine-3-yl]pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-(2-methyl-2-azaspiro[3,3]heptan-6-yl)pyrazole-4-yl]pyrazolo[1,5-a]pyrazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-(2-methyl-2-azapiro[3,3]heptan-6-yl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-(1-methylazetidine-3-yl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[4-[(2RS)-4-methylmorpholine-2-yl]pyrazole-1-yl]pyrrolo[1,2-b]pyridazine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(5-methyl-1H-pyrazole-3-yl)pyrazolo[1,5-a]pyridine-4-yl]-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-(2-oxaspiro[3,3]heptan-6-yl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-1-[6-[1-(3-cyano-1-bicyclo[1.1.1]pentanyl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-1-[6-[3-fluoro-1-(oxetan-3-yl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-[1-(hydroxymethyl)cyclopropyl]pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-[1-(cyanomethyl)cyclopropyl]pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-[(1-cyanocyclopropyl)methyl]pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-[(3-methyloxetan-3-yl)methyl]pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-(3-cyano-3-fluorocyclobutyl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-[(3R*)-5,5-difluorooxan-3-yl]pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-[(3R*)-5,5-difluorooxan-3-yl]pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-(3-cyanocyclobutyl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-(3-cyanocyclobutyl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-(1-methylpiperidine-4-yl)pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-[(3RS)-1-methylpyrrolidine-3-yl]pyrazole-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(4-methylpyrazole-1-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(3-methylpyrazole-1-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(6-pyrazole-1-ylpyrrolo[1,2-b]pyridazin-4-yl)pyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-(6-imidazole-1-ylpyrrolo[1,2-b]pyridazin-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-1-[6-[4-(methoxymethyl)pyrazole-1-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[4-(difluoromethyl)pyrazole-1-yl]pyrrolo[1,2-b]pyridazin-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[4-(cyanomethyl)pyrazole-1-yl]pyrrolo[1,2-b]pyridazin-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[6-(2-oxopyridine-1-yl)pyrrolo[1,2-b]pyridazin-4-yl]pyrroridine-3-carbonitrile, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(4-methylimidazole-1-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(3-methyl-1,2,4-triazole-1-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(4-methyltriazole-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[2-[1-(1-bicyclo[1.1.1]pentanyl)pyrazole-4-yl]flo[3,2-b]pyridine-7-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[2-(4-methylpyrazole-1-yl)flo[3,2-b]pyridine-7-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-[2-(1-propan-2-ylpyrazole-4-yl)flo[3,2-b]pyridine-7-yl]pyrrolidine-3-carbonitrile, (3R,4S)-3-cyclopropyl-1-[2-(1-cyclopropylpyrazole-4-yl)flo[3,2-b]pyridine-7-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[5-[1-(oxetan-3-yl)pyrazole-4-yl]-1,3-benzothiazole-7-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[5-[1-(difluoromethyl)pyrazole-4-yl]-1,3-benzothiazole-7-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[5-(1-methylpyrazole-4-yl)-1,3-benzothiazole-7-yl]-2-oxopyrrolidine-3-carbonitol, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-(1-methylpyrazole-4-yl)-2,1-benzothiazole-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-(oxetan-3-yl)pyrazole-4-yl]-[1,3]thiazolo[5,4-c]pyridine-4-yl]-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-(difluoromethyl)pyrazole-4-yl]-[1,3]thiazolo[5,4-c]pyridine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-(2,2-difluoroethyl)pyrazole-4-yl]-[1,3]thiazolo[5,4-c]pyridine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-[1-(3-methoxycyclobutyl)pyrazole-4-yl]-[1,3]thiazolo[5,4-c]pyridine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-1-[6-[1-(3-cyanocyclobutyl)pyrazole-4-yl]-[1,3]thiazolo[5,4-c]pyridine-4-yl]-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonilicate, (3R,4S)-3-cyclopropyl-1-[6-(1-cyclopropylpyrazole-4-yl)-[1,3]thiazolo[5,4-c]pyridine-4-yl]-4-methyl-2-oxopyrrolidine-3-carbonilicate, and (3R,4S)-3-cyclopropyl-4-methyl-1-[6-[1-(1-methylazetidine-3-yl)pyrazole-4-yl]-[1,3]thiazolo[5,4-c]pyridine-4-yl]-2-oxopyrrolidine-3-carbonilicate The present invention provides a compound selected from any one of the following, or a pharmaceutically acceptable salt thereof.

[0053] In the 35th embodiment, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure (for example, according to any one of the Prior Embodiments) or a pharmaceutically acceptable salt thereof.

[0054] definition As used herein, the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” Typically, “optionally substituted” means replacing a hydrogen radical in a given structure with a radical of a specified substituent. Specific substituents are described in the definitions and descriptions of compounds and their examples. Unless otherwise indicated, an optionally substituted group may have substituents at each of its substituted positions, and the substituents may be identical or different at all positions if more than one position in any given structure can be substituted with more than one substituent selected from the specified group. In some embodiments, an optionally substituted group may be substituted with one or more substituents, each of which may be the same or different. In some embodiments, “one or more” substituents may be one, two, three, four, five, six, and so on, each of which may be the same or different. In some embodiments, “one or more” substituents may be 1 to 6, 1 to 4, 1 to 3, or 1 to 2 substituents, each of which may be the same or different.

[0055] As used herein, "halogen" or "halo" may be fluorine, chlorine, bromine, or iodine.

[0056] As used herein, "hydroxyl" or "hydroxy" refers to the -OH group.

[0057] As used herein, the number of carbon atoms in a group is defined by the prefix "C" in this specification. x-xx This is explicitly stated by ", where x and xx are integers. For example, "C 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms.

[0058] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. 1-4 The term "alkyl" refers to alkyl groups that have 1 to 4 carbon atoms. 1‐3 "Alkyl" and "C 1‐2 The term "alkyl" should be interpreted accordingly. 1~4 Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Where indicated as "optionally substituted," the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (usually 1 to 3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0059] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein, in which at least one of its hydrogen atoms is replaced by a halo atom. 1-4 The term "haloalkyl" refers to a C atom as defined herein, in which at least one of the hydrogen atoms is replaced by a halo atom. 1-4 It refers to an alkyl group. Similarly, "C 1-6 The term "haloalkyl" refers to a C atom as defined herein, in which at least one of the hydrogen atoms is replaced by a halo atom. 1-6 Refers to an alkyl group. 1-4 Haloalkyl or C1-6 A haloalkyl group may be a polyhaloalkyl group containing a monohaloalkyl group, a dihaloalkyl group, or a perhaloalkyl group. Monohalo C 1-4 Alkyl or monohalo C 1-6 Alkyls may have one iodine, bromo, chloro, or fluoro group within the alkyl group. Dihalo C 1-4 Alkyl, Dihalo C 1-6 Alkyl, polyhalo C 1-4 alkyl and polyhalogen C 1-6 Alkyl groups may have two or more identical halo atoms or combinations of different halo groups within the alkyl group. Typically, polyhalo C 1-4 The alkyl group contains a maximum of 9, 8, 7, 6, 5, 4, 3, or 2 halo groups. Typically, polyhalo C 1-6 The alkyl group contains a maximum of 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 halo groups. 1-4 Haloalkyl or C 1-6 Non-limiting examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoropentyl, and monochlorohexyl. Perhalo C 1-4 Alkyl or perhalo C 1-6 Alkyl groups are C atoms in which all hydrogen atoms are replaced by halo atoms. 1-4 Alkyl or C 1-6 This refers to an alkyl group.

[0060] As used herein, the term "oxo" (=O) refers to an oxygen atom bonded to a carbon or sulfur atom by a double bond. Examples include carbonyl, sulfinyl, or sulfonyl groups (-C(O)-, -S(O)-, or -S(O)2-), such as ketones, aldehydes, or parts of acids, esters, amides, lactones, or lactam groups.

[0061] As used herein, the terms “aryl,” “aryl group,” “aryl ring,” “aromatic group,” and “aromatic ring” are interchangeable and refer to groups with 6 to 12 members (i.e., C 6-10 This refers to an aromatic monocyclic or bicyclic carbocyclic system of the aryl group. Examples of aryl groups include phenyl and naphthyl, but are not limited to these.

[0062] As used herein, the terms “heteroaryl,” “heteroaryl group,” “heteroaromatic,” and “heteroaromatic ring” are used interchangeably to refer to a 5- to 10-membered aromatic monocyclic or bicyclic ring system having at least one heteroatom (e.g., oxygen, sulfur, nitrogen, or a combination thereof), wherein the N may be oxidized (e.g., N(O)) or quaternized, and the S may be optionally oxidized to sulfoxides and sulfones. In some embodiments, the heteroacyl is a 5- to 6-membered heteroaryl. Examples of “heteroaryl” include heteroaromatic groups condensed with a phenyl group or a non-aromatic heteroring, such as tetrahydrofuran, pyran, pyrrolidine, piperidine, etc. Examples of heteroaryls include pyrrole, pyridyl, pyrazole, thienyl, furanil, oxazolyl, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, thiazolyl, indolyl, indazolyl, benzofuranil, and quinokialinyl. In some embodiments, the heteroaryl is selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, and pyrrole.

[0063] As used herein, the term "cycloalkyl" refers to a group of 3 to 12 carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl), 3 to 8 carbon atoms (i.e., C 3-8 Cycloalkyl, or 5-7 carbon atoms (i.e., C 5-7 This refers to a fully saturated monocyclic or bicyclic (e.g., condensed, helical, or crosslinked) hydrocarbon group of a cycloalkyl group. 3-8 Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0064] As used herein, the term “heterocycloalkyl” refers to a fully saturated 4- to 12-membered monocyclic or bicyclic (e.g., bridging, condensed, or spirodicyclic) ring system having at least one heteroatom (e.g., oxygen, sulfur, nitrogen, or a combination thereof). In some embodiments, the heterocycloalkyl is a 4- to 10-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered monocyclic heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 7-membered monocyclic heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 7- to 10-membered bicyclic heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 7- to 8-membered bicyclic heterocycloalkyl.

[0065] The term "heterocyclic" refers to a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. Heterocyclic groups can be monocyclic or bicyclic (e.g., bridging, condensed, or spirodicyclic rings). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and piperidinyl. Examples of bicyclic heterocyclyl groups include those formed by the condensation of an unsaturated heterocyclic radical with another unsaturated heterocyclic radical, a cycloalkyl, an aryl, or a heteroaryl ring, such as tetrahydro-3H-[1,2,3]triazolo[4,5-c]pyridinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5-oxabicyclo[2.1.1]hexanyl, and 9-azabicyclo[3.3.1]nonanyl. In some embodiments, the heterocyclyl group is a 4- to 6-membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 4- to 7-membered monocyclic saturated heterocyclyl group. In some embodiments, the heterocyclyl group is a 3- to 7-membered monocyclic saturated heterocyclyl group. In some embodiments, the heterocyclyl group is an 8- to 10-membered bicyclic heterocyclyl group. In some embodiments, the heterocyclyl group is an 8-10 membered bicyclic saturated heterocyclyl group.

[0066] As used herein, the term “helical” ring means a bicyclic system in which both rings share one common atom. An example of a helical ring is 2-oxa-6-azaspiro[3.3]heptanyl.

[0067] The term "condensed" ring refers to a system of two rings that share two adjacent ring atoms. A condensed heterocycle contains at least one ring atom, which is a heteroatom selected from O, N, and S, in the system (e.g., 3-oxabicyclo[3.1.0]hexane).

[0068] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic portion linked by two non-adjacent ring atoms (e.g., 5-oxabicyclo[2.1.1]hexane).

[0069] The phrase "pharmaceutically acceptable" indicates that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with the other components of the formulation and / or the mammals it treats.

[0070] Also, formulas (I-1), (I-2), (I-1), (I-2), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II -9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (III-1), (III-2), (II Compounds of I-3), (III-4), (III-5), (IV-1), (IV-2), (IV-3), (IV-4), or (IV-5), as well as all stereoisomers (including diastereoisomers and enantiomers), rotational isomers, tautomers, isotope-labeled compounds (including deuterium substitutions), and intrinsically formed moieties (e.g., polymorphs, solvates, and / or hydrates) are also included in this disclosure. Salts, in particular pharmaceutically acceptable salts, are also included where moieties capable of forming salts exist. Compounds of this disclosure (including their salts, hydrates, and solvates) may form polymorphs intrinsically or by design.

[0071] When used herein, the terms “a,” “an,” “the,” and similar terms used in connection with this disclosure (particularly in connection with the claims) should be construed to encompass both singular and plural forms unless otherwise indicated herein or unless the context clearly contradicts this. The use of all examples or illustrative language provided herein (e.g., “~etc.”) is intended merely to illustrate this disclosure in a favorable manner and, unless otherwise claimed, does not limit the scope of this disclosure.

[0072] If the compounds provided herein are sufficiently basic or acidic to form salts of stable, non-toxic acids or bases, preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts include organic acid addition salts formed using acids that form physiologically acceptable anions, such as tosylates, methanesulfons, acetates, citrates, malons, tartrates, succinates, benzoates, ascorbicates, α-ketoglutanates, or α-glycerophosphates. Inorganic salts may also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates, and carbonates.

[0073] Pharmaceutically acceptable salts can be obtained by reacting a sufficiently basic compound, such as an amine, with a suitable acid that yields a physiologically acceptable anion, using standard procedures well known in the art. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be produced.

[0074] pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, or magnesium salts. Salts derived from organic bases include primary, secondary, or tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substituted cycloalkenylamines, and disubstituted cyclo Salts of alkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocycloalkylamines, diheterocycloalkylamines, triheterocycloalkylamines, or mixed amines of diamines and triamines, wherein at least two of the substituents on the amine may be different and may be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl groups. Examples include, but are not limited to, salts of mixed amines. Also included are amines in which two or three substituents combine with an amino nitrogen to form a heterocycloalkyl or heteroaryl group.Non-limiting examples of amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, morpholine, or N-ethylpiperidine. Carboxylic acid amides, including other carboxylic acid derivatives such as carboxamides, lower alkylcarboxamides, or dialkylcarboxamides, may also be useful.

[0075] It will be understood by those skilled in the art that the compounds of this disclosure may have chiral centers and therefore may exist in different stereoisomeric forms. As used herein, the terms “optical isomer” or “stereoisomer” refer to any of the various stereoisomeric structures that may exist for a given compound of this disclosure. It will be understood that substituents may be bonded to the chiral center of a carbon atom. Therefore, this disclosure encompasses enantiomers, diastereomers, or racemates of the compounds.

[0076] Some of the compounds described herein contain one or more chiral centers or axes, and therefore may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- by absolute stereochemistry. According to this disclosure, any structure without specified stereochemistry should be understood to encompass all the various stereoisomers (e.g., diastereomers and enantiomers) in their pure or substantially pure form, and mixtures thereof (e.g., racemic mixtures or mixtures enriched with enantiomers). Methods for preparing such optically active forms (e.g., racemic separation by recrystallization techniques, synthesis from optically active starting materials by chiral synthesis, or chromatographic separation using a chiral stationary phase) are well known in the art. In some embodiments, the compounds described herein are isolated stereoisomers, where each compound has one stereocenter and the stereoisomer is in the R configuration. In other embodiments, the compounds described herein are isolated stereoisomers, where each compound has one stereocenter and the stereoisomer is in the S configuration. In one embodiment, the compounds described herein are isolated stereoisomers, each having two stereocenters, and the stereoisomer is in an RR configuration. In one embodiment, the compounds described herein are isolated stereoisomers, each having two stereocenters, and the stereoisomer is in an RS configuration. In one embodiment, the compounds described herein are isolated stereoisomers, each having two stereocenters, and the stereoisomer is in an SR configuration. In one embodiment, the compounds described herein are isolated stereoisomers, each having two stereocenters, and the stereoisomer is in an SS configuration. In one embodiment, the compounds described herein are racemic mixtures, each having one or two stereocenters.

[0077] If a specific stereoisomer of a compound is indicated by name or structure, the stereochemical purity of that compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the weight percentage of the desired stereoisomer relative to the total weight of all stereoisomers.

[0078] If a specific enantiomer of a compound is indicated by name or structure, the stereochemical purity of that compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the weight percentage of the desired enantiomer relative to the total weight of all stereoisomers.

[0079] If the stereochemistry of a disclosed compound is named or described structurally, and the named or described structure encompasses two or more stereoisomers (e.g., a diastereomer pair), it should be understood that it contains one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers. Furthermore, it should be understood that the stereoisomeric purity of the named or described stereoisomer is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. Stereoisomeric purity means the weight percentage of the desired stereoisomer encompassed by the name or structure relative to the total weight of all stereoisomers.

[0080] If a disclosed compound is named or indicated by a structure that does not exhibit stereochemistry, and the compound has one chiral center, the name or structure should be understood to encompass one enantiomer of the compound in its pure or substantially pure form, and mixtures thereof (e.g., racemic mixtures of the compound, and mixtures in which one enantiomer is concentrated compared to its corresponding optical isomer).

[0081] Unless otherwise specified, the compounds of this disclosure are intended to include any conceivable stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or they may be divided using prior art (e.g., chiral SFC or CHIRALPAK, available from DAIEL). RTM and CHIRALCEL RTM (Separation is achieved using an appropriate solvent or solvent mixture on an HPLC chromatography column, etc., to achieve good separation.) If the compound contains a double bond, the substituent may be in an E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomer forms are also intended to be included.

[0082] If a disclosed compound is named or described structurally without indicating its stereochemistry, and for example, if the compound has at least two chiral centers, its name or structure should be understood to encompass one stereoisomer in a pure or substantially pure form, and mixtures thereof (such as mixtures of stereoisomers, and mixtures of stereoisomers in which one or more stereoisomers are concentrated compared to other stereoisomers).

[0083] The disclosed compounds may exist in tautomeristic forms, and mixtures and isolated individual tautomers are intended. All such forms are included within the scope of this disclosure. Furthermore, some compounds may exhibit polymorphism. The terms “tautomer” or “tautomeristic form” refer to structural isomers of different energies that are interconvertible across a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization. A concrete example of a proton tautomer is an imidazole moiety in which a proton can move between two ring nitrogens. Valence tautomers include interconversions via several rearrangements of bonding electrons.

[0084] Furthermore, the compounds of this disclosure (including their salts) may also be obtained in the form of their hydrates or may include other solvents used for their crystallization. The compounds of this disclosure can, intrinsically or by design, form solvates with pharmaceutically acceptable solvents (including water), and therefore this disclosure is intended to encompass both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of this disclosure (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and known to be harmless to recipients, such as water and ethanol. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0085] Compounds of this disclosure comprising a group capable of acting as a hydrogen bond donor and / or acceptor may form cocrystals with suitable cocrystal-forming agents. These cocrystals may be prepared from the compounds by known cocrystal-forming procedures. Such procedures include grinding, heating, co-sublimation, eu-melting, or contacting the compound with a cocrystal-forming agent under crystallization conditions in solution, thereby isolating the formed cocrystals. Suitable cocrystal-forming agents include those described in WO2004 / 078163. Accordingly, this disclosure further provides cocrystals comprising the compounds described herein.

[0086] In one embodiment, the present disclosure provides a deuterated compound disclosed herein, in which any or more positions occupied by hydrogen may include enrichment by deuterium beyond the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced by deuterium at an abundance at least 3340 times higher than the natural abundance of deuterium, such as 0.015% (i.e., at least 50.1% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each specified deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). In one embodiment, hydrogen is present at all positions in its natural abundance.

[0087] In another embodiment, the disclosure is a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0088] As used herein, the term “pharmaceutically acceptable carrier” includes, as will be understood by those skilled in the art, generally recognized as safe (GRAS) solvents, dispersions, surfactants, antioxidants, preservatives (e.g., antimicrobial agents, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), and similar substances, as well as combinations thereof (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289–1329). Its use in therapeutic or pharmaceutical compositions is intended unless any conventional carrier is incompatible with the active ingredient.

[0089] Formulations can be prepared using conventional dissolution and mixing procedures. For example, a bulk active pharmaceutical ingredient (i.e., the compound of the Disclosure or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complex-forming agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the Disclosure are typically formulated into pharmaceutical dosage forms to provide a drug with easily adjustable dosages and to provide a simple and easy-to-handle product for the patient.

[0090] Pharmaceutical compositions (or formulations) for a particular use can be packaged in a variety of ways depending on the method used to administer the drug. Generally, articles for sale include a container in which the pharmaceutical formulation in an appropriate form is placed. Suitable containers are known to those skilled in the art and include, for example, bottles (made of plastic and glass), pouches, ampoules, plastic bags, and metal cylinders. The container may also include an anti-tampering mechanism to prevent accidental access to the contents of the package. In addition, a label describing the contents of the container is placed on top of the container. The label may also include appropriate warnings.

[0091] Pharmaceutical compositions containing the compounds of this disclosure are generally formulated for parenteral or oral administration.

[0092] For example, the oral pharmaceutical compositions of this disclosure may be in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including, but not limited to, liquids, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional inert diluents, lubricants, or buffers, as well as excipients, such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0093] Typically, a pharmaceutical composition contains an active ingredient, a) Diluents, for example, lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine, b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol, in the case of tablets as well. c) Binders, e.g., aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, if desired. d) Disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and / or e) A tablet or gelatin capsule containing an absorbent, coloring agent, flavoring agent, and sweetener.

[0094] The tablets may be coated with a film or enteric coating according to methods known in the art.

[0095] Compositions suitable for oral administration include compounds of the Disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the Art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide a refined and palatable preparation as a pharmacopoeia. Tablets may contain an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia gum; and lubricants such as magnesium stearate, stearic acid or talc. Tablets are either uncoated or coated with known techniques that slow their disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0096] Parenteral compositions (e.g., intravenous (IV) formulations) are aqueous isotonic solutions or suspensions. Parenteral compositions may be sterilized and / or contain excipients, such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution accelerators, salts for adjusting osmotic pressure, and / or buffers. In addition, they may also contain other therapeutically valuable substances. Compositions are generally prepared according to conventional mixing, granulation, or coating methods, respectively, and contain about 0.1–7.5% or about 1–50% of the active ingredient.

[0097] The compounds or pharmaceutically acceptable salts described herein may be used to reduce or inhibit the activity of TYK2, or otherwise to affect the properties and / or behavior of TYK2, such as stability, phosphorylation, kinase activity, and interactions with other proteins.

[0098] How to use In some embodiments, the Disclosure provides a method for inhibiting TYK2 activity in a subject in which TYK2 activity needs to be inhibited, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0099] As used herein, the terms “inhibit,” “inhibit,” or “to inhibit” mean the reduction or suppression of a given medical condition, symptom, disorder, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0100] One embodiment of the present disclosure is a method for treating a disease or disorder in which inhibition of TYK2 is effective, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the method described herein treats a disease or disorder in which inhibition of TYK2 is effective, wherein the disease or disorder is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, head trauma, neurodegeneration, liver disease, inflammatory bowel disease These include Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes mellitus (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, autoimmune diseases, osteoporosis, multiple sclerosis, endometriosis, menstrual pain, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis, and sunburn.

[0101] The term "autoimmune disorders" includes diseases or disorders that involve an inappropriate immune response to natural antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), childhood steatorrhea, dermatomyositis, diabetes mellitus type 1, Goodpasture syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, Sjögren's syndrome, temporal arteritis, and Wegener's granulomatosis.

[0102] The term "inflammatory disorders" includes diseases or disorders involving acute or chronic inflammation, such as allergies, asthma, atopic dermatitis, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis.

[0103] The term "cancer" includes diseases or disorders that involve the abnormal growth and / or proliferation of cells, such as glioma, thyroid cancer, breast cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumors, pancreatic cancer, cholangiocarcinoma, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., high microsatellite instability colorectal cancer).

[0104] As used herein, the terms “subject” and “patient” may be used interchangeably and mean mammals requiring treatment, such as humans, companion animals (e.g., dogs, cats, etc.), livestock (e.g., cattle, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human requiring treatment.

[0105] As used herein, the terms “to treat” or “treatment” mean to obtain a desired pharmacological and / or physiological effect. The effect may be therapeutic and may include partially or substantially achieving one or more of the following results: partial or complete reduction of the degree of a disease, disorder or syndrome; remission or improvement of clinical symptoms or indicators associated with the disorder; or delay, inhibit, or reduce the likelihood of progression of a disease, disorder or syndrome.

[0106] The effective dose of the compound provided herein or a pharmaceutically acceptable salt thereof administered to the subject may range from 10 μg to 500 mg.

[0107] The administration of the compounds described herein or their pharmaceutically acceptable salts to mammals includes any preferred method of delivery. The administration of the compounds described herein or their pharmaceutically acceptable salts to mammals includes administering the compounds described herein or their pharmaceutically acceptable salts to mammals topically, enterally, parenterally, percutaneously, permucosally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally, via topical, enteral, parenteral, percutaneous, permucosally, intramucosally, intravitreally, intracisterna magna, epidurally, intravaginally, intravitreally, intradurally, intradurally, intravitreally, intracisterna magna, epidurally, intravaginally, intravitreally, intradurally, intradurally, intravaginally, intramuscularly, intradurally, intravitreally, intracisterna magna, epidurally, intravaginally, intravaginally, intramurally, intradurally, intravitreally, intracisterna magna, epidurally, intravaginally, intravaginally, intramurally, intradurally, intravitreally, intracisterna magna, epidurally, intravaginally, intravaginally, intradurally, intradurally, intravitreally, intracisterna magna, epidurally, intravaginally, intradurally, intravitreally, intradurally, intradurally, intravaginally, intradurally, intradurally, intradurally, intravitreally, intracisterna magna, epidurally, intravaginally, intravitreally, intradurally, intradurally, intrad

[0108] Accordingly, the compounds described herein or their pharmaceutically acceptable salts may be administered orally and systemically in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an absorbable food carrier. They may be encapsulated in hard-shell or soft-shell gelatin capsules, compressed into tablets, or directly incorporated into the patient's diet. For oral therapeutic administration, the compounds described herein or their pharmaceutically acceptable salts may be combined with one or more excipients and may be used in the form of orally ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, or wafers. Such compositions and preparations should contain at least about 0.1% of the active compound. The percentage of the compositions and preparations may, of course, vary and may, conveniently, be about 2 to about 60% by weight of a given unit dosage form. The amount of the active compound in such therapeutically useful compositions may be such that an effective dose level is achieved.

[0109] Tablets, lozenges, pills, capsules, etc. may contain: binders, e.g., tragacanth gum, acacia, corn starch, or gelatin; excipients, e.g., dicalcium phosphate; disintegrants, e.g., corn starch, potato starch, alginic acid, etc.; lubricants, e.g., magnesium stearate; or sweeteners, e.g., sucrose, fructose, lactose, or aspartame; or flavoring agents.

[0110] The active compound may also be administered intravenously or intraperitoneally by injection or injection. A solution of the active compound or a salt thereof may be prepared in water and optionally mixed with a non-toxic surfactant.

[0111] Examples of pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions or dispersions containing the active ingredient, or sterile powders containing the active ingredient suitable for on-demand preparation of sterile solutions or dispersions for injection or infusion. In all cases, the final dosage form must be sterile, liquid, and stable under manufacturing and storage conditions.

[0112] A sterile injection solution can be prepared by incorporating the required amount of the active compound into a suitable solvent containing various other components listed above, and then, if necessary, by filter sterilization. In the case of sterile powders for preparing a sterile injection solution, preferred preparation methods may be vacuum drying and freeze-drying techniques, which allow for obtaining powders of the active component present in a pre-sterilized filtered solution and any further desired components.

[0113] Examples of solid carriers include pulverized solids such as talc, clay, microcrystalline cellulose, silica, and alumina. Useful liquid carriers include water, alcohol, glycol, or water-alcohol / glycol mixtures, in which the compounds described herein or their pharmaceutically acceptable salts can be dissolved or dispersed at an effective level, optionally with the help of a non-toxic surfactant.

[0114] Useful doses of the compounds described herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective doses in mice and other animals to humans are known to those skilled in the art; see, for example, U.S. Patent No. 4,938,949, which is incorporated in whole by reference.

[0115] The amount of the compound or a pharmaceutically acceptable salt described herein required for use in treatment may vary depending not only on the specific salt selected, but also on the route of administration, the nature of the condition being treated, and the patient's age and condition, and is ultimately at the discretion of the attending physician or clinician. However, generally, the dose may range from about 0.1 to about 10 mg / kg body weight per day.

[0116] The compounds described herein or pharmaceutically acceptable salts thereof can, for convenience, be administered in unit dosage forms containing, for example, 0.01 to 10 mg or 0.05 to 1 mg of the active ingredient per unit dosage form. In some embodiments, doses of 5 mg / kg or less may be preferred.

[0117] The desired dose may, for convenience, be provided as a single dose or as divided doses administered at appropriate intervals.

[0118] The methods of this disclosure may include a kit, which includes a compound described herein or a pharmaceutically acceptable salt thereof, and explanatory materials that can explain how to administer a compound described herein or a pharmaceutically acceptable salt thereof, or a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, to cells or subjects. This should be interpreted as encompassing other embodiments of kits known to those skilled in the art, such as a kit comprising a solvent (e.g., a sterile solvent) for dissolving or suspending a compound described herein or a pharmaceutically acceptable salt thereof, or a composition, before administering the compound described herein or a pharmaceutically acceptable salt thereof, or a composition, to cells or subjects. In some embodiments, the subject may be a human.

[0119] The compounds of this disclosure can be synthesized by synthetic routes involving processes similar to those well known in the chemical field, particularly considering the descriptions contained herein. Starting materials are generally available from commercial sources such as Sigma-Aldrich or can be readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed., Springer-Verlag, Berlin (also available from the Beilstein online database)). The protection of functional groups by protecting groups, the protecting groups themselves, and their cleavage reactions are discussed in, for example, JFWMcOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; TW Greene and PGMWuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999; “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; “Methoden der organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974; and H.-D. Jakubke and H. Jeschkeit, “Aminosaurens, Peptides, Proteins” (Amino (Acids, Peptides, Proteins) are described in Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, among others.A key characteristic of protecting groups is that they can be easily removed, for example, by solvolysis, reduction, photolysis, or alternatively, under physiological conditions (e.g., enzymatic cleavage) (i.e., undesirable secondary reactions do not occur).

[0120] Salts of the compounds of the Disclosure having at least one base can be prepared by methods known to those skilled in the art. For example, acid addition salts of the compounds of the Disclosure are conventionally obtained, for example, by treating the compound with an acid or a suitable anion exchange reagent. The salts can be converted back to the free compounds by methods known to those skilled in the art. The acid addition salts can be converted, for example, by treatment with a suitable basic agent.

[0121] Any of the resulting mixtures of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, or racemates based on the physicochemical differences of their constituent components, for example by chromatography and / or fractional crystallization.

[0122] In compounds containing an asymmetric carbon atom, the compound exists in the form of individual optically active isomers or as mixtures thereof, for example, as a racemic mixture or a diastereomer mixture. A diastereomer mixture can be separated into its individual diastereomers based on their physicochemical differences by methods known to those skilled in the art, for example, by chromatography and / or fractional recrystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or moscherate), separating the diastereomers, and converting the individual diastereomers into their corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using commercially available chiral HPLC columns.

[0123] The disclosure further includes any variations of the process in which the reactants are used in the form of their salts or optically pure materials. The compounds and intermediates of the disclosure can also be converted to each other according to methods widely known to those skilled in the art.

[0124] For illustrative purposes, the reactions described below provide possible routes for synthesizing major intermediates as well as the compounds of this disclosure. For a more detailed description of the individual reaction steps, see the Examples section below. While specific starting materials and reagents are illustrated in the scheme and described below, it is readily possible to provide a variety of derivatives and / or reaction conditions using other starting materials and reagents instead. Furthermore, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. [Examples]

[0125] Unless otherwise stated, the compounds in the examples were analyzed or purified according to one of the purification methods described below.

[0126] Aq. means aqueous solution. Bn stands for benzyl. Boc stands for tert-butoxycarbonyl. (BPin)2 means bis(pinacolato)diborone, br stands for broad. t-BuBrettphos Pd G3 means [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, t-BuOH stands for tertiary butanol. n-BuLi means n-butyllithium, °C stands for degrees Celsius. CDCl3 stands for deuterochloroform. Cs2CO3 means cesium carbonate. δ stands for chemical shift. d means a double line, DAST stands for (diethylamino) sulfur trifluoride. dd means double double lines, DCE stands for 1,2-dichloroethane. DCM stands for dichloromethane. DEA stands for diethylamine. DIBAL-H stands for diisobutylaluminum hydride. DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine. DMA stands for N,N-dimethylacetamide. DMAP stands for 4-dimethylaminopyridine. DMEDA stands for N,N'-dimethylethane-1,2-diamine. DMF stands for N,N-dimethylformamide. DMSO stands for dimethyl sulfoxide. DMSO-d6 stands for hexaduterodimethyl sulfoxide. EDCI stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride. Et means ethyl, EtOH means ethanol. RINKAN means ethyl acetate. Eq. means equivalent. "Mel" means gram. HCl means hydrochloric acid. HCO2H means formic acid. 1 1H NMR stands for Proton Nuclear Magnetic Resonance. H2O means water. HOBt stands for 1-hydroxybenzotriazole. HPLC stands for High-Pressure Liquid Chromatography. h represents time, IPA stands for 2-propanol. K2CO3 means potassium carbonate. KF stands for potassium fluoride. KOH stands for potassium hydroxide. K3PO4 means tripotassium phosphate. L stands for liter. LCMS stands for Liquid Chromatography Mass Spectrometry. LDA stands for lithium diisopropylamide. m means multiple lines, M stands for mole. Me stands for methyl. Me4t-BuXPhos means methanesulfonate (2-di-tert-butylphosphin-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), MeCN stands for acetonitrile. MeI stands for iodomethane. MeOH means methanol. MeOD-d4 means deuteromethanol. mg means milligrams. MgSO4 means magnesium sulfate. MHz stands for megahertz. "Mins" means minutes. mL means milliliter. "Ov." means millimoles. MS m / z refers to the mass spectral peak. MsCl stands for methanesulfonyl chloride. N2 means nitrogen. NaBH4 stands for sodium borohydride. NaBH3CN means sodium borocyanohydride. Na2CO3 means sodium carbonate. NaH stands for sodium hydride. NaHCO3 means sodium bicarbonate. NaIO4 means sodium periodate. NaOH stands for sodium hydroxide. Na2SO4 means sodium sulfate. NBS stands for N-bromosuccinimide. NH3 means ammonia. NH4Cl means ammonium chloride. NH4OH is ammonium hydroxide, P(cy)3 stands for tricyclohexylphosphine. Pd(amphos)Cl2 means bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), Pd(t-Bu3P)2 means bis(tri-tert-butylphosphine)palladium(0), Pd2(dba)3 means Tris(dibenzylideneacetone)dipalladium(0), Pd(dppf)Cl2 means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd(dtbpf)Cl2 means [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), PdCl2(PPh3)2 means bis(triphenylphosphine)palladium(II) dichloride. Pd / C stands for palladium-carbon. Pd-132 stands for dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II), PE stands for petroleum ether. PEPPSI-IPr catalyst means [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II) dichloride, PMB stands for para-methoxybenzyl. PMBCl stands for paramethoxybenzyl chloride. POCl3 stands for phosphorus oxychloride. q means quadruple lines, rt means room temperature. RT stands for retention time. RuCl3 stands for ruthenium(III) chloride. RuPhosPdG3 means (2-dicyclohexylphosphin-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate, 's' means a single line. sat. means saturation. SEM stands for [2-(trimethylsilyl)ethoxy]methylacetal, Select-F stands for 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate), SFC stands for supercritical fluid chromatography. SOCl2 means thionyl chloride. "soln" means solution. t means triple line, TBAB stands for tetra-n-butylammonium bromide. TBAF stands for tetrabutylammonium fluoride. TBME stands for tert-butylmethyl ether. TEA stands for triethylamine. TFA stands for trifluoroacetic acid. Tf2O refers to trifluoromethanesulfonic anhydride. THF stands for tetrahydrofuran. THP stands for tetrahydropyran. TLC stands for Thin-Layer Chromatography. TMSCN stands for trimethylsilyl cyanide. TsCl stands for p-toluenesulfonyl chloride. TsOH stands for para-toluenesulfonic acid. μL means microliter. μmol means micromol, Xanthophos means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, XPhos Pd G3 means (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate. RuPhosPdG3 stands for (2-dicyclohexylphosphin-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate.

[0127] According to the first process, the compound of formula (I-1) can be prepared from the compounds of formulas (II) and (III), as shown in Scheme 1. [ka]

[0128] LG 1 The group is a detaching group, typically a halide, mesylate, or triflate, preferably Cl or a triflate.

[0129] The compound of formula (I-1) can be prepared according to the Buchwald-Hartwig cross-coupling reaction of process step (a). Typical conditions include the reaction of the amide of formula (II) with the compound of formula (III) in a suitable solvent, at high temperature, and optionally under microwave irradiation, in the presence of a suitable palladium catalyst, a suitable inorganic base, and a suitable phosphine ligand. Preferred conditions include the reaction of the compounds of formulas (II) and (III) in the presence of RuPhos PdG3, xanthophos, or Me4t-BuXPhos, optionally in combination with Pd2(dba)3, in the presence of a suitable base such as K2CO3, K3PO4, or Cs2CO3, in a suitable solvent such as dioxane, THF, or toluene, at 25°C to 120°C, and optionally under microwave irradiation.

[0130] According to the second process, the compound of formula (I-1A) (wherein X2 is CR) S The compounds can be prepared from the compounds of formulas (II), (IV), and (V), as shown in Scheme 2. [ka]

[0131] LG 1 and LG 2 is a detaching group, typically a halide, mesylate, or triflate, preferably Cl, Br, or triflate. W is a boronic acid, or a suitable boronate ester such as pinacol boronic acid ester.

[0132] The compound of formula (V) can be obtained from the compounds of formulas (II) and (IV) according to process step a), as previously described in Scheme 1.

[0133] Step b) The compound of formula (I-1A) is converted to the compound of formula (V) and R by a palladium-catalyzed cross-coupling reaction. S It can be prepared from W. Typical cross-coupling reaction conditions involve a palladium catalyst containing a suitable phosphine ligand, in the presence of an inorganic base, in a suitable solvent, at room temperature to the reflux temperature of the reactants, and optionally in the presence of microwave irradiation. Preferred conditions involve XPhos Pd G3, Pd(dppf)Cl2, Pd(amphos)Cl2, or Pd(dtbpf)Cl2, and the compound of formula (V) and R in the presence of a suitable base such as Na2CO3, K2CO3, K3PO4, or KF, in a suitable solvent such as dioxane or toluene, optionally in the presence of water, at 70°C to 100°C. S This includes the reaction of W.

[0134] According to the third process, Q1 and Q2 are C, X1 and X3 are N, and X2 is CR. SThe compound of formula (I-1B) can be prepared from the compounds of formulas (II), (VI), (VII), and (VIII), as shown in Scheme 3. [ka]

[0135] Step c) The compound of formula (VII) can be prepared by the reaction of the compounds of formula (II) and (VI) at 0°C to high temperatures in the presence of a suitable strong base and a suitable aprotic polar solvent. Preferred conditions include the reaction of the compound of formula (II) and the compound of formula (VI) at ambient temperature in the presence of NaH in DMSO or DMF.

[0136] Step d) The compound of formula (VIII) can typically be prepared from the compound of formula (VII) by a reduction reaction in a suitable alcohol solvent such as MeOH, in the presence of a suitable hydrogenation catalyst such as Pd / C, under an atmosphere of H2.

[0137] Step e) The compound of formula (I-1B) is condensed in a suitable polar aprotic solvent such as DMF in the presence of a suitable acidic catalyst such as TsOH at a high temperature such as between 50°C and 80°C to produce the diamine and aldehyde of formula (VIII), R S It can be prepared from CHO.

[0138] According to the fourth process, the compound of formula (I-1C) (wherein R) X5 (wherein H is not present) can be prepared from compounds of formulas (II), (IX), and (X), as shown in Scheme 4. [ka]

[0139] W is a boronic acid, or a suitable boronate ester such as pinacol boronic acid ester.

[0140] The compound of formula (X) can be prepared from the compounds of formulas (II) and (IX) according to process step (a) as described in scheme 1 above, or according to process step c) as described in scheme 3 above.

[0141] The compound of formula (I-1C) is converted by a Suzuki-type cross-coupling reaction with the compound of formula (X) and R, as described in step b) of scheme 2 above. X5 It can be prepared from W. Preferred conditions are the compound of formula (X) and R in a suitable solvent such as aqueous dioxane or t-amyl alcohol at 70°C to 100°C in the presence of a PEPPSI-IPR catalyst, BrettPhos Pd G3, t-BuBrettphos Pd G3, Pd(t-Bu3P)2, Pd(dtbpf)Cl2, or Pd(amphos)Cl2, and a suitable base such as CsF, K2CO3, or K3PO4. X5 Includes reactions with W.

[0142] Alternatively, the compound of formula (I-1C) undergoes a process step (f), a palladium-catalyzed cross-coupling reaction using a suitable alkyl or aryl stannane, and a Still reaction to form the compound of formula (X) and R X5 It can be prepared from Sn(alkyl)3. Typical cross-coupling reaction conditions include a palladium catalyst containing a suitable phosphine ligand, in a suitable aqueous solvent, in the presence of an inorganic base, and at a temperature of 90-100°C, in the presence of a suitable catalyst such as Pd(OAc)2, a suitable ligand such as P(Cy)3, an optional additive, typically in the presence of CsF, in a suitable solvent such as dioxane, and at a high temperature such as 90-100°C, with the compound of formula (X) and R X5 This includes reactions with Sn(butyl)3.

[0143] According to the fifth process, the compound of formula (I-1A) can be prepared from the compounds of formulas (V) and (XI), as shown in Scheme 5. [ka]

[0144] Hal is a halogen, preferably Cl, Br, or I.

[0145] Step f) The compound of formula (XI) can be prepared from the compound of formula (V) according to step (g), boronate ester formation, which is achieved by treating with a suitable boronate (e.g., (BPin)2) in the presence of a suitable inorganic base (e.g., K2CO3 or KOAc) and a suitable catalyst (e.g., Pd(dppf)Cl2 or Pd2(dba)3) in a suitable nonpolar solvent such as MeCN, between room temperature and high temperature.

[0146] The compound of formula (I-1A) can be prepared from the compound of formula (XI) by following process step b), the Suzuki coupling reaction, as described in schemes 2 and 4 above.

[0147] According to the sixth process, the compound of formula (I-1A) can be prepared from the compounds of formulas (II), (IV), and (IIIA), as shown in Scheme 6. [ka]

[0148] The compound of formula (IIIA) is converted to the compound of formula (IV) and R according to process step b), as described in schemes 2 and 4 above, via the Suzuki coupling reaction. S It can be prepared from W. Preferred conditions are the compound of formula (IV) and R in aqueous toluene at about 110°C in the presence of Pd(OAc)2, PPh3, Na2CO3. S Includes reactions with W.

[0149] The compound of formula (IA) can be obtained from the compounds of formulas (IIIA) and (II) according to process step (a), as described in scheme 1 above.

[0150] According to the seventh process, the compound of formula (I-1A) can be prepared from the compound of formula (V) as shown in scheme 7. [ka]

[0151] R S The compound of formula (I-1A) is N-bonded, and the compound of formula (I-1A) can be prepared according to step (h), a metal-catalyzed cross-coupling reaction, for example, a Ullmann-type copper-mediated coupling reaction. Typical conditions include the compound of formula (V) and R in a suitable solvent at high temperature in the presence of a suitable inorganic or organic base. S The reaction involves H, a copper catalyst, and a suitable ligand. Preferred conditions include the reaction of the compound of formula (V) and R in the presence of a suitable ligand such as CuI, N1,N2-dimethylethane-1,2-diamine, L-proline, 4,7-dimethoxy-1,10-phenanthroline, or pyridine-2-carboxylic acid, a suitable inorganic base such as K2CO3, Cs2CO3, K3PO4, or KOtBu, in an optional solvent such as dioxane, toluene, or DMSO, at 90°C to 120°C, and optionally under microwave irradiation. S This includes reactions with H.

[0152] Alternatively, the compound of formula (I-1A) undergoes a Buchwald-type cross-coupling reaction in process step (a) with the compound of formula (V) and R, as described in Scheme 1 above. S It can be prepared from H.

[0153] According to the eighth process, the compound of formula (I-1C) (wherein R) X5 (wherein H is not H) can be prepared from compounds of formulas (X) and (XII), as shown in Scheme 8. [ka]

[0154] The compound of formula (XII) can be prepared from the compound of formula (X) according to process step (i), the formation of an alkyltin compound. Preferred conditions include the reaction of the compound of formula (X) with Sn(Bu)3 in toluene at 100°C in the presence of Pd(dtbpf)Cl2.

[0155] The compound of formula (I-1C) is, as described in scheme 4 above, compound (XII) and R according to process step (f). X5 It can be prepared from Hal.

[0156] According to the ninth process, the compound of formula (I-2) can be prepared from the compounds of formulas (II) and (XIII), as shown in scheme 9. [ka]

[0157] The compound of formula (I-2) can be prepared from the compounds of formulas (XIII) and (II) according to process step (h), as described in scheme 7 above.

[0158] Compounds of formulas (I-1), (I-2), (I-1A), (I-1B), (I-1C), (V), or (X) can be converted to alternative compounds of formula (I-1). These conversions can be achieved by standard chemical transformations, such as halogenation including the above transformation steps, alkylation of heteroatoms such as N via reductive amination, alkylation in the presence of an inorganic base, palladium or copper-mediated Suzuki reaction, copper carbenoid-mediated N-alkylation, or fluorination.

[0159] Compounds of formulas (II), (III), (IV), (VI), (IX), and (XIII) are commercially available and can also be prepared by methods known in the literature or by analogy to the methods described in the experimental section below.

[0160] Those skilled in the art will fully understand that it may be necessary to utilize a suitable protecting group strategy to prepare the compounds of formulas (I-1) and (I-2). Typical protecting groups may include carbamates and preferably Boc for protecting the amine, a tosyl group for protecting the imidazole N atom, a THP or SEM group for protecting the pyrazole N atom, and a PMB group for protecting the amide N.

[0161] [Table 1-1] [Table 1-2]

[0162] Preparation 1 3-ethyl-2-oxopyrrolidine-3-carbonitrile [ka] Part A: To a solution of ethyl 2-cyanobutanoate (20 g, 141.7 mmol) in THF (450 mL), sodium tert-butoxide (15 g, 156 mmol) was added, and then tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (33 g, 147.8 mmol) in THF (350 mL) was carefully added dropwise, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 0.1 M HCl and extracted with ethyl HCl. The combined organic matter was successively washed with water and saturated brine, dried, and evaporated under reduced pressure to obtain ethyl 4-((tert-butoxycarbonyl)amino)-2-cyano-2-ethylbutanoate (40 g), which was used without further purification.

[0163] Part B: Ethyl 4-((tert-butoxycarbonyl)amino)-2-cyano-2-ethylbutanoate (Part A) was dissolved in dioxane, and 3 equivalents of a 10% HCl dioxane solution were added. The reaction mixture was stirred overnight at room temperature, then evaporated under reduced pressure to obtain ethyl 4-amino-2-cyano-2-ethylbutanoate hydrochloride, which was used without further purification.

[0164] Part C: Ethyl 4-amino-2-cyano-2-ethylbutanoate hydrochloride (Part B) was dissolved in EtOH (25V), NaHCO3 (2 equivalents) was added, and the reaction mixture was stirred at 40°C for 48 hours. After cooling, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (SiO2) to obtain 3-ethyl-2-oxopyrrolidine-3-carbonitrile (3 g, 16.5%). 1 H NMR (400 MHz, CDCl3) δ: 6.90 (s, 1H), 3.54 (ddd, 1H), 3.47-3.39 (m, 1H), 2.62 (ddd, 1H), 2.23 (ddd, 1H), 2.16-2.02 (m, 1H), 1.76 (dq, 1H), 1.18 (td, 3H).

[0165] Preparation 2 3-Cyclobutyl-2-oxopyrrolidine-3-Carbonitrile [ka] 3-Cyclobutyl-2-oxopyrrolidine-3-carbonitrile was prepared from tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide and ethyl 2-cyano-2-cyclobutyl acetate according to the procedure described in Preparation 1. 1 H NMR (400 MHz, CDCl3) δ 6.82 (s, 1H), 3.49 (td, 1H), 3.44-3.32 (m, 1H), 2.76 (p, 1H), 2.56 (dt, 1H), 2.20-2.16 (m, 5H), 1.94 (p, 2H).

[0166] Preparation 3 Ethyl 2-cyano-2-(oxetan-3-yl)acetate [ka] To a solution of oxetane-3-one (50 g, 0.69 mol) and ethyl 2-cyanoacetate (78.5 g, 0.69 mol) in DMSO (1 L), diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate (175.7 g, 0.69 mol), followed by L-proline (159.8 g, 1.39 mol), was added, and the mixture was stirred at 25°C for 48 hours. The reaction mixture was poured into 2 L of saturated citric acid solution and extracted with ethyl acetate (4 × 500 mL). The combined organic matter was washed with saturated sodium 2CO3 aqueous solution (300 mL), dried, and evaporated to dryness under vacuum in (MgSO4). The residue was purified by vacuum distillation (internal temperature: 100°C), followed by column chromatography (SiO2, 25%~50% siRNA / PE) to obtain ethyl 2-cyano-2-(oxetan-3-yl) acetate as a pale yellow oily substance (81 g, 69%). 1 HNMR (400MHz, CDCl3) δ: 4.90 (dd, 2H), 4.61 (dt, 2H), 4.29 (q, 2H), 3.91 (d, 1H), 3.67-3.43 (m, 1H), 1.35 (t, 3H).

[0167] Preparation 4 Ethyl 2-cyano-2-cyclopropyl acetate [ka] To a solution of 2-cyclopropylacetonitrile (200 g, 2.47 mol) in DMF (2.2 L), CO(OEt)2 (728 g, 6.16 mol), followed by t-BuOK (719 g, 6.41 mol), was added in small amounts at 20°C. After the addition was complete, the mixture was heated at 50°C for 20 hours. The reaction mixture was cooled to room temperature and poured into 4.0 L of ice water. The mixture was extracted with MTBE (3 × 1 L). The combined organic matter was dried (MgSO4) and evaporated to dryness under vacuum. The residue was purified by vacuum distillation (external temperature: 100°C, internal temperature: 59°C) to obtain ethyl 2-cyano-2-cyclopropyl acetate as a yellow oil (300 g, 79%). 1 H NMR (400 MHz, CDCl3) δ: 4.31 (q, 2H), 3.25 (d, 1H), 1.51-1.22 (m, 4H), 0.82- 0.67 (m, 2H), 0.63-0.40 (m, 2H).

[0168] Preparation 5 Ethyl(3R)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropyl-3-methylbutanoate [ka] Cs2CO3 (103 g, 316 mmol) and TBAB (13.6 g, 42.2 mmol) were added to a solution of tert-butyl(R)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (50 g, 211 mmol) and ethyl 2-cyano-2-cyclopropyl acetate (Preparation 4, 32.3 g, 211 mmol) in toluene (500 mL), and the reaction mixture was stirred at 30°C for 8 hours. The pH of the mixture was adjusted to approximately 5 by gradually adding 1N HCl at 0-10°C, the mixture was stirred for 30 minutes, and extracted with ELISA (2 × 100 mL). The combined organic matter was dried (MgSO4) and evaporated under reduced pressure to obtain ethyl(3R)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropyl-3-methylbutanoate as a colorless oil (65 g, 99%).

[0169] Preparation 6 Ethyl(3S)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropyl-3-methylbutanoate [ka] Ethyl(3S)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropyl-3-methylbutanoate was prepared from tert-butyl(S)-5-methyl-1,2,3-oxathiazolidined-3-carboxylate 2,2-dioxide and ethyl 2-cyano-2-cyclopropyl acetate (Preparation 4) according to the procedure described in Preparation 5.

[0170] Preparation 7 Ethyl(3S)-4-((tert-butoxycarbonyl)amino)-2-cyano-3-methyl-2-(oxetan-3-yl)methylbutanoate [ka] Ethyl(3S)-4-((tert-butoxycarbonyl)amino)-2-cyano-3-methyl-2-(oxetan-3-yl)butanoate was obtained as a yellow oil (102 g, 93%) from tert-butyl(S)-5-methyl-1,2,3-oxathiazolidined-3-carboxylate 2,2-dioxide and ethyl2-cyano-2-(oxetan-3-yl)acetate (Preparation 3) by following the same procedure as described in Preparation 5.

[0171] Preparation 8 Ethyl 4-((tert-butoxycarbonyl)amino)-2-cyano-2-(oxetan-3-yl)butanoate [ka] Ethyl 4-((tert-butoxycarbonyl)amino)-2-cyano-2-(oxetan-3-yl)butanoate was obtained as a yellow oil (17.2 g, 93.2%) from ethyl 2-cyano-2-(oxetan-3-yl)acetate (Preparation 3) and tert-butyl 1,2,3-oxathiazolidined-3-carboxylate 2,2-dioxide according to the procedure described in Preparation 5.

[0172] Preparation 9 (4R)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] TsOH (79.7 g, 418 mmol) was added to a solution of ethyl (3R)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropyl-3-methylbutanoate (Preparation 5, 65.0 g, 209 mmol) in ethyl (500 mL), and the reaction mixture was stirred at 50°C for 1 hour. The mixture was concentrated under vacuum, the residue was dissolved in MeCN (500 mL), K2CO3 (86.8 g, 628 mmol) was added, and the mixture was stirred at 50°C for 5 hours. The cooled reaction mixture was filtered, the filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (SiO2, 50-100% ethyl / PE) to obtain (4R)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile as a colorless oil (22 g, 64%). 1 HNMR: (400 MHz, CDCl3) δ: 7.49 (d, 1H), 3.53 (dd, 1H), 3.16-3.02 (m, 1H), 2.56 (dt, 1H), 1.32 (dd, 3H), 1.14-0.91 (m, 1H), 0.89-0.48 (m, 4H).

[0173] Preparation 10 (4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] (4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile was prepared from ethyl(3S)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropyl-3-methylbutanoate (Preparation 6) according to the procedure described in Preparation 9 (20 g, 63%). 1 HNMR (400 MHz, CDCl3) δ: 7.49 (d, 1H), 3.53 (dd, 1H), 3.16-3.02 (m, 1H), 2.56 (dt, 1H), 1.32 (dd, 3H), 1.14-0.91 (m, 1H), 0.89-0.48 (m, 4H).

[0174] Preparation 11 (4S)-4-methyl-3-(oxetan-3-yl)-2-oxopyrrolidine-3-carbonitrile [ka] A solution of ethyl(3S)-4-((tert-butoxycarbonyl)amino)-2-cyano-3-methyl-2-(oxetan-3-yl)butanoate (Preparation 7, 100 g, 306 mmol) in THF (1 L) was cooled to 0°C. NaH (18.38 g, 459 mmol) was added gradually, and the mixture was heated to 20°C and stirred for 10 hours. The mixture was quenched with water (400 mL) and extracted with ELISA (3 × 400 ml). The combined organic matter was dried (MgSO4) and concentrated. The residue was purified by column chromatography (SiO2, 50-100% ELISA / PE) to obtain (4S)-4-methyl-3-(oxetan-3-yl)-2-oxopyrrolidine-3-carbonitrile as a yellow oil (34 g, 61.6%). 1 HNMR (400 MHz, CDCl3) δ: 7.15 (d, 1H), 5.03 (dt, 1H), 4.95-4.63 (m, 3H), 3.58 (dd, 1H), 3.48 (ddd, 2H), 3.14 (dd, 1H), 3.00 (dt, 1H), 2.40 (dd, 1H), 1.32 (d, 2H), 1.10-0.84 (m, 1H).

[0175] Preparation 12 3-(oxetane-3-yl)-2-oxopyrrolidine-3-carbonilicate [ka] 3-(oxetan-3-yl)-2-oxopyrrolidine-3-carbonitrile was obtained from ethyl 4-((tert-butoxycarbonyl)amino)-2-cyano-2-(oxetan-3-yl)butanoate (Preparation 8) as a white solid, 4.1 g, 46.7%. LCMS m / z = 167 [M+H] + .

[0176] Preparation 13 (5R)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile [ka] Part A: Cs2CO3 (128 g, 391 mmol) and TBAB (16.8 g, 52.2 mmol) were added to ethyl 2-cyano-2-cyclopropyl acetate (Preparation 4, 40 g, 261 mmol) in MeCN (500 mL), and the solution was stirred at room temperature for 30 minutes. tert-butyl(R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (62 g, 261 mmol) was added, and the reaction mixture was stirred at 30°C for 10 hours. The mixture was concentrated under vacuum, and the residue was diluted with H2O (200 mL) and siRNA (500 mL). The pH was adjusted to approximately 5 by gradually adding 1N HCl at 0-10°C. The mixture was extracted with HCl (500 mL and 2 × 200 mL), the combined organic matter was washed with saturated NaHCO3 aqueous solution (200 mL), dried with (MgSO4), and concentrated under vacuum to obtain ethyl(4R)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropylpentanoate as a yellow oil (81 g).

[0177] Part B: TsOH·H2O (98.1 g, 515 mmol) was added to a solution of ethyl(4R)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropylpentanoate (80 g, 257 mmol) in ethyl(500 mL) and the solution was stirred at 50°C for 1 hour. The mixture was concentrated under vacuum and the residue was dissolved in MeCN (800 mL). K2CO3 (106.9 g, 773 mmol) was added and the reaction mixture was stirred at 50°C for 6 hours. The cooled reaction mixture was concentrated under vacuum, washed with H2O (500 mL), and extracted with ethyl(500 mL and 300 mL). The combined organic matter was dried in (MgSO4) and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 50-100% Â1 / PE) to obtain (5R)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile as a white solid (27.1 g, 64%). 1 HNMR (400 MHz, CDCl3) δ: 6.94 (d, 1H), 4.07-3.64 (m, 1H), 2.71 (dd, 1H), 2.50 (dd, 1H), 2.22 (dd, 1H), 1.78 (dd, 1H), 1.34 (dd, 3H), 1.28-1.12 (m, 1H), 0.87-0.50 (m, 4H).

[0178] Preparations 14 and 15 (3S,5R)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile and (3R,5R)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile [ka] (5R)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 13, 15.0 g, 91.4 mmol) was separated by SFC (Chiralpak IC, 250 × 30 mm, 5 μm, 30% MeOH (+0.1% NH4OH) in CO2) to obtain the title compound.

[0179] Peak 1, Preparation 14, (3S,5R)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile as a pale yellow solid (6.80 g, 45%). LCMS m / z = 165 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 6.85 (s, 1H), 3.86 (dd, 1H), 2.51 (dd, 1H), 2.23 (dd, 1H), 1.35 (d, 3H), 1.29-1.17 (m, 1H), 0.83-0.58 (m, 4H). [α]= 24.2° c=1.0g / 100 mL MeOH.

[0180] Peak 2, Preparation 15, (3R,5R)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile as a pale yellow solid (7.70 g, 51%). LCMS m / z = 165 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 6.27 (s, 1H), 3.94 (dt, 1H), 2.72 (dd, 1H), 1.79 (dd, 1H), 1.31 (t, 3H), 1.23 (ddd, 1H), 0.87-0.56 (m, 4H). [α]= -42.6° c=1.1g / 100 mL MeOH.

[0181] Preparation 16 (5S)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile [ka] The title compound was prepared as a white solid (33 g, 77%) from ethyl 2-cyano-2-cyclopropyl acetate (Preparation 4) and tert-butyl(S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide using a two-part process similar to the process described for Preparation 13. 1HNMR (400 MHz, CDCl3) δ: 6.75 (d, 1H), 4.11-3.71 (m, 1H), 2.71 (dd, 1H), 2.51 (dd, 1H), 2.23 (dd, 1H), 1.79 (dd, 1H), 1.41-1.29 (m, 3H), 1.28-1.13 (m, 1H), 0.93-0.45 (m, 4H).

[0182] Preparations 17 and 18 (3R,5S)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile and (3S,5S)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile [ka] (5S)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 16, 15.0 g, 91.4 mmol) was separated by SFC (Chiralpak IC, 250 × 30 mm, 5 μm, 30% MeOH (+0.1% NH4OH) in CO2) to obtain the title compound.

[0183] Peak 1, Preparation 17, (3R,5S)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile as a pale yellow solid (6.60 g). LCMS m / z = 165 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 6.60 (s, 1H), 3.94 (dt, 1H), 2.72 (dd, 1H), 1.79 (dd, 1H), 1.34 (t, 3H), 1.23 (tt, 1H), 0.98-0.40 (m, 4H). [α]= -25.2° c=1.0g / 100 mL MeOH.

[0184] Peak 2, Preparation 18, (3S,5S)-3-cyclopropyl-5-methyl-2-oxopyrrolidine-3-carbonitrile as a pale yellow solid (7.7g). LCMS m / z = 165 [M+H] + ;1 HNMR (400 MHz, CDCl3) δ: 6.27 (s, 1H), 3.94 (dt, 1H), 2.72 (dd, 1H), 1.79 (dd, 1H), 1.31 (t, 3H), 1.23 (ddd, 1H), 0.87-0.56 (m, 4H). [α]= 43.2° c=1.0g / 100 mL MeOH.

[0185] Preparations 19 and 20 (3S,4R)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile and (3R,4R)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] (4R)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 9, 18.50 g, 112.66 mmol) was separated by SFC (Chiralpak IC, 250 × 30 mm, 5 μm, eluted with 30% MeOH (0.1% NH4OH) in CO2) to obtain the following.

[0186] Peak 1, Preparation 19, (3S,4R)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile as a white solid (6.90 g, 37%). LCMS m / z = 165 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 6.81 (s, 1H), 3.54 (ddd, 1H), 3.10 (t, 1H), 3.05-2.91 (m, 1H), 1.32 (d, 3H), 1.09-0.95 (m, 1H), 0.81-0.58 (m, 4H).

[0187] Further elution yielded the following:

[0188] Peak 2, preparation 20, (3R,4R)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile as a yellow solid (10.50 g, 57%). LCMS m / z = 165 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 6.81 (s, 1H), 3.53 (ddd, 1H), 3.10 (dd, 1H), 2.57 (dd, 1H), 1.34 (t, 3H), 1.17-0.97 (m, 1H), 0.83- 0.54 (m, 4H).

[0189] Preparations 21 and 22 (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile and (3S,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] (4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 10, 16.50 g) was separated by SFC (Chiralpak IC, 250 × 30 mm, 5 μm, eluted with 30% MeOH (0.1% NH4OH) in CO2) to obtain the title compound.

[0190] Peak 1, Preparation 21, (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile as a yellow solid (8.90 g). LCMS m / z = 165 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 7.21 (s, 1H), 3.56-3.44 (m, 1H), 3.07 (dd, 1H), 2.55 (dt, 1H), 1.33 (d, 3H), 1.08 (dt, 1H), 0.78-0.51 (m, 4H).

[0191] Peak 2, Preparation 22, (3S,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (7.30 g) as a yellow solid. LCMS m / z = 165 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 7.20-6.78 (m, 1H), 3.64-3.38 (m, 1H), 3.10 (t, 1H), 3.05-2.88 (m, 1H), 1.40-1.14 (m, 3H), 1.03 (tt, 1H), 0.83-0.53 (m, 4H).

[0192] Preparation 23 (3S,4S)-4-methyl-3-(oxetan-3-yl)-2-oxopyrrolidine-3-carbonitrile and [ka] (4S)-4-methyl-3-(oxetan-3-yl)-2-oxopyrrolidine-3-carbonitrile (Preparation 11) was separated by SFC (Chiralpak IC, 250 × 30 mm, 5 μm, eluted with 30% MeOH (0.1% NH4OH) in CO2) to obtain the following.

[0193] Peak 1, (3R,4S)-4-methyl-3-(oxetan-3-yl)-2-oxopyrrolidine-3-carbonitrile, is a white solid (16.4 g, 51.3%).

[0194] Peak 2, Preparation 23, (3S,4S)-4-methyl-3-(oxetan-3-yl)-2-oxopyrrolidine-3-carbonitrile as a white solid (13.20 g, 41.3%). LCMS m / z = 181 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 6.87 (s, 1H), 5.07 (t, 1H), 4.97-4.62 (m, 3H), 3.71-3.32 (m, 2H), 3.14-2.77 (m, 2H), 1.04 (d, 3H).

[0195] Preparation 24 tert-butyl(S)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide [ka] Part 1. Boc2O (367.3 g, 1.68 mol) was added dropwise at 0-10°C to a mixture of (S)-2-aminobutan-1-ol (150 g, 1.68 mol) in DCM (1 L), and the resulting mixture was stirred at 30°C for 6 hours. The mixture was concentrated under vacuum to obtain tert-butyl(S)-(1-hydroxybutan-2-yl)carbamate (318.5 g, 100%) as a pale yellow oil, which was used in Part 2 without further purification.

[0196] Part 2. A solution of SOCl2 (330 g, 2.77 mol) in MeCN (1000 mL) was cooled to -35°C, and tert-butyl(R)-(1-hydroxybutan-2-yl)carbamate (Part 1, 210 g, 1.11 mol) from MeCN (500 mL) was added. The mixture was stirred at -35°C for 1 hour. Then, pyridine (438.86 g, 5.55 mol) was added dropwise to the mixture, and the mixture was slowly heated to 30°C and stirred for a further 8 hours. The mixture was poured into ice water (1 L) and extracted with RINKAN (2 × 1 L). The combined organic matter was washed with a saturated aqueous solution of NaHCO3 (500 mL), dried, and evaporated to dryness under vacuum to obtain tert-butyl(4S)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide as a brown oily substance (250 g, 96%), which was used in Part 3 without further purification.

[0197] Part 3. Tert-butyl(4S)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (Part 2, 250 g, 1.06 mol) was dissolved in MeCN (1 L) and H2O (1 L) at 20°C. RuCl3·3H2O (833 mg, 3.19 mmol) was added at 0°C, followed by the addition of NaIO4 (340.9 g, 1.59 mol) in small increments. The resulting mixture was stirred at 15°C for 2 hours. The reaction mixture was filtered, and the filtrate was extracted with ELISA (2 × 800 mL). The combined organic matter was washed with saturated NaHSO3 aqueous solution (500 mL) and NaHCO3 aqueous solution (500 mL), dried, and concentrated in (MgSO4). The residue was triturated with n-Hep / EtOH (20:1, 220 mL), and the solid was collected by filtration to obtain tert-butyl(S)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide as a white solid (150 g, 56%). 1 HNMR (400 MHz, CDCl3) δ: ppm 4.66 (dd, 1H), 4.44-4.13 (m, 2H), 1.91 (ddd, 2H), 1.57 (s, 9H), 1.01 (t, 3H).

[0198] Preparation 25 (5S)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile [ka] Part 1: Cs2CO3 (128 g, 391 mmol) and TBAB (16.84 g, 52.2 mmol) were added at 10°C to a solution of ethyl 2-cyano-2-cyclopropyl acetate (Preparation 4, 40 g, 261 mmol) in MeCN (500 mL), and the mixture was stirred for 30 minutes. To this, tert-butyl(S)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (Preparation 24, 65.62 g, 261 mmol) was added, and the resulting mixture was stirred at 30°C for 10 hours. The reaction mixture was evaporated to dryness under vacuum, and the residue was partitioned into H2O (200 mL) and siRNA (500 mL). The pH was adjusted to approximately 5 with 1 M HCl at 10°C, and then extracted with siRNA (500 mL and 2 × 200 mL). The combined organic compounds were washed with a saturated aqueous solution of NaHCO3 (200 mL), dried, and evaporated to dryness to obtain ethyl(4S)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropylhexanoate (solution in siRNA, 900 mL), which was immediately used in Part 2.

[0199] Part 3. TsOH·H2O (99.33 g, 522 mmol) was added at room temperature to a solution of ethyl(4S)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropylhexanoate (Part 1, 84.71 g, 261 mmol) in ethyl(900 mL) and the mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in MeCN (800 mL) and K2CO3 (108.27 g, 783 mmol) was added in small increments, and the resulting mixture was stirred at 50°C for 5 hours. The reaction mixture was cooled to room temperature and evaporated to dryness under vacuum. The residue was partitioned into H2O (500 mL) and ethyl(500 mL). The combined organic matter was dried in (MgSO4) and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 0-50% Â1 / PE) to obtain (5S)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile as a white solid (28.2 g, 61%). 1HNMR (400 MHz, CDCl3) δ: 6.65 (d, 1H), 3.85-3.47 (m, 1H), 2.70 (dd, 1H), 2.48 (dd, 1H), 2.28-2.12 (m, 1H), 1.82 (dd, 1H), 1.68 (ddd, 1H), 1.62-1.48 (m, 1H), 1.30-1.16 (m, 1H), 1.00 (td, 3H), 0.85-0.55 (m, 4H).

[0200] Preparations 26 and 27 (3R,5S)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile and (3S,5S)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile [ka] (5S)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile (prepared 25, 15 g, 84.2 mmol) was separated by SFC (ChiralPak IC, 150 × 4.6 mm, 3 μm, 5-40% MeOH (+0.1% NH4OH) in CO2) to obtain the title compound as an off-white solid.

[0201] Peak 1, Preparation 26 (4.30 g, 29%), (3R,5S)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile LCMS m / z = 179 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 6.58 (s, 1H), 3.74-3.44 (m, 1H), 2.48 (dd, 1H), 2.26 (dd, 1H), 1.76-1.65 (m, 1H), 1.60 (dd, 1H), 1.33-1.16 (m, 1H), 1.00 (t, 3H), 0.83-0.51 (m, 4H). [α] = -15.4° (c=1.1g / 100 mL, MeOH).

[0202] Peak 2, Preparation 27 (7.60 g, 51%), (3S,5S)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile LCMS m / z = 179 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 6.58 (s, 1H), 3.85-3.56 (m, 1H), 2.70 (dd, 1H), 1.82 (dd, 1H), 1.69 (d, 1H), 1.65-1.48 (m, 1H), 1.22 (tt, 1H), 1.00 (t, 3H), 0.88-0.54 (m, 4H). [α] = 38.0° (c=1.0g / 100 mL, MeOH).

[0203] Preparation 28 tert-butyl(R)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide [ka] Part 1. Boc2O (244.85 g, 1.12 mol) was added dropwise at 0-10°C to a mixture of (R)-2-aminobutan-1-ol (100 g, 1.12 mol) in THF (1 L), and the resulting mixture was stirred at 30°C for 6 hours. The mixture was concentrated under vacuum to obtain tert-butyl(R)-(1-hydroxybutan-2-yl)carbamate (212.32 g, 100%) as a pale yellow oil, which was used in Part 2 without further purification.

[0204] Part 2. A solution of SOCl2 (330 g, 2.77 mol) in MeCN (1000 mL) was cooled to -35°C, and tert-butyl(R)-(1-hydroxybutan-2-yl)carbamate (Part 1, 210 g, 1.11 mol) from MeCN (500 mL) was added. The mixture was stirred at -35°C for 1 hour. Then, pyridine (438.86 g, 5.55 mol) was added dropwise to the mixture, and the mixture was slowly heated to 30°C and stirred for a further 5 hours. The mixture was poured into ice water (1 L) and extracted with RINKAN (2 × 1 L). The combined organic matter was washed with a saturated aqueous solution of NaHCO3 (500 mL), dried, and evaporated to dryness under vacuum to obtain tert-butyl(4R)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide as a brown oily substance (230 g, 88%), which was used in Part 3 without further purification.

[0205] Part 3. Tert-butyl(4R)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (Part 2, 230 g, 977 mol) was dissolved in MeCN (1 L) and H2O (1 L) at 20°C. RuCl3·3H2O (767 mg, 2.93 mmol) was added at 0°C, followed by the addition of NaIO4 (313.6 g, 1466 mmol) in small increments. The resulting mixture was stirred at 20°C for 1 hour. The reaction mixture was filtered, and the filtrate was extracted with ELISA (2 × 800 mL). The combined organic matter was washed with saturated NaHSO3 aqueous solution (500 mL) and NaHCO3 aqueous solution (500 mL), dried, and concentrated in (MgSO4). The residue was triturated with n-Hep / EtOH (20:1, 220 mL), and the solid was collected by filtration to obtain tert-butyl(R)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide as a white solid (180 g, 73%). 1 HNMR (400 MHz, CDCl3) δ: MHz, CDCl3) δ: ppm 4.66 (dd, 1H), 4.44-4.13 (m, 2H), 1.91 (ddd, 2H), 1.57 (s, 9H), 1.01 (t, 3H).

[0206] Preparation 29 (5R)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile [ka] Part 1: Cs2CO3 (128 g, 391 mmol) and TBAB (16.84 g, 52.2 mmol) were added at 10°C to a solution of ethyl 2-cyano-2-cyclopropyl acetate (Preparation 4, 40 g, 261 mmol) in MeCN (500 mL), and the mixture was stirred for 30 minutes. To this, tert-butyl(R)-4-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (Preparation 28, 65.62 g, 261 mmol) was added, and the resulting mixture was stirred at 30°C for 10 hours. The reaction mixture was evaporated to dryness under vacuum, and the residue was partitioned into H2O (200 mL) and siRNA (500 mL). The pH was adjusted to approximately 5 with 1 M HCl at 10°C, and then extracted with siRNA (500 mL and 2 × 200 mL). The combined organic compounds were washed with a saturated aqueous solution of NaHCO3 (200 mL) and dried to obtain ethyl(4R)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropylhexanoate (solution in HCl, 900 mL) in (MgSO4), which was immediately used in Part 2.

[0207] Part 2. TsOH·H2O (99.33 g, 522 mmol) was added at room temperature to a solution of ethyl (4R)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropylhexanoate (Part 1, 84.71 g, 261 mmol) in ethyl (900 mL), and the mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in MeCN (800 mL), and K2CO3 (108.27 g, 783 mmol) was added in small amounts, and the resulting mixture was stirred at 50°C for 5 hours. The reaction mixture was cooled to room temperature and evaporated to dryness under vacuum. The residue was partitioned into H2O (500 mL) and ethyl (500 mL). The combined organic matter was dried in (MgSO4) and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 0-50% Â1 / PE) to obtain (5R)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile as a white solid (32.8 g, 70%). 1 HNMR (400 MHz, CDCl3) δ: 6.65 (d, 1H), 3.85-3.47 (m, 1H), 2.70 (dd, 1H), 2.48 (dd, 1H), 2.28-2.12 (m, 1H), 1.82 (dd, 1H), 1.68 (ddd, 1H), 1.62-1.48 (m, 1H), 1.30-1.16 (m, 1H), 1.00 (td, 3H), 0.85-0.55 (m, 4H).

[0208] Preparations 30 and 31 (3S,5R)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile and (3R,5R)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile [ka] (5R)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile (prepared 29, 20 g, 112.21 mmol) was separated by SFC (ChiralPak IC, 150 × 4.6 mm, 3 μm, 5-40% MeOH (+0.1% NH4OH) in CO2) to obtain the title compound as a pale yellow solid.

[0209] Peak 1, Preparation 30 (5.85g, 39%), (3S,5R)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile LCMS m / z = 179 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 6.58 (s, 1H), 3.74-3.44 (m, 1H), 2.48 (dd, 1H), 2.26 (dd, 1H), 1.76-1.65 (m, 1H), 1.60 (dd, 1H), 1.33-1.16 (m, 1H), 1.00 (t, 3H), 0.83-0.51 (m, 4H). [α] = 14.7° (c=1.1g / 100 mL, MeOH).

[0210] Peak 2, Preparation 31 (7.85g, 52%), (3R,5R)-3-cyclopropyl-5-ethyl-2-oxopyrrolidine-3-carbonitrile LCMS m / z = 179 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 6.58 (s, 1H), 3.85-3.56 (m, 1H), 2.70 (dd, 1H), 1.82 (dd, 1H), 1.69 (d, 1H), 1.65-1.48 (m, 1H), 1.22 (tt, 1H), 1.00 (t, 3H), 0.88-0.54 (m, 4H). [α] = -39.0° (c=1.0g / 100 mL, MeOH).

[0211] Preparation 32 tert-butyl(R)-5-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide [ka] Part 1. A mixture of NHBn2 (126.27 g, 640 mmol) and (R)-2-ethyloxirane (60.0 g, 832 mmol) in EtOH (600 mL) was stirred at 50°C for 20 hours. The mixture was concentrated under vacuum to obtain (R)-1-(dibenzylamino)butan-2-ol as a yellow oil (172.43 g, 100%), which was used in Part 2 without further purification.

[0212] Part 2. To a solution of (R)-1-(dibenzylamino)butan-2-ol (Part 1, 172.43 g, 640 mmol) in MeOH (800 mL), Pd(OH)2 / C (20 g, 20% purity) was added under N2. The resulting mixture was degassed, purged with H2 (3 times), and the reaction mixture was stirred at 50°C under H2 (1 atm) for 5 hours. After filtration, the filtrate was concentrated to obtain (R)-1-aminobutan-2-ol as a colorless oil (57.46 g, approximately 100%), which was used in Part 3 without further purification.

[0213] Part 3. To a solution of (R)-1-aminobutan-2-ol (57.46 g, 640 mmol) in THF, Boc2O (140.74 g, 645 mmol) was added, and the mixture was stirred at 30°C for 6 hours. The mixture was concentrated to obtain tert-butyl(R)-(2-hydroxybutyl)carbamate as a colorless oil (120.50 g, 99%), which was used in Part 4 without further purification.

[0214] Part 4. Tert-butyl(R)-(2-hydroxybutyl)carbamate (Part 3, 110 g, 581 mmol) in MeCN (500 mL) was added to a solution of SOCl2 (173 g, 1453 mmol) in MeCN (1000 mL) at -40°C. After the addition was complete, the reaction mixture was stirred at -25°C for 1 hour. Pyridine (230 g, 2.90 mol) was added, and the mixture was slowly heated to 30°C and stirred for a further 10 hours. The mixture was poured into ice water (1 L) and extracted with ELISA (2 × 1 L). The combined organic layers were washed with saturated NaHCO3 aqueous solution (500 mL), dried, and concentrated to obtain tert-butyl(5R)-5-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide as a brown oil (125 g, 91%).

[0215] Part 5. Tert-butyl(5R)-5-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (Part 4, 125 g, 531 mmol) was dissolved in MeCN (1 L) and H2O (1 L) at 20°C. RuCl3.3H2O (694.41 mg, 2.66 mmol) was added in small increments, followed by NaIO4 (170.44 g, 797 mmol). After addition, the mixture was stirred at 20°C for 2 hours. The reaction mixture was filtered, and the filtrate was extracted with ELISA (3 × 500 mL). The combined organic matter was washed with saturated NaHSO3 aqueous solution (500 mL) and NaHCO3 aqueous solution (500 mL), dried (MgSO4), and evaporated to dryness under vacuum. The residue was triturated with n-Hep / EtOH (10:1, 200 mL) and filtered to obtain tert-butyl(R)-5-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide as a white solid (118 g, 88%). 1 HNMR (400 MHz, CDCl3) δ: 4.78 (dd, 1H), 4.07 (dd, 1H), 3.68 (t, 1H), 1.97 (dd, 1H), 1.89-1.71 (m, 1H), 1.57 (s, 9H), 1.09 (t, 3H).

[0216] Preparation 33 (4R)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile [ka] The title compound was prepared from tert-butyl(R)-5-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (Preparation 32) as a yellow oil (43 g, 74%) using a method similar to that described for (Preparation 29). 1 HNMR (400 MHz, CDCl3) δ: .31 (s, 1H), 7.23 (s, 1H), 3.55 (ddt, 1H), 3.19-2.95 (m, 1H), 2.89-2.65 (m, 1H), 2.36 (dtd, 1H), 1.99-1.79 (m, 1H), 1.69-1.53 ​​(m, 1H), 1.09-0.87 (m, 4H), 0.80-0.47 (m, 4H).

[0217] Preparations 34 and 35 (3S,4R)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile and (3R,4R)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile [ka] (4R)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (Preparation 33) was separated by SFC (ChiralPak IC, 150 × 4.6 mm, 3 μm, 30% MeOH (+0.1% NH4OH) in CO2) to obtain the title compound as a pale yellow solid.

[0218] Peak 1, Preparation 34 (8.60 g, 43%), (3S,4R)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile. LCMS m / z = 179 [M+H] + ; 1HNMR (400 MHz, CDCl3) δ: 7.06 (s, 1H), 3.56 (ddd, 1H), 3.09 (t, 1H), 2.87-2.65 (m, 1H), 2.04-1.77 (m, 1H), 1.79-1.48 (m, 2H), 1.22-0.83 (m, 4H), 0.87-0.43 (m, 4H). [α] = 11.1° (c=1.0g / 100 mL, MeOH).

[0219] Peak 2, Preparation 35 (9.40 g, 47%), (3R,4R)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile. LCMS m / z = 179 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 7.07 (s, 1H), 3.55 (ddd, 1H), 3.15 (dd, 1H), 2.44-2.20 (m, 1H), 1.90 (ddd, 1H), 1.79-1.53 ​​(m, 2H), 1.22-0.91 (m, 4H), 0.82-0.41 (m, 4H). [α] = 66.1° (c=1.1g / 100 mL, MeOH).

[0220] Preparation 36 tert-butyl(S)-5-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide [ka] The title compound was prepared from (S)-2-ethyloxirane as a white solid (120 g, 90%) using a five-part procedure similar to that described for Preparation 32. 1 HNMR (400 MHz, CDCl3) δ: 4.78 (dd, 1H), 4.07 (dd, 1H), 3.68 (t, 1H), 1.97 (dd, 1H), 1.89-1.71 (m, 1H), 1.57 (s, 9H), 1.09 (t, 3H).

[0221] Preparation 37 (4S)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile [ka] The title compound was prepared from tert-butyl(S)-5-ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (Preparation 36) as a yellow oil (42.1 g, 72%) using a two-part procedure similar to that described for Preparation 29. 1 HNMR (400 MHz, CDCl3) δ: 7.31 (s, 1H), 7.23 (s, 1H), 3.55 (ddt, 1H), 3.19-2.95 (m, 1H), 2.89-2.65 (m, 1H), 2.36 (dtd, 1H), 1.99-1.79 (m, 1H), 1.69-1.53 ​​(m, 1H), 1.09-0.87 (m, 4H), 0.80-0.47 (m, 4H).

[0222] Preparations 38 and 39 (3S,4S)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile and (3R,4S)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile [ka] (4S)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (Preparation 37) was separated by SFC (ChiralPak IC, 150 × 4.6 mm, 3 μm, 30% MeOH (+0.1% NH4OH) in CO2) to obtain the title compound as a yellow solid.

[0223] Peak 1, Preparation 38 (9.50 g, 47%), (3S,4S)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile. LCMS m / z = 179 [M+H] + ; 1HNMR (400 MHz, CDCl3) δ: 7.07 (s, 1H), 3.55 (ddd, J=1H), 3.15 (dd, 1H), 2.44-2.20 (m, 1H), 1.90 (ddd, 1H), 1.79-1.53 ​​(m, 2H), 1.22-0.91 (m, 4H), 0.82-0.41 (m, 4H). [α] = -67.7° (c=1.0g / 100 mL, MeOH).

[0224] Peak 2, preparation 39 (8.80 g, 44%), (3R,4S)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile. LCMS m / z = 179 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ: 7.06 (s, 1H), 3.56 (ddd, 1H), 3.09 (t, 1H), 2.87-2.65 (m, 1H), 2.04-1.77 (m, 1H), 1.79-1.48 (m, 2H), 1.22-0.83 (m, 4H), 0.87-0.43 (m, 4H). [α] = -11.2° (c=0.97g / 100 mL, MeOH).

[0225] preparation 40 (R)-3-Cyclopropyl-1-(4-Methoxybenzyl)-2-Oxopyrrolidine-3-carboxylic acid [ka] Part A: To a solution of (S)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (Example 1D, WO20160159773, 2.0 g, 13.3 mmol) in DMF (15 mL), NaH (639 mg, 16.0 mmol, 60% purity) was added at 0°C, and the mixture was stirred for 30 minutes. PMBCl (2.3 g, 14.7 mmol) was added, and the mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (20 mL) and extracted with siRNA (3 × 25 mL). The combined organic matter was washed with brine (60 mL), dried, and concentrated to obtain (S)-3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbonitrile as an orange oil (4.0 g, crude).

[0226] Part B: To a solution of (S)-3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbonitrile (Part A, 4.0 g, 14.80 mmol) in DMF (2 mL), NaOH (6 M, 30 mL) was added, and the mixture was stirred at 50°C for 64 hours. The mixture was adjusted to pH 5-6 with 4 M HCl, diluted with water (20 mL), and extracted with ELISA (3 × 15 mL). The combined organic matter was washed with brine (30 mL), dried, and evaporated under reduced pressure to obtain (R)-3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylic acid as a white solid (4.0 g, crude). 1 H NMR (500 MHz, CDCl3) δ: 7.14 (d, 2H), 6.86 (d, 2H), 4.50 (d, 1H), 4.29 (d, 1H), 3.80 (s, 3H), 3.20-3.16 (m, 2H), 2.48-2.41 (m, 1H), 1.92-1.89 (m, 1H), 1.39-1.36 (m, 1H), 0.54-0.48 (m, 3H), 0.30-0.22 (m, 1H).

[0227] Preparation 41 (R)-3-Cyclopropyl-N-Methoxy-1-(4-Methoxybenzyl)-N-Methyl-2-Oxopyrrolidine-3-Carboxamide [ka] A solution of (R)-3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylic acid (preparation 40, 3.5 g, 12.1 mmol), DIPEA (4.7 g, 36.3 mmol), HOBt (2.0 g, 14.5 mmol), EDCI (5.1 g, 26.6 mmol), and N,O-dimethylhydroxylamine hydrochloride (3.0 g, 30.2 mmol) in DCM (70 mL) was stirred at 25°C for 16 hours. The mixture was diluted with water (70 mL) and extracted with SiO (3 × 50 mL). The combined organic phase was washed with brine (60 mL), dried, and concentrated under vacuum in (Na₂SO₄). The residue was purified by column chromatography (SiO2, 0-50% Â1 / PE) to obtain (R)-3-cyclopropyl-N-methoxy-1-(4-methoxybenzyl)-N-methyl-2-oxopyrrolidine-3-carboxamide as a colorless oil (3.3 g, 82%). LCMS m / z = 333.2 [M+H] + .

[0228] Preparation 42 (S)-3-Cyclopropyl-1-(4-Methoxybenzyl)-2-Oxopyrrolidine-3-Caraldehyde [ka] To a solution of (R)-3-cyclopropyl-N-methoxy-1-(4-methoxybenzyl)-N-methyl-2-oxopyrrolidine-3-carboxamide (Preparation 41, 3.8 g, 11.34 mmol) in DCM (30 mL), DIBAL-H (1 M, 22.7 mL) was added under N2 at -78°C, and the mixture was stirred for 2 hours. The mixture was diluted with saturated NH4Cl aqueous solution (50 mL) and extracted with ELISA (3 × 40 mL). The combined organic matter was washed with brine (80 mL), dried, and concentrated under vacuum using (Na2SO4). The residue was purified by column chromatography (SiO2, 0-20% ELISA / PE) to obtain (S)-3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbaldehyde as a colorless oil (2.1 g, 67%). 1 H NMR (400 MHz, CDCl3) δ: 9.80 (br s, 1H), 7.14 (d, 2H), 6.86 (d, 2H), 4.44 (d, 1H), 4.30 (d, 1H), 3.81 (s, 3H), 3.14 (t, 2H), 2.46-2.41 (m, 1H), 1.55-1.51 (m, 1H), 1.27-1.25 (m, 1H), 0.74-0.71 (m, 1H), 0.60-0.57 (m, 2H), 0.23-0.12 (m, 1H).

[0229] Preparation 43 (R)-3-Cyclopropyl-3-(difluoromethyl)-1-(4-methoxybenzyl)pyrrolidin-2-one [ka] To a solution of (S)-3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbaldehyde (prepared 42 mg, 500 mg, 1.83 mmol) in DCM (5 mL), DAST (590 mg, 0.5 mL) was added at 0°C. The mixture was heated to 25°C and stirred for 16 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic matter was washed with brine (30 mL), dried, and concentrated under vacuum using (Na₂SO₄). The residue was purified by column chromatography (SiO₂, 0-20% ethyl acetate / PE) to obtain (R)-3-cyclopropyl-3-(difluoromethyl)-1-(4-methoxybenzyl)pyrrolidine-2-one as a colorless oil (347 mg, 64%). LCMS m / z = 296.2 [M+H] + .

[0230] Preparation 44 (R)-3-Cyclopropyl-3-(difluoromethyl)pyrrolidine-2-one [ka] To a solution of (R)-3-cyclopropyl-3-(difluoromethyl)-1-(4-methoxybenzyl)pyrrolidine-2-one (prepared 43 mg, 3.17 mmol) in MeCN (10 mL) and H2O (1 mL), cerium ammonium nitrate (1.9 g, 3.52 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated. The crude product was purified by preparative TLC (33% ethyl acetate / PE) to obtain (R)-3-cyclopropyl-3-(difluoromethyl)pyrrolidine-2-one as a white solid (130 mg, 63%). 1H NMR (500 MHz, CDCl3) δ: 6.11-5.88 (m, 2H), 3.37-3.33 (m, 2H), 2.54-2.47 (m, 1H), 1.86-1.83 (m, 1H), 1.09-1.04 (m, 1H), 0.70-0.66 (m, 1H), 0.64-0.57 (m, 1H), 0.50-0.48 (m, 1H), 0.32-0.30 (m, 1H).

[0231] Preparation 45 (S)-3-Cyclopropyl-3-(Hydroxymethyl)-1-(4-Methoxybenzyl)pyrrolidin-2-one [ka] To a solution of (S)-3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbaldehyde (prepared 42 mg, 800 mg, 2.93 mmol) in MeOH (10 mL), NaBH4 (554 mg, 14.63 mmol) was slowly added at 0°C, and the reaction mixture was stirred at 40°C for 16 hours. The mixture was evaporated under reduced pressure, and the residue was diluted with water (10 mL) and extracted with ELISA (3 × 15 mL). The combined organic matter was washed with brine (30 mL), dried, and evaporated under reduced pressure to obtain (S)-3-cyclopropyl-3-(hydroxymethyl)-1-(4-methoxybenzyl)pyrrolidine-2-one as a colorless oil (343 mg, 42.6%). LCMS m / z = 276.2 [M+H] + .

[0232] Preparation 46 (S)-(3-Cyclopropyl-1-(4-Methoxybenzyl)-2-Oxopyrrolidine-3-yl)methylmethanesulfonate [ka] To a solution of (S)-3-cyclopropyl-3-(hydroxymethyl)-1-(4-methoxybenzyl)pyrrolidine-2-one (prepared 45 mg, 343 mg, 1.25 mmol) in DCM (10 mL), TEA (379 mg, 3.74 mmol) and MsCl (214 mg, 1.87 mmol) were added at 0°C. The mixture was stirred at 25°C for 3 hours, then diluted with water (10 mL) and extracted with DCM (3 × 15 mL). The combined organic matter was washed with brine (30 mL), dried, and concentrated to obtain (S)-(3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-yl)methylmethanesulfonate as a yellow oil (453 mg, crude). LCMS m / z = 354.1 [M+H] + .

[0233] Preparation 47 (R)-2-(3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-yl)acetonitrile [ka] To a solution of (S)-(3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-yl)methylmethanesulfonate (prepared 46 mg, 453 mg, 1.28 mmol) in DMSO (6 mL), NaCN (94.3 mg, 1.92 mmol) and NaI (19.2 mg, 0.128 mmol) were added, and the reaction mixture was stirred at 150 °C for 3 hours. The cooled mixture was diluted with water (15 mL), extracted with siRNA (10 mL x 3), washed with brine (30 mL), dried, and concentrated in (Na2SO4). The crude product was purified by column chromatography (SiO2, 0-20% siRNA / PE) to obtain (R)-2-(3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-yl)acetonitrile as a colorless oil (285 mg, 78%). LCMS m / z = 285.2 [M+H] + .

[0234] Preparation 48 (R)-2-(3-cyclopropyl-2-oxopyrrolidine-3-yl)acetonitrile [ka] (R)-2-(3-cyclopropyl-2-oxopyrrolidine-3-yl)acetonitrile was obtained from (R)-2-(3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-yl)acetonitrile (Preparation 47) as a colorless solid (93.2 mg, 57%) according to the procedure described in Preparation 44. 1 H NMR (500 MHz, CDCl3) δ: 5.83 (s, 1H), 3.39-3.35 (m, 2H), 2.67 (q, 2H), 2.26-2.21 (m, 1H), 2.13-2.11 (m, 1H), 1.11-1.07 (m, 1H), 0.64-0.53 (m, 1H), 0.52-0.48 (m, 2H), 0.38-0.35 (m, 1H).

[0235] Preparation 49 4-Chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (5.0 g, 32.8 mmol) in DMF (80 mL), NaH (1.75 g, 60% purity, 39.3 mmol) was added at 0°C. The mixture was stirred at 20°C for 30 minutes, and then TsCl (9.4 g, 49.16 mmol) was added. The reaction mixture was stirred at 20°C for 1 hour, quenched with water (30 mL), and extracted with siRNA (3 × 20 mL). The combined organic matter was washed with brine (20 mL), dried, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, 9-17% siRNA / PE) to obtain 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a white solid (6.1 g, yield 60.7%). 1H NMR (400 MHz, CDCl3) δ: 8.29 (d, 1H), 8.04 (d, 2H), 7.75 (d, 1H), 7.26 (d, 2H), 7.17 (d, 1H), 6.68 (d, 1H), 2.36 (s, 3H).

[0236] preparation 50 4-Chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 49, 2.0 g, 6.52 mmol) in THF (50 mL), LDA (2 M, 3.91 mL) was added at -70°C, and the solution was stirred for 30 minutes. I2 (2.0 g, 7.82 mmol) was added, and the reaction mixture was stirred at 20°C for 1 hour. The mixture was quenched with water (30 mL) and extracted with siRNA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried, and concentrated under vacuum in (Na2SO4). The crude product was purified by column chromatography (SiO2, 9-17% siRNA / PE) to obtain 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a white solid (800 mg, 28.4%). 1 H NMR (400 MHz, CDCl3) δ: 8.27 (d, 1H), 8.09 (d, 2H), 7.28 (d, 2H), 7.15 (d, 1H), 7.10 (s, 1H), 2.38 (s, 3H).

[0237] Preparation 51 4-Chloro-2-(1-methyl-1H-pyrazole-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (prepared 50 mg, 500 mg, 1.16 mmol) in dioxane (3 mL) and H2O (0.3 mL), 1-methylpyrazole-4-boronic acid pinacol ester (289.6 mg, 1.39 mmol), K2CO3 (320.7 mg, 2.32 mmol), and Pd(dppf)Cl2 (84.9 mg, 0.116 mmol) were added, and the reaction mixture was stirred at 100°C for 3 hours. The cooled mixture was concentrated under vacuum, and the residue was purified by column chromatography (SiO2, 6-50% Â / PE) to obtain 4-chloro-2-(1-methyl-1H-pyrazole-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a yellow solid (287 mg, 64%). 1 H NMR (400 MHz, CDCl3) δ: 8.35-8.30 (m, 1H), 7.75-7.64 (m, 4H), 7.18-7.14 (m, 3H), 6.55 (s, 1H), 4.00 (s, 3H), 2.32 (s, 3H).

[0238] Preparation 52 4-Chloro-2-(2-methoxypyridine-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ka] 4-chloro-2-(2-methoxypyridine-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine was obtained as a yellow solid (1.6 g, 83%) from 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 50) and (2-methoxypyridine-4-yl)boronic acid by following the same procedure as described in Preparation 51. LCMS m / z = 414.2 [M+H] + .

[0239] Preparation 53 (3R,4S)-3-cyclopropyl-4-methyl-1-(2-(1-methyl-1H-pyrazole-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of 4-chloro-2-(1-methyl-1H-pyrazole-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 51, 290 mg, 0.75 mmol) and (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 21, 307.7 mg, 1.87 mmol) in dioxane (1 mL), RuPhos Pd G3 (62.7 mg, 0.075 mmol) and K2CO3 (310.8 mg, 2.25 mmol) were added at 25°C, and the reaction mixture was stirred at 100°C for 2 hours under microwave irradiation and N2. The cooled reaction product was concentrated under reduced pressure and purified by column chromatography (6-50% siRNA / PE) to obtain (3R,4S)-3-cyclopropyl-4-methyl-1-(2-(1-methyl-1H-pyrazole-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-2-oxopyrrolidine-3-carbonitrile as a yellow oily substance (400 mg, crude). 1 H NMR (400 MHz, CDCl3) δ: 8.41 (d, 1H), 7.75-7.73 (m, 3H), 7.67 (s, 1H), 7.19-7.15 (m, 3H), 6.49 (s, 1H), 4.00 (s, 3H), 3.96-3.92 (m, 1H), 3.76-3.71 (m, 1H), 3.55-3.53 (m, 1H), 2.34 (s, 3H), 1.32-1.27 (m, 3H), 1.11-1.10 (m, 1H), 0.78-0.72 (m, 4H).

[0240] Preparation 54 (S)-3-Cyclopropyl-1-(2-(1-methyl-1H-pyrazole-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of 4-chloro-2-(1-methyl-1H-pyrazole-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 51, 350.0 mg, 0.905 mmol) and (S)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (Example 1D, WO20160159773, 339.7 mg, 2.26 mmol) in dioxane (10 mL), K2CO3 (375.1 mg, 2.71 mmol) and RuPhos Pd G3 (75.7 mg, 0.090 mmol) were added, and the reaction mixture was stirred at 100°C for 2 hours under microwave irradiation and N2. The cooled mixture was treated with H2O (15 mL) and extracted with Âr (3 × 10 mL). The combined organic phases were washed with brine (20 mL) and concentrated under vacuum with (Na2SO4). The crude product was purified by column chromatography (SiO2, 25-100% siRNA / PE) to obtain (S)-3-cyclopropyl-1-(2-(1-methyl-1H-pyrazole-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-2-oxopyrrolidine-3-carbonitrile as a yellow oil (430 mg, 95%). LCMS m / z = 501.1 [M+H] + .

[0241] Preparation 55 (R)-3-Cyclopropyl-1-(2-(1-methyl-1H-pyrazole-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-2-oxopyrrolidine-3-carbonitrile [ka] (R)-3-cyclopropyl-1-(2-(1-methyl-1H-pyrazole-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-2-oxopyrrolidine-3-carbonitrile was prepared as a yellow oil from 4-chloro-2-(1-methyl-1H-pyrazole-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 51) and (R)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (WO20160159773) according to the procedure described in Preparation 54. LCMS m / z = 501.1 [M+H] + .

[0242] Preparation 56 (S)-3-Cyclopropyl-1-(2-(2-Methoxypyridine-4-yl)-1-Tosyl-1H-Pyrrolo[2,3-b]pyridine-4-yl)-2-Oxopyrrolidine-3-Carbonitrile [ka] (S)-3-cyclopropyl-1-(2-(2-methoxypyridine-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-2-oxopyrrolidine-3-carbonitrile was prepared as a yellow solid (80 mg, 70.6%) from 4-chloro-2-(2-methoxypyridine-4-yl)-1-tosyl-1H-pyrrololo[2,3-b]pyridine (Preparation 52) and (S)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (Example 1D, WO20160159773) according to the procedure described in Preparation 54. LCMS m / z = 528.3 [M+H] + .

[0243] Preparation 57 (R)-3-Cyclopropyl-1-(2-(2-Methoxypyridine-4-yl)-1-Tosyl-1H-Pyrrolo[2,3-b]pyridine-4-yl)-2-Oxopyrrolidine-3-Carbonitrile [ka] (R)-3-cyclopropyl-1-(2-(2-methoxypyridine-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-2-oxopyrrolidine-3-carbonitrile was prepared as a white solid, 110 mg, in yield 43.2%, from 4-chloro-2-(2-methoxypyridine-4-yl)-1-tosyl-1H-pyrrololo[2,3-b]pyridine (Preparation 52) and (R)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (WO20160159773) according to the procedure described in Preparation 54. LCMS m / z = 528.3 [M+H] + .

[0244] Preparation 58 4-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine [ka] To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (25.0 g, 13.02 mmol) in acetone (250 mL), TsCl (37.2 g, 195.4 mmol) and 2M NaOH (97.6 mL) were added at 0°C, and the reaction mixture was stirred at 25°C for 3 hours. The solid was filtered, washed with acetone / H2O (v / v=1 / 1), collected, and dried under vacuum to obtain 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (45.6 g, yield 91%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 8.76 (s, 1H), 8.08 (d, 2H), 7.77 (d, 1H), 4.32 (d, 2H), 6.70 (d, 1H), 2.40 (s, 3H).

[0245] Preparation 59 4-Chloro-6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine [ka] To a solution of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (preparation 47, 10 g, 32.5 mmol) in THF (200 mL), LDA (2 M, 24.37 mL) was added dropwise under N2 at -78°C, and the mixture was stirred at -78°C for 1 hour. A solution of I2 (10.7 g, 42.2 mmol) in THF (50 mL) was added dropwise, and the mixture was stirred at -78°C for 1 hour. The reaction product was quenched with saturated NH4Cl aqueous solution (5 mL), diluted with H2O (10 mL), and extracted with siRNA (3 × 20 mL). The combined organic extract was washed with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (SiO2, 9-25% siRNA / PE) to obtain 4-chloro-6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (6.0 g, 42.6%) as a yellow solid. LCMS m / z = 433.9 [M+H] + .

[0246] Preparation 60 4-Chloro-6-(1-methyl-1H-pyrazole-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine [ka] To a solution of 4-chloro-6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (prepared 59 mg, 300 mg, 0.692 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (216 mg, 1.04 mmol) in dioxane (3 mL) and water (0.3 mL), Pd(dppf)Cl2 (50.6 mg, 0.069 mmol) and K3PO4 (294 mg, 1.38 mmol) were added, and the reaction mixture was stirred at 30°C for 12 hours. The reaction mixture was treated with H2O (5 mL) and extracted with siRNA (3 × 5 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and then purified by preparative TLC (50% PE / siRNA) to obtain 4-chloro-6-(1-methyl-1H-pyrazole-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (129 mg, yield 48%) as a rose-pink solid. LCMS m / z = 388.0 [M+H] + .

[0247] Preparation 61 (3R,4S)-3-cyclopropyl-4-methyl-1-(6-(1-methyl-1H-pyrazole-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of 4-chloro-6-(1-methyl-1H-pyrazole-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (preparation 60, 100 mg, 0.258 mmol) and (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (preparation 21, 84.7 mg, 0.516 mmol) in dioxane (5 mL), Pd2(dba)3 (23.6 mg, 0.0258 mmol), xanthophos (14.9 mg, 0.0258 mmol), and K3PO4 (76.6 mg, 0.361 mmol) were added, and the reaction mixture was stirred under N2 at 70°C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 6-50% siRNA / PE) to obtain (3R,4S)-3-cyclopropyl-4-methyl-1-(6-(1-methyl-1H-pyrazole-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-2-oxopyrrolidine-3-carbonitrile (160 mg, crude) as a colorless, rubbery substance. LCMS m / z = 516.2 [M + H] + .

[0248] Preparation 62 1-(4-bromo-1H-pyrrole-2-yl)ethane-1-one [ka] Amberlyst® 15 (3.97 g) was added at room temperature to a solution of 1-(1H-pyrrole-2-yl)ethane-1-one 1 (44 g, 403 mmol) in THF (442 mL). The mixture was cooled to -30°C, and NBS (71.8 g, 403 mmol) was added gradually. The resulting mixture was stirred for 2 hours, then warmed to room temperature and filtered. The filtrate was diluted with saturated sodium sulfite aqueous solution, and the resulting mixture was extracted with DCM (twice). The combined organic matter was evaporated to dryness under vacuum, and the residue was dissolved in TBME. The solution was washed with NaHCO3 (twice) and brine, dried (Na2SO4), and concentrated under reduced pressure to obtain 1-(4-bromo-1H-pyrrole-2-yl)ethane-1-one as a white solid, which was used without further purification (76.2 g). LCMS m / z = 188.0 [M+H] + .

[0249] Preparation 63 (E)-1-(4-bromo-1H-pyrrole-2-yl)-3-(dimethylamino)propa-2-en-1-one [ka] A solution of 1-(4-bromo-1H-pyrrole-2-yl)ethane-1-one (prepared 62, 76.2 g, 0.36 mol) in DMF-DMA (390 mL) was heated overnight to 85°C. The yellow suspension was diluted with heptane, and the resulting solid was collected by filtration. The filtration cake was washed with heptane and dried to obtain (E)-1-(4-bromo-1H-pyrrole-2-yl)-3-(dimethylamino)propa-2-en-1-one as a light brown solid (61.5 g, 69%). LCMS m / z = 243.1 [M+H] + .

[0250] Preparation 64 6-Bromopyrrolo[1,2-b]pyridazine-4-ol [ka] KO tBu (42.6 g, 379 mmol) was gradually added to a solution of (E)-1-(4-bromo-1H-pyrrole-2-yl)-3-(dimethylamino)propa-2-en-1-one (Preparation 63, 61.5 g, 253 mmol) in NMP (1.85 L), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled on an ice / water bath, O-(4-nitrobenzoyl)hydroxylamine (69.1 g, 379 mmol) was added, and the resulting mixture was stirred at 0°C for 1 hour, then at room temperature overnight. The mixture was cooled to 0°C, and saturated NH4Cl aqueous solution (500 mL) was added dropwise. The mixture was diluted with H2O (500 mL), the pH was adjusted to 3-4 with 2N HCl aqueous solution, and extracted with TBME (3 times). The combined organic matter was concentrated to half its volume, washed with H2O (2 times) and brine, and then evaporated to dryness under vacuum. The residue was filtered through a silica pad (0-100% Â1 / Heptane) to obtain 6-bromopyrrolo[1,2-b]pyridazine-4-ol (58 g, 54%), which was used without further purification. LCMS m / z = 213.0 [M+H] + .

[0251] Preparation 65 6-Bromopyrrolo[1,2-b]pyridazine-4-yltrifluoromethanesulfonate [ka] Anhydrous trifluoromethanesulfonic acid (88.3 g, 313 mmol) was added at 0°C to a solution of 6-bromopyrrolo[1,2-b]pyridazin-4-ol (prepared 64 g, approximately 140 mmol, purity approximately 50%) and TEA (32.5 g, 321 mmol) in DCM (870 mL). The mixture was stirred for 1 hour while cooling, then at room temperature for 2 hours. The mixture was diluted with DCM, washed twice with Na2CO3 and brine, dried (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 0-2% TBME / heptane) to obtain 6-bromopyrrolo[1,2-b]pyridazin-4-yltrifluoromethanesulfonate as a dark oil (21.1 g, 43%). LCMS m / z = 344.6 [M+H] +.

[0252] Preparation 66 1-(6-bromopyrrolo[1,2-b]pyridazine-4-yl)-2-oxopyrrolidine-3-carbonitrile [ka] A solution of 6-bromopyrrolo[1,2-b]pyridazine-4-yltrifluoromethanesulfonate (65 mg, 100 mg, 0.290 mmol), 2-oxopyrrolidine-3-carbonitrilate (47.9 mg, 0.435 mmol), xanthophos (16.8 mg, 0.029 mmol), Pd2(dba)3 (26.5 mg, 0.029 mmol), and K2CO3 (80.1 mg, 0.580 mmol) in toluene (2 mL) was stirred at 80°C for 2 hours under N2. The cooled mixture was concentrated under reduced pressure and purified by column chromatography (4-50% Â / PE) to obtain 1-(6-bromopyrrolo[1,2-b]pyridazine-4-yl)-2-oxopyrrolidine-3-carbonitrilate (50 mg, 56.6%) as a yellow solid. LCMS m / z = 305.0 [M+H] + .

[0253] Preparation 67 1-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3-(methoxymethyl)-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of 6-bromopyrrolo[1,2-b]pyridazine-4-yltrifluoromethanesulfonate (prepared 65 mg, 100 mg, 0.290 mmol) and 3-(methoxymethyl)-2-oxopyrrolidine-3-carbonitrile (67 mg, 0.435 mmol) in THF (5 mL), xanthophos (16.8 mg, 0.029 mmol), Pd2(dba)3 (26.5 mg, 0.029 mmol), and Cs2CO3 (132 mg, 0.406 mmol) were added, and the reaction mixture was stirred under N2 at 70°C for 4 hours. The cooled reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 6-50% Â1 / PE) to obtain 1-(6-bromopyrrollo[1,2-b]pyridazin-4-yl)-3-(methoxymethyl)-2-oxopyrrolidine-3-carbonitrile (95 mg, 94%) as a yellow oil. LCMS m / z = 349.0 [M+H] + .

[0254] Preparation 68 (3R,4S)-1-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] A solution of 6-bromopyrrolo[1,2-b]pyridazine-4-yltrifluoromethanesulfonate (Preparation 65, 2.0 g, 5.80 mmol), (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 21, 1.05 g, 6.38 mmol), Pd2(dba)3 (530.7 mg, 0.58 mmol), xanthophos (335.3 mg, 0.58 mmol), and K3PO4 (1.72 g, 8.11 mmol) in dioxane (20 mL) was stirred at 70°C for 1 hour under N2. The mixture was concentrated under vacuum, and the crude product was subjected to column chromatography (SiO2, 9-25%). Purification by HCl / PE yielded (3R,4S)-1-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (3.2 g, crude) as a yellow solid.1 H NMR (400 MHz, CDCl3) δ: 8.01 (d, 1H), 7.79 (s, 1H), 6.94 (d, 1H), 6.61 (s, 1H), 4.13-4.06 (m, 1H), 3.80-3.50 (m, 1H), 3.11-3.01 (m, 1H), 1.41 (d, 3H), 1.22-1.13 (m, 1H), 0.80-0.75 (m, 4H).

[0255] Preparation 69 (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)pyrroridine-3-carbonilicate [ka] To a mixture of (3R,4S)-1-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitride (prepared 68, 10.2 g, 28.39 mmol), B2Pin2 (14.42 g, 56.79 mmol), and AcOK (8.36 g, 85.18 mmol) in dioxane (150 mL), Pd(dppf)Cl2·DCM (2.32 g, 2.84 mmol) was added under N2 conditions, and the mixture was stirred at 90°C for 16 hours. The reaction mixture was filtered, the filtrate was evaporated to dryness under vacuum, and the residue was purified by column chromatography (SiO2, 25% siRNA / PE) to obtain (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)pyrrolidine-3-carbonitrile as a yellow solid (6g, 49.5%). LCMS m / z = 407.2 [M+H] + .

[0256] Preparation 70 (S)-1-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of 6-bromopyrrolo[1,2-b]pyridazine-4-yltrifluoromethanesulfonate (Preparation 65, 200.0 mg, 0.58 mmol) and (S)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (Example 1D, WO20160159773, 95.7 mg, 0.638 mmol) in dioxane (8 mL), Pd2(dba)3 (53.1 mg, 0.058 mmol), xanthophos (33.5 mg, 0.058 mmol), and K3PO4 (172.2 mg, 0.812 mmol) were added, and the reaction mixture was stirred under N2 at 70°C for 2 hours. The reaction mixture was washed with H2O (10 mL) and extracted with siRNA (3 × 10 mL). The combined organic extracts were washed with brine (15 mL), dried, evaporated to dryness (Na2SO4), and purified by column chromatography (SiO2, 6-50% Â1 / PE) to obtain (S)-1-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (195 mg, 97.5%) as a yellow solid. LCMS m / z = 347.1 [M + H] + .

[0257] Preparation 71~93 The following compounds were prepared from 6-bromopyrrolo[1,2-b]pyridazine-4-yltrifluoromethanesulfonate (Preparation 65) and a suitable lactam, following a procedure similar to that described in Preparation 70. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11]

[0258] Preparation 94 (3R,4S)-1-(6-bromo-7-fluoropyrrolo[1,2-b]pyridazin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] To a mixture of (3R,4S)-1-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (prepared 68 mg, 100 mg, 0.278 mmol) in MeCN (2.8 mL), Select-F (118.3 mg, 0.334 mmol) was added at 0°C, and the reaction mixture was stirred at this temperature for 30 minutes. The mixture was concentrated under vacuum and purified by column chromatography (25% siRNA / PE) to obtain (3R,4S)-1-(6-bromo-7-fluoropyrrolo[1,2-b]pyridazin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (40 mg, 38.1%) as a yellow solid. LCMS m / z = 377.0 [M+H] + .

[0259] Preparation 95 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine [ka] A mixture of 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylic acid (intermediate 1, step 5, WO2014 / 039595, 300 mg, 1.16 mmol) in concentrated HCl (5 mL, purity 36%) was stirred at 100°C for 15 hours. The cooled mixture was evaporated under reduced pressure, and the residue was purified by HPLC-1 (gradient 17-47%) to obtain 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine (60 mg, yield 24.1%) as a white solid. LCMS m / z = 214.2, 216.2 [M+H] + .

[0260] Preparation 96 2-Bromo-8-chloroimidazo[1,2-b]pyridazine [ka] 2-Bromo-8-hydroxyimidazo[1,2-b]pyridazine (prepared 53 mg, 20.0 mg, 0.093 mmol) and DIPEA (36.2 mg, 0.28 mmol) were slowly added to POCl3 (3.29 g, 21.46 mmol), and the reaction mixture was stirred at 120°C for 3 hours. Further POCl3 (10.0 mL) was added, and the reaction mixture was stirred at 120°C for a further 15 hours. The cooled reaction mixture was concentrated under vacuum, quenched with H2O (1.0 mL), and then purified by HPLC-1 (gradient 25-55%) to obtain 2-bromo-8-chloroimidazo[1,2-b]pyridazine (21 mg, 97%) as a yellow solid. LCMS m / z = 234.0 [M+H] + .

[0261] Preparation 97 (3R,4S)-1-(2-bromoimidazo[1,2-b]pyridazin-8-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of 2-bromo-8-chloroimidazo[1,2-b]pyridazine (Preparation 96, 100 mg, 0.430 mmol) and (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 21, 77.7 mg, 0.473 mmol) in dioxane (2 mL), Pd2(dba)3 (39.4 mg, 0.043 mmol), xanthophos (24.9 mg, 0.043 mmol), and K3PO4 (127.9 mg, 0.602 mmol) were added, and the mixture was stirred under N2 at 70°C for 3 hours. The cooled mixture was concentrated under vacuum, and the crude product was purified by column chromatography (SiO2, 0-10% siRNA / PE) to obtain (3R,4S)-1-(2-bromoimidazo[1,2-b]pyridazin-8-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (100 mg, 64.5%) as a green oily substance. LCMS m / z = 360.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 8.29-8.26 (m, 1H), 7.97-7.90 (m, 2H), 4.80-4.74 (m, 1H), 4.37-4.31 (m, 1H), 3.01-2.98 (m, 1H), 1.43 (d, 3H), 1.20-1.17 (m, 1H), 0.80-0.70 (m, 4H).

[0262] Preparation 98 6-Bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine [ka] A solution of 6-bromopyrrolo[2,1-f][1,2,4]triazine-4(3H)-one (3.0 g, 14.0 mmol) in POCl3 (50 mL) was stirred at 100°C for 3 hours. The reaction mixture was evaporated under vacuum, and the residue was dissolved in DCM (60 mL). The pH was adjusted to approximately 7 with aqueous NaHCO3 solution. The combined organic matter was dried (Na2SO4) and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 20-35% siRNA / PE) to obtain 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine as a white solid (2.6 g, 80%). LCMS m / z = 231.5 [M+H] + .

[0263] Preparation 99 (3R,4S)-1-(6-bromopyrrolo[2,1-f][1,2,4]triazine-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] (3R,4S)-1-(6-bromopyrrolo[2,1-f][1,2,4]triazine-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile was obtained as a white solid, 50.0 mg, in yield 32.3%, from 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine and (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 21) according to the procedure described in Preparation 97. LCMS m / z = 360.0 [M+H] + .

[0264] preparation 100 (3R,4S)-1-(2-amino-3-nitropyridine-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 21, 94.6 mg, 0.576 mmol) in DMSO (5.0 mL), NaH (25.4 mg, 0.634 mmol, 60% purity) was added, and the mixture was stirred for 1 hour. 4-chloro-3-nitropyridine-2-amine (100 mg, 0.576 mmol) in DMSO (1.0 mL) was added, and the reaction mixture was stirred at 20°C for 2 hours. The mixture was quenched with water (0.5 mL), and then purified by preparative HPLC-2 (gradient 35-65%) to obtain (3R,4S)-1-(2-amino-3-nitropyridine-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (25 mg, 14.4%) as a yellow solid. LCMS m / z = 302.2 [M+H] + .

[0265] Preparation 101 (3R,4S)-3-cyclopropyl-1-(2,3-diaminopyridine-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of (3R,4S)-1-(2-amino-3-nitropyridine-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (prepared 100 mg, 0.10 mmol) in MeOH (10.0 mL), Pd / C (6 mg, purity 10%) was added, and the reaction mixture was stirred under 15 Psi of H2 at 20°C for 30 minutes. The mixture was filtered, and the filtrate was washed with MeOH. The filtrate was concentrated under vacuum to obtain (3R,4S)-3-cyclopropyl-1-(2,3-diaminopyridine-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonitrile (30 mg, crude) as a yellow oil. LCMS m / z = 272.1 [M+H] + .

[0266] Preparation 102 Dimethyl 1-(2-(1-methyl-1H-pyrazole-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate [ka] To a mixture of 2-bromo-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one (100 g, 543.04 mmol) and Cs2CO3 (707.73 g, 2.17 mol) in DMF (2 L), dimethyl 1H-pyrazole-3,5-dicarboxylate (231.3 g, 814.56 mmol) was added, and the reaction mixture was stirred at 20°C for 12 hours. The reaction product was filtered, the filtrate was concentrated under vacuum, and the residue was partitioned into DCM (600 mL) and water (500 mL) and extracted with siRNA (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (10%-50%, ethyl acetate in PE) to obtain dimethyl 1-(2-(1-methyl-1H-pyrazole-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate (115 g, 69%) as a brown solid. LCMS m / z = 307.1 [M+H] + .

[0267] Preparation 103 4-Hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid [ka] Part A: To a solution of dimethyl 1-(2-(1-methyl-1H-pyrazole-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate (Preparation 102, 100 g, 326.51 mmol) in EtOH (1000 mL), ammonium acetate (125.84 g, 1.63 mol) was added, and the reaction mixture was stirred under high pressure at 130 °C for 72 hours. The cooled reaction mixture was diluted with water (500 mL), and the mixture was filtered. The filtered cake was washed with water (4 × 100 mL), and evaporated under reduced pressure to obtain methyl 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (85 g, crude) as an off-white solid.

[0268] Part B: To a suspension of methyl 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (60 g, 219.58 mmol) in water (600 mL), sulfuric acid (150 mL) was added, and the reaction mixture was stirred at 90 °C for 12 hours. The cooled mixture was filtered, the filter cake was washed with water (300 mL), and dried to obtain 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (55 g, 97%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ: 11.65 (brs, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.32 (s, 1H), 3.87 (s, 3H).

[0269] Preparation 104 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-ol [ka] 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (Preparation 103, 5 g, 19.29 mmol) was dissolved in thiolane 1,1-dioxide (70 mL) and stirred at 300°C for 2 hours. The cooled mixture was purified by column chromatography (SiO2, 10-100%, SiO2 / PE, and 1-10% MeOH / DCM) to obtain 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-ol (4.2 g, 50%) as a white solid. LCMS m / z = 216.2 [M+H] + .

[0270] Preparation 105 4-Chloro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine [ka] To a suspension of 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-ol (Preparation 104, 10 g, 46.47 mmol) in MeCN (100 mL), phosphoryl trichloride (44 g, 286.96 mmol) was added, and the reaction mixture was stirred under N2 at 80°C for 2 hours. The reaction mixture was cooled to 0°C, water (200 mL) was added dropwise, and the mixture was then neutralized to pH 8 with 2N NaHCO3. The mixture was extracted with DCM (3 × 100 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to obtain 4-chloro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine (10.5 g, yield 92.7%) as a yellow solid. LCMS m / z = 234.1 [M+H] + .

[0271] Preparation 106 Ethyl 1-cyano-4-methyl-1H-pyrazole-5-carboxylate [ka] 2-chloroacetonitrile (13.55 mL, 214.05 mmol) was added dropwise at 20°C to a mixture of ethyl 4-methyl-1H-pyrazole-5-carboxamide (30 g, 194.60 mmol) and Cs2CO3 (76.08 g, 233.51 mmol) in DMF (300 mL), and the mixture was stirred at this temperature for 16 hours. The mixture was combined with another batch (20 g of ethyl 4-methyl-1H-pyrazole-5-carboxamide). The combined mixture was poured into water (1000 mL), extracted with ethyl 4-methyl-1H-pyrazole-5-carboxamide (3 × 500 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, 9% ethyl 1-cyano-4-methyl-1H-pyrazole-5-carboxylate (37 g) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ: 7.42 (s, 1H), 5.46 (s, 2H), 4.42 (q, 2H), 2.28 (s, 3H), 1.42 (t, 3H).

[0272] Preparation 107 Ethyl 1-(2-amino-2-oxoethyl)-4-methyl-1H-pyrazole-5-carboxylate [ka] Sulfuric acid (55 mL) was added at 25°C to a mixture of ethyl 1-cyano-4-methyl-1H-pyrazole-5-carboxylate (Preparation 106, 37 g, 191.51 mmol) in TFA (170 mL), and the mixture was stirred at this temperature for 16 hours. The mixture was concentrated, and the residue was added dropwise to an ice bath. The mixture was extracted with DCM (3 × 200 mL), the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain ethyl 1-(2-amino-2-oxoethyl)-4-methyl-1H-pyrazole-5-carboxylate (40 g, 99%) as a white solid. 1H NMR (400MHz, CDCl3) : 8.70 (br s, 2H), 7.50 (s, 1H), 7.08 (br s, 1H), 6.01 (br s, 1H), 5.31 (s, 2H), 4.39 (q, 2H), 2.30 (s, 3H), 1.39 (t, 3H).

[0273] Preparation 108 3-Methylpyrazolo[1,5-a]pyrazine-4,6-diol [ka] t-BuONa (43.68 g, 454.51 mmol) was added at 25°C to a mixture of ethyl 1-(2-amino-2-oxoethyl)-4-methyl-1H-pyrazole-5-carboxylate (preparation 107, 40 g, 189.38 mmol) in EtOH (4 L), and the mixture was stirred at 70°C for 14 hours. The mixture was cooled to 0°C, concentrated HCl was added to adjust the pH to 6-7, and the mixture was evaporated under reduced pressure to obtain 3-methylpyrazolo[1,5-a]pyrazine-4,6-diol (53 g, crude) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ: 11.68 (br.s, 1H), 7.57 (s, 1H), 5.09 (s, 2H), 2.26 (s, 3H).

[0274] Preparation 109 4,6-Dichloro-3-methylpyrazolo[1,5-a]pyrazine [ka] 3-methylpyrazolo[1,5-a]pyrazine-4,6-diol (prepared 108, 20 g, 121.10 mmol) was added to phosphoryl trichloride (100 mL) at 20°C, then pyridine hydrochloride (13.99 g, 121.10 mmol) was added, and the mixture was stirred at 120°C for 16 hours. The mixture was added dropwise to water (200 mL), extracted with DCM (3 × 100 mL), and the combined organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue purified by column chromatography (SiO₂, 16% siRNA / PE) to obtain 4,6-dichloro-3-methylpyrazolo[1,5-a]pyrazine (5.6 g, 23%) as a pale yellow solid. 1 H NMR (400MHz, CDCl3): 8.31 (s, 1H), 7.84 (s, 1H), 2.56 (s, 3H).

[0275] Preparation 110 (3R,4S)-1-(6-chloropyrazolo[1,5-a]pyrazine-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 21, 157.2 mg, 0.957 mmol) and NaH (31.9 mg, 0.798 mmol, 60% purity) in DMF (10 mL) were stirred at 25°C for 5 minutes. 4,6-dichloropyrazolo[1,5-a]pyrazine (150.0 mg, 0.798 mmol) was added, and the reaction mixture was stirred for 20 minutes. The mixture was concentrated under vacuum, and the crude product was purified by column chromatography (10-20% Â / PE) to obtain (3R,4S)-1-(6-chloropyrazolo[1,5-a]pyrazine-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (205 mg, 81.4%) as a white solid. 1H NMR (500 MHz, CDCl3) δ: 8.37 (s, 1H), 8.02 (d, 1H), 7.18 (s, 1H), 4.22-4.18 (m, 1H), 3.94-3.87 (m, 1H), 3.11-3.06 (m, 1H), 1.42 (d, 3H), 1.19-1.16 (m, 1H), 0.82-0.72 (m, 4H).

[0276] Preparation 111 (3R,4S)-1-(6-chloro-3-methylpyrazolo[1,5-a]pyrazine-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] (3R,4S)-1-(6-chloro-3-methylpyrazolo[1,5-a]pyrazine-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile was obtained as white crystals from 4,6-dichloro-3-methylpyrazolo[1,5-a]pyrazine (Preparation 109) and (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 21) by following a procedure similar to that described in Preparation 110. 1 H NMR (400 MHz, CDCl3) δ: 8.31 (s, 1H), 7.84 (s, 1H), 4.07-4.03 (m, 1H), 3.94-3.89 (m, 1H), 3.19-3.09 (m, 1H), 2.36 (s, 3H), 1.43 (d, 3H), 1.22-1.19 (m, 1H), 0.83-0.73 (m, 4H).

[0277] Preparation 112 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine [ka] To a solution of 3-bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (100.0 mg, 0.493 mmol) in dioxane (8.0 mL), (Bpin)2 (375.2 mg, 1.48 mmol), Pd(dppf)Cl2 (36.0 mg, 49.25 mmol), and KOAc (145.0 mg, 1.48 mmol) were added, and the reaction mixture was stirred under N2 at 90°C for 16 hours. The mixture was diluted with water (10 mL) and extracted with SiO2 (15 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash column (PE / siRNA = 1 / 0 to 2 / 1) to obtain 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (53.3 mg, crude) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm: 7.76 (s, 1H), 4.97 (s, 2H), 4.22-4.19 (m, 4H), 1.30 (s, 12H).

[0278] Preparation 113 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1,8-naphthyridine-2(1H)-one [ka] 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1,8-naphthyridine-2(1H)-one was obtained from 6-bromo-3,4-dihydro-1,8-naphthyridine-2(1H)-one as a yellow solid, 150 mg, in yield 62.1%, according to the procedure described in Preparation 112. LCMS m / z = 275.1 [M+H] + .

[0279] Preparation 114 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one [ka] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one was obtained from 5-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one as a yellow solid (500 mg, yield 65.3%) according to the procedure described in Preparation 112. LCMS m / z = 261.0 [M+H] + .

[0280] Preparation 115 1-(2,2-difluorocyclopropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] 1-(2,2-difluorocyclopropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was obtained from 4-bromo-1-(2,2-difluorocyclopropyl)-1H-pyrazole (Preparation 132) as a yellow oil (40 mg, 33%) according to the procedure described in Preparation 112. LCMS m / z = 270.8 [M+H] + .

[0281] Preparation 116 1-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one [ka] The title compound was prepared from 5-bromo-1-(difluoromethyl)pyridine-2(1H)-one as a yellow solid (200 mg, 74%) using a method similar to that described for Preparation 112. LCMS m / z = 272.1 [M+H] + .

[0282] Preparation 117 1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300.0 mg, 1.55 mmol) in DMF (5.0 mL), NaH (92.8 mg, 2.32 mmol, 60% purity) was added at 0°C, and the mixture was stirred at 25°C for 30 minutes. CD3I (268.9 mg, 1.86 mmol) was added, and the reaction was stirred at 25°C for 1 hour. The mixture was slowly quenched with water (10 mL) and extracted with  (10 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (PE / siRNA = 1 / 0 to 10 / 1) to obtain 1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (272.3 mg, 83.4%) as a colorless oil. LCMS m / z = 212.0 [M+H] + .

[0283] Preparation 118 tert-butyl 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate [ka] To a solution of 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (1 g, 5.02 mmol) in DCM (50 mL), TEA (1.53 g, 15.07 mmol) and tert-butoxycarbonyl tert-butyl carbonate (2.19 g, 10.05 mmol) were added, and the mixture was stirred at 20°C for 18 hours. The reaction mixture was evaporated to dryness under vacuum, and the residue was purified by column chromatography (SiO2, 10% Â / PE) to obtain tert-butyl 5-bromo-2,3-dihydropyrrolo[2,3-b]pyridine-1-carboxylate as an orange solid (0.54 g, 36%), which was used without further purification.

[0284] Preparation 119 (1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-yl)boronic acid [ka] Part 1: To a solution of 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (1 g, 5.02 mmol) in DCM (50 mL), TEA (1.53 g, 15.07 mmol) and tert-butoxycarbonyl tert-butyl carbonate (2.19 g, 10.05 mmol) were added, and the mixture was stirred at 20°C for 18 hours. The reaction mixture was evaporated to dryness under vacuum, and the residue was purified by column chromatography (SiO2, 10% Â / PE) to obtain tert-butyl 5-bromo-2,3-dihydropyrrolo[2,3-b]pyridine-1-carboxylate as an orange solid (0.54 g, 36%), which was used in Part 2 without further purification.

[0285] Part 2. To a solution of tert-butyl 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.54 g, 1.81 mmol) and (Bpin)2 (687 mg, 2.71 mmol) in dioxane (20 mL), KOAc (531 mg, 5.42 mmol) was added, followed by Pd(dppf)Cl2 (132 mg, 0.181 mmol). The reaction was stirred under N2 at 90°C for 12 hours. The mixture was concentrated under vacuum to obtain (1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-yl)boronic acid (0.4 g, crude) as a black solid, which was used without further purification. LCMS m / z = 265.1 [M+H] + .

[0286] Preparation 120 1-(Bicyclo[1.1.1]pentan-1-yl)-1H-pyrazole [ka] To a solution of the compound bicyclo[1.1.1]pentan-1-ylhydrazine (240 mg, 1.40 mmol, 2HCl) in EtOH (8 mL), 1,1,3,3-tetramethoxypropane (253 mg, 1.54 mmol) was added, and concentrated HCl (163 mg, 4.49 mmol) was added. The mixture was stirred at 80°C for 16 hours. The mixture was extracted with DCM (3 × 20 mL), the combined organic matter was washed with brine (30 mL), dried, and concentrated under reduced pressure to obtain 1-(1-bicyclo[1.1.1]pentanyl)pyrazole as a brown oily substance (130 mg, 69%), which was used without further purification. LCMS m / z = 135.3 [M+H] + .

[0287] Preparation 121 1-(Bicyclo[1.1.1]pentan-1-yl)-4-iodo-1H-pyrazole [ka] To a solution of 1-(bicyclo[1.1.1]pentan-1-yl)-1H-pyrazole (prepared 120 mg, 0.894 mmol) in AcOH (5 mL), NIS (201 mg, 0.894 mmol) was added, and the resulting mixture was stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure, the residue was diluted with H2O (20 mL), and extracted with DCM (3 × 20 mL). The combined organic matter was washed with brine (30 mL), dried with (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 9-16% siRNA / PE) to obtain 1-(1-bicyclo[1.1.1]pentan-1-yl)-4-iodo-1H-pyrazole as a pink oil (90 mg, 39%). LCMS m / z = 261.1 [M+H] + .

[0288] Preparation 122 5-Methoxy-2-(tributylstannyl)pyridine [ka] To a solution of 2-bromo-5-methoxypyridine (1 g, 5.32 mmol) in THF (10 mL), n-BuLi (2.5 M, 2.55 mL) was added at -70°C. After stirring for 30 minutes, tributyl(chloro)stannane (2.08 g, 6.38 mmol, 1.73 mL) was added, and the mixture was heated to 20°C and stirred for 2 hours. The mixture was quenched with an excess amount of KF aqueous solution and extracted with  (3 × 20 mL). The combined organic matter was washed with brine (20 mL), dried, and evaporated to dryness under vacuum using (Na₂SO₄). The residue was purified by column chromatography (SiO₂, 9-16%  / PE) to obtain 5-methoxy-2-(tributylstannyl)pyridine as a colorless oil (0.35 g, 17%). LCMS m / z = 400.1 [M+H] + .

[0289] Preparation 123 3,4-Dichloro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine [ka] To a solution of 4-chloro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine (preparation 105, 250.0 mg, 1.07 mmol) in DMF (5 mL), NCS (142.9 mg, 1.07 mmol) was added, and the reaction mixture was stirred at 50°C for 2 hours. The mixture was quenched with H2O (20 mL) and extracted with siRNA (20 mL x 2). The combined layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by flash column (16-50% siRNA / PE) to obtain 3,4-dichloro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine (180 mg, 62.8%) as a yellow solid. 1 H NMR (500 MHz, CDCl3) δ ppm: 8.38 (s, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.87 (s, 1H), 3.97 (s, 3H).

[0290] Preparation 124 4,6-Dichloro-3-fluoropyrazolo[1,5-a]pyrazine [ka] To a solution of Selectfluor™ (367.1 g, 1.03 mmol) in MeCN (1500 mL) and AcOH (150 mL), 4,6-dichloropyrazolo[1,5-a]pyrazine (150 g, 798 mmol) was added at 20 °C, and the resulting mixture was stirred at 100 °C for 72 hours. The solvent was removed by evaporation, the solvent was diluted with water (500 mL), and extracted with DCM (2 × 500 mL). The combined organic matter was washed with brine (500 mL), dried to (Na₂SO₄), and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO₂, 0-50%, siRNA / PE) to obtain a solid, which was further purified by preparative HPLC-5 (gradient: 40-70%) to obtain 4,6-dichloro-3-fluoropyrazolo[1,5-a]pyrazine as an off-white solid (30.2 g, 18%). LCMS m / z = 205.9 [M+H] + .

[0291] Preparation 125 (3R,4S)-1-(6-chloro-3-fluoropyrazolo[1,5-a]pyrazine-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] A solution of 4,6-dichloro-3-fluoropyrazolo[1,5-a]pyrazine (63.1 mg, 0.384 mmol) and NaH (12.82 mg, 0.320 mmol, 60% purity) in DMF (3.0 mL) was stirred at 25°C for 5 minutes. (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 21, 66 mg, 0.320 mmol) was added, and the mixture was stirred at 25°C for 20 minutes. The mixture was concentrated under reduced pressure and purified by column chromatography (33% Â / PE) to obtain (3R,4S)-1-(6-chloro-3-fluoropyrazolo[1,5-a]pyrazine-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (76 mg, 71%) as a white solid. LCMS m / z = 334.0 [M+H] + .

[0292] Preparation 126 (3R,4S)-3-cyclopropyl-1-(3-fluoro-6-(tributylstannyl)pyrazolo[1,5-a]pyrazine-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonilicate [ka] To a solution of (3R,4S)-1-(6-chloro-3-fluoropyrazolo[1,5-a]pyrazine-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (prepared 125 mg, 200 mg, 0.599 mmol) in toluene (5.0 mL), (SnBu3)2 (521.5 mg, 0.899 mmol) and Pd(dtbpf)Cl2 (39.1 mg, 0.060 mmol) were added under N2 conditions, and the reaction mixture was stirred at 100°C for 20 hours. The mixture was added to water (10 mL) and extracted with ELISA (10 mL x 3). The combined layers were washed with brine (30 mL), dried with Na2SO4, filtered, and concentrated under vacuum to obtain the crude product, which was purified by flash column (PE / siRNA = 10 / 1 to 3 / 1) to obtain (3R,4S)-3-cyclopropyl-1-(3-fluoro-6-(tributylstannyl)pyrazolo[1,5-a]pyrazine-4-yl)-4-methyl-2-oxopyrrolidine-3-carbonitrile (70 mg, yield 19.9%) as a yellow oil. 1 H NMR (500 MHz, CDCl3) δ: 7.98 (s, 1H), 7.78 (d, 1H), 4.24-4.17 (m, 1H), 3.77-3.72 (m, 1H), 3.16-3.12 (m, 1H), 1.67-1.61 (m, 6H), 1.42 (d, 3H), 1.37-1.29 (m, 12H), 0.93-0.91 (m, 10H), 0.90-0.75 (m, 4H).

[0293] Preparation 127 (3S,4R)-1-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of 6-bromopyrrolo[1,2-b]pyridazine-4-yltrifluoromethanesulfonate (Preparation 65, 100 mg, 0.290 mmol) and (3S,4R)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 19, 52.3 mg, 0.319 mmol) in dioxane (5 mL), Pd2(dba)3 (26.5 mg, 0.029 mmol), xanthophos (16.8 mg, 0.029 mmol), and K3PO4 (86.1 mg, 0.406 mmol) were added at 25 °C. The mixture was stirred under N2 at 70 °C for 1 hour. The mixture was diluted with H2O (10 mL) and extracted with siRNA (3 × 10 mL). The combined organic compounds were washed with brine (20 mL), dried, and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 6-25% Â1 / PE) to obtain (3S,4R)-1-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile as a yellow solid (100 mg, 96%). LCMS m / z = 360.9 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 8.01 (d, 1H), 7.79 (d, 1H), 6.95 (d, 1H), 6.61 (d, 1H), 4.09-4.06 (m, 1H), 3.85-3.80 (m, 1H), 3.10-3.03 (m, 1H), 1.42 (d, 3H), 1.18-1.13 (m, 1H), 0.81-0.76 (m, 4H).

[0294] Preparation 128 4-(tert-butyl)1-ethyl-2-cyano-2-cyclopropyl-3-methylene succinate [ka] To a solution of ethyl 2-cyano-2-cyclopropyl acetate (Preparation 4, 6.7 g, 43.7 mmol) in THF (10 mL), tert-butyl propiolate (6.07 g, 48.1 mmol) and Pd(PPh3)4 (1.52 g, 1.31 mmol) were added, and the mixture was stirred under N2 at 25°C for 24 hours. The mixture was evaporated to dryness under vacuum, and the residue was purified by column chromatography (SiO2, 0-10% siRNA / PE) to obtain 4-(tert-butyl)1-ethyl 2-cyano-2-cyclopropyl-3-methylene succinate as a brown oily substance (9.6 g, 79%). 1 H NMR (500 MHz, CDCl3) δ: 6.65 (s, 1H), 6.23 (s, 1H), 4.32-4.24 (m, 2H), 1.50 (s, 9H), 1.38-1.29 (m, 4H), 0.87-0.85 (m, 2H), 0.73-0.68 (m, 2H).

[0295] Preparation 129 tert-butyl 4-cyano-4-cyclopropyl-1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carboxylate [ka] To a solution of 4-(tert-butyl)1-ethyl 2-cyano-2-cyclopropyl-3-methylene succinate (Preparation 128, 9.6 g, 34.4 mmol) in EtOH (100 mL), PMBNH2 (7.07 g, 51.6 mmol) and TEA (6.96 g, 68.7 mmol) were added, and the mixture was stirred at 80°C for 20 hours. The mixture was evaporated to dryness under vacuum, and the residue was purified by column chromatography (0-25% siRNA / PE) to obtain tert-butyl 4-cyano-4-cyclopropyl-1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carboxylate as a brown oil (9.5 g, 75%). LCMS m / z = 371.3 [M+H] + .

[0296] Preparation 130 4-Cyano-4-cyclopropyl-1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid [ka] To a solution of tert-butyl 4-cyano-4-cyclopropyl-1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carboxylate (Preparation 129, 1.0 g, 2.70 mmol) in DCM (10 mL), 2,6-lutidine (5.8 g, 54 mmol, 6.29 mL) and TMSOTf (6.0 g, 27 mmol, 4.89 mL) were added at 20°C, and the mixture was stirred at 20°C for 24 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC-6 (gradient: 23-53%) to obtain 4-cyano-4-cyclopropyl-1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid as a yellow oil (830 mg, 98%).

[0297] Preparation 131 S-ethyl 4-cyano-4-cyclopropyl-1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carbothioate [ka] To a solution of 4-cyano-4-cyclopropyl-1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (prepared 130 mg, 830 mg, 2.64 mmol) in DCM (10 mL), DMAP (41.5 mg, 0.340 mmol), DCC (817.2 mg, 3.96 mmol), and EtSH (410.2 mg, 6.60 mmol) were added at 20°C, and the mixture was stirred at 20°C for 4 hours. The mixture was concentrated and purified by column chromatography (SiO2, 25-50% Â / PE / ) to obtain S-ethyl 4-cyano-4-cyclopropyl-1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carbothioate as a pale yellow oil (418 mg, 44%). LCMS m / z = 358.8 [M+H] + .

[0298] Preparation 132 3-Cyclopropyl-4-Formyl-1-(4-Methoxybenzyl)-2-Oxopyrrolidine-3-Carbonitrile [ka] To a solution of S-ethyl 4-cyano-4-cyclopropyl-1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carbothioate (preparation 131, 410 mg, 1.14 mmol) in DCM (10 mL), Pd / C (121.7 mg, 10 mol%, purity 10%) and Et3SiH (399 mg, 3.43 mmol) were added at 25°C, and the mixture was stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by TLC (SiO2, 50% PE / Â) to obtain 3-cyclopropyl-4-formyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbonitrile as a yellow, rubbery substance (300 mg, 88%). LCMS m / z = 316.7 [M+H] + .

[0299] Preparation 133 3-Cyclopropyl-4-(difluoromethyl)-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbonitrile [ka] DAST (3.7 g, 22.7 mmol, 3 mL) was added at 25°C to a solution of 3-cyclopropyl-4-formyl-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbonitrile (prepared 132 mg, 1.01 mmol) in DCM (3 mL), and the mixture was stirred at 25°C for 16 hours. The reaction product was quenched with H2O (10 mL) and extracted with siRNA (3 × 5 mL). The combined organic matter was washed with brine (10 mL), dried (Na2SO4), evaporated to dryness under vacuum, and the residue was purified by column chromatography (SiO2, 25-50% siRNA / PE) to obtain 3-cyclopropyl-4-(difluoromethyl)-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbonitrile as a yellow solid (140 mg, 43%). LCMS m / z = 320.7 [M+H] + .

[0300] Preparation 134 3-Cyclopropyl-4-(difluoromethyl)-2-oxopyrrolidine-3-carbonitrile [ka] CAN (513.4 mg, 0.937 mmol) was added at 25°C to a solution of 3-cyclopropyl-4-(difluoromethyl)-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbonitrile (Preparation 133, 100 mg, 0.312 mmol) in MeCN (10 mL) and H2O (2 mL), and the resulting mixture was stirred at 25°C for 24 hours. The reaction product was diluted with H2O (10 mL) and extracted with siRNA (3 × 5 mL). The combined organic matter was washed with brine (10 mL), dried (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by TLC (50% PE / siRNA) to obtain 3-cyclopropyl-4-(difluoromethyl)-2-oxopyrrolidine-3-carbonitrile as a colorless oil (60 mg, 96%). 1H NMR (400 MHz, CDCl3) δ: 6.35-5.98 (m, 2H), 3.63-2.92 (m, 3H), 1.25-1.22 (m, 1H), 0.88-0.75 (m, 4H).

[0301] Preparation 135 1-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3-cyclopropyl-4-(difluoromethyl)-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of 6-bromopyrrolo[1,2-b]pyridazine-4-yltrifluoromethanesulfonate (Preparation 65, 94.0 mg, 0.272 mmol) and 3-cyclopropyl-4-(difluoromethyl)-2-oxopyrrolidine-3-carbonitrile (Preparation 134, 60.0 mg, 0.300 mmol) in dioxane (10 mL), K3PO4 (81.0 mg, 0.381 mmol), xanthophos (15.8 mg, 27.3 μmol), and Pd2dba3 (25.0 mg, 27.3 μmol) were added at 25 °C. The mixture was stirred under N2 at 70 °C for 16 hours. The mixture was evaporated to dryness under vacuum, and the residue was purified by column chromatography (SiO2, 6-25% Â1 / PE) to obtain 1-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3-cyclopropyl-4-(difluoromethyl)-2-oxopyrrolidine-3-carbonitrile as a pale yellow solid (63 mg, 59%). LCMS m / z = 395.0 [M+H] + .

[0302] Preparation 136 1-(2,2-difluorocyclopropyl)-1H-pyrazole [ka] NaI (558 mg, 3.72 mmol) was added under N2 conditions to a solution of 1-vinyl-1H-pyrazole (1.0 g, 10.63 mmol) in THF (8.0 mL), and the mixture was heated to 70°C. TMSCF3 (5.3 g, 37.2 mmol) was added dropwise at 70°C, and the resulting mixture was stirred at 70°C for 16 hours. The reaction mixture was evaporated to dryness under vacuum, the residue was diluted with DCM (50 ml), the precipitate was removed by filtration, and discarded. The combined filtrate was evaporated to dryness under vacuum to obtain 1-(2,2-difluorocyclopropyl)-1H-pyrazole as a brown oily substance (1.2 g, 78%). LCMS m / z = 145.2 [M+H] + .

[0303] Preparation 137 4-Bromo-1-(2,2-difluorocyclopropyl)-1H-pyrazole [ka] Br2 (0.333 mg, 2.08 μmol) was added to a solution of 1-(2,2-difluorocyclopropyl)-1H-pyrazole (Preparation 136, 200 mg, 1.39 mmol) in DCM (5 mL) under N2 at 10°C, and the mixture was stirred at 25°C for 1.5 hours. The solution was quenched with 10% Na2SO3 aqueous solution (50 mL). The organic matter was separated, washed with brine (50 mL), dried (Na2SO4), and evaporated to dryness under vacuum to obtain 4-bromo-1-(2,2-difluorocyclopropyl)-1H-pyrazole as a brown oily substance (280 mg, 90%). 1 H NMR (400 MHz, CDCl3) δ: 7.53 (s, 1H), 7.51 (s, 1H), 4.08-4.03 (m, 1H), 2.23-2.19 (m, 1H), 2.11-2.05 (m, 1H).

[0304] Preparation 138 3-(4-bromo-1H-pyrazole-1-yl)cyclobutan-1-one [ka] To a solution of cyclobutanone-4-bromo-1H-pyrazole (500 mg, 3.40 mmol) in DMF (1 mL), NaH (163 mg, 4.08 mmol, 60% purity) was added at 0°C. The mixture was stirred at 25°C for 30 minutes, and 3-bromocyclobutan-1-one (557.5 mg, 3.74 mmol) was added. The mixture was stirred at 20°C for 1 hour. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic matter was washed with brine (10 mL), dried, and evaporated to dryness under vacuum using (Na₂SO₄). The residue was purified by flash chromatography (SiO₂, 0-25% ethyl acetate / PE) to obtain 3-(4-bromo-1H-pyrazole-1-yl)cyclobutan-1-one as a white solid (80 mg, 11%). 1 H NMR (400 MHz, CDCl3) δ: 7.55 (s, 2H), 5.03-4.96 (m, 1H), 3.81-3.74 (m, 2H), 3.60-3.53 (m, 2H).

[0305] Preparation 139 4-Bromo-1-(3,3-difluorocyclobutyl)-1H-pyrazole [ka] DAST (75 mg, 61.44 uL) was added to a solution of 3-(4-bromo-1H-pyrazole-1-yl)cyclobutan-1-one (prepared 138 mg, 50 mg, 0.233 mmol) in DCM (2 mL), and the mixture was stirred at 25°C for 16 hours. The mixture was diluted with H2O (5 mL) and extracted with siRNA (3 × 10 mL). The combined organic matter was washed with brine (30 mL), dried (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by preparative TLC (20% siRNA / PE) to obtain 4-bromo-1-(3,3-difluorocyclobutyl)-1H-pyrazole as a white solid (22 mg, 40%). 1 H NMR (500 MHz, CDCl3) δ: 7.53 (s, 1H), 7.49 (s, 1H), 4.71-4.64 (m, 1H), 3.20-3.11 (m, 4H).

[0306] Preparation 140 3-(4-bromo-1H-pyrazole-1-yl)pyridine [ka] To a solution of 4-bromo-1H-pyrazole (500 mg, 3.40 mmol) and pyridine-3-ylboronic acid (836 mg, 6.80 mmol) in pyridine (25 mL), Cu(OAc)2 (309 mg, 1.70 mL) was added, and the mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography (SiO2, 0-100% Â / PE) to obtain 3-(4-bromo-1H-pyrazole-1-yl)pyridine as a white solid (500 mg, 66%). LCMS m / z = 226.1 [M+H] + .

[0307] Preparation 141 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol) in DCM (10 mL), TEA (1.6 g, 15.46 mmol) and MsCl (590 mg, 5.15 mmol) were added at 0°C, and the mixture was stirred at 25°C for 16 hours. The reaction product was diluted with H2O (20 mL). The mixture was extracted with DCM (2 × 20 mL), the combined organic extract was washed with brine (2 × 20 mL), dried with (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 5-10% ethyl acetate / PE) to obtain 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a colorless oil (901 mg, 64%). 1H NMR (500 MHz, CDCl3) δ: 8.33 (s, 1H), 8.02 (s, 1H), 3.32 (s, 3H), 1.33 (s, 12H).

[0308] Preparation 142 1-(2-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.258 mmol), 1-chloro-2-ethoxyethane (33.6 mg, 0.309 mmol), and K2CO3 (125 mg, 0.902 mol) in DMF (1.5 mL) was stirred overnight at 70°C. The reaction mixture was diluted with ELISA and washed with NaHCO3, H2O, and brine. The combined organic matter was dried with (Na2SO4) and evaporated to dryness under vacuum to obtain 1-(2-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, which was used without further purification. LCMS m / z = 267 [M+H] + .

[0309] Preparation 143 7-Chloro-2-(1-methyl-1H-pyrazole-4-yl)flo[3,2-b]pyridine [ka] To a solution of 7-chloro-2-iodofl[3,2-b]pyridine (400 mg, 1.43 mmol) in dioxane (2.5 mL) and H2O (0.9 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (313 mg, 1.50 mmol), NaHCO3 (144 mg, 1.72 mmol), and Pd(dppf)Cl2 (105 mg, 0.143 mmol) were added under N2, and the mixture was stirred under N2 at 80°C for 3 hours. The mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, 0-10% Â / PE) to obtain 7-chloro-2-(1-methyl-1H-pyrazole-4-yl)fl[3,2-b]pyridine as a brown solid (180 mg, 53%). 1 H NMR (400 MHz, CDCl3) δ: 8.36 (d, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.18 (d, 1H), 6.91 (s, 1H), 4.00 (s, 3H).

[0310] Preparation 144 Methyl 1'-methyl-1'H,2H-[3,4'-bipirazole]-5-carboxylate [ka] Part 1: Dimethyl oxalate (3.8 g, 32.2 mmol) and NaOMe (2.6 g, 48.33 mmol) were added to a solution of 1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one (2.0 g, 16.11 mmol) in MeOH (35 mL). The mixture was stirred at 15°C for 16 hours. The mixture was cooled in an ice bath and the pH was adjusted to approximately 3 with 2N HCl. The resulting solid was collected and concentrated to obtain methyl(Z)-2-hydroxy-4-(1-methyl-1H-pyrazole-4-yl)-4-oxobuta-2-enoate as a yellow solid (1.8 g, yield 53%), which was used without further purification. 1H NMR (500 MHz, DMSO-d6) δ: 8.68 (s, 1H), 8.17 (s, 1H), 6.83 (s, 1H), 3.91 (s, 3H), 3.84 (s, 3H).

[0311] Part 2: Hydrazine hydrate (557 mg, 11.1 mmol) was added to a solution of methyl(Z)-2-hydroxy-4-(1-methyl-1H-pyrazole-4-yl)-4-oxobuta-2-enoate (Part 1, 1.8 g, 8.56 mmol) in AcOH (8 mL), and the mixture was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature, the pH was adjusted to approximately 7 with aqueous NaHCO3 solution, and extracted with SiO2 (2 × 50 mL). The combined organic matter was washed with brine (30 mL), dried in (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 15-50% SiO2 / PE) to obtain methyl 1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-carboxylate as a colorless oil (1.1 g, yield 62%). 1 H NMR (400 MHz, DMSO-d6) δ: 13.61 (s, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 6.88 (s, 1H), 3.83 (s, 3H), 3.78 (s, 3H).

[0312] Preparation 145 1'-Methyl-1'H,2H-[3,4'-bipirazole]-5-carboxylic acid [ka] To a solution of methyl 1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-carboxylate (Preparation 144, 1.1 g, 5.33 mmol) in THF (10 mL) and water (1 mL), NaOH (427 mg, 10.7 mmol) was added, and the mixture was stirred at 60°C for 5 hours. Most of the solvent was removed, the pH was adjusted to approximately 3, and the resulting solid was collected to obtain 1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-carboxylic acid as a yellow solid (1 g, 98%). 1H NMR (500 MHz, DMSO-d6) δ ppm: 13.18 (s, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 6.86 (s, 1H), 3.87 (s, 3H).

[0313] Preparation 146 N-(2,2-dimethoxyethyl)-1'-methyl-1'H,2H-[3,4'-bipirazole]-5-carboxamide [ka] To a solution of 1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-carboxylic acid (prepared 145 mg, 900 mg, 4.68 mmol) in DMF (10 mL), HATU (3.57 g, 9.37 mmol) was added. After stirring the mixture for 15 minutes, TEA (1.42 g, 14.05 mmol, 1.96 mL) and 2,2-dimethoxyethane-1-amine (591 mg, 5.62 mmol) were added, and the reaction mixture was stirred at 25°C for 5 hours. The mixture was diluted with H2O (50 mL) and extracted with DCM (3 × 50 mL). The combined organic matter was washed with brine (50 mL), dried, and evaporated to dryness under vacuum (Na2SO4). The residue was purified by column chromatography (SiO2, 4-9% MeOH / DCM) to obtain N-(2,2-dimethoxyethyl)-1'-methyl-1'H,2H-[3,4'-bipirazole]-5-carboxamide as a white solid (1.1 g, 84%). 1 H NMR (500 MHz, CDCl3) δ: 7.72-7.69 (m, 2H), 6.79 (s, 1H), 4.58-4.56 (m, 1H), 3.95 (s, 3H), 3.48 (s, 6H), 3.27-3.23 (m, 2H).

[0314] Preparation 147 2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4(5H)-one [ka] Part A: A mixture of N-(2,2-dimethoxyethyl)-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-carboxamide (Preparation 146, 1.0 g, 3.58 mmol) in HCl (5 M, 15 mL) was stirred at 20°C for 10 minutes. The solid was collected by filtration, and the filtration cake was washed with water (20 mL) and EtOH (20 mL), dried under vacuum to obtain 7-hydroxy-2-(1-methyl-1H-pyrazole-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one as a white solid (805 mg, crude), which was used without further purification.

[0315] Part B: A solution of 7-hydroxy-2-(1-methyl-1H-pyrazole-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one (Part A, 800 mg, 3.43 mmol) in CH3SO2H (10 mL) was stirred at 50°C for 20 hours. The reaction mixture was evaporated to dryness, and the residue was purified by preparative HPLC-12 (gradient: 0-25%) to obtain 2-(1-methyl-1H-pyrazole-4-yl)pyrazole[1,5-a]pyrazine-4(5H)-one as a white solid (350 mg, 47%). 1 H NMR (500 MHz, DMSO-d6) δ ppm: 11.21 (s, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.63 (d, 1H), 7.17 (s, 1H), 6.84-8.81 (m, 1H), 3.88 (s, 3H).

[0316] Preparation 148 4-Chloro-2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine [ka] A solution of 2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4(5H)-one (prepared 147, 150 mg, 0.697 mmol) in POCl3 (15 mL) was stirred at 120°C for 4 hours. The mixture was concentrated under vacuum, and the residue was partitioned into SiO4 (20 mL) and water (50 mL), and extracted with SiO4 (3 × 20 mL). The combined organic matter was washed with brine (20 mL), evaporated to dryness in (Na2SO4) under vacuum, and 4-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine was obtained as a gray solid (110 mg, 67%), which was used without further purification. 1 H NMR (500 MHz, CDCl3) δ: 8.26 (d, 1H), 8.96 (s, 1H), 7.88 (s, 1H), 7.62 (d, 1H), 6.90 (d, 1H), 4.01 (s, 3H).

[0317] Preparation 149 (3R,4S)-1-(2-bromo-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] A solution of (3R,4S)-1-(2-bromoimidazo[1,2-b]pyridazin-8-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (prepared 97 mg, 150 mg, 0.416 mmol) and Select-F (147.6 mg, 0.416 mmol) in MeCN (5 mL) was stirred at 0°C for 2 hours, and then heated to 25°C while stirring for 20 hours. The reaction mixture was quenched with water (50 mL) and extracted with ELISA (3 × 20 mL). The combined organic matter was washed with brine (20 mL), dried, and evaporated to dryness under vacuum with (Na₂SO₄). The residue was purified by preparative HPLC-3 (gradient: 48-78%) to obtain (3R,4S)-1-(2-bromo-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile as a white solid (20 mg, 13%). LCMS m / z = 380.0 [M+H] + .

[0318] Preparation 150 7-Chloro-5-(methylthio)imidazo[1,2-c]pyrimidine [ka] 2-chloroacetaldehyde (4.5 g, 56.93 mmol) was added at 25°C to a solution of 6-chloro-2-(methylthio)pyrimidine-4-amine (5.0 g, 28.5 mmol) in dioxane (50 mL), and the resulting mixture was stirred at 95°C for 16 hours. The mixture was evaporated to dryness, diluted with H2O (40 mL), and extracted with ethyl acetate (3 × 20 mL). The combined extract was washed with brine (50 mL), dried to (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 6-16% ethyl acetate / PE) to obtain 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine as a yellow solid (1.0 g, 18%). The aqueous phase was concentrated under reduced pressure to obtain additional 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine as an orange solid (3.8 g, crude). LCMS m / z = 200.0 [M+H] +.

[0319] Preparation 151 7-Chloroimidazo[1,2-c]pyrimidine-5-ol [ka] A solution of KOH (4.0 g, 70.42 mmol) in H2O (50 mL) was slowly added to a solution / suspension of 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine (preparation 150, 3.7 g, 18.53 mmol) in MeOH (20 mL), and the mixture was then stirred at 80°C for 2 hours. The reaction mixture was adjusted to pH 6-7 with 2N HCl. The solid was collected by filtration, washed with MeOH, and dried under reduced pressure to obtain 7-chloroimidazo[1,2-c]pyrimidine-5-ol as a gray solid (2 g, 63%). 1 H NMR (400 MHz, DMSO-d6) δ: 13.16-12.76 (m, 1H), 7.70 (s, 1H), 7.54 (s, 1H), 6.62 (s, 1H).

[0320] Preparation 152 7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-ol [ka] To a solution of 7-chloroimidazo[1,2-c]pyrimidine-5-ol (Preparation 151, 1.5 g, 8.85 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.7 g, 17.69 mmol) in IPA (20 mL), K3PO4 (2 M, 13.3 mL), Pd2(dba)3 (810 mg, 0.885 mmol), and Xphos (422 mg, 0.885 mmol) were added at 25 °C, and the mixture was stirred under N2 at 100 °C for 16 hours. The mixture was concentrated under reduced pressure to obtain an aqueous syrup, which was partitioned into H2O (50 mL) and SiO (30 mL). The mixture was filtered to remove the orange organic phase. The aqueous phase was adjusted to pH 6 with 2N HCl, and the mixture was concentrated under reduced pressure to obtain a yellow solid. The yellow solid was treated with DCM / MeOH (10:1, 50 mL) with stirring at 25°C for 3 hours. The obtained solid was collected by filtration, washed with 10:1 DCM / MeOH (2 × 30 mL), and dried under vacuum to obtain 7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-ol as a gray solid (1.5 g), which was used without further purification. 1 H NMR (400 MHz, MeOH-d4) δ: 8.34 (s, 1H), 8.09 (s, 1H), 7.95 (d, 1H), 7.66 (d, 1H), 7.00 (s, 1H), 3.99 (s, 3H).

[0321] Preparation 153 5-Chloro-7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine [ka] TEA (752 mg, 7.43 mmol) was added at 25°C to a solution of 7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-ol (prepared 152 mg, 800 mg, 3.72 mol) in POCl3 (3.0 mL). The resulting mixture was stirred at 100°C for 16 hours. The reaction product was evaporated to dryness under vacuum, and the residue was purified by preparative HPLC-13 (gradient: 0-25%) to obtain 5-chloro-7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine as a brown solid (60 mg, 7%). 1 H NMR (400 MHz, CDCl3) δ: 8.03-8.01 (m, 2H), 7.81-7.72 (m, 3H), 3.99 (s, 3H).

[0322] Preparation 154 6-Bromo-4-methoxypyrazolo[1,5-a]pyridine [ka] To a solution of Selectfluor™ (5.15 g, 14.5 mmol) in MeCN (50 mL), 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (3 g, 13.2 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 12 hours. The reaction mixture was concentrated, treated with water (100 mL), and extracted with DCM (2 × 100 mL). The combined organic matter was washed with brine (100 mL), dried (Na₂SO₄), and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO₂, 0-30%, Â / PE) and preparative HPLC-7 (gradient: 37-60%), followed by lyophilization to obtain 6-bromo-4-methoxypyrazolo[1,5-a]pyridine as an off-white solid (205 mg, 6.3%). 1 H NMR (400 MHz, DMSO-d6) δ: 8.56 (d, 1H), 8.04 (d, 1H), 6.77 (s, 1H), 3.96 (s, 3H).

[0323] Preparation 155 6-Bromo-3-fluoropyrazolo[1,5-a]pyridine-4-ol [ka] A mixture of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (preparations 154, 200 mg, 0.816 mmol) in an aqueous HBr solution (165 mg, 0.816 mmol, 20 mL, 40% purity) was stirred at 120°C for 12 hours. The mixture was concentrated, and the residue was purified by preparative HPLC-7 (gradient: 8-48%), followed by lyophilization to obtain 6-bromo-3-fluoropyrazolo[1,5-a]pyridine-4-ol as an off-white solid (150 mg, 80%). 1 H NMR (400 MHz, DMSO-d6) δ: 11.32 (br,s, 1H), 8.40 (s, 1H), 7.96 (d, 1H), 6.44 (s, 1H).

[0324] Preparation 156 6-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrazolo[1,5-a]pyridine-4-ol [ka] To a solution of 6-bromo-3-fluoropyrazolo[1,5-a]pyridine-4-ol (prepared 155 mg, 100 mg, 0.433 mmol) in dioxane (5 mL) and H2O (0.5 mL), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (158 mg, 1.08 mmol), PEPPSi-IPr (29.5 mg, 0.087 mmol), and K2CO3 (179.5 mg, 1.30 mmol) were added, and the mixture was stirred under N2 at 100°C for 16 hours. Additional 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (105.6 mg, 1.08 mmol) and PEPPSi-IPr (29.5 mg, 0.087 mmol) were added, and the mixture was stirred under N2 at 100°C for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic matter was washed with brine (60 mL), dried, and evaporated to dryness under vacuum using (Na2SO4). The residue was purified by column chromatography (SiO2, 0-2% ethyl acetate / PE) to obtain 6-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrazolo[1,5-a]pyridine-4-ol as an orange solid (50.4 mg, crude). LCMS m / z = 269.0 [M+H] + .

[0325] Preparation 157 6-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate [ka] To a solution of 6-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrazolo[1,5-a]pyridine-4-ol (prepared 156 mg, 40 mg, 0.149 mmol) in THF (3 mL), DIPEA (96.4 mg, 0.746 mmol) and Tf2NPh (79.9 mg, 0.224 mmol) were added, and the mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic matter was washed with brine (20 mL), dried, and evaporated to dryness under vacuum using (Na2SO4). The residue was purified by column chromatography (SiO2, 0-25% RINKAN / PE) to obtain 6-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate as a white solid (33.8 mg), which was used without further purification. 1 H NMR (500 MHz, CDCl3) δ: 8.47 (s, 1H), 8.09 (s, 1H), 7.91 (d, 1H), 7.26 (t, 1H), 7.18 (s, 1H).

[0326] Preparation 158 1-amino-3-bromo-5-methoxypyridine-1-ium-2,4-dinitrophenolate [ka] To a solution of 3-bromo-5-methoxypyridine (50.0 g, 266 mmol) in MeCN (500 mL), O-(2,4-dinitrophenyl)hydroxylamine (58.3 g, 293 mmol) was added with stirring at 20-25°C, and the resulting mixture was heated to 40°C for 16 hours. The mixture was cooled to 20°C, the solid was collected by filtration, and the filtration cake was washed with MTBE (100 mL). The solid was dried under vacuum without heat for 1 hour to obtain 1-amino-3-bromo-5-methoxypyridine-1-ium-2,4-dinitrophenolate as a yellow solid (75 g, 73%). 1H NMR (400 MHz, MeOH-d4) δ: 8.75 (d, 1H), 8.60 (t, 1H), 8.52-8.49 (m, 1H), 8.19-8.18 (m, 1H), 7.99 (dd, 1H), 6.65 (d, 1H), 4.03 (s, 3H).

[0327] Preparation 159 Ethyl 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate and ethyl 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate [ka] To a solution of 1-amino-3-bromo-5-methoxypyridine-1-ium-2,4-dinitrophenolate (preparation 158, 90 g, 232 mmol) in DMF (1500 mL), K2CO3 (64.3 g, 465 mmol), followed by ethylpropane-2-inoate (45.61 g, 465 mmol), was added, and the mixture was stirred at 20°C for 48 hours. The reaction mixture was diluted with H2O (800 mL) and extracted with ethylpropane (3 × 500 mL). The combined organic matter was dried (Na2SO4) and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 3-50% Â / PE) to obtain a mixture of ethyl 6-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate and ethyl 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate as a yellow solid (80 g, 57.5%), which was used without further separation. 1 H NMR (400MHz, CDCl3) δ: 8.31 (s, 2H), 6.73 (s, 1H), 4.29 (q, J=6.8 Hz, 2H), 4.01 (s, 3H), 1.27-1.37 (m, 3H).

[0328] Preparation 160 6-bromo-4-methoxypyrazolo[1,5-a]pyridine and 4-bromo-6-methoxypyrazolo[1,5-a]pyridine [ka] Sulfuric acid (276 g, 2.81 mol, 150 mL) was added to a solution of ethyl 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate and ethyl 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (Preparation 159, 46.6 g, 155 mmol, approximately 3:1 mixture) in water (300 mL), and the reaction mixture was stirred under N2 at 90°C for 16 hours. The reaction mixture was quenched with NaOH (2N) until the pH became 8, extracted with ELISA (3 × 350 mL), and the combined organic matter was dried (Na₂SO₄) and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 5-50% ethyl / PE) to obtain a mixture of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine and 4-bromo-6-methoxypyrazolo[1,5-a]pyridine in an approximately 4:1 ratio as a yellow solid (20 g, 75%). NMR of the main component (6-bromo-4-methoxypyrazolo[1,5-a]pyridine) was performed. 1 H NMR (CDCl3, 400 MHz) δ: 8.28 (s, 1H), 7.85 (d, 1H), 6.63 (d, 1H), 6.46 (d, 1H), 3.96 (s, 3H).

[0329] Preparation 161 4-Methoxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine [ka] To a solution of approximately 4:1 mixture of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine and 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (prepared 160, 60 g, 264 mmol) in dioxane (500 mL) and water (50 mL), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66 g, 317 mmol), Pd(dppf)Cl2DCM (10.8 g, 13.2 mmol) and K2CO3 (73 g, 528 mmol) were added, and the mixture was stirred under N2 at 90°C for 2 hours. The reaction mixture was diluted with 2O (250 mL), extracted with ELISA (3 × 200 mL), and the combined organic matter was dried (Na2SO4) and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 5-50% siRNA / PE) to obtain 4-methoxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine as a white solid (46 g, 76% yield). 1 H NMR (400 MHz, CDCl3) δ: 8.27 (s, 1H), 7.86 (d, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 6.62 (s, 1H), 6.47 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H).

[0330] Preparation 162 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-ol [ka] A solution of 4-methoxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine (preparation 161, 46 g, 202 mmol) in an aqueous HBr solution (600 mL, 40% purity) was stirred at 120°C for 72 hours. The reaction mixture was concentrated to obtain a residue, which was treated with saturated NaHCO3 until the pH was 8 and extracted with DCM (3 × 250 mL). The combined organic matter was dried with (Na2SO4) and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 5-10% MeOH / DCM) to obtain 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-ol as a gray solid (40 g, 93%). LCMS m / z = 215.1 [M+H] + .

[0331] Preparation 163 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate [ka] 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate was prepared from 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-ol (Preparation 162) as a white solid (22 g, 68%) using a method similar to that described for Preparation XX. 1 H NMR (400 MHz, CDCl3) δ: 8.60 (s, 1H), 8.00 (d, 1H), 7.74 (s, 1H), 7.64 (s, 1H), 7.23 (s, 1H), 6.68 (d, 1H), 3.99 (s, 3H).

[0332] Preparation 164 1-Methyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole [ka] To a solution of 4-iodo-1-methyl-1H-pyrazole (4.0 g, 19.2 mmol) and ethinyltrimethylsilane (2.83 g, 28.9 mmol, 4.08 mL) in TEA (40 mL), Pd(PPh3)2Cl2 (1.35 g, 1.92 mmol) and CuI (366 mg, 1.92 mmol) were added, and the mixture was stirred under N2 at 100°C for 4 hours. The mixture was quenched with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic matter was washed with brine (50 mL), dried, evaporated to dryness under vacuum, and the residue was purified by column chromatography (SiO2, 0-33% Â / PE) to obtain 1-methyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole as a brown solid (2.3 g, 66%). 1 H NMR (500 MHz, CDCl3) δ: 7.57 (s, 1H), 7.49 (s, 1H), 3.87 (s, 3H), 0.22 (s, 9H).

[0333] Preparation 165 4-(1-methyl-1H-pyrazole-4-yl)buta-3-in-2-one [ka] To a solution of 1-methyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole (Preparation 164, 2.3 g, 12.6 mmol) and acetyl chloride (1.2 g, 15.1 mmol) in DCM (200 mL), AlCl3 (8.4 g, 63.09 mmol) was added. The mixture was stirred at 0°C for 15 minutes. The mixture was quenched with water (50 mL) and extracted with DCM (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried, and concentrated in (Na2SO4). The residue was purified by column chromatography (SiO2, 0-50% Â / PE) to obtain 4-(1-methyl-1H-pyrazole-4-yl)buta-3-in-2-one as a yellow solid (1.2 g, 61.5%). 1H NMR (400 MHz, CDCl3) δ: 7.68 (s, 1H), 7.64 (s, 1H), 3.91 (s, 3H), 2.39 (s, 3H).

[0334] Preparation 166 tert-butyl((mesitylsulfonyl)oxy)carbamate [ka] A solution of 2,4,6-trimethylbenzenesulfonyl chloride (10.0 g, 45.7 mmol) and tert-butylhydroxycarbamate (6.7 g, 50.3 mmol) in THF (160 mL) was stirred at 0°C. TEA (5.6 g, 54.0 mmol, 7.7 mL) was slowly added over 2 minutes, and the mixture was stirred at 0°C for 1 hour. The mixture was evaporated to dryness, the residue was treated with water (100 mL), and extracted with DCM (3 × 50 mL). The combined organic matter was washed with brine (100 mL), dried, and concentrated under reduced pressure in (Na₂SO₄). The residue was purified by column chromatography (SiO₂, 0-10% Â / PE) to obtain tert-butyl((mesitylsulfonyl)oxy)carbamate as a white solid (8.5 g, 58.6%). 1 H NMR (400 MHz, DMSO-d6) δ: 11.12 (s, 1H), 7.10 (s, 2H), 2.54 (s, 6H), 2.26 (s, 3H), 1.21 (s, 9H).

[0335] Preparation 167 O-(mesitylsulfonyl)hydroxylamine [ka] To a solution of tert-butyl((mesitylsulfonyl)oxy)carbamate (Preparation 166, 8.5 g, 26.79 mmol), TFA (20 mL) was added at 0°C, and the resulting mixture was stirred at 20°C for 3 hours. The reaction mixture was diluted with ice water (40 mL) and stirred at 20°C for 30 minutes. The solid was collected by filtration to obtain O-(mesitylsulfonyl)hydroxylamine as a white solid (5.0 g, 87%). 1 H NMR (500 MHz, DMSO-d6) δ: 6.77 (s, 2H), 2.51 (s, 6H), 2.18 (s, 3H).

[0336] Preparation 168 1-amino-3-methoxypyridine-1-ium-2,4,6-trimethylbenzenesulfonate [ka] To a solution of O-(mesitylsulfonyl)hydroxylamine (prepared 1675.0 g, 23.2 mmol) in DCM (70 mL), 3-methoxypyridine (2.8 g, 25.6 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The solvent was concentrated to obtain 1-amino-3-methoxypyridine-1-ium 2,4,6-trimethylbenzenesulfonate as a yellow solid (7.0 g, 93%), which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ: 8.57 (s, 1H), 8.49 (s, 2H), 8.38-8.40 (m, 1H), 7.87-7.90 (m, 2H), 6.73 (s, 2H), 3.94 (s, 3H), 2.47 (s, 6H), 2.15 (s, 3H).

[0337] Preparation 169 1-(4-methoxy-2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-yl)ethane-1-one [ka] To a solution of 4-(1-methyl-1H-pyrazole-4-yl)buta-3-in-2-one (Preparation 165, 1.2 g, 7.76 mmol) and 1-amino-3-methoxypyridine-1-ium 2,4,6-trimethylbenzenesulfonate (Preparation XX, 1.5 g, 11.6 mmol) in EtOH (60 mL), K2CO3 (3.2 g, 23.3 mmol) was added, and the mixture was stirred at 25°C for 14 hours. The mixture was quenched with water (50 mL) and extracted with ethylethanol (3 × 30 mL). The combined organic matter was washed with brine (50 mL), dried, and evaporated to dryness under vacuum using (Na2SO4). The residue was purified by column chromatography (SiO2, 0-25% siRNA / PE) to obtain 1-(4-methoxy-2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-yl)ethane-1-one as a yellow solid (880 mg, 42%). 1 H NMR (400 MHz, CDCl3) δ: 8.13 (d, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 6.76-6.81 (m, 1H), 6.59 (d, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 2.59 (s, 3H).

[0338] Preparation 170 1-(4-hydroxy-2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-yl)ethane-1-one [ka] To a solution of 1-(4-methoxy-2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-yl)ethane-1-one (prepared 169 mg, 800 mg, 2.96 mmol) in DCM (10 mL), BBr3 (1.1 g, 4.44 mmol) was added under N2 at 0°C, and the mixture was stirred at 25°C for 12 hours. The mixture was quenched with water (20 mL), neutralized with K2CO3, and extracted with DCM (3 × 20 mL). The combined organic matter was washed with brine (50 mL), dried, and evaporated to dryness under vacuum with (Na2SO4). The residue was purified by column chromatography (SiO2, 0-9% MeOH / DCM) to obtain 1-(4-hydroxy-2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-yl)ethane-1-one (334 mg, yield 44.04%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ: 8.03-8.06 (m, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 6.95-6.99 (m, 1H), 6.85-6.88 (m, 1H), 4.02 (s, 3H), 2.35 (s, 3H).

[0339] Preparation 171 2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-ol [ka] To a solution of 1-(4-hydroxy-2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-yl)ethane-1-one (prepared 170, 300 mg, 1.17 mmol) in H2O (0.8 mL) at 25°C, H2SO4 (20.7 g, 211 mmol) was added, and the mixture was stirred at 150°C for 4 hours. The mixture was evaporated to dryness under vacuum, and the residue was purified by preparative HPLC-14 (gradient: 15-45%) to obtain 2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-ol as a grayish-white solid (190 mg, 76%). 1H NMR (500 MHz, DMSO-d6) δ: 8.13-8.15 (m, 2H), 7.86 (s, 1H), 6.75 (s, 1H), 6.64-6.67 (m, 1H), 6.44 (d, 1H), 3.90 (s, 3H).

[0340] Preparation 172 2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate [ka] To a solution of 2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-ol (prepared 171 mg, 150 mg, 0.700 mmol) in DCM (10 mL), Tf2O (593 mg, 2.10 mmol) and TEA (213 mg, 2.10 mmol) were added under N2 at 0°C, and the resulting mixture was stirred at 0°C for 4 hours. The mixture was quenched with water (30 mL) and extracted with DCM (3 × 10 mL). The combined organic matter was washed with brine (30 mL), dried, and evaporated to dryness under vacuum with (Na2SO4). The crude material was purified by column chromatography (SiO2, 0-50% siRNA / PE) to obtain 2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate as a white solid (106 mg, 44%). 1 H NMR (500 MHz, DMSO-d6) δ: 8.82 (d, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.50 (d, 1H), 6.94-6.97 (m, 2H), 3.91 (s, 3H).

[0341] Preparation 173 3-(1-methyl-1H-pyrazole-4-yl)-3-oxopropannitrile [ka] To a solution of ethyl 1-methyl-1H-pyrazole-4-carboxylate (3.5 g, 22.7 mmol) in THF (20 mL) at -70°C, NaHMDS (68.1 mL, 68.1 mmol) was added under N2 conditions, and the mixture was stirred at 25°C for 3 hours. The reaction product was quenched with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic matter was washed with brine (50 mL), dried, and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 0-50% Â / PE) to obtain 3-(1-methyl-1H-pyrazole-4-yl)-3-oxopropanenitrile as a white solid (2.47 g, 73%). 1 H NMR (400 MHz, CDCl3) δ: 7.99 (s, 1H), 7.92 (s, 1H), 3.95 (s, 3H), 3.78 (s, 2H).

[0342] Preparation 174 1'-methyl-1H,1'H-[3,4'-bipirazole]-5-amine [ka] To a solution of 3-(1-methyl-1H-pyrazole-4-yl)-3-oxopropanenitrile (Preparation 173, 1.0 g, 6.70 mmol) in EtOH (20 mL), hydrazine hydrate (671 mg, 13.4 mmol) was added, and the mixture was stirred at 90°C for 24 hours. The mixture was evaporated to dryness to obtain 1'-methyl-1H,1'H-[3,4'-bipyrazole]-5-amine as a yellow oil (1.0 g, 92%). 1 H NMR (400 MHz, DMSO-d6) δ: 7.83 (s, 1H), 7.60 (s, 1H), 5.45 (s, 1H), 4.57 (br s, 2H), 3.79 (s, 3H).

[0343] Preparation 175 2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-7-ol [ka] To a solution of 1'-methyl-1H,1'H-[3,4'-bipyrazole]-5-amine (Preparation 174, 1.0 g, 6.13 mmol) in EtOH (15 mL), sodium(E)-3-ethoxy-3-oxopropane-1-ene-1-oleate (2.1 g, 18.4 mmol) was added at 25 °C, and the mixture was stirred at 100 °C for 6 hours. 2N HCl was added to adjust the pH to 5-6. The solid was collected by filtration to obtain 2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-7-ol as a yellow solid (0.75 g, 57%). 1 H NMR (400 MHz, DMSO-d6) δ: 8.21 (s, 1H), 7.89 (s, 1H), 7.81 (d, 1H), 6.36 (s, 1H), 5.66 (d, 1H), 3.89 (s, 3H).

[0344] Preparation 176 7-Chloro-2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine [ka] To a solution of 2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-7-ol (prepared 175 mg, 700 mg, 3.25 mmol) in dioxane (10 mL), TEA (658 mg, 6.51 mmol) and POCl3 (1.3 g, 8.13 mmol) were added at 25°C, and the mixture was stirred at 100°C for 6 hours. The mixture was adjusted to pH=7 with 2N NaOH, diluted with water (30 mL), and extracted with DCM (3 × 30 mL). The combined organic matter was washed with brine (30 mL), dried, and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 0-50% ethyl acetate / PE) to obtain 7-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine as a yellow solid (360 mg, 47%). 1H NMR (500 MHz, MeOH-d4) δ ppm: 8.40 (d, 1H), 8.23 ​​(s, 1H), 8.05 (s, 1H), 7.19 (d, 1H), 6.99 (s, 1H), 4.00 (s, 3H).

[0345] Preparation 177 5-Bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine [ka] To a solution of 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (300 mg, 0.926 mmol) in DMF (5 mL), NaH (37 mg, 0.926 mmol, 60% purity) was added, followed by SEMCl (170 mg, 1.02 mmol). The resulting mixture was stirred at 20°C for 2 hours. The mixture was diluted with H2O (1 mL), concentrated, and the residue was obtained. This residue was purified by column chromatography (SiO2, 6-25% Â / PE) to obtain 5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine as a white solid (350 mg, 83%). 1 H NMR (400 MHz, CDCl3) δ: 8.60 (d, 1H), 7.97 (d, 1H), 5.81 (s, 2H), 3.63-3.67 (m, 2H), 0.90-0.94 (m, 2H), 0.05 (s, 9H).

[0346] Preparation 178 (3R,4S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of 5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (Preparation 177, 200 mg, 0.440 mmol) and (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 21, 72.3 mg, 0.440 mmol) in dioxane (5 mL), K2CO3 (183 mg, 1.32 mmol), CuI (16.8 mg, 0.088 mmol), and N,N'-dimethylethane-1,2-diamine (15.5 mg, 0.176 mmol) were added, and the reaction mixture was stirred under N2 at 100°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 5-25% Â1 / PE) to obtain (3R,4S)-1-(5-bromo-1-((2-(trimethylsilyl))ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile as a colorless, rubbery substance (130 mg, 60%). 1 H NMR (400 MHz, CDCl3) δ: 9.06 (d, 1H), 8.55 (d, 1H), 5.75 (s, 2H), 4.21-4.26 (m, 1H), 3.73-3.79 (m, 1H), 3.59-3.63 (m, 2H), 3.10-3.14 (m, 1H), 1.41 (d, 3H), 1.11-1.26 (m, 2H), 0.72-0.85 (m, 5H), 0.04 (s, 9H).

[0347] Preparation 179 (3R,4S)-3-cyclopropyl-4-methyl-1-(5-(1-methyl-1H-pyrazole-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-2-oxopyrrolidine-3-carbonilicate [ka] To a solution of (3R,4S)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (prepared 178 mg, 130 mg, 0.265 mmol) in dioxane (5 mL) and water (0.5 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (110 mg, 0.530 mmol), KF (46.2 mg, 0.795 mmol), and Pd(dppf)Cl2 (19.4 mg, 0.027 mmol) were added under N2 conditions, and the mixture was stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 5-50% Â1 / PE) to obtain (3R,4S)-3-cyclopropyl-4-methyl-1-(5-(1-methyl-1H-pyrazole-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-2-oxopyrrolidine-3-carbonitrile as a brown solid (70 mg, 54%). 1 H NMR (500 MHz, CDCl3) δ: 8.74-8.90 (m, 2H), 7.87-7.90 (m, 2H), 5.80 (s, 2H), 3.65-4.25 (m, 7H), 3.11-3.26 (m, 1H), 1.24-1.27 (m, 4H), 0.81-0.95 (m, 6H), 0.04 (s, 9H).

[0348] Preparation 180 3-Bromo-1-(1-methyl-1H-pyrazole-4-yl)-1H-pyrazolo[3,4-c]pyridine [ka] To a solution of 3-bromo-1H-pyrazolo[3,4-c]pyridine (200 mg, 1.01 mmol) in DMF (5 mL), (1-methyl-1H-pyrazole-4-yl)boronic acid (191 mg, 1.51 mmol), Cu(OAc)2 (184 mg, 1.01 mmol), and pyridine (400 mg, 5.05 mmol) were added, and the mixture was stirred at 50°C for 40 hours. The mixture was purified by preparative HPLC-2 (gradient: 25-55%) to obtain 3-bromo-1-(1-methyl-1H-pyrazole-4-yl)-1H-pyrazolo[3,4-c]pyridine as a white solid (80 mg, 28%). LCMS m / z = 280.0 [M+H] + .

[0349] Preparation 181~183 The title compound was prepared from a suitable bromide (RBr) and a suitable boronic acid / ester (RBY) using a method similar to that described for Preparation 180. [Table 3-1] [Table 3-2]

[0350] Preparation 184 3-Bromo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)-1H-pyrazolo[3,4-c]pyridine [ka] To a solution of 3-bromo-1H-pyrazolo[3,4-c]pyridine (1.0 g, 5.05 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g, 5.05 mmol) in DMSO (10 mL), Cu(OAc)2 (459 mg, 2.52 mmol), 2-(2-pyridyl)pyridine (789 mg, 5.05 mmol), and Cs2CO3 (3.29 g, 10.1 mmol) were added at 25°C. The mixture was stirred at 100°C for 16 hours. The mixture was quenched with water (50 mL) and extracted with ELISA (3 × 30 mL). The combined organic layers were washed with H2O (5 × 50 ml), dried (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 25-66% siRNA / PE) to obtain 3-bromo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)-1H-pyrazolo[3,4-c]pyridine as a yellow solid (170 mg, 10%). 1 H NMR (500 MHz, CDCl3) δ: 9.07 (s, 1H), 8.47 (d, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.58 (d, 1H), 5.46-5.48 (m, 1H), 4.08-4.12 (m, 1H), 3.73-3.78 (m, 1H), 2.16-2.18 (m, 2H), 2.15-2.16 (m, 1H), 1.66-1.75 (m, 3H).

[0351] Preparation 185 3-Bromo-1-(1H-pyrazole-4-yl)-1H-pyrazolo[3,4-c]pyridine hydrochloride [ka] A solution of 3-bromo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)-1H-pyrazolo[3,4-c]pyridine (prepared 184 mg, 110 mg, 0.316 mmol) in HCl / dioxane (4 M, 3.93 mL) was stirred at 25 °C for 1 hour. The mixture was concentrated under vacuum to obtain 3-bromo-1-(1H-pyrazole-4-yl)-1H-pyrazolo[3,4-c]pyridine hydrochloride (70 mg, 74%). LCMS m / z = 264.0 [M+H] + .

[0352] Preparation 186 3-Bromo-1-(1-(oxetan-3-yl)-1H-pyrazole-4-yl)-1H-pyrazolo[3,4-c]pyridine [ka] A solution of 3-bromo-1-(1H-pyrazole-4-yl)-1H-pyrazolo[3,4-c]pyridine hydrochloride (prepared 185 mg, 70 mg, 0.265 mmol), 3-iodooxetane (48.8 mg, 0.265 mmol), and Cs2CO3 (173 mg, 0.530 mmol) in DMF (4 mL) was stirred at 60°C for 16 hours. The reaction mixture was diluted with  (20 mL), washed with H2O (3 × 20 mL × 3), and evaporated to dryness under vacuum. The residue was purified by preparative TLC (50%  / PE) to obtain 3-bromo-1-(1-(oxetan-3-yl)-1H-pyrazole-4-yl)-1H-pyrazolo[3,4-c]pyridine as a white solid (50 mg, 59%). 1 H NMR (400 MHz, CDCl3) δ: 9.10 (s, 1H), 8.49 (d, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.61 (d, 1H), 5.51-5.59 (m, 1H), 5.12-5.15 (m, 4H).

[0353] Preparation 187 3-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine [ka] To a solution of 3,4-dihydro-2H-pyran (19.12 g, 227.25 mmol) in DMF (300 mL), 3-bromo-1H-pyrazolo[3,4-c]pyridine (15 g, 75.8 mmol) and toluene-4-sulfonic acid (13.04 g, 75.8 mmol) were added, and the mixture was stirred at 100°C for 12 hours under an N2 atmosphere. The mixture was diluted with water (300 mL) and extracted with RINKAN (3 × 300 mL). The combined organic matter was washed with water (3 × 500 mL) and brine (500 mL), dried, and concentrated under reduced pressure in (Na₂SO₄). The residue was purified by column chromatography (SiO2, 9-50% Â1 / PE) to obtain 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine as a yellow solid (16.6 g, 78%). 1 H NMR (400MHz, CDCl3) δ: 9.16 (s, 1H), 8.41 (d, 1H), 7.53 (dd, 1H), 5.80 (dd, 1H), 4.04-3.97 (m, 1H), 3.83-3.74 (m, 1H), 2.54-2.40 (m, 1H), 2.19-2.11 (m, 2H), 1.80-1.66 (m, 3H).

[0354] Preparation 188 (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-3-yl)pyrrolidine-3-carbonil [ka] To a solution of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (Preparation 187, 16.6 g, 58.84 mmol) in DMSO (300 mL), (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 21, 9.66 g, 58.8 mmol), copper iodide (4.48 g, 23.53 mmol), pyridine-2-carboxylic acid (2.90 g, 23.53 mmol), and Cs2CO3 (38.34 g, 118 mmol) were added, and the mixture was stirred at 110°C for 12 hours under an N2 atmosphere. The mixture was diluted with water (300 mL) and extracted with ELISA (3 × 300 mL). The combined organic layers were washed with water (300 mL x 3) and brine (500 mL), dried, and concentrated under reduced pressure using (Na2SO4). The residue was purified by column chromatography (SiO2, 9-50% Â1 / PE) to obtain (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyrrolidine-3-yl)pyrrolidine-3-carbonitrile as a yellow solid (14 g, 65%). LCMS m / z = 366.2 [M+H] + .

[0355] Preparation 189 (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(1H-pyrazolo[3,4-c]pyridine-3-yl)pyrrolidine-3-carbonil hydrochloride [ka] HCl / dioxane (4M, 200 mL) was added at 20°C to a solution of (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-3-yl)pyrrolidine-3-carbonitrilate (Preparation 188, 14 g, 38.31 mmol) in dioxane (50 mL), and the mixture was stirred at 30°C for 12 hours. The mixture was filtered, the filter cake was collected, dried under reduced pressure, and subsequently freeze-dried to obtain (3R,4S)-3-cyclopropyl-4-methyl-2-oxo-1-(1H-pyrazolo[3,4-c]pyridine-3-yl)pyrrolidine-3-carbonitrilate hydrochloride as a yellow solid (8.3 g, 68%). LCMS m / z = 282.1 [M+H] + .

[0356] Preparation 190 5-Bromo-2-(propa-1-in-1-yl)pyrimidine [ka] To a solution of 2,5-dibromopyrimidine (5.0 g, 21 mmol) in dioxane (50 mL), tributyl(propa-1-in-1-yl) stannane (7.6 g, 23.1 mmol) and Pd(PPh3)2Cl2 (1.5 g, 2.10 mmol) were added at 25°C, and the resulting mixture was stirred under N2 at 80°C for 16 hours. The mixture was quenched with 0.5 N NaOH (30 mL) and NaHCO3 aqueous solution (30 mL) and stirred at 25°C for 1 hour. The mixture was then diluted with H2O (50 mL) and extracted with ELISA (3 × 80 mL). The combined organic matter was washed with brine (200 mL), dried, and evaporated to dryness under vacuum (Na2SO4). The residue was purified by column chromatography (SiO2, 5-16% Â / PE) to obtain 5-bromo-2-(propa-1-in-1-yl)pyrimidine as a yellow solid (1.9 g, 47%). 1 H NMR (400 MHz, CDCl3) δ: 8.72 (s, 2H), 2.10 (s, 3H).

[0357] Preparation 191 3-Bromopyrrolo[1,2-a]pyrimidine [ka] Under N2 conditions, a solution of 5-bromo-2-(propa-1-in-1-yl)pyrimidine (preparation 190, 1.9 g, 10 mmol) in DMA (20 mL) was mixed with TEA (7.1 g, 70 mmol), followed by CuI (3.8 g, 20 mmol), and the mixture was stirred at 140 °C for 3 hours. The reaction product was diluted with H2O (50 mL) and extracted with siRNA (3 × 30 mL). The combined organic matter was washed with brine (60 mL), dried, and evaporated to dryness under vacuum using (Na2SO4). The residue was purified by column chromatography (SiO2, 6-16% siRNA / PE) to obtain 3-bromopyrrolo[1,2-a]pyrimidine as a yellow solid (130 mg, 6.6%). 1 H NMR (400 MHz, MeOD-d4) δ: 8.81 (d, 1H), 8.01 (d, 1H), 7.38-7.40 (m, 1H), 6.96-6.99 (m, 1H), 6.59 (d, 1H).

[0358] Preparation 192 3-Bromo-6-iodopyrrolo[1,2-a]pyrimidine [ka] To a solution of 3-bromopyrrolo[1,2-a]pyrimidine (prepared 191 mg, 130 mg, 0.66 mmol) in DCM (10 mL), NIS (74.2 mg, 0.33 mol) was added at 20°C, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, 5-15% Â / PE) to obtain 3-bromo-6-iodopyrrolo[1,2-a]pyrimidine as a yellow solid (136 mg, 64%). 1 H NMR (400 MHz, DMSO-d6) δ: 8.63 (s, 1H), 8.08 (d, 1H), 7.25 (d, 1H), 6.74 (d, 1H).

[0359] Preparation 193 (3R,4S)-1-(3-bromopyrrolo[1,2-a]pyrimidine-6-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of 3-bromo-6-iodopyrrolo[1,2-a]pyrimidine (preparation 192, 190 mg, 0.588 mmol) in DMSO (10 mL), (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (preparation 21, 96.6 mg, 0.588 mmol), L-proline (27.1 mg, 0.235 mmol), CuI (22.4 mg, 0.118 mmol), and K2CO3 (244 mg, 1.77 mmol) were added, and the resulting mixture was stirred under N2 at 100°C for 3 hours. The reaction product was diluted with H2O (30 mL) and extracted with siRNA (3 × 20 mL). The combined organic matter was washed with brine (50 mL), dried, and evaporated to dryness under vacuum in (Na2SO4). The residue was purified by column chromatography (SiO2, 6-25% Â1 / PE) to obtain (3R,4S)-1-(3-bromopyrrolo[1,2-a]pyrimidine-6-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile as a yellow, rubbery substance (130 mg, 62%). LCMS m / z = 360.9 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 8.11 (d, 1H), 7.97 (d, 1H), 6.78 (d, 1H), 6.70 (d, 1H), 3.83-3.88 (m, 1H), 3.57-3.63 (m, 1H), 3.17-3.23 (m, 1H), 1.42 (d, 3H), 1.17-1.21 (m, 1H), 0.79-0.84 (m, 4H).

[0360] Preparation 194 tert-butyl5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate [ka] Boc2O (406 mg, 1.86 mmol) was added under N2 conditions to a solution of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.55 mmol) and TEA (313 mg, 3.10 mmol) in DCM (6 mL) and THF (6 mL), and the resulting mixture was stirred at 20°C for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (SiO2, 0-10% Â / PE) to obtain tert-butyl 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a white solid (0.6 g, 92%). 1 H NMR (500 MHz, CDCl3) δ: 8.53 (s, 1H), 7.85 (d, 1H), 7.80 (s, 1H), 1.66 (s, 9H).

[0361] Preparation 195 (3R,4S)-1-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of tert-butyl 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Preparation 194, 100 mg, 0.236 mmol) and (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 21, 46.6 mg, 0.284 mmol) in DMSO (3 mL), t-BuOK (53 mg, 0.473 mmol), CuI (4.50 mg, 0.024 mmol), and N,N'-dimethylmethanediamine (1.75 mg, 0.024 mmol) were added under N2 conditions, and the resulting mixture was stirred at 100°C for 1 hour under microwave irradiation. The mixture was purified by preparative HPLC-2 (gradient: 40-70%) to obtain (3R,4S)-1-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile as a white solid. The reaction was repeated four times to obtain approximately 50 mg of the product. LCMS m / z = 361.0 [M+H] + .

[0362] Preparation 196 Ethyl 4-((1-methyl-1H-pyrazole-4-yl)ethynyl)thiazole-5-carboxylate [ka] To a solution of 4-ethynyl-1-methyl-1H-pyrazole (607 mg, 5.72 mmol) and ethyl 4-bromothiazole-5-carboxylate (900 mg, 3.81 mmol) in DMF (8 mL), CuI (36.3 mg, 0.190 mmol), Pd(PPh3)4 (308 mg, 0.267 mmol), and TEA (1.2 g, 11.4 mmol) were added at 25°C, and the resulting mixture was stirred under N2 at 70°C for 3 hours. The mixture was diluted with H2O (20 mL) and extracted with siRNA (3 × 20 mL). The combined organic matter was washed with brine (30 mL), dried, and evaporated to dryness under vacuum in (Na2SO4). The residue was purified by column chromatography (SiO2, 5-50% Â1 / PE) to obtain ethyl 4-((1-methyl-1H-pyrazole-4-yl)ethynyl)thiazole-5-carboxylate as a yellow solid (830 mg, 83%). LCMS m / z = 262.0 [M+H] + .

[0363] Preparation 197 4-((1-methyl-1H-pyrazole-4-yl)ethinyl)thiazole-5-carboxamide [ka] To a solution of ethyl 4-((1-methyl-1H-pyrazole-4-yl)ethynyl)thiazole-5-carboxylate (prepared 196 mg, 1.76 mmol) in MeOH (2 mL), methanolic ammonia solution (7 M, 10 mL) was added at 25 °C. The mixture was stirred in a 30 mL sealed tube at 15 psi at 70 °C for 24 hours. The mixture was evaporated to dryness under vacuum, and the residue was purified by column chromatography (SiO2, 50-100% Â / PE) to obtain 4-((1-methyl-1H-pyrazole-4-yl)ethynyl)thiazole-5-carboxamide as a pale yellow solid (233 mg, 57%). LCMS m / z = 233.0 [M+H] + .

[0364] Preparation 198 6-(1-methyl-1H-pyrazole-4-yl)thiazolo[5,4-c]pyridine-4(5H)-one [ka] To a solution of 4-((1-methyl-1H-pyrazole-4-yl)ethinyl)thiazolo-5-carboxamide (prepared 197 mg, 230 mg, 0.990 mmol) in THF (10 mL), t-BuONa (133 mg, 1.39 mmol) was added at 25°C, and the mixture was stirred at 70°C for 4 hours. The mixture was concentrated and purified by column chromatography (SiO2, 50-100% Â / PE) to obtain 6-(1-methyl-1H-pyrazole-4-yl)thiazolo[5,4-c]pyridine-4(5H)-one as a white solid. LCMS m / z = 233.1 [M+H] + .

[0365] Preparation 199 4-Chloro-6-(1-methyl-1H-pyrazole-4-yl)thiazolo[5,4-c]pyridine [ka] A solution of 6-(1-methyl-1H-pyrazole-4-yl)thiazolo[5,4-c]pyridine-4(5H)-one (prepared 198 mg, 150 mg, 0.646 mmol) in POCl3 (6 mL) was stirred at 110°C for 5 hours. The reaction mixture was evaporated to dryness under vacuum, and the residue was treated with 5N NaOH to adjust the pH to approximately 7-8. The mixture was diluted with H2O (10 mL) and extracted with ELISA (3 × 15 mL). The combined organic matter was washed with brine (20 mL), dried to (Na2SO4), and evaporated to dryness under vacuum to obtain 4-chloro-6-(1-methyl-1H-pyrazole-4-yl)thiazolo[5,4-c]pyridine as a yellow solid (72 mg, 44%). LCMS m / z = 251.0 [M+H] + .

[0366] Preparation 200 (E)-N'-(4,6-dichloropyridine-2-yl)-N,N-dimethylformimidoamide [ka] DMF-DMA (4.57 g, 38.3 mmol) was added to a solution of 4,6-dichloropyridine-2-amine (5 g, 30.7 mmol) in EtOH (150 mL), and the reaction mixture was heated to 85°C for 75 minutes. The reaction mixture was evaporated to dryness under vacuum to obtain (E)-N'-(4,6-dichloropyridine-2-yl)-N,N-dimethylformimidoamide as a brown oily substance (6.6 g, crude), which was used without further purification. 1 H NMR (500 MHz, DMSO-d6) δ: 8.43 (s, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 3.12 (s, 3H), 3.00 (s, 3H).

[0367] Preparation 201 (E)-N'-(4,6-dichloropyridine-2-yl)-N-hydroxyformimidoamide [ka] NH2OH·HCl (3.06 g, 44.02 mmol) was added under N2 conditions to a solution of (E)-N'-(4,6-dichloropyridine-2-yl)-N,N-dimethylformimamide (prepared 200 ml, 6.0 g, 27.5 mmol) in MeOH (120 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness under vacuum, and the residue was triturated with water. The solid was collected by filtration and washed with water. The product was freeze-dried to obtain (E)-N'-(4,6-dichloropyridine-2-yl)-N-hydroxyformimamide (5.1 g, 90%). 1 H NMR (500 MHz, DMSO-d6) δ: 10.44 (s, 1H), 9.87-9.90 (m, 1H), 7.66-7.71 (m, 1H), 7.11-7.15 (m, 2H).

[0368] Preparation 202 5,7-Dichloro-[1,2,4]triazolo[1,5-a]pyridine [ka] (E)-N'-(4,6-dichloropyridine-2-yl)-N-hydroxyformimidoamide (Preparation 201, 5.0 g, 24.27 mmol) and Eaton's reagent (20 mL) were combined and heated to 105°C for 20 minutes. The mixture was diluted with ice water, basicized to pH=8 with solid K2CO3, and the resulting solution was extracted with ELISA (3 × 50 mL). The combined organic matter was dried (Na2SO4) and evaporated to dryness under vacuum to obtain 5,7-dichloro-[1,2,4]triazolo[1,5-a]pyridine as a yellow solid (4.6 g, crude). 1 H NMR (500 MHz, DMSO-d6) δ: 8.66 (s, 1H), 8.15 (d, 1H), 7.76 (d, 1H).

[0369] Preparation 203 (3R,4S)-1-(7-chloro-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of (3R,4S)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (Preparation 21, 87.3 mg, 0.532 mmol) and 5,7-dichloro-[1,2,4]triazolo[1,5-a]pyridine (Preparation 202, 100 mg, 0.532 mmol) in DMF (2 mL), NaH (25.5 mg, 0.638 mmol, 60% purity) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic compounds were washed with brine (30 mL), dried, and evaporated to dryness under vacuum to obtain (3R,4S)-1-(7-chloro-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile as a yellow solid (150 mg, crude), which was used without further purification. LCMS m / z = 316.0 [M+H] + .

[0370] Preparation 204 4-Chloro-6-(1-methyl-1H-pyrazole-4-yl)thieno[3,2-d]pyrimidine [ka] To a solution of 6-bromo-4-chlorothieno[3,2-d]pyrimidine (300 mg, 1.20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (625 mg, 3.01 mmol), and Na2CO3 (382 mg, 3.61 mmol) in toluene (2 mL) and H2O (0.2 mL), Pd(OAc)2 (32.4 mg, 0.144 mmol) and PPh3 (94.6 mg, 0.361 mmol) were added at 25°C, and the mixture was stirred at 110°C for 2 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic matter was washed with brine (20 mL), dried, and evaporated to dryness under vacuum in (Na2SO4). The residue was purified by preparative HPLC-8 (gradient: 37-57%) to obtain 4-chloro-6-(1-methyl-1H-pyrazole-4-yl)thieno[3,2-d]pyrimidine as a white solid (110 mg, 36%). 1 H NMR (500 MHz, CDCl3) δ: 8.87 (s, 1H), 8.28 (s, 1H), 8.02 (s, 1H), 7.64 (s, 1H), 3.94 (s, 3H).

[0371] Preparation 205 7-Bromoimidazo[1,2-a]pyridine-5-amine [ka] A solution of 4-bromopyridine-2,6-diamine (1.0 g, 5.32 mmol) and 2-chloroacetaldehyde (1.6 g, 7.98 mmol) in EtOH (10 mL) was stirred at 90°C for 2 hours. The mixture was evaporated to dryness under vacuum, and the residue was purified by column chromatography (SiO2, 5-10% MeOH / DCM) to obtain 7-bromoimidazo[1,2-a]pyridine-5-amine as a white solid (1.1 g, 98%). 1 H NMR (400 MHz, MeOH-d4) δ: 8.03 (d, 1H), 7.90 (d, 1H), 7.25 (s, 1H), 6.70 (s, 1H).

[0372] Preparation 206 7-Bromo-5-chloroimidazo[1,2-a]pyridine [ka] t-BuONO (486.3 mg, 4.72 mmol, 560.91 uL) was added to CuCl2 (634 mg, 4.72 mmol) in CH3CN (20 mL) at 0°C. 7-Bromoimidazo[1,2-a]pyridine-5-amine (prepared 205 mg, 500 mg, 2.36 mmol) was added, and the internal temperature was raised to 25°C during the addition. The resulting mixture was stirred at 25°C for 3 hours. The reaction product was diluted to pH=8 with Depositphotos (40 mL), followed by saturated NaHCO3. The resulting suspension was filtered, the filter cake was collected, and treated with Depositphotos / saturated NaHCO3 (30 ml / 100 ml, ×2) and stirred for 10 minutes. The combined filtrate was concentrated, and the residue was purified by column chromatography (SiO2, 0-25% Â / PE) to obtain 7-bromo-5-chloroimidazo[1,2-a]pyridine as a yellow solid (400 mg, 73%). 1 H NMR (500 MHz, MeOH-d4) δ: 8.02 (s, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.36 (s, 1H).

[0373] Preparation 207 5-Chloro-7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-a]pyridine [ka] To a solution of 7-bromo-5-chloroimidazo[1,2-a]pyridine (206 mg, 300 mg, 1.30 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (297 mg, 1.43 mmol), and CsF (394 mg, 2.59 mmol) in t-amyl alcohol (4 mL), Pd(amphos)Cl2 (92.3 mg, 0.130 mmol) was added at 25 °C, and the resulting mixture was stirred under N2 at 70 °C for 16 hours. The mixture was diluted with water (50 mL) and extracted with siRNA (3 × 20 mL). The combined organic matter was washed with brine (20 mL), dried, and evaporated to dryness under vacuum in (Na2SO4). The residue was purified by column chromatography (SiO2, 0-6% MeOH / DCM) to obtain 5-chloro-7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-a]pyridine as a brown solid (140 mg, 46%). 1 H NMR (500 MHz, MeOH-d4) δ: 8.18 (s, 1H), 8.01 (s, 1H), 7.93 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.44 (s, 1H), 3.97 (s, 3H).

[0374] Preparation 208 Ethyl(3S)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-isopropyl-3-methylbutanoate [ka] To a solution of ethyl 2-cyano-3-methylbutanoate (25.0 g, 161.09 mmol) in MeCN (300 mL), TBAB (10.39 g, 32.2 mmol) and Cs2CO3 (78.73 g, 241.63 mmol) were added, and the solution was stirred at 20°C for 1 hour. Tert-butyl(5S)-5-methyl-2,2-dioxo-1,2,3-oxathiazolidine-3-carboxylate (38.22 g, 161.1 mmol) was added in batches at 25°C, then heated to 30°C and stirred for 16 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. H2O (300 mL) and aqueous HCl (1 mol / L) were added to adjust the pH to 3. The aqueous phase was extracted with ELISA (200 mL x 3), and the combined organic layers were dried to obtain ethyl(3S)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-isopropyl-3-methylbutanoate (50.32 g, crude) as a yellow liquid, which was used without further purification.

[0375] Preparation 209 (3R,4S)-3-isopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile [ka] To a solution of ethyl(3S)-4-((tert-butoxycarbonyl)amino)-2-cyano-2-isopropyl-3-methylbutanoate (Preparation 208, 50 g, 160.05 mmol) in ethyl(HCl) (600 mL), toluene-4-sulfonic acid (60.8 g, 320.1 mmol) was added, and the solution was heated to 50°C and stirred for 1 hour. The mixture was concentrated under vacuum, the residue was suspended in MeCN (700 mL), K2CO3 (66.4 g, 480.1 mmol) was added, and the mixture was stirred at 50°C for 16 hours. The reaction product was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: PE / Â1 = 5:1 to 1:1) to obtain (4S)-3-isopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (15 g, yield 56.4%) as a colorless liquid. This was further purified by SFC (ChiralPak IG, 250 × 50 mm, ID 10 μm), mobile phase: 150 mL / min, 15% (0.1% NH3H2O ​​in MeOH), column temperature: 40°C to obtain peak 1, 9.0 g, 60%) as a yellow oily substance, and peak 2, (3R,4S)-3-isopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (4.35 g, 29%) as a pale yellow solid. Stereochemistry was determined by 2D nmr. LCMS m / z = 167.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ ppm: 6.55 (s, 1H), 3.62-3.58 (m, 1H), 3.06-2.97 (m, 2H), 2.21-2.15 (m, 1H), 1.27-1.21 (m, 9H).

[0376] Preparation 210, (1s,3s)-3-methoxycyclobutylmethanesulfonate [ka] To a solution of (1s,3s)-3-methoxycyclobutan-1-ol (250 mg, 2.45 mmol) and TEA (743.1 mg, 7.34 mmol) in DCM (10 mL), MsCl (500 mg, 4.36 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with NH3·H2O (1 mL) and MeOH (1 mL). Water (20 mL) was added, and the mixture was extracted with DCM (20 mL x 3). The collected organic matter was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain (1s,3s)-3-methoxycyclobutylmethanesulfonate (200 mg, crude) as a yellow oil, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ: = 4.71-4.65 (m, 1H), 3.61-3.56(m, 1H), 3.26 (s, 3H), 3.00 (s, 3H), 2.89-2.83 (m, 2H), 2.30-2.24 (m, 2H).

[0377] Preparation 211 3-Cyano-3-methylcyclobutylmethanesulfonate [ka] 3-Cyano-3-methylcyclobutylmethanesulfonate was obtained from 3-hydroxy-1-methylcyclobutan-1-carbonitride and MsCl in a yellow oily substance, 170 mg, crude, according to the procedure described in Preparation 210. 1 H NMR (400MHz, CDCl3) δ: = 5.22-5.04 (m, 1H), 3.11-3.05 (m, 1H), 3.05-3.02 (m, 3H), 2.92-2.86 (m, 1H), 2.66-2.60 (m, 1H), 2.50-2.32 (m, 1H), 1.59 (d, J = 18.8 Hz, 3H).

[0378] Preparation 212, 2-Methyloxetane-3-yltrifluoromethanesulfonate [ka] To a solution of 2-methyloxetane-3-ol (200 mg, 2.27 mmol) and DIPEA (1.47 g, 11.35 mmol) in DCM (10 mL), Tf2O (1.60 g, 5.68 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with NH3·H2O (1 mL) and MeOH (1 mL). Water (20 mL) was added, and the mixture was extracted with DCM (20 mL x 3). The combined organic matter was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain 2-methyloxetane-3-yltrifluoromethanesulfonate (200 mg, crude) as a yellow oil, which was used without further purification.

[0379] Preparation 213 3-(4-bromo-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile [ka] To a solution of 3-cyanocyclobutylmethanesulfonate (0.35 g, 2.00 mmol) in DMF (6 mL), Cs2CO3 (1.30 g, 4.00 mmol) and 4-bromo-1H-pyrazole (293.60 mg, 2.00 mmol) were added, and the reaction mixture was stirred at 90°C for 2 hours. The mixture was concentrated under vacuum and purified by column chromatography (PE / Â=3:1) to obtain 3-(4-bromo-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile (500 mg, yield 88.6%) as a white solid. LCMS m / z = 228.1 [M+H] + .

[0380] Preparation 214 4-bromo-1-(2-oxaspiro[3,3]heptan-6-yl)-1H-pyrazole [ka] 4-bromo-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrazole was obtained from 2-oxaspiro[3.3]heptan-6-ylmethanesulfonate and 4-bromo-1H-pyrazole as a colorless oily substance, 540 mg, with a yield of 68.3%, following a procedure similar to that described in Preparation 213. LCMS m / z = 245.1 [M+H] + .

[0381] Preparation 215, 4-Bromo-1-((1r,3r)-3-methoxycyclobutyl)-1H-pyrazole [ka] To a solution of 4-bromo-1H-pyrazole (391.45 mg, 2.66 mmol) in DMF (3 mL), Cs2CO3 (2.17 g, 6.66 mmol) was added at 20°C. (1s,3s)-3-methoxycyclobutylmethanesulfonate (210 mg, 400 mg, 2.22 mmol) was slowly added, and the reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was concentrated under vacuum, and water (40 mL) was added. The mixture was extracted with DCM (20 mL x 3), and the combined organic extract was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC-2 (gradient 11-41%) to obtain 4-bromo-1-((1r,3r)-3-methoxycyclobutyl)-1H-pyrazole (300 mg, yield 58.5%) as a colorless oil. LCMS m / z = 232.7 [M+H] + .

[0382] Preparation 216, 3-(4-bromo-1H-pyrazole-1-yl)-1-methylcyclobutan-1-carbonitrile [ka] 3-(4-bromo-1H-pyrazole-1-yl)-1-methylcyclobutan-1-carbonitrile was obtained as a yellow solid, 100 mg, 51.5% from 4-bromo-1H-pyrazole and 3-cyano-3-methylcyclobutylmethanesulfonate (Preparation 211) by following the same procedure as described in Preparation 215, except that the crude product was purified by preparative HPLC-18 (gradient: 37-67%). LCMS m / z = 241.8 [M+H] + .

[0383] Preparation 217, 4-Bromo-1-(2-methyloxetan-3-yl)-1H-pyrazole [ka] To a solution of 4-bromo-1H-pyrazole (133.51 mg, 0.908 mmol) and 2-methyloxetan-3-yltrifluoromethanesulfonate (200 mg, 0.908 mmol) in DMF (10 mL), K2CO3 (376.65 mg, 2.73 mmol) was added at 15°C, and the reaction mixture was stirred at 85°C for 30 hours. The reaction product was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by preparative HPLC-16 (gradient: 27-47%) to obtain 4-bromo-1-(2-methyloxetan-3-yl)-1H-pyrazole (50 mg, yield 25.4%) as a light brown oily substance. LCMS m / z = 217.2 [M+H] + .

[0384] Preparation 218 4-Bromo-3-fluoro-1-(oxetan-3-yl)-1H-pyrazole [ka] A solution of 3-iodooxetane (334.6 mg, 1.82 mmol), K2CO3 (377.02 mg, 2.73 mmol), and 4-bromo-3-fluoro-1H-pyrazole (0.15 g, 0.909 mmol) in DMF (3 mL) was stirred at 90°C for 2 hours. The reaction mixture was concentrated under vacuum. The crude product was purified by preparative HPLC-18 (gradient: 33-53%) to obtain 4-bromo-3-fluoro-1-(oxetan-3-yl)-1H-pyrazole (130 mg, yield 64.7%) as a white solid. LCMS m / z = 220.9 [M+H] + .

[0385] Preparation 219, (1s,3s)-3-(4-bromo-1H-pyrazole-1-yl)-1-methylcyclobutan-1-ol [ka] To a solution of 3-(4-bromo-1H-pyrazole-1-yl)cyclobutan-1-one (prepared 138 mg, 2.09 mmol) in 10 mL of THF at 0°C, MeMgBr (3 M, 1.05 mL) was added dropwise. The reaction mixture was stirred for 16 hours, and the ice bath was heated to room temperature. The reaction mixture was quenched by adding 20 mL of saturated NH4Cl aqueous solution at 25°C, and then diluted with water (80 mL). The mixture was extracted with DCM (100 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative H...

Claims

1. Compounds of formula (I-1) or (I-2): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof [in the formula, Q １ and Q ２ Each of these independently represents either C or N. X １ N, N-R Ｘ１ , or CR Ｘ１ And, X ２ S, N-R Ｘ２ , or CR Ｘ２ And, X ３ is N, O, S, or C—R Ｘ３ wherein, provided that X ２ is S, X ３ cannot be S or O X ４ is N or C-R Ｘ４ And, X ５ , C-R Ｘ５ And, X ６ is N or C-R Ｘ６ And, Y １ is N or C-R Ｙ１ And, Y ２ N-R Ｙ２ or CR Ｙ２ And, Y ３ is N or C-R Ｙ３ And, Y ４ is N or C-R Ｙ４ And, Y ５ , C-R Ｙ５ And, Y ６ , C-R Ｙ６ And, R Ｘ１ , R Ｘ３ , R Ｘ４ , and R Ｘ６ These are H, Halogen, -CN, and -NR, respectively, independently. １ａ R １ｂ , -OR １ｃ , C １－４ Alkyl and C １－４ Selected from haloalkyls, R Ｘ２ and R Ｘ５ These are H, Halo, CN, and -NR, respectively, independently. １ａ R １ｂ , -OR １ｃ , C １－６ Alkyl, C ３－８ Cycloalkyl, and R Ｓ Selected from, here, R Ｘ２ and R Ｘ５ The C represented by １－６ Alkyl and the C ３－８ Each cycloalkyl group contains one or more R ８ Replaced by optional selection, R Ｙ１ , R Ｙ３ , R Ｙ４ , and R Ｙ６ These are H, Halogen, -CN, and -NR, respectively, independently. １ａ R １ｂ , -OR １ｃ , C １－４ Alkyl and C １－４ Selected from haloalkyls, R Ｙ２ and R Ｙ５ These are H, Halogen, -CN, and -NR, respectively, independently. １ａ R １ｂ , -OR １ｃ , C １－６ Alkyl, C ３－８ Cycloalkyl, and R Ｓ Selected from, here, R Ｙ２ and R Ｙ５ The C represented by １－６ Alkyl and the C ３－８ Each cycloalkyl group contains one or more R ８ Replaced by optional selection, R Ｓ Independently, C ６－１０ Selected from aryls, 4-7 membered monocyclic heterocyclines, and 5-10 membered heteroaryls, where R Ｓ The C represented by ６－１０ The aryl, the 4- to 7-membered monocyclic heterocyclyl, and the 5- to 10-membered heteroaryl each contain one or more R ７ Replaced by optional selection, R １ 、R ２ 、R ３ 、R ４ 、R ５ 、R ６ are each independently selected from H, halo, -CN, -NR １ａ R １ｂ 、-OR １ｃ 、C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, where the C １ 、R ２ 、R ３ 、R ４ 、R ５ 、and R ６ represented by alkyl, the C １－６ cycloalkyl, the C ３－８ aryl, the 4- to 10-membered heterocycloalkyl, and the 5- to 10-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halo, -CN, -NR ６－１０ １ａ R １ｂ 、-OR １ｃ １－６ alkyl, and C ３－８ cycloalkyl,​​ R ７ These are independently: Halo, -CN, -NR １ａ R １ｂ , -NR １ａ C(O)R １ｄ , -OR １ｃ , -C(O)OR １ｃ , -C(O)NR １ａ R １ｂ , -SO ２ R １ｅ , C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ Selected from aryls, 4-7 membered monocyclic heterocycloalkyls, 7-10 membered bicyclic heterocycloalkyls, and 5-6 membered heteroaryls, where R ７ The C represented by １－６ alkyl, the C １－６ Haloalkyl, the above C ３－６ Cycloalkyl, the C ６－１０ The aryl, the 4- to 7-membered monocyclic heterocycloalkyl, the 7- to 10-membered bicyclic heterocycloalkyl, and the 5- to 6-membered heteroaryl each contain one or more R ７ａ Replaced by optional selection, Alternatively, R ７ Two of them, together with those intervening atoms, C １－６ Forming a 3- to 7-membered monocyclic heterocycline which is optionally substituted with one or two substituents independently selected from alkyl and oxo (=O), R ７ａ Each instance independently represents Halo, -CN, and C. １－４ Alkyl, C １－４ Haloalkyl, C ３－６ Cycloalkyl, -NR １ａ R １ｂ , -OR １ｃ , and selected from 4-6 member monocyclic heterocycloalkyl groups, where the C １－４ alkyl, the C ３－６ Cycloalkyls and the aforementioned 4-6 membered monocyclic heterocycloalkyls are, respectively, C １－３ Alkyl, -OR １ｃ , CN, and halo are optionally substituted with one or more substituents independently selected from these groups. R ８ Each instance independently produces Halo, -CN, and -NR. １ａ R １ｂ , -OR １ｃ , -C(O)OR １ｃ , C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ The aryl group is a 4- to 7-membered monocyclic heterocycloalkyl group, or a 5- to 6-membered heteroaryl group, where R ８ The C represented by １－６ alkyl, the C １－６ Haloalkyl, the above C ３－６ Cycloalkyl, the C ６－１０ The aryl, the 4- to 7-membered monocyclic heterocycloalkyl, and the 5- to 6-membered heteroaryl are, respectively, halo and C. １－４ Alkyl, C １－４ Haloalkyl, C ３－６ Cycloalkyl, -NR １ａ R １ｂ , -OR １ｃ and optionally substituted with one or more substituents independently selected from 4-6 membered monocyclic heterocycloalkyl groups, R １ａ and R １ｂ These are, independently, H or C １－４ It is alkyl, R １ｃ H, C １－４ Alkyl or C １－４ It is a haloalkyl, R １ｄ C １－４ Alkyl or -OR １ｅ And, R １ｅ C １－４ It is alkyl, Here, R Ｘ１ , R Ｘ２ , R Ｘ３ , R Ｘ４ , R Ｘ５ , and R Ｘ６ At least one of them is R, not H. Ｙ１ , R Ｙ２ , R Ｙ３ , R Ｙ４ , R Ｙ５ , and R Ｙ６ At least one of them is not H.

2. (i) Q １ C is Q ２ Is it C? (ii) Q １ If N is Q ２ Is C, or (iii) Q １ C is Q ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is N.

3. The aforementioned compound is represented by formula (I-1), (i) X １ CR Ｘ１ X ２ CR Ｘ２ X ４ is N or CR Ｘ４ X ５ CR Ｘ５ X ６ N is X ３ However, N, S, O, and CR Ｘ３ Selected from, or (ii) X １ N is X ２ CR Ｘ２ X ４ is N or CR Ｘ４ X ５ CR Ｘ５ X ６ CR Ｙ６ X ３ However, N, S, and CR Ｘ３ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the above.

4. R Ｘ２ and R Ｘ５ One of them is R Ｓ The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the other is H.

5. The aforementioned compound is represented by formula (I-2), (i) Y １ N is Y ２ N-R Ｙ２ Y ３ N is Y ４ CR Ｙ４ Y ５ CR Ｙ５ Y ６ CR Ｙ６ Is it, (ii) Y １ CR Ｙ１ Y ２ N-R Ｙ２ Y ３ N is Y ４ CR Ｙ４ Y ５ CR Ｙ５ Y ６ CR Ｙ６ Is it, (iii) Y １ CR Ｙ１ Y ２ CR Ｙ２ Y ３ N is Y ４ CR Ｙ４ Y ５ CR Ｙ５ Y ６ CR Ｙ６ is, or (iv) Y １ N is Y ２ N-R Ｙ２ Y ３ CR Ｙ３ Y ４ N is Y ５ CR Ｙ５ Y ６ CR Ｙ６ The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof.

6. R Ｙ２ and R Ｙ５ One of them is R Ｓ The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein the other is H.

7. The aforementioned compound is given by the following formula: 【Chemistry 2-1】 【Chemistry 2-2】 The compound according to claim 1, which is represented by one of the or a pharmaceutically acceptable salt thereof.

8. R Ｘ２ However, it is a monocyclic heterocyclyl with 4 to 7 members or a heteroaryl with 5 to 10 members, where R Ｘ２ The 4-7 member monocyclic heterocyclil or the 5-10 member heteroaryl represented by each of the following is one or two R ７ Replaced by choice, R Ｘ５ The compound according to any one of claims 1 to 4 and 7, or a pharmaceutically acceptable salt thereof, wherein if present, it is H.

9. R Ｘ５ However, it is a monocyclic heterocyclyl with 4 to 7 members or a heteroaryl with 5 to 10 members, where R Ｘ５ The 4-7 member monocyclic heterocyclil or the 5-10 member heteroaryl represented by each of the following is one or two R ７ Replaced by choice, R Ｘ２ The compound according to any one of claims 1 to 4 and 7, or a pharmaceutically acceptable salt thereof, wherein if present, it is H.

10. The aforementioned compound is the following formula: 【Transformation 3】 The compound according to claim 1, which is represented by one of the or a pharmaceutically acceptable salt thereof.

11. R Ｙ２ However, R Ｓ And R Ｓ However, it is a monocyclic heterocyclyl with 4 to 7 members or a heteroaryl with 5 to 10 members, where R Ｓ The 4-7 member monocyclic heterocyclil or the 5-10 member heteroaryl represented by each of the following is one or two R ７ Replaced by choice, R Ｙ５ The compound according to any one of claims 1, 2, 5, 6, and 10, wherein H is present, or a pharmaceutically acceptable salt thereof.

12. R Ｙ５ However, R Ｓ And R Ｓ However, it is a monocyclic heterocyclyl with 4 to 7 members or a heteroaryl with 5 to 10 members, where R Ｓ The 4-7 member monocyclic heterocyclil or the 5-10 member heteroaryl represented by each of the following is one or two R ７ Replaced by choice, R Ｙ２ The compound according to any one of claims 1, 2, 5, 6, and 10, wherein H is present, or a pharmaceutically acceptable salt thereof.

13. R Ｓ However, each of these is selected from pyrazine, pyridazine, pyridine, pyridine-2(1H)-one, pyrazole, pyrazolopyridine, pyrimidine, pyrrolopyridine, isoxazole, imidazole, imidazopyridine, indazole, thiazole, triazole, thiazolopyridine, and triazolopyridine, and each of these is R ７ The compounds according to claims 8, 9, 11, and 12, or pharmaceutically acceptable salts thereof, which are optionally substituted with one or two of the above.

14. R Ｓ but, 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 Selected from, in the formula, 【Transformation 5】 However, X ２ , X ５ , Y ２ , or Y ５ This represents a connection to, n represents 0, 1, or 2, A compound according to any one of claims 8, 9, 11, and 12, or a pharmaceutically acceptable salt thereof, wherein m represents 0 or 1.

15. R ７ However, independently, Halo, -CN, -NR １ａ R １ｂ , -NR １ａ C(=O)R １ｄ , -OR １ｃ , -C(O)NR １ａ R １ｂ , -SO ２ R １ｅ , C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Selected from cycloalkyls, 4-7 membered monocyclic heterocycloalkyls, 7-8 membered bicyclic heterocycloalkyls, and 5-6 membered heteroaryls, where R ７ The C represented by １－６ alkyl, the C １－６ Haloalkyl, the above C ３－６ Cycloalkyls, the 4-7 member monocyclic heterocycloalkyls, the 7-8 member bicyclic heterocycloalkyls, and the 5-6 member heteroaryls each have 1-3 R groups. ７ａ Replaced by optional selection, Alternatively, R ７ Two of them, together with those intervening atoms, C １－６ A 3- to 7-membered monocyclic heterocycline is formed by optionally substituting with one or two substituents independently selected from alkyl and =O, R ７ａ However, each time it appears, independently, C １－３ Alkyl, Halo, -CN, -OR １ｃ , C ３－６ Selected from cycloalkyls and 4-6 membered monocyclic heterocycloalkyls, where R ７ａ The C represented by １－３ alkyl, the C ３－６ Cycloalkyl and the aforementioned 4-6 member monocyclic heterocycloalkyl are, respectively, C １－３ Optionally substituted with one or two substituents independently selected from alkyl, -OH, and CN, R １ａ and R １ｂ However, each is independent of H or C １－４ It is alkyl, R １ｃ However, H or C １－４ Alkyl or C １－４ It is a haloalkyl, R １ｄ However, C １－４ Alkyl or -OR １ｅ And, R １ｅ However, C １－４ A compound according to any one of claims 8, 9, and 11 to 14, which is alkyl, or a pharmaceutically acceptable salt thereof.

16. R ７ is independently Cl, F, -CN, -OH, -OCH ３ , -O-CHF ２ , -CH ３ , -CD ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CHF ２ , -CH ２ CHF ２ , -CF ３ , -CH ２ -OH, -CH(OH)-CH ３ , -CH ２ OCH ３ , -CH ２ CH ２ OCH ２ CH ３ , -CH ２ -CN, -N(CH ３ ) ２ , -C(O)-NH-CH<000035​​​​​​​​​​​​​​​​​ 【Transformation 6】 Selected from, in the formula, 【Transformation 7】 However, R Ｓ A compound according to any one of claims 8, 9, and 11-14, or a pharmaceutically acceptable salt thereof, representing a bond to.

17. R ７ Two of them, together with those intervening atoms, C １－６ The compound according to any one of claims 8, 9, and 11-14, or a pharmaceutically acceptable salt thereof, forming a 3- to 7-membered monocyclic heterocycline optionally substituted with one or two substituents independently selected from alkyl and =O.

18. R Ｓ but, 【Transformation 8】 Selected from, in the formula, 【Chemistry 9】 However, X ２ , X ５ , Y ２ , or Y ５ A compound according to claim 17, or a pharmaceutically acceptable salt thereof, representing a bond to.

19. R １ , R ２ , R ３ , R ４ , R ５ , and R ６ However, each is independent of H, -CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Selected from cycloalkyls and 4- to 6-membered heterocycloalkyls, where the C １－６ Alkyl is -CN or -OR １ｆ Replaced by optional selection, R １ｆ However, C １－４ A compound according to any one of claims 1 to 18, which is alkyl, or a pharmaceutically acceptable salt thereof.

20. R １ , R ２ , R ３ , R ４ , R ５ , and R ６ However, each is independent of H, CN, and -CH. ３ ien-CH ２ CH ３ Cyclopropyl, cyclobutyl, -CHF ２ ien-CH ２ -O-CH ３ ,CH ２ -CN, and 【Chemistry 10】 A compound according to claim 19, or a pharmaceutically acceptable salt thereof, selected from the above.

21. R １ and R ２ However, each is independent of H, CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Selected from cycloalkyls and 4- to 10-membered heterocycloalkyls, where the C １－６ Alkyl is -CN or -OR １ｆ Replaced by optional selection, R ３ and R ４ However, H and C are independent of each other. １－６ Alkyl and C １－６ Selected from haloalkyls, R ５ and R ６ However, each is independent of H or C １－６ It is alkyl, R １ｆ However, C １－４ A compound according to any one of claims 1 to 18, which is alkyl, or a pharmaceutically acceptable salt thereof.

22. R １ and R ２ However, each is independent of H, CN, and -CH. ３ ien-CH ２ CH ３ ,-CHF ２ Cyclopropyl, cyclobutyl, -CH ２ -O-CH ３ ien-CH ２ -CN, and 【Chemistry 11】 Selected from, R ３ and R ４ However, independently of each other, H and -CH ３ ien-CH ２ CH ３ , and -CHF ２ Selected from, R ５ and R ６ However, independently of each other, H and -CH ３ , and -CH ２ CH ３ A compound according to claim 21, or a pharmaceutically acceptable salt thereof, selected from the above.

23. R Ｘ１ , R Ｘ３ , R Ｘ４ , and R Ｘ６ However, each is independent of H, Halo, and C. １－４ Selected from alkyl groups, R Ｙ１ , R Ｙ３ , R Ｙ４ , and R Ｙ６ However, each is independent of H, Halo, and C. １－４ A compound according to any one of claims 1 to 22, selected from alkyl groups, or a pharmaceutically acceptable salt thereof.

24. R Ｘ１ , R Ｘ３ , R Ｘ４ , and R Ｘ６ However, each is independent of H, Cl, F, and CH. ３ Selected from, R Ｙ１ , R Ｙ３ , R Ｙ４ , and R Ｙ６ However, each is independent of H, Cl, F, and CH. ３ A compound according to claim 23, or a pharmaceutically acceptable salt thereof, selected from the above.

25. R Ｘ１ , R Ｘ３ , R Ｘ４ , and R Ｘ６ However, it is H, R Ｙ１ , R Ｙ３ , R Ｙ４ , and R Ｙ６ The compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein H is present.

26. The aforementioned compound is given by the following formula: 【Chemistry 12】 It is represented by or a pharmaceutically acceptable salt thereof, in the formula, R Ｘ１ However, it is H or halo, R Ｘ２ However, one or two R ７ It is a five-member heteroaryl that is optionally substituted, R Ｘ３ However, it is H or halo, R Ｘ５ However, one or two R ７ A five-membered or six-membered heteroaryl that is optionally substituted, R Ｙ２ However, one or two R ７ It is a five-member heteroaryl that is optionally substituted, R １ and R ２ However, each is independent of -CN or C ３－６ It is a cycloalkyl, R ３ and R ４ However, each is independent of H or C １－３ The compound according to claim 1, wherein it is alkyl.

27. R Ｘ２ , R Ｘ５ , or R Ｙ２ The five-membered or six-membered heteroaryl represented by is a pyrazole or pyridine, each of which is one R ７ The compound according to claim 26, or a pharmaceutically acceptable salt thereof, which is optionally substituted.

28. R Ｘ２ , R Ｘ５ , or R Ｙ２ The five-membered or six-membered heteroaryl represented by the following formula: 【Chemistry 13】 The compound according to claim 26, or a pharmaceutically acceptable salt thereof, represented by one of the following.

29. R ７ But, hello, C １－４ Alkyl, C １－４ The compound according to claim 27 or 28, which is a haloalkyl or a 4-6 member monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from oxygen and nitrogen.

30. R ７ However, F, -CH ３ ,-CHF ２ ien-CH ２ CH ３ ,or 【Chemistry 14】 The compound according to claim 29, or a pharmaceutically acceptable salt thereof.

31. R １ However, it is CN, and R ２ However, C ３－６ It is a cycloalkyl, R ３ However, H is R ４ However, C １－３ A compound according to any one of claims 26 to 30, which is alkyl, or a pharmaceutically acceptable salt thereof.

32. R １ However, it is CN, and R ２ However, it is cyclopropyl, and R ３ However, H is R ４ However, -CH ３ The compound according to claim 31, or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

34. A method for inhibiting tyrosine kinase 2 (TYK2) activity in a subject in which tyrosine kinase 2 (TYK2) activity needs to be inhibited, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 33.

35. A method for treating a disease or disorder that is effective by inhibition of tyrosine kinase 2 (TYK2) in a subject, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 33.

36. The aforementioned diseases or disorders include inflammation, autoimmune diseases, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, head trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, and green The method according to claim 35, wherein the condition is internal organ failure, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, autoimmune diseases, osteoporosis, multiple sclerosis, endometriosis, menstrual pain, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis, and sunburn.

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