Tyrosine kinase 2 inhibitor and its use

Abstract

Provided is a compound of formula (I): TIFF2025523507000477.tif5785, or a pharmaceutically acceptable salt thereof, which is useful for the inhibition of TYK2 and the treatment of various TYK2-mediated conditions or diseases.

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 354,914, filed Jun. 23, 2022. The entire contents of the foregoing application are hereby expressly incorporated by reference herein.

[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 in any combination with a pharmaceutically acceptable carrier for the manufacture of pharmaceutical preparations, 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 secreted by cells and have specific effects on cell-cell interactions and communication. Cytokine pathways mediate a wide range of biological functions, including many aspects of inflammation and immunity, mainly through extracellular signaling.

[0004] Tyrosine kinase 2 (TYK2) is a cytoplasmic protein kinase that associates with cytokine receptors and is a member of the Janus kinase (JAK) family, which plays 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, engagement of cytokine with cognate receptors causes activation of the receptor-associated JAKs, which in turn leads to JAK-mediated tyrosine phosphorylation of signal transducer and activator of transcription (STAT) proteins and ultimately activation of transcription of specific gene sets (Schindler et al, 2007, J. Biol. Chem. 282:20059-63). A number of cytokines known to activate the JAK family include the interferon (IFN) family (IFN-alpha, IFN-beta, IFN-omega, limitin, IFN-gamma, IL-10, IL-19, IL-20, IL-22), the glycoprotein (gp)130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, leptin, IL-12, IL-23), the gammaC 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-chain family (EPO, GH, PRL, TPO), the receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and the G protein-coupled receptor (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, W.T. & O’Shea, J.J., 2006, Immunity 25:695-697). Consistent with this, primary cells derived from TYK2-deficient humans lack type I interferon, IL-6, IL-10, IL-12, and IL-23 signaling. TYK2 signaling with other members of the JAK family in the following combinations: TYK2 / JAK1, TYK2 / JAK2, TYK2 / JAK1 / JAK2.

[0006] Inappropriate JAK activity can result from mutations, overexpression, or inappropriate regulation, dysregulation or deregulation, as well as overproduction or underproduction of growth factors or cytokines, and thus has been shown by studies to cause various biological cellular responses related to cell growth, cell differentiation, cell function, survival, apoptosis, and cell motility. Inappropriate JAK activity is involved in 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 diseases 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 into development are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain of the JAK protein (also referred to as the JH1 or “Janus Homology 1” domain), preventing the catalytic activity of the kinase by blocking ATP, downstream phosphorylation, and resulting pathway signaling (Bryan et al., J. Med. Chem. 2018, 61, 9030-9058).

[0008] Due to the high homology of the ATP active site within the entire kinome, especially within the JAK family, achieving high selectivity for specific JAK family members while maintaining selectivity within the kinome is a significant challenge. As a result, many of the JAK inhibitors being developed are either pan-JAK inhibitors or are moderately selective for one or more JAK family members. These inhibitors have shown promising results in the treatment of autoimmune diseases, but have also been observed to have undesirable side effects that result in a narrow therapeutic index, suggesting the need for improved therapies.

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

[0010] There remains a need for potent compounds that exhibit high selectivity for TYK2 over other members of the JAK family as potential therapeutic agents for treating diseases or disorders responsive to TYK2 inhibition. SUMMARY OF THE INVENTION

[0011] The present disclosure provides compounds that are TYK2 inhibitors. In a first aspect, the present disclosure relates to a compound of formula I:

Chemical formula

[0012] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0013] In yet another aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibition of TYK2 in a subject, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.

[0014] Another aspect of the present disclosure relates to the use of at least one compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or disorder responsive to inhibition of TYK2. Also provided is a compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder responsive to inhibition of TYK2. The use of a compound described herein or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder responsive to inhibition of TYK2 is also included in the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful for the treatment of diseases or disorders mediated by TYK2. In some embodiments, the compounds of the present disclosure are TYK2 inhibitors.

[0016] Compounds and Compositions In a first embodiment, the present disclosure provides a compound of formula (I):

CHEMICAL

[0017] In a second embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1A is H or -CH3, and the remaining variable moieties are as described in the first aspect or the first embodiment.

[0018] In a third embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 3 is independently H or -CH3, and the remaining variable moieties are as described in the first aspect or the first or second embodiment.

[0019] In a fourth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, two Rs 3 together with the atom to which they are attached form a C 3~6 cycloalkyl or a 5- to 6-membered monocyclic heterocyclic ring, each of which is optionally substituted with 1 to 3 Rs 5 and the remaining variable moieties are as described in the first aspect or the first or second embodiment.

[0020] In the fifth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, two Rs 3 together with the atoms to which they are attached form cyclopropane, cyclobutane, cyclopentane, tetrahydropyran, or piperidine, each of which is optionally substituted by one to three Rs 5 and the remaining variable moieties are as described in the first aspect or the first, second, or fourth embodiment.

[0021] In the sixth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, two Rs 3 together with the atoms to which they are attached form

Chemical formula

Chemical formula

[0022] In the seventh embodiment, the compounds of the present disclosure are of formula (III), (IV), (V), (VI), (VII), (VIII), or (IX):

Chemical formula

[0023] In the eighth embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each R 5is independently H, -CN, or CH3, and the remaining variable moieties are as described in the first aspect or the first, second, fourth, fifth, sixth, or seventh embodiment.

[0024] In a ninth embodiment, for a compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, ring C is a 5- to 9-membered monocyclic or bicyclic heteroaryl optionally substituted by 1 to 3 Rs C and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0025] In a tenth embodiment, for a compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, ring C is pyrazine, pyrazolo[1,5-a]pyrimidine, pyridine, pyrimidine, pyrimidinone, or thiazole, each of which is optionally substituted by 1 to 3 Rs C and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0026] In an eleventh embodiment, for a compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, ring C is

Chemical formula

Chemical formula

[0027] In the 12th embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, ring C is

Chemical formula

Chemical formula

[0028] In the 13th embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each R C is independently halo, -NR N1 R N2 -, -OR O1 -, -SR 7 -, -SO2-R 7 -, -C(O)-NR N3 R N4 -, -C(O)-R 7 C 1~3 alkyl, C 3~6 cycloalkyl, a 4- to 9-membered monocyclic or bicyclic heterocyclyl, phenyl, or a 5- to 6-membered heteroaryl, wherein C C represented by R 1~3 alkyl, C 3~6 cycloalkyl, a 4- to 9-membered monocyclic or bicyclic heterocyclyl, phenyl, and a 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 R C1 . When R 7 is C 1~3 alkyl, R O1 is H, C 1~4 alkyl, C 1~4 alkyl, C3~6 Cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, 5- to 6-membered heteroaryl, and R O1 represented C 1~4 alkyl is independently selected from 1 to 3 substituents selected from halo, CN, C 1~3 alkoxy, C 3~6 cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, where C 3~6 cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, and 5- to 6-membered R O1 represented heteroaryl are each optionally substituted with 1 to 2 substituents independently selected from halo, C 1~3 alkyl, CN, OH, and C 1~3 alkoxy; R N1 is H or C 1~3 alkyl, and R N2 is ring D or -C 1~3 alkylene-ring D, ring D is a 3- to 7-membered monocyclic or bicyclic carbocyclic ring, or a 4- to 7-membered monocyclic heterocyclyl, where the 3- to 7-membered monocyclic carbocyclic ring and 4- to 7-membered monocyclic heterocyclyl represented by ring D are each optionally substituted with 1 or 2 substituents independently selected from halo, C 1~6 alkyl, and -C 1~4 alkoxy, and R N1 and R N2 are each independently H or C 1~4 alkyl, where the C N1 alkyl represented by R N2 and R 1~4 is each optionally substituted with halo, C 1~3 alkoxy, or -NR N3 R N4 or R N1 is H or C 1~2 alkyl, and R N2 is ring D or -C 1~2 alkylene-ring D, Ring D is a 3- to 6-membered monocyclic or bicyclic carbocyclic ring, or a 4- to 6-membered monocyclic heterocyclic ring, wherein the 3- to 6-membered monocyclic carbocyclic ring and the 4- to 6-membered monocyclic heterocyclic ring represented by Ring D are each optionally substituted with one or two substituents independently selected from halo, C 1~3 alkyl and C 1~3 alkoxy, each R N3 is independently H or C 1~3 alkyl, each R N4 is independently H or C 1~3 alkyl, and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.

[0029] Alternatively, as part of the thirteenth embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or pharmaceutically acceptable salts thereof, each R C is independently halo, -NR N1 R N2 -, -OR O1 -, -SR 7 -, -SO2-R 7 -, -C(O)-NR N3 R N4 -, -C(O)-R 7 -, -C(O)H, -C(O)OH, -C(O)OR 7 , C 1~6 alkyl, C 2~4 alkenyl, C 3~6 cycloalkyl, a 4- to 9-membered monocyclic or bicyclic heterocyclic ring, phenyl, or a 5- to 6-membered heteroaryl, wherein the C C alkyl, the C 1~6 alkenyl, the C 2~4 cycloalkyl, the 4- to 9-membered monocyclic or bicyclic heterocyclic ring, the phenyl, and the 5- to 6-membered heteroaryl represented by R 3~6 are each optionally substituted with 1 to 3 R C1 s, R 7 is C 1~3 alkyl, R O1 is H, C 1~4 alkyl, C 1~4 alkyl, C 3~6 cycloalkyl, a 4- to 8-membered monocyclic or bicyclic heterocyclyl, or a 5- to 6-membered heteroaryl, where the C O1 alkyl represented by R 1~4 is optionally substituted with 1 to 3 substituents independently selected from halo, OH, CN, C 1~3 alkoxy, C 3~6 cycloalkyl, and C 1~3 alkyl or a 4- to 6-membered monocyclic heterocyclyl optionally substituted with C 1~3 alkoxy and is optionally substituted with 1 to 3 substituents independently selected therefrom, and the C O1 cycloalkyl, the 4- to 8-membered monocyclic or bicyclic heterocyclyl, and the 5- to 6-membered heteroaryl represented by R 3~6 are each optionally substituted with 1 to 2 substituents independently selected from halo, C 1~3 alkyl, C 1~3 alkyl-C 1~3 alkoxy, CN, OH, and C 1~3 alkoxy, R N1 and R N2 are each independently H or C 1~6 alkyl, where the C N1 alkyl and the C N2 alkyl represented by R 1~6 are each optionally substituted with halo, C 1~4 alkoxy, or -NR N3 R N4 or R N1 is H or C 1~3 alkyl, R N2 is ring D or -C 1~3 alkylene-ring D, Ring D is a monocyclic or bicyclic carbocyclic ring having 3 to 7 members, or a monocyclic heterocyclic ring having 4 to 7 members, wherein the monocyclic carbocyclic ring having 3 to 7 members and the monocyclic heterocyclic ring having 4 to 7 members represented by Ring D are each halo, C 1~6 alkyl, and -C 1~4 optionally substituted with one or two substituents independently selected from alkoxy, R N1 and R N2 are each independently H or C 1~4 alkyl, wherein the C N1 alkyl represented by R N2 and R 1~4 is each optionally substituted with halo, C 1~3 alkoxy, or -NR N3 R N4 or each R N3 is independently H or C 1~3 alkyl, each R N4 is independently H or C 1~3 alkyl, and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiments.

[0030] In the fourteenth embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, Ring D is cyclobutane, cyclopropane, bicyclo[1.1.1]pentane, spiro[2.2]pentane, azetidine, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, or thietane, each of which is optionally substituted with one or two substituents independently selected from halo, C 1~2 alkyl, and C 1~2 alkoxy, and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiments.

[0031] In the 15th embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, ring D is [Chemical formula] wherein each of these is optionally substituted with one or two substituents independently selected from F, -CH3, and -OCH3, and the remaining variable moieties are as described in the first aspect or the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, or 14th embodiment.

[0032] In the 16th embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R O1 represents a 4- to 6-membered monocyclic heterocyclyl, or the C O1 alkyl substituent represented by R 1~4 is oxetane, azetidine, or tetrahydrofuran, each of which is optionally substituted with one or two substituents independently selected from C 1~3 alkyl, halo, CN, OH, or C 1~3 alkoxy, and the 5- to 6-membered heteroaryl represented by R O1 is pyrazole, triazole, pyridine, pyrazine, pyrimidine, or pyridazine, each of which is optionally substituted with one or two substituents independently selected from C 1~3 alkyl, halo, CN, OH, or C 1~3 alkoxy, and the remaining variable moieties are as described in the first aspect or the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, or 13th embodiment. Alternatively, as part of the 16th embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R O1a 4- to 8-membered monocyclic or bicyclic heterocyclyl represented by, or R O1 a C represented by 1~4 The alkyl substituent is oxetane, azetidine, pyrrolidine, 2-oxaspiro[3.3]heptanyl, or tetrahydrofuran, each of which is a C 1~3 alkyl, halo, CN, OH, C 1~3 alkyl-C 1~3 alkoxy, or C 1~3 alkoxy and is optionally substituted with 1 to 2 substituents independently selected therefrom, and R O1 The 5- to 6-membered heteroaryl represented by is pyrazole, triazole, pyridine, pyrazine, pyrimidine, or pyridazine, each of which is a C 1~3 alkyl, halo, CN, OH, or C 1~3 alkoxy and is optionally substituted with 1 to 2 substituents independently selected therefrom, and the remaining variable moieties are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0033] In the seventeenth embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, the 4- to 6-membered monocyclic heterocyclyl is

Chemical formula

Chemical formula

[0034] Alternatively, as part of the seventeenth embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, the 4- to 6-membered monocyclic heterocyclyl is

Chemical formula

Chemical formula

[0035] In the eighteenth embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharmaceutically acceptable salt thereof, each R cis independently selected from F, -CH3, -CHF2, -CF3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CF2CH3, -CF2CFH2, -CFHCFH2, -CH(CH3)2, -CF(CH3)2, -C(CH3)3, -CH2OH, -CH2OCH3, -CH2CH2CH2OCH3, -CH(CH3)OCH3, -C(CH3)2OCH3, -CH2OCH2CH3, -CH2-cyclopropyl, -CH(CH3)-SO2CH3, OH, -OCH3, -OCH2CH2OCH3, -OCH2CH2CH2OCH3, -OCH2CH2N(CH3)2, -OCH(CH3)CH2OCH3, -OCH(CH3)CN, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)H, -C(O)CH3, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH3)CH(CH3)2, -NHCH2CH2CH2F, -NHCH2CHF2, -NHCH2C(F)CH3, -NHCH2CH2OCH3, -NHCH2CH(CH3)N(CH3)2, -NHCH2C(CH3)2OCH3, -NHCH2CH2C(F)CH3, -NHCH2CH(CH3)OCH3, -NHCH(CH3)CH(CH3)OCH3, -N(CH3)CH2CH2OCH3, -NHC(O)CH3, -SCH3, -SO2CH3,

Chem.

[0036] In the nineteenth embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R C Each C represented by 3~6 cycloalkyl is selected from cyclobutane, cyclopentane, and cyclopropane, R C Each 4- to 9-membered monocyclic or bicyclic heterocyclyl represented by is independently selected from azetidine, morpholine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, oxaazaspiro[3.5]nonane, oxabicyclo[2.2.1]heptane, oxetane, piperidine, piperazine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene dioxide, and tetrahydropyran, R C Each of the 5- to 6-membered heteroaryl represented by is independently selected from oxazole, pyrazole, pyridine, pyrimidine, and thiazole, wherein each of C 3~6 cycloalkyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 R C1 and the remaining variable parts are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0037] Alternatively, as part of the nineteenth embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R C Each C represented by 3~6The cycloalkyl is selected from cyclobutane, cyclopentane, and cyclopropane, R C each 4- to 9-membered monocyclic or bicyclic heterocyclyl represented by is independently selected from azetidine, morpholine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, oxaazaspiro[3.5]nonane, oxabicyclo[2.1.1]hexane, oxabicyclo[2.2.1]heptane, oxetane, piperidine, piperazine, pyrrolidine, dihydrofuran, tetrahydrofuran, tetrahydrothiophene dioxide, and tetrahydropyran, R C each of the 5- to 6-membered heteroaryl represented by is independently selected from oxazole, pyrazole, pyridine, pyrimidine, triazole, and thiazole, wherein each of C 3~6 the cycloalkyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 R C1 and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0038] In the twentieth embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each of C C represented by R 3~6 the cycloalkyl is

Chemical formula

Chemical formula

[0039] Alternatively, as part of the twentieth embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or pharmaceutically acceptable salts thereof, R C Each of the C 3~6 cycloalkyls represented by is [Chemistry] selected independently from, R C Each of the 4- to 9-membered monocyclic heterocyclyls represented by is independently [Chemistry] selected independently from, R C Each of the phenyls represented by is [Chemistry] and R C Each of the 5- to 6-membered heteroaryls represented by is independently [Chemistry] selected independently from, wherein [Chemical formula] - represents a bond to ring C, n is 0, 1, 2, or 3 as allowed by valence, and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0040] In the twenty-first embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R C each of the C 3~6 represented by cycloalkyl is [Chemical formula] R C each of the 4- to 6-membered monocyclic heterocyclyl represented by is [Chemical formula] selected independently from R C each of the phenyls represented by is [Chemical formula] selected independently from R C each of the 5- to 6-membered heteroaryls represented by is independently [Chemical formula] selected independently from, wherein [Chemical formula] - represents the fused ring C, and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0041] Alternatively, as part of the 21st embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or pharmaceutically acceptable salts thereof, R C Each of the C 3~6 represented by cycloalkyl is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0042] In the 22nd embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or pharmaceutically acceptable salts thereof, each R C1 is halo, OH, -NR N3 R N4 , -CN, -C(O)-R 7, -SO2-R 7 , C 1~3 alkoxy, C 1~3 haloalkoxy, C 3~6 cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, and C 1~4 independently selected from alkyl, wherein C 1~4 the C represented by 1~4 alkyl is optionally substituted by 1 to 3 substituents independently selected from C 3~5 cycloalkyl, C 1~3 alkoxy, OH, and halo, and R C1 the C represented by 1~3 alkoxy is optionally substituted by 1 to 3 substituents independently selected from C 1~3 alkoxy and halo, and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment. Alternatively, as part of the twenty-second embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each R C1 is halo, OH, -NR N3 R N4 , -CN, -C(O)-R 7 , -SO2-R 7 , C 1~3 alkoxy, C 1~3 haloalkoxy, C 3~6 cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, and C 1~4 independently selected from alkyl, wherein R C1 the C represented by 1~4 alkyl is optionally substituted by 1 to 3 substituents independently selected from C 3~5 cycloalkyl, 4- to 8-membered monocyclic heterocyclyl, C 1~3 alkoxy, OH, CN, -NR N3 R N4 , and halo, and R C1 the C represented by 1-3 alkoxy is C 1~3Optionally substituted with 1 to 3 substituents independently selected from alkoxy and halo, and the remaining variable moieties are as described in the first embodiment or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment.

[0043] In the twenty-third embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or pharmaceutically acceptable salts thereof, each R C1 is independently selected from F, -CN, -C(O)CH3, -C(O)-cyclopropyl, -SO2-CH3, -SO2-CH2CH3, OH, -OCH3, -OCH2CH2OCH3, -OCHF2, -N(CH3)2, -CH3, -CH2CH3, -CH(CH3) 2、 -CH2CH2OH, -CH2CH2OCH3, -CH2-cyclopropyl, -CH2F, -CHF2, -CF3, cyclobutyl, cyclopropyl, [Chemical formula] is independently selected from, and the remaining variable moieties are as described in the first embodiment or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment. Alternatively, as part of the twenty-third embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or pharmaceutically acceptable salts thereof, each R C1is selected independently from F, -CN, -C(O)CH3, -C(O)-cyclopropyl, -SO2-CH3, -SO2-CH2CH3, OH, -OCH3, -OCH2CH2OCH3, -OCHF2, -N(CH3)2, -CH2CH2N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2OH, -CH2CH2OCH3, -CH2OCH3, -CH2-cyclopropyl, -CH2F, -CHF2, -CF3, -CH2CF3, -CF(CH3)2, -C(OH)(CH3)2, -CH2CN, -CHFCH3, -CF2CH2OCH3, cyclobutyl, cyclopropyl,

Chemical formula

[0044] In the twenty-fourth embodiment, for a compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R 1 is halo, -CN, C 1~3 alkoxy, C 1~3 alkyl, and C 1~3 1 to 3 Rs independently selected from haloalkyl 8 optionally substituted by 1~4 alkyl, and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment. Alternatively, as part of the twenty-fourth embodiment, for a compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R 1 is halo, -CN, -NR 2 R 4, C 1~3 alkoxy, C 1~3 alkyl, and C 1~3 one to three Rs independently selected from haloalkyl 8 optionally substituted C 1~4 alkyl, where R 2 and R 4 are each independently H or C 1~3 alkyl, and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty - first, twenty - second, or twenty - third embodiment.

[0045] In the twenty - fifth embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R 1 is - CH3, - CH2CH3, or - CH2CH2OCH3, and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty - first, twenty - second, or twenty - third embodiment. Alternatively, as part of the twenty - fifth embodiment, for the compounds of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R 1 is - CH3, - CH2CH3, - NH2, - NHCH3, - N(CH3)2, - OCH3, or - CH2CH2OCH3, and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty - first, twenty - second, or twenty - third embodiment.

[0046] In the 26th embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each R O1 is independently H, C 1~3 alkyl, or C 3~6 cycloalkyl, wherein the C O1 alkyl and C 1~3 cycloalkyl represented by R 3~6 are optionally substituted by C 1~3 alkoxy, and the remaining variable moieties are as described in the first embodiment or the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, or 25th embodiment.

[0047] In the 27th embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, each R O1 is independently H, -CH3, -CH2-CH2-OCH3,

Chemical formula

[0048] In the 28th embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R N1 and R N2 are each independently H, or C 1~3 alkyl optionally substituted by C 1~3represents alkyl, and the remaining variable moieties are as described in the first embodiment or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty - first, twenty - second, twenty - third, twenty - fourth, twenty - fifth, twenty - sixth, or twenty - seventh embodiment.

[0049] In the twenty - ninth embodiment, for the compound of formula (I), (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, R N1 and R N2 each independently represents H, -CH3, or -CH2-CH2-OCH3, and the remaining variable moieties are as described in the first embodiment or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty - first, twenty - second, twenty - third, twenty - fourth, twenty - fifth, twenty - sixth, twenty - seventh, or twenty - eighth embodiment.

[0050] In the thirtieth embodiment, the compounds of the present disclosure are of formula (X) or (XI):

Chemical formula

[0051] In a 31st embodiment, a compound of the present disclosure has the formula (XA), (XIA), (XIB), (XIC), or (XID):

Chemical formula

[0052] In a 32nd embodiment, for a compound of formula (X), (XI), (XA), (XIA), (XIB), (XIC), or (XID), or a pharmaceutically acceptable salt thereof, each R C is independently -NHCH3, -NHCH2CH2OCH3, -CH3, -CH2CH3, -CH(CH3)2, -CF2CH3, -CF(CH3)2,

Chemical formula

[0053] In a 33rd embodiment, for a compound of formula (X), (XI), (XA), (XIA), (XIB), (XIC), or (XID), or a pharmaceutically acceptable salt thereof, R Cis a 4- to 6-membered monocyclic heterocyclyl independently selected from tetrahydrofuran and tetrahydropyran, each of which is optionally substituted with 1 to 3 R C1 and the remaining variable moieties are as described in Embodiment 30 or 31.

[0054] In Embodiment 34, for a compound of formula (X), (XI), (XA), (XIA), (XIB), (XIC), or (XID), or a pharmaceutically acceptable salt thereof, R C is

Chemical formula

Chemical formula

[0055] In Embodiment 35, for a compound of formula (X), (XI), (XA), (XIA), (XIB), (XIC), or (XID), or a pharmaceutically acceptable salt thereof, R C is

Chemical formula

Chemical formula

[0056] In Embodiment 36, for a compound of formula (X), (XI), (XA), (XIA), (XIB), (XIC), or (XID), or a pharmaceutically acceptable salt thereof, each R C1 is F, and the remaining variable moieties are as described in Embodiment 30, 31, 32, 33, or 34.

[0057] In another embodiment, the compounds of the present disclosure have the formula (XII):

Chemical formula

[0058] In a 37th embodiment, the present disclosure provides a compound described herein (e.g., any one of the compounds of Examples 1 to 411), or a pharmaceutically acceptable salt thereof.

[0059] In a 38th embodiment, the present disclosure provides N-(1'-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(4-(1,1-difluoroethyl)-6-methoxypyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(oxetan-3-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(1,1-difluoroethyl)-6-(2-methoxyethoxy)-3,6-dihydropyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(1,1-difluoroethyl)-6-(3-methoxycyclobutoxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-(1,1-difluoroethyl)-5-fluoropyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-(1,1-difluoroethyl)-5-methoxypyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-(1,1-difluoroethyl)-4-methoxypyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(1,1-difluoroethyl)-6-(methylamino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1’-(6-(1,1-difluoroethyl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-acetamido-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(tetrahydrofuran-3-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-hydroxytetrahydrofuran-3-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(dimethylamino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(oxetan-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(3-methoxycyclobutyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Cyclobutyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(tetrahydrofuran-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(tetrahydrofuran-2-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2,5-Dimethylpyrazolo[1,5-a]pyrimidin-7-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1'-(6-Methyl-2-(methylthio)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1-(2-(1,1-Difluoroethyl)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide, N-(1-(4-(1,1-Difluoroethyl)pyrimidin-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide, N-(1-(6-(1,1-Difluoroethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide, N-(1-(6-(Tetrahydrofuran-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide, N-(1-(2-(1,1-Difluoroethyl)-6-methoxypyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide, N-(1-(2-(1,1-Difluoroethyl)-6-(methylamino)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide, N-(1'-(4-(1,1-Difluoroethyl)pyrimidin-2-yl)-2-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(1,1-Difluoroethyl)pyrimidin-4-yl)-2-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1-(2-(1,1-Difluoroethyl)pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide, N-(1-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide, N-(1’-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1’,2’-dihydrospiro[cyclobutane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclobutane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1,1-difluoroethyl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclobutane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1’,2’-dihydrospiro[cyclopentane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopentane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1,1-difluoroethyl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopentane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1’,2,2’,3,5,6-hexahydrospiro[pyran-4,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2,2’,3,5,6-hexahydrospiro[pyran-4,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1,1-difluoroethyl)pyridin-2-yl)-1’,2,2’,3,5,6-hexahydrospiro[ pyran-4,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-((2-methoxyethyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[ cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-((2-methoxyethyl)(methyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[ cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(azetidin-1-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[ cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-morpholinopyrimidin-4-yl)-1’,2’-dihydrospiro[ cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)-1’,2’-dihydrospiro[ cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-cyclopropyl-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[ cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(tert-butyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[ cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-methoxy-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[ cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1'-(2-(Methoxymethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-Butyl-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(Ethoxymethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-Cyclobutyl-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-Methyl-2-(trifluoromethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-Cyclopropylmethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-Difluoromethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-Ethyl-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-Methyl-2-propylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-Isopropyl-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(5-Fluoro-2,6-dimethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2,6-Dimethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-Methyl-2-(1-methylcyclopropyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-Methyl-2-(tetrahydro-2H-pyran-3-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(3-Methoxypropyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, trans-rac-N-(1'-(6-(2-Cyanocyclopropyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, cis-rac-N-(1'-(6-(2-Cyanocyclopropyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-(3-Cyanocyclobutyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1’-(6-((1s,3s)-3-Cyanocyclobutyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-((1r,3r)-3-Cyanocyclobutyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1-(6-(1,1-Difluoroethyl)pyridin-2-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide, N-(1’-(Thiazol-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(5-Methylthiazol-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-(1,1-Difluoroethyl)thiazol-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4,5-Dimethylthiazol-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-(Tetrahydro-2H-pyran-3-yl)thiazol-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(5-Methyl-4-(tetrahydrofuran-3-yl)thiazol-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(oxetan-3-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-fluorooxetan-3-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1,1-difluoroethyl)-4-(2-methoxyethoxy)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-methoxyoxetan-3-yl)pyridin-2-yl)-1’,2’,5’,7a’-tetrahydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)propionamide, N-(1’-(6-(1,1-difluoroethyl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)propionamide, N-(1’-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)-3-methoxypropanamide, N-(1’-(6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridin-2-yl)-1’,2’,4’,7’-tetrahydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(methylsulfonyl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-hydroxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-methyl-2-(1-(methylsulfonyl)ethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-dioxidotetrahydrothiophen-3-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-(2-methoxyethoxy)pyrimidin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-methyl-2-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1'-(6-(1,1-difluoroethyl)pyrazin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(7-oxabicyclo[2.2.1]heptan-2-yl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-methyl-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(1-methoxycyclobutyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-methyl-2-phenylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-methyl-2-(pyridin-3-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-methyl-2-(pyridin-4-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-methyl-[2,2'-bipyrimidin]-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-methyl-2-(2-methyloxazol-4-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1’-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Fluorophenyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(pyridin-2-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(piperidin-1-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-Isopropyl(methyl)amino)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(Dimethylamino)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(1-methylpiperidin-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(1-methylpiperidin-2-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(1-(methylsulfonyl)piperidin-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1-Acetylpiperidin-4-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1-Isopropylpiperidin-4-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(2-methylcyclopropyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(2,2-Dimethylcyclopropyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3,3-Difluorocyclopentyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(Hydroxymethyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-5-fluoro-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-5-fluoropyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(2-Methoxypropan-2-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1-Methoxyethyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1-Methoxyethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(2-Methoxypropan-2-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-hydroxypyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-oxo-1,2-dihydropyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(methylsulfonyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Methoxypyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-Cyclobutoxy-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((3-methyloxetan-3-yl)methoxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(2-(dimethylamino)ethoxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(oxetan-3-yloxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((1-methyl-1H-pyrazol-3-yl)oxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-Cyanocyclopropoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((1-methyl-1H-pyrazol-4-yl)oxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(pyrazin-2-yloxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(pyridazin-4-yloxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((1-ethylazetidin-3-yl)oxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((1-methyl-1H-1,2,3-triazol-5-yl)oxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-Cyanoethoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(Cyano(cyclopropyl)methoxy)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(isopropylamino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-((Cyclopropylmethyl)amino)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(propylamino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Cyclobutylamino)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((2-methoxy-2-methylpropyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(Bicyclo[1.1.1]pentan-1-ylamino)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(((1-fluorocyclopropyl)methyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(((1-methoxycyclopropyl)methyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((oxetan-2-ylmethyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((oxetan-2-ylmethyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((3-fluoropropyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((3-methoxybutan-2-yl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(thietan-3-ylamino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(ethylamino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(((1s,3s)-3-fluorocyclobutyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-((2-fluoropropyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-((3-fluorobutyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-((2-methoxypropyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(((1s,3s)-3-methoxycyclobutyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-((2-methoxy-2-methylcyclopropyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1'-(2-(1,1-difluoroethyl)-6-(((1-methylazetidin-2-yl)methyl)amino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(1,1-difluoroethyl)-6-((1-(oxetan-3-yl)ethyl)amino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(1,1-difluoroethyl)-6-(spiro[2.2]pentan-1-ylamino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(1,1-difluoroethyl)-6-((2-methoxycyclopropyl)amino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(1,1-difluoroethyl)-6-((1-methoxypropan-2-yl)amino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(1,1-difluoroethyl)-6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(1,1-difluoroethyl)-6-((2-(dimethylamino)propyl)amino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-((tetrahydrothiophen-3-yl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-((2-methylcyclopropyl)amino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-(difluoromethyl)-4-methylpiperazin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3,3-difluoropyrrolidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-(2-methoxyethoxy)pyrrolidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3,4-dihydroxypyrrolidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-methoxypiperidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-Hydroxypyrrolidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(Dimethylamino)-4-methylpyrimidin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-((2-Methoxyethyl)amino)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-(Dimethylamino)pyrrolidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-Hydroxyazetidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-Cyanoazetidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-Fluoroazetidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-Cyano-3-(fluoromethyl)azetidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-Cyano-3-ethylazetidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-(Difluoromethoxy)azetidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-Cyano-3-(2-methoxyethyl)azetidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-Cyano-3-methylazetidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-(Difluoromethyl)azetidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-Cyano-3-(difluoromethyl)azetidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Methyl-6-(3-(methylsulfonyl)azetidin-1-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-(Ethylsulfonyl)azetidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-Hydroxy-3-methylazetidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Methyl-6-morpholinopyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Methyl-6-(4-methylpiperazin-1-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Methyl-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-((3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Methyl-6-(piperazin-1-yl)pyrimidin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-(2-Hydroxyethyl)piperazin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-morpholinopyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Hydroxypyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-(Dimethylamino)pyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Cyanoazetidin-1-yl)-6-methylpyridin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Fluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Cyano-3-(fluoromethyl)azetidin-1-yl)-6-methylpyridin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Cyano-3-ethylazetidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Cyano-3-(2-methoxyethyl)azetidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Cyano-3-methylazetidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-(Difluoromethyl)azetidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Cyano-3-(difluoromethyl)azetidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(3-(methylsulfonyl)azetidin-1-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-(Ethylsulfonyl)azetidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Hydroxy-3-methylazetidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3,3-difluoropyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-methoxypiperidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(4-(cyclopropanecarbonyl)-4-methoxypiperidin-1-yl)-6-methylpyridin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(4-hydroxypiperidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(4-(2-methoxyethyl)piperazin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-methyl-2-(2-methylazetidin-1-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-hydroxy-3-methylpyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Hydroxyazetidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(6-methylpyridin-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(6-methoxypyridin-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1-Cyclobutyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1-Ethyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(5-(Difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1-Isopropyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(1H-pyrazol-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1-cyclopropylmethyl)-1H-pyrazol-4-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(6-methoxypiperidin-3-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-methyl-2-(2-methylthiazol-5-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-methyl-6-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-methyl-6-(1-methylsulfonyl-1H-pyrazol-4-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-ethyl-1H-pyrazol-4-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Methyl-6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(5-(Difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-Isopropyl-1H-pyrazol-4-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-Cyclopropyl-1H-pyrazol-4-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Methyl-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6’-Methoxy-4-methyl-[2,3’-bipyridin]-6-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-Azetidin-3-yl)-1H-pyrazol-4-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-(1,1-Difluoroethyl)pyrimidin-2-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1,1-Difluoroethyl)pyridin-2-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Amino-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-(1,1-Difluoroethyl)pyrimidin-2-yl)-1-methyl-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)pyrimidin-4-yl)-1-methyl-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1,1-Difluoroethyl)pyridin-2-yl)-1-methyl-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Methyl-6-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, 3-(1’-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)-1,1-dimethylurea, N-(1’-(6-(1-fluorocyclopropyl)-4-methylpyrimidin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, Ethyl 2-(4-(6’-acetamidospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-6-methylpyrimidin-2-yl)-2,2-difluoroacetate, N-(1’-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-chloro-2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(cyclopropylamino)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(oxetan-3-ylamino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(2-Hydroxy-2-methylpropoxy)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1,1-Difluoroethyl)-2-(2-methoxyethoxy)pyridin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(2-Fluoroethoxy)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoro-2-hydroxyethyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1,1-Difluoro-2-hydroxyethyl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, Ethyl 6-(6’-acetamidospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-2-(1,1-difluoroethyl)pyrimidine-4-carboxylate, N-(1’-(2-(1,1-Difluoroethyl)-6-(hydroxymethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(1-hydroxyethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, 6-(6’-Acetamidospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-2-(1,1-difluoroethyl)pyrimidine-4-carboxylic acid, N-(1’-(2-(1,1-Difluoroethyl)-6-(3-hydroxypropyl)pyrimidine-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(4,5-dihydrofuran-3-yl)pyrimidine-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (S)-N-(1’-(2-(1,1-Difluoroethyl)-6-(tetrahydrofuran-3-yl)pyrimidine-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-((methylamino)methyl)pyrimidine-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(Azetidin-1-ylmethyl)-2-(1,1-difluoroethyl)pyrimidine-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(1-methyl-1H-1,2,4-triazol-3-yl)pyrimidine-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(1-ethyl-5-fluoro-1H-pyrazol-4-yl)pyrimidine-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-cyanoethyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(cyanomethyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoropropyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-fluoropyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-methyl-6-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, 1-(1’-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)-3-methylurea, 1-(1’-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)urea, 1-(1’-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)urea, N-(1’-(2-(1,1-difluoroethyl)-6-(5-fluoro-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, Methyl (1’-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)carbamate, N-(1’-(2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-methoxypyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-ethyl-2-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1,1-difluoro-2-methoxyethyl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-methyl-6-(1,1,2-trifluoroethyl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-methoxycyclobutyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Methyl-2-(2-(methylsulfonyl)ethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (R)-N-(1’-(6-Ethyl-2-(tetrahydrofuran-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-ethylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoro-2-methoxyethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (S)-N-(1’-(2-(1,1-Difluoroethyl)-6-(3-hydroxy-3-methylpentyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(3-(tert-Butoxy)propyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(3-methoxypropyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(3-hydroxy-3-methylbutyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-pentylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (Z)-N-(1’-(2-(1,1-Difluoroethyl)-6-(2-ethoxyvinyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(2-ethoxyethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Fluoro-6-methylpyrimidin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-Fluoro-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Methyl-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-Isopropoxy-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1'-(6-Ethoxy-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-(2-Methoxy-2-methylpropoxy)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-(((1R,3S)-3-Hydroxycyclopentyl)oxy)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-(((1R,3S)-3-Methoxycyclopentyl)oxy)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, (R)-N-(1'-(4-Methyl-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-Cyclobutoxy-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(4-Methyl-6-(oxetan-3-yloxy)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-((1s,3s)-3-Hydroxycyclobutoxy)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1’-(6-((1s,3s)-3-Methoxycyclobutoxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-((1s,3s)-3-Cyanocyclobutoxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-((1s,3s)-3-(Methoxymethyl)cyclobutoxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-((1r,3r)-3-Fluorocyclobutoxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Methyl-6-((1s,3s)-3-methylcyclobutoxy)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-((1s,3s)-3-Fluorocyclobutoxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(4-Methyl-6-(((1s,4s)-4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(((1s,3s)-3-Methoxycyclobutyl)methoxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-((1-Methoxycyclobutyl)methoxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(Cyclopropylmethoxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(((1R,3S)-3-Fluorocyclopentyl)oxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(Cyclopentyloxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(2-Fluoroethoxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(2,2-Difluoropropoxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(2-Methoxyethoxy)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (R)-N-(1’-(4-Methyl-6-(oxetan-2-ylmethoxy)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (R)-N-(1’-(2-(1,1-difluoroethyl)-6-((1-methylpyrrolidin-3-yl)oxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(2-methoxyethoxy)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-isopropoxy-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3,3-difluorocyclobutoxy)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-methyl-2-((3-methyloxetan-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-methyl-2-(oxetan-3-ylmethoxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1'-(6-Methyl-2-((1s,3s)-3-methylcyclobutoxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-((1s,3s)-3-cyano-3-fluorocyclobutoxy)-6-methylpyridin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(cyclopropylmethoxy)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-((1s,3s)-3-fluorocyclobutoxy)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(6-Methyl-2-(((1s,4s)-4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(((1s,3s)-3-methoxycyclobutyl)methoxy)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1'-(2-(2-methoxy-2-methylpropoxy)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, (R)-N-(1'-(6-Methyl-2-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, N-(1’-(2-((1s,3s)-3-Cyanocyclobutoxy)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-((1s,3s)-3-(Methoxymethyl)cyclobutoxy)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-((1r,3r)-3-Fluorocyclobutoxy)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-((1-Methoxycyclobutyl)methoxy)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(Cyclopentyloxy)-6-methylpyridin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (R)-N-(1’-(6-Methyl-2-(oxetan-2-ylmethoxy)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(3-fluoropyridin-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-Cyclobutyl-1H-pyrazol-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-Difluoroethyl)-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(1-(cyanomethyl)-1H-pyrazol-4-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(1-fluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-methyl-2-(oxetan-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(methoxymethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(2-fluoropropan-2-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoroethyl)-6-(1H-pyrazol-4-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(1,1-difluoro-2-methoxyethyl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (S)-N-(1’-(6-(3-cyanopyrrolidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (R)-N-(1’-(6-(3-cyanopyrrolidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (S)-N-(1’-(6-(3-cyano-3-methylpyrrolidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (S)-N-(1’-(6-(3-Hydroxy-3-methylpyrrolidin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)-4-methylpyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (R)-N-(1’-(2-(3-Cyanopyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (S)-N-(1’-(2-(3-Cyanopyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, (R)-N-(1’-(2-(3-Cyano-3-methylpyrrolidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, N-(1’-(2-(3-Isobutylazetidin-1-yl)-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, and N-(1’-(6-Methyl-2-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide, A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, is provided.

[0060] In the 39th embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g., according to any one of the preceding embodiments), or a pharmaceutically acceptable salt thereof.

[0061] The compounds and intermediates described herein can be used as the isolated compounds themselves. Alternatively, when there are sites capable of forming salts, the compounds or intermediates may be isolated and used as their corresponding salts. As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds described herein. "Salts" include, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds described herein and that are generally not undesirable biologically or otherwise. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts due to the presence of amino groups and / or carboxyl groups or groups similar thereto.

[0062] Pharmaceutically acceptable acid addition salts can be formed using inorganic or organic acids such as, for example, acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.

[0063] Examples of inorganic acids that can induce salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0064] Examples of organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0065] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0066] Examples of inorganic bases from which salts can be derived include, for example, ammonium salts and metals in columns I through XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, and particularly preferred salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0067] Examples of organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines containing naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Specific organic amines include isopropylamine, benzathine, cholineate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0068] Salts can be synthesized from compounds containing basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by reacting these compounds in their free acid form with a stoichiometric amount of a suitable base (e.g., hydroxides, carbonates, bicarbonates of Na, Ca, Mg, or K), or by reacting these compounds in their free base form with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water, an organic solvent, or a mixture of the two. In general, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable when feasible. A list of additional suitable salts can be found, for example, in “Remington’s Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa. (1985), and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0069] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the accompanying examples and preparations using appropriate isotopically labeled reagents in place of the previously used unlabeled reagents. In one embodiment, the present disclosure provides deuterated compounds or pharmaceutically acceptable salts thereof described herein.

[0070] Pharmaceutically acceptable solvates according to the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O, d6-acetone, and d6-DMSO.

[0071] Since the compounds of the present disclosure may contain chiral centers, those skilled in the art will recognize that they may exist in different stereoisomeric forms. As used herein, the terms "optical isomers" or "stereoisomers" refer to any of the various stereoisomeric configurations that may exist for a given compound of the present disclosure. It is understood that substituents may be attached at chiral centers of carbon atoms. Accordingly, the present disclosure encompasses enantiomers, diastereomers, or racemates of the compounds.

[0072] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The terms "racemic" or "rac" are used to designate a racemic mixture where appropriate. When specifying the stereochemistry of a compound of the present invention, a single stereoisomer whose relative and absolute configuration of two chiral centers is known is designated using the conventional RS system (e.g., (1S,2S)). "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. An optically resolved compound of unknown absolute configuration can be designated as (+) or (-) depending on the direction (right-handed or left-handed) in which it rotates plane-polarized light at the wavelength of the sodium D line. Alternatively, an optically resolved compound can be defined by the respective retention times of the corresponding enantiomers / diastereomers by chiral HPLC.

[0073] Some of the compounds described herein contain one or more asymmetric centers or axes and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- from the perspective of absolute stereochemistry.

[0074] Unless otherwise specified, the compounds of the present disclosure are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and mixtures of intermediates. The optically active (R) and (S) stereoisomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns such as CHIRALPAK® and CHIRALCEL® available from DAICEL Corp. using a solvent or solvent mixture suitable to achieve good separation). When the compound contains a double bond, the substituents may be in the E or Z configuration. When the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents may have the cis or trans configuration. All tautomeric forms are also intended to be included.

[0075] Method of Use The compounds disclosed herein have TYK2 activity. As used herein, "TYK2 inhibitory activity" refers to the ability of a compound or composition to induce a detectable decrease in TYK2 activity, in vivo or in vitro (e.g., at least a 10% decrease in TYK2 activity as measured by a given assay such as the bioassays described in the Examples and known in the art).

[0076] In certain embodiments, the present disclosure provides a method for treating a subject in need of a method for treating a disease or disorder responsive to inhibition of TYK2 activity (referred to herein as a "TYK2-mediated disease or disorder" or a "disease or disorder mediated by TYK2"). The method comprises administering to the subject a compound described herein (e.g., a compound of formula (I) described in any one of embodiments 1-38), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0077] In certain embodiments, the present disclosure provides for the use of a compound described herein (e.g., a compound of formula (I) described in any one of Embodiments 1 to 38), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a TYK2-mediated disorder or disease in a subject in need thereof.

[0078] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound of formula (I) described in any one of Embodiments 1 to 38), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for use in the treatment of a TYK2-mediated disorder or disease in a subject in need thereof.

[0079] In some embodiments, the disease or disorder responsive to inhibition of TYK2 activity is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, cutaneous 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, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, autoimmune disease, osteoporosis, multiple sclerosis, endometriosis, dysmenorrhea, vaginitis, candidiasis, cancer, fibrosis, systemic sclerosis, 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.

[0080] In certain embodiments, the foregoing methods relate to a subject that is a mammal. In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human.

[0081] As used herein, the terms "effective amount" and "therapeutically effective amount" can be used interchangeably. It means an amount effective to treat or reduce the severity of one or more of the diseases, disorders, or conditions described herein. In some embodiments, the effective dose can be between 10 μg and 500 mg.

[0082] The compounds and compositions according to the methods of the present disclosure may be administered using any amount and any route of administration effective to treat or reduce the severity of one or more of the diseases, disorders or conditions listed above.

[0083] In certain embodiments, the present disclosure relates to the aforementioned methods of administering the compound parenterally. In certain embodiments, the present disclosure relates to the aforementioned methods of administering the compound intramuscularly, intravenously, subcutaneously, orally, by inhalation, rectally, intrathecally, topically, or intranasally. In certain embodiments, the present disclosure relates to the aforementioned methods of administering the compound systemically.

[0084] The compounds of the present disclosure can be used as pharmaceutical compositions (e.g., a compound of the present invention and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically acceptable carrier" includes solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial 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 combinations thereof that are generally recognized as safe (GRAS) to those skilled in the art (see, e.g., Remington’s Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Its use in therapeutic or pharmaceutical compositions is contemplated, except where conventional carriers are incompatible with the active ingredient. For the purposes of the present disclosure, solvates and hydrates are considered to be pharmaceutical compositions comprising a compound of the present invention and a solvent (i.e., solvate) or water (i.e., hydrate).

[0085] Formulations may be prepared using conventional dissolution and mixing procedures. For example, a bulk drug substance (i.e., a compound of the present invention, or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compounds of the present invention are typically formulated into pharmaceutical dosage forms so as to provide a readily controllable drug dosage and to provide a product that is elegant and easily handled for administration to a patient.

[0086] The pharmaceutical composition (or formulation) for use may be packaged in various means depending on the method used to administer the drug. Generally, articles for distribution include a container in which a pharmaceutical formulation in a suitable form is disposed. Suitable containers are known to those skilled in the art and include, for example, substances such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include an anti-tampering mechanism to prevent inadvertent access to the contents of the package. In addition, the container has a label thereon that describes the contents of the container. The label may also include appropriate cautions.

[0087] Pharmaceutical compositions containing the compounds of the present disclosure are generally formulated for parenteral administration, oral administration, or use as suppositories.

[0088] For example, the oral pharmaceutical compositions of the present disclosure may be in solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in liquid form (including, without limitation, solutions, suspensions or emulsions). The pharmaceutical composition can be subjected to conventional formulation processes such as, for example, sterilization, and / or can contain conventional inert diluents, lubricants, or buffering agents, as well as preservatives, stabilizers, wetting agents, emulsifying agents and buffering agents, etc.

[0089] Typically, the pharmaceutical composition contains the active ingredient a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; also in the case of tablets c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; optionally d) disintegrants such as starch, agar, alginic acid or its sodium salt, or a foaming mixture; and / or e) Tablets or gelatin capsules containing the absorbent, coloring agent, flavoring agent and sweetening agent together.

[0090] The tablets may be film-coated or enteric-coated according to methods known in the art.

[0091] Compositions suitable for oral administration include tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or the compounds of the present disclosure in the form of syrups or elixirs. Compositions intended for oral use are prepared by 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 sweetening agents, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients are, 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; binding agents such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, time-delay substances such as glyceryl monostearate or glyceryl distearate may be used. Preparations 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 arachis oil, liquid paraffin, or olive oil.

[0092] Parenteral compositions (e.g., intravenous (IV) formulations) are aqueous isotonic solutions or suspensions. The parenteral compositions can be sterilized and / or can contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solubilizing agents, salts for adjusting osmotic pressure, and / or buffers. Additionally, they can also contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating, or coating methods respectively and contain the active ingredient in an amount of about 0.1 - 7.5% or about 1 - 50%.

[0093] The compounds or pharmaceutical compositions of the present disclosure for use in a subject (e.g., a human) are usually administered orally or parenterally at a therapeutic dose. When administered intravenously by infusion, the dosage may depend on the infusion rate at which the IV formulation is administered. Generally, the therapeutically effective dosage of the compound, pharmaceutical composition, or a combination thereof depends on the species, body weight, age, and individual condition of the subject, the disorder or disease being treated, or the severity thereof. A physician, pharmacist, clinician, or veterinarian, who is skilled in the art, can readily determine the respective effective amount of the active ingredient necessary to prevent, treat, or suppress the progression of the disorder or disease.

[0094] The above administration characteristics can advantageously be demonstrated in in vitro and in vivo tests using mammals such as mice, rats, dogs, monkeys, or isolated organs, tissues, and their preparations. The compounds of the present invention can be applied in vitro in the form of a solution, e.g., an aqueous solution, and in vivo either enterally, parenterally, preferably intravenously, e.g., as a suspension or in an aqueous solution. The dosage in vitro may be in the range between about 10-3 molar concentration and 10-9 molar concentration.

[0095] Definitions As used herein, the terms "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. This term includes mammals such as humans. Usually, the animal is a mammal. The subject also refers to, for example, primates (e.g., male or female humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. Preferably, the subject is a human.

[0096] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0097] As used herein, the terms "treat," "treating," or "treatment" with respect to any disease, condition, or disorder refer to the management and care of a patient for the purpose of combating the disease, condition, or disorder and include the administration of a compound of the invention to obtain the desired pharmaceutical and / or physiological effect. The effect can be therapeutic and includes, for example: partially or completely reducing the degree of the disease, condition, or disorder; improving or ameliorating the clinical symptoms, complications, or indicators associated with the disease, condition, or disorder; delaying, suppressing, or reducing the likelihood of progression of the disease, condition, or disorder; or partially or substantially achieving one or more of eliminating the disease, condition, or disorder. In certain embodiments, the effect can be preventing the onset of symptoms or complications of the disease, condition, or disorder.

[0098] As used herein, the term "cancer" has the meaning commonly accepted in the art. This term can broadly refer to abnormal cell growth.

[0099] As used herein, the term "autoimmune disease" has the meaning commonly accepted in the art. This term can broadly refer to diseases in which the host's immune system targets or attacks the host's normal or healthy tissues.

[0100] As used herein, the term "myelination" has the meaning commonly accepted in the art. This term can broadly mean the process by which myelin is produced.

[0101] As used herein, the terms "myelin-related disease or disorder", "demyelinating disorder", or "demyelinating disease" have the meaning commonly accepted in the art. These terms can broadly refer to diseases or disorders associated with damage to myelin.

[0102] As used herein, a subject "in need of" treatment is a subject (preferably a human) who would benefit biologically, medically, or in terms of quality of life from such treatment.

[0103] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "optionally substituted" refers to 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 the compounds and their examples. Unless otherwise specified, an optionally substituted group may have substituents at each substitutable position of the group, and when two or more positions in any given structure may be substituted with two or more substituents selected from the specified groups, the substituents may be the same or different at all positions. In some embodiments, an optionally substituted group can be substituted with one or more substituents, each of which may be the same or different. In some embodiments, the "one or more" substituents can be 1, 2, 3, 4, 5, 6, etc. substituents, each of which may be the same or different. In some embodiments, the "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.

[0104] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. "C 1~4 alkyl" refers to an alkyl having 1 to 4 carbon atoms. "C 1~3 alkyl" and "C 1~2 alkyl" should be interpreted accordingly. Representative examples of "C 1~4 alkyl" include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. Similarly, the alkyl moiety of an alkoxy (i.e., the alkyl moiety) has the same definition as above. When indicated as "optionally substituted", the alkane radical or alkyl moiety may be unsubstituted or may be substituted with one or more substituents (generally 1 to 3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0105] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety (i.e., --O--C 1~4 alkyl group, where C 1~4 alkyl is as defined herein) attached via an oxygen bridge. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, etc. Preferably, the alkoxy group has about 1 to 4 carbons, more preferably about 1 to 2 carbons. The term "C 1~4 alkoxy" should be construed accordingly. 1~2

[0106] As used herein, the term "C 1~4 alkoxyC 1~4 alkyl" refers to a C 1~4 alkyl group as defined herein, wherein at least one hydrogen atom is replaced by C 1~4 alkoxy. The C 1~4 alkoxyC 1~4 alkyl group is linked via the alkyl group throughout the remainder of the molecule described herein.

[0107] The number of carbon atoms in the group is indicated herein by the prefix "C x~xx ", where x and xx are integers. For example, "C 1~3 alkyl" is an alkyl group having 1 to 3 carbon atoms.

[0108] "Halogen" or "halo" may be fluorine, chlorine, bromine, or iodine.

[0109] As used herein, the term "halo-substituted -C 1~4 alkyl" or "C 1~4 haloalkyl" refers to a C 1~4 alkyl group as defined herein, wherein at least one hydrogen atom is replaced by a halo atom. The C 1~4 haloalkyl group is mono-halo-C​1~4 Alkyl, dihalo-C 1~4 Alkyl, or perhalo-C 1~4 Polyhalo-C containing alkyl 1~4 Can be alkyl. Monohalo-C 1~4 Alkyl can have one iodine, bromo, chloro or fluoro within the alkyl group. Dihalo-C 1~4 Alkyl group and polyhalo-C 1~4 The alkyl group can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Usually, polyhalo-C 1~4 The alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. C 1~4 Non-limiting examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Perhalo-C 1~4 The alkyl group is a C 1~4 alkyl group in which all hydrogen atoms are replaced by halo atoms.

[0110] The term "aryl" refers to an aromatic carbocyclic monocyclic ring or a bicyclic fused ring system containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0111] The term "heteroaryl" refers to an aromatic radical of a 5- to 12-membered ring containing 1 to 4 heteroatoms selected from N, O, and S. Optionally, a nitrogen atom in the heteroaryl may be quaternized. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic compound". The heteroaryl group may be monocyclic or bicyclic. Examples of monocyclic heteroaryl include, for example, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, furanyl, oxadiazolyl, thiophenyl, and the like. Bicyclic heteroaryl includes groups in which one or more monocyclic heteroaryl rings are fused to one or more aryl rings or heteroaryl rings. Non-limiting examples include pyrazolopyridinyl, pyrazolopyridinyl, benzotriazolyl, imidazopyridinyl, and indolyl.

[0112] The term "carbocyclic ring" or "carbocyclyl" refers to a saturated or partially unsaturated hydrocarbon ring of 4 to 12 members and may exist as a monocyclic, bicyclic ring (including fused, spiro, or bridged carbocyclic rings), or a spiro ring. Examples of bicyclic carbocyclyl groups include, for example, an unsaturated carbocyclic radical fused to another unsaturated carbocyclic radical, cycloalkyl, or aryl, such as 2,3-dihydroindenyl, decahydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless otherwise specified, the carbocyclic ring generally contains 4 to 10 ring members.

[0113] The term "C3-6 cycloalkyl" refers to a completely saturated carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0114] The term "heterocyclic ring" or "heterocyclyl" refers to a 4- to 12-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from N, O, and S. The heterocyclyl group may be monocyclic or bicyclic (e.g., bridged, fused, or spiro bicyclic 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, for example, an unsaturated heterocyclic radical fused to another unsaturated heterocyclic radical, a cycloalkyl ring, an aryl ring, 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 6-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- to 10-membered bicyclic saturated heterocyclyl group.

[0115] As used herein, the term "spiro" ring means a bicyclic system in which both rings share one common atom. Examples of spiro rings include 2-oxa-6-azaspiro[3.3]heptanyl and the like.

[0116] The term "fused" ring refers to two ring systems that share two adjacent ring atoms. The fused heterocyclic ring has at least one ring system containing a ring atom that is a heteroatom selected from O, N, and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0117] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety connected at two non-adjacent ring atoms (e.g., 5-oxabicyclo[2.1.1]hexane).

[0118] The term "pharmaceutically acceptable" indicates that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or the mammal being treated therewith.

[0119] Unless otherwise specified, the term "compounds of the present disclosure" refers to compounds of formula (I), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitution). When moieties capable of forming salts are present, salts, particularly pharmaceutically acceptable salts, are likewise included.

[0120] As used herein, the terms "a", "an", "the" and similar terms used in the context of the present invention (particularly in the context of the claims) are to be construed to cover both the singular and the plural forms, unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples or exemplary language provided herein (e.g., "such as") is merely intended to better illustrate the invention and does not limit the scope of the invention as otherwise claimed.

[0121] The intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms may be encompassed within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) involve interconversion via the movement of a proton, such as the isomerization of keto-enol and imine-enamine. A specific example of a proton tautomer is an imidazole moiety where a proton can move between two ring nitrogens. Valence tautomers involve interconversion by some rearrangement of the bonding electrons.

[0122] In one embodiment, the present disclosure relates to the compounds of formula (I) as defined herein in free form. In one embodiment, the present disclosure relates to the compounds of formula (I) as defined herein in salt form. In one embodiment, the present disclosure relates to the compounds of formula (I) as defined herein in acid addition salt form. In a further embodiment, the present disclosure relates to the compounds of formula (I) as defined herein in the form of pharmaceutically acceptable salts. In yet a further embodiment, the present disclosure relates to the compounds of formula (I) as defined herein in the form of pharmaceutically acceptable acid addition salts. In yet a further embodiment, the present disclosure relates to any one of the compounds of the examples in free form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the examples in salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the examples in acid addition salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the examples in the form of pharmaceutically acceptable salts. In yet another embodiment, the present disclosure relates to any one of the compounds of the examples in the form of pharmaceutically acceptable acid addition salts.

[0123] The compounds of the present disclosure may be synthesized by synthetic routes including processes similar to those well-known in the chemical art, especially in light of 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., prepared by methods generally described in Louis F. Fieser and Mary F. Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), including nutritional supplements (also available via the Beilstein online database), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin).

[0124] For illustrative purposes, the reaction schemes shown below provide possible routes for synthesizing the main intermediates, similar to the compounds of the present disclosure. For a more detailed description of the individual reaction steps, refer to the Examples section below. Specific starting materials and reagents are shown in the schemes and are described below, but other starting materials and reagents can be easily substituted to provide various derivatives and / or reaction conditions.

[0125] According to the first process, the compound of formula (I) can be prepared from the compounds of formula (II’) and (III’) as shown in Scheme 1.

Chemical formula

[0126] Hal is a halogen, usually Cl or Br. The compound of formula (I) can be prepared from the compounds of formula (II’) and (III’) by a backward Hartwig cross-coupling reaction in process step (a). Typical conditions include the reaction of the amide of formula (III’) with the halide of formula (II’) in a suitable solvent, in the presence of a suitable palladium catalyst in the presence of a suitable phosphine ligand, in the presence of a suitable inorganic base, at a high temperature, optionally under microwave irradiation. Preferred conditions include reacting the compounds of formula (II’) and (III’) at 70 °C to 120 °C, in a suitable solvent such as dioxane, DMF, or THF, in the presence of a suitable base such as Cs2CO3, NaOtBu, Zn(OAc)2, or K3PO4, in combination with Pd2(dba)3, in the presence of Brettphos Pd G3, Xantphos Pd G3, Xantphos Pd G4, RuPhos Pd G3, CPhos Pd G3, Josiphos, or Xantphos.

[0127] According to the second process, the compound of formula (I) can be prepared from the compounds of formula (IV’) and (V’) as shown in Scheme 2.

Chemical formula

[0128] Hal is a halogen, usually Cl or Br. The compound of formula (I) can be prepared from the compound of formula (IV’) and the halide of formula (V’) by the backward Hartwig reaction of process step (a) as described above in Scheme 1.

[0129] Alternatively, the compound of formula (I) can be prepared from the compound of formula (IV’) and the halide of formula (V’) by process step (b) (alkylation reaction at room temperature to high temperature in the presence of a suitable inorganic or organic base and a suitable polar aprotic solvent). Preferred conditions include reacting the compound of formula (IV’) with the compound of formula (V’) at room temperature to 100 °C in the presence of NaH, KHMDS, KOtBu, K3PO4, Cs2CO3, or K2CO3 in DMSO, DMF, or THF.

[0130] Alternatively, the compound of formula (I) can be prepared from the compound of formula (IV’) and the halide of formula (V’) by the Ullmann-type copper-mediated coupling reaction of process step (c). Typical conditions include reacting the compound of formula (IV’) with the compound of formula (V’) and a copper catalyst at high temperature, optionally in the presence of a suitable ligand and a suitable inorganic or organic base in a suitable solvent. Preferred conditions include reacting at 40 °C to 120 °C, optionally in a solvent such as dioxane or DMSO, in the presence of Cu or CuI, optionally in the presence of a suitable ligand such as N 1 ,N 2 -dimethylethane-1,2-diamine or L-proline, and reacting the compound of formula (IV’) with the halide of formula (V’) in the presence of a suitable inorganic base such as K2CO3 or K3PO4.

[0131] According to a third process, the compounds of formula (II’) and (IV’) can be prepared from the compounds of formula (III’), (V’), (VI’), (VII’), and (VIII’) as shown in Scheme 3.

Chemical formula

[0132] Hal is a halogen, preferably Br or Cl. PG is a suitable N-protecting group, usually a carbamate, preferably Boc.

[0133] The compound of formula (II’) can be prepared from the compounds of formulas (VI’) and (V’) by process steps (a), (b), or (c) as described above in Schemes 1 and 2.

[0134] The compound of formula (VII’) can be prepared from the compound of formula (VI’) according to the protection of the N atom in process step (d). Typical conditions include reacting the compound of formula (VI’) with Boc2O at approximately room temperature in the presence of a coupling agent such as DMAP in a suitable solvent such as THF.

[0135] The compound of formula (VIII’) can be prepared from the compounds of formulas (VII’) and (III’) according to process step (a) as previously described in Scheme 1.

[0136] The compound of formula (IV’) can be prepared from the compound of formula (VIII’) according to the deprotection reaction in process step (e). Typical conditions include reacting the compound of formula (VIII’) with a suitable acid such as TFA or HCl in DCM at room temperature.

[0137] According to a fourth process, the compound of formula (VI’) can be prepared from the compounds of formulas (IX’), (X’), (XI’), and (XII’) as shown in Scheme 4.

Chemical formula

[0138] Hal is a halogen, preferably Br or Cl. LG is a leaving group and is typically a halide or a sulfonate. The compound of formula (X’) can be prepared from the compound of formula (IX’) according to the addition reaction in process step (f). Preferred conditions include reacting the compound of formula (IX’) with a suitable halogenating agent such as pyridinium tribromide in a suitable alcohol solvent such as t-BuOH at room temperature.

[0139] The compound of formula (XI’) can be prepared from the compound of formula (X’) according to the reduction reaction in process step (g). Preferred conditions include reacting the compound of formula (X’) in the presence of zinc and acetic acid at room temperature.

[0140] The compound of formula (XII’) can be prepared from the compound of formula (XI’) by an alkalization reaction in process step (h). Typical conditions include reacting the compound of formula (XI’) with R 3 LG in a suitable solvent such as DMF or THF at room temperature in the presence of a strong organic or inorganic base such as NaH, n-BuLi, LiHMDS or TMEDA.

[0141] The compound of formula (VI’) can be prepared from the compound of formula (XII’) according to the carbonyl group reduction reaction in process step (i). Preferred conditions include reacting the compound of formula (XII’) with a reducing agent, typically LiAlH4 or NaBH4, together with BF3.Et2O in a suitable solvent such as THF at room temperature to 60 °C.

[0142] The compounds of formula (III’), (V’), (IX’), and R 3 LG may be commercially available or prepared in a manner similar to methods known in the literature or described in the following experimental section.

[0143] The compounds of formula (I), (II’), (IV’), (VI’), and (VIII’) may be converted to alternative compounds of formula (I), (II’), (IV’), (VI’), and (VIII’) by standard chemical transformations known to those skilled in the art. Examples of these transformations include, but are not limited to, the following. · Reacting an aryl or heteroaryl halide with an amine or alcohol (optionally in the presence of a suitable base) to provide an aryl or heteroaryl amine or ether, · Reacting an aryl or heteroaryl halide with an amine or alcohol according to the backward Hartwig reaction of process step (a) as described above in Scheme 1 to provide an aryl or heteroaryl amine or ether, · Reacting an aryl or heteroaryl halide with an alkyl or aryl boronic acid ester or acid using Suzuki reaction conditions to provide an alkyl or aryl substituted aryl or heteroaryl group, · Reacting an alkyl or heteroaryl halide with an alkyl or aryl zinc reagent using Negishi reaction conditions to provide an alkyl or aryl substituted aryl or heteroaryl group, · Reacting an aryl or heteroaryl halide with a substituted alkyne using Sonogashira - type reaction conditions to provide an alkenyl substituted aryl or heteroaryl group, · In a transition - metal photocatalytic reaction, reacting an aryl or heteroaryl halide with a cycloalkyl, or a 4 - to 7 - membered monocyclic heterocyclyl, substituted halide, or 1,3 - dioxoisoindoline carboxylate to provide a 4 - to 7 - membered monocyclic heterocyclyl substituted aryl or heteroaryl compound, · Reacting an aryl or heteroaryl halide with an alkyl thiolate salt to provide an alkylthio - substituted aryl or heteroaryl group, · Reducing an alkene or alkyne under hydrogenation conditions to provide the corresponding alkyl compound, · Using a suitable oxidizing agent such as KMnO4 to oxidize an alkoxyvinyl group to provide an ester, · Cleaving a vinyl ether under acidic conditions to provide a methyl ketone, · Reacting a ketone with a Grignard reagent to provide a tertiary alcohol, ·Use MCPBA or ruthenium trichloride hydrate together with IO4 to oxidize the alkylthio group to provide an alkylsulfonyl group. ·Alkylate an aryl or heteroaryl alcohol according to the alkylation reaction of process step (b) as described above in Scheme 2. ·Use an alkyl halide in the presence of an inorganic base to alkylate a heteroatom such as O or N to provide a secondary amine or an ether. ·Use a redox catalyst to C-H alkylate a heteroaryl group with a 4- to 7-membered monocyclic or heterocyclic halide to provide a 4- to 7-membered monocyclic or heterocyclic heteroaryl group. ·Reduce aminate the N atom to provide a secondary amine. ·Use a fluorinating agent such as DAST to fluorinate an alcohol or a carbonyl group. ·Use TBAF to fluorinate an aryl or heteroaryl chloride to provide an aryl or heteroaryl fluoride. ·Use a chlorinating agent such as SOCl2 to chlorinate a primary alcohol to provide an alkyl chloride. ·Hydrolyze a carboxylic acid ester to provide a carboxylic acid, or ·Use a palladium catalyst to dehalogenate a heteroaryl halide to provide a heteroaryl.

[0144] One skilled in the art will understand that it may be necessary to utilize suitable protecting group strategies for the preparation of the compounds of formula (I). Typical protecting groups may include 2,4-dimethoxybenzyl or carbamate groups, preferably Boc for the protection of amines, or benzyl groups for the protection of phenolic OH.

[0145] Furthermore, it will be understood that in order to obtain the compounds of the present invention, it may be necessary or desirable to perform the transformations in an order different from that described in the scheme, or to change one or more of the transformations.

Examples

[0146] Abbreviations: AcOH = acetic acid; AIBN = 2,2’-azobis(2-methylpropionitrile); Aq. = aqueous; BF3.Et2O = boron trifluoride diethyl ether; Bn = benzyl; BnOH = benzyl alcohol; Boc = tert-butoxycarbonyl; Boc2O = di-tert-butyl dicarbonate br = broad; Brettphos Pd G3 = [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate; t-BuOH = tert-butanol t-BuONa = sodium tert-butoxide; n-BuLi = n-butyllithium °C = degrees Celsius; CDCl3 = deuterated chloroform; CS2 = carbon disulfide; Cs2CO3 = cesium carbonate; CuI = copper(I) iodide; δ = chemical shift; d = doublet; DAST = (diethylamino)sulfur trifluoride; dd = double doublet; DCM = dichloromethane; DIPEA = N-ethyldiisopropylamine or N,N-diisopropylethylamine; DMAP = 4-(dimethylamino)pyridine; DME = 1,2-dimethoxyethane; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; DMSO-d6 = hexadeuterodimethyl sulfoxide; dtbbpy = 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine; Et = ethyl; EtOH = ethanol; EtOAc = ethyl acetate; Eq. = equivalent FeSO4 = iron(II) sulfate; g = gram; HCl = hydrochloric acid; HCO2H = formic acid; 1 H NMR = proton nuclear magnetic resonance; H2O = water; HPLC = high performance liquid chromatography; h = hour; IPA = 2-propanol; K2CO3 = potassium carbonate; KF = potassium fluoride; KHMDS = potassium hexamethyldisilazide; KOH = potassium hydroxide; KOtBu = potassium tert-butoxide; K3PO4 = potassium tribasic phosphate; L = liter; LCMS = liquid chromatography mass spectrometry; LiAlH4 = lithium aluminum hydride; LiHMDS = lithium hexamethyldisilazide; m = multiplet; M = mole; MCPBA = 3-chloroperoxybenzoic acid; Me = methyl; MeCN = acetonitrile; MeI = methyl iodide; MeOH = methanol; MeOH-d4 = deuterated methanol; mg = milligram; MgSO4 = magnesium sulfate; MHz = megahertz; mins = minute; mL = milliliter; mmol = millimole; MS m / z = mass spectrum peak; N2 = nitrogen; NaBH4 = sodium borohydride; NaBH3CN = sodium cyanoborohydride; Na2CO3 = sodium carbonate; NaH = sodium hydride; NaHCO3 = sodium bicarbonate; NaOH = sodium hydroxide; NaOtBu = sodium tert-butoxide; NaOMe = sodium methoxide; Na2SO3 = sodium thiosulfate; Na2SO4 = sodium sulfate; NBS = N-bromosuccinimide; NH3 = ammonia; NH4Cl = ammonium chloride; NH4OH is ammonium hydroxide, NiCl 2. glyme = dichloro(dimethoxyethane)nickel; PE = petroleum ether; Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(DPEPhos)Cl2 = dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II); Pd(OAc)2 = palladium(II) acetate; Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0); POCl3 = phosphorus(V) oxychloride; q = quartet; rt = room temperature; RT = retention time; RuPhos Pd G3 = (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; s = singlet; sat. = saturated; soln. = solution t = triplet; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; TMEDA = 1,2-bis(dimethylamino)ethane; μL = microliter; μmol = micromole; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Xantphos-Pd G3 = [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate; Zn(OAc)2 = zinc acetate.

[0147] General method Preparation 1 3,3-Dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one [Chemical formula] To a solution of 6-chloro-1H-pyrrolo[3,2-c]pyridine (8.0 g, 52.4 mmol) in t-BuOH (250 mL) was added pyridinium tribromide (50.4 g, 157 mmol) over 15 minutes. The reaction mixture was stirred at 25 °C for 16 hours. The mixture was diluted with water (400 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give 3,3-dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (16.7 g, 97.6% yield) as a yellow solid. 1 1H NMR: (400 MHz, CDCl3) δ: ppm 9.07 (s, 1H), 8.56 (s, 1H), 7.01 (s, 1H).

[0148] Substituted synthesis To a stirred solution of t-BuOH and THF (5.0 L) was added 6-chloro-1H-pyrrolo[3,2-c]pyridine (1.70 kg, 11.14 mol) and H2O (1.7 L) at room temperature. After stirring for 20 minutes, NBS (6.346 kg, 35.65 mol) was added in portions over 4 hours at 20 - 25 °C. After complete addition, the reaction mixture was stirred for an additional 2 hours. The reaction mixture was poured into ice water (25 L), and the resulting solid was filtered off and dried at 45 - 50 °C for 24 hours to obtain 3,3-dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (3.40 kg, 93.5%) as a yellow solid. HNMR (400 MHz, DMSO-d6) δ (ppm): 12.01 (brs, 1H), 8.58 (s, 1H), 7.05 (d, 1H).

[0149] Preparation 2 6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one

Chemical formula

[0150] Substituted synthesis A solution of 3,3-dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (Preparation 1, 3.40 kg, 0.418 mol) in H2O (20 L) was stirred, and a solution of Na2SO3 (5.252 kg, 41.67 mol) in H2O (15 L) was added thereto at room temperature over 1.5 hours. The mixture was stirred at 25 °C for 2 hours and then filtered. The resulting solid was washed with H2O and dried at 45 - 50 °C for 24 hours to obtain 6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (1.70 kg, 96.8%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.99 (brs, 1H), 8.06 (s, 1H), 6.86 (s, 1H), 3.56 (s, 2H).

[0151] Preparation 3 6'-Chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one [Chemical formula] A solution of 6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (Preparation 2, 2.0 g, 11.9 mmol) in DMF (10 mL) was added dropwise to a stirred suspension of NaH (2.9 g, 71.2 mmol, purity 60%) in DMF (30 mL) at 0 °C under N2. After the reaction mixture was stirred for 15 minutes, a solution of 1,2-dibromoethane (6.7 g, 35.6 mmol) in dry DMF (4.0 mL) was added dropwise. The brown reaction mixture was stirred at room temperature for 18 hours, then filtered and concentrated under vacuum. After adding H2O (400 mL), the mixture was extracted with EtOAc (200 mL × 5). The combined organic layers were washed with H2O (200 mL × 3) and brine (100 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was slurried in EtOAc and PE, filtered, and dried to obtain 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one (1 g, 43.3% yield) as a yellow solid. 11H NMR: (500 MHz, DMSO-d6) δ: ppm 11.19 (s, 1H), 7.94 (s, 1H), 6.96 (s, 1H), 1.78 - 1.75 (m, 2H), 1.57 - 1.54 (m, 2H).

[0152] Alternative synthesis A mixture of THF (7.0 L), 6-chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (Preparation 2, 650 g, 3.856 mol), and diisopropylamine (819.33 g, 8.097 mol) was cooled to -30 °C. n-BuLi (6.169 L, 15.42 mol, 2.5 M in n-hexane) was added dropwise under an N2 atmosphere. After stirring at this temperature for 4 hours, the mixture was warmed to 10 °C. 1,2-Dibromoethane (1.449 kg, 7.711 mol) was added dropwise, and the resulting mixture was stirred at 30 °C - 35 °C for 48 hours. The reaction mixture was quenched with 4 M aqueous HCl (30 L), and the pH was adjusted to saturation with Na2CO3. The mixture was filtered, and the resulting solid was dried to obtain 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one (650 g, 86.6%) as a yellow solid. 1 1HNMR (400 MHz, DMSO-d6) δ (ppm): 11.20 (brs, 1H), 7.93 (s, 1H), 6.96 (s, 1H), 1.77 - 1.74 (m, 2H), 1.57 - 1.54 (m, 2H).

[0153] Preparation 4 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

Chemical formula

[0154] Alternative synthesis To a stirred solution of 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-2'(1'H)-one (Preparation 3, 1.2 kg, 6.166 mol) in THF (8.0 L) was added NaBH4 (466.55 g, 12.33 mol) in one portion at 25 °C over 20 minutes. Then, BF3·Et2O (2.45 kg, 17.265 mol) was added dropwise at 20 °C over 5 hours under a N2 atmosphere. After complete addition, the reaction mixture was stirred for an additional 2 hours. The reaction mixture was quenched with 6N aqueous HCl (20 L) and stirred vigorously at 25 °C for 16 hours. The mixture was basified to pH = 9 with 6N aqueous NaOH using ice cooling and then filtered. The filter cake was dissolved in 2N aqueous HCl (7 L), and the solution was stirred at 25 °C for 2 hours and then basified to pH = 9 with 6N aqueous NaOH using ice cooling. The resulting solid was filtered off and dried to give 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (974.50 g, 87.50%) as a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 7.32 (s, 1H), 6.92 (brs, 1H), 6.30 (s, 1H), 3.59 (s, 2H), 1.01 - 0.98 (m, 4H).

[0155] Preparation 5 tert-Butyl 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate [Chemical formula] To a solution of 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4, 300 mg, 1.66 mmol) and DMAP (20.3 mg, 0.166 mmol) in THF (2 mL) were added Boc2O (725 mg, 3.32 mmol) and TEA (420 mg, 4.15 mmol). The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated and purified by chromatography on silica gel (PE / EtOAc 15 / 1 - 3 / 1) to give 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate (274 mg, 58.8% yield) as a white solid. 1 1H NMR: (400 MHz, CDCl3) δ: ppm 7.84 - 7.71 (m, 1H), 7.59 (s, 1H), 3.97 (s, 2H), 1.63 (s, 9H), 1.18 - 1.10 (m, 4H).

[0156] Alternative synthesis 6'-Chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4, 800 g, 4.43 mol) was dissolved in THF (5 L). DMAP (541.6 g, 4.43 mol) and Boc2O (2.416 kg, 11.072 mol) were added, and the mixture was stirred at 20 °C for 5 h. EtOAc (4 L) was added, and the mixture was washed with saturated NH4Cl (2 L x 5). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was triturated with n-heptane (1 L) at ambient temperature for 0.5 h and then filtered to afford tert-butyl 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate (900 g, 72.38%) as an off-white solid. 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 7.73 (s, 1H), 7.47 (s, 1H), 3.98 (s, 2H), 1.51 (s, 9H), 1.17 - 1.13 (m, 4H).

[0157] Preparation 6 tert-Butyl 6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate

Chem.

[0158] Alternative synthesis To a solution of tert-butyl 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate (Preparation 5, 150 g, 534.285 mmol) in dioxane (1.20 L) were added acetamide (63.12 g, 1.069 mol), K2CO3 (134.7 g, 1.069 mol), Pd2(dba)3 (34.25 g, 37.4 mmol) and XantPhos (43.28 g, 74.8 mmol). The reaction mixture was degassed with N2 and stirred at 100 °C for 16 h. The reaction mixture was diluted with EtOAc (10 L) and filtered through a pad of Celite®. The filtrate was washed with water (3 L × 3), the organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was triturated with PE / EtOAc = 8:1, filtered and air-dried to give tert-butyl 6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate as a yellow solid. 1 HNMR(400 MHz,DMSO-d6)δ(ppm):10.30(brs,lH),8.34(s,1H),7.62(d,1H),3.93(s,2H),2.05(s,3H),1.53(s,9H),1.10 - 1.06(m,4H).

[0159] Preparation 7 N-(1'-(2'-Dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide

Chemical formula

[0160] Alternative synthesis To a solution of tert-butyl 6'-acetamidospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-carboxylate (Preparation 6, 800 g, 2.637 mol) in DCM (3.0 L) was added TFA (3.007 kg, 26.372 mol) at room temperature and the reaction was stirred at 25 °C for 15 h. The mixture was concentrated and the residue was diluted with H2O (3.0 L). The solution was basified to pH = 9 with saturated aqueous Na2CO3 solution. After filtration, the filter cake was washed with saturated aqueous Na2CO3 solution (2.0 L). After drying at 45 - 50 °C for 24 h, the solid was slurried in DCM / n-heptane (1.0 L / 1.0 L) at room temperature. The solid was collected by filtration and dried to give N-(1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide (510.4 g, 95.2%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ (ppm): 10.01 (brs, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 6.64 (s, 1H), 3.54 (s, 2H), 2.01 (s, 3H), 0.96 - 0.92 (m, 4H).

[0161] Preparation 8 6'-Chloro-2-methylspiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one

Chem.

[0162] Preparation 9 6'-Chlorospiro[cyclobutane-1,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one

Chem.

[0163] Preparation 10 6'-Chlorospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one

Chemical Structure

[0164] Preparation 11 6'-Chloro-2,3,5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one

Chemical formula

[0165] Preparation 12 6'-Chloro-2-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] trifluoroacetate

Chemical formula

[0166] Preparation 13 6'-chloro-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-c]pyridine]

Chemical Structure

[0167] Preparation 14 6’-Chloro-1’,2’-dihydrospiro[cyclopentane-1,3’-pyrrolo[3,2-c]pyridine]

Chem.

[0168] Preparation 15 6’-Chloro-1’,2,2’,3,5,6-hexahydrospiro[pyran-4,3’-pyrrolo[3,2-c]pyridine]

Chem.

[0169] Preparation 16 1-(6-Chloro-4-(2-methoxyethoxy)pyridin-2-yl)ethan-1-one

Chem.

[0170] Preparation 17 4-(Benzyloxy)-2-chloro-5-fluoro-6-methylpyrimidine

Chemical Structure

[0171] Preparation 18 Methyl 4-(benzyloxy)-5-fluoro-6-methylpyrimidine-2-carboxylate

Chemical formula

[0172] Preparation 19 1-(4-(Benzyloxy)-5-fluoro-6-methylpyrimidin-2-yl)ethan-1-one [Chemical Structure] To a solution of methyl 4-(benzyloxy)-5-fluoro-6-methylpyrimidine-2-carboxylate (Preparation 18, 3.1 g, 11.22 mmol) in THF (30 mL), MeMgBr (3 M, 3.8 mL) was slowly added dropwise at -70 °C under N2, and the mixture was stirred at -70 °C for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl solution (30.0 mL), treated with H2O (20 mL), and extracted with EtOAc (40 mL × 3). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, concentrated, and then purified by column chromatography on silica gel (PE / EtOAc = 15 / 1 to 3 / 1) to give 1-(4-(benzyloxy)-5-fluoro-6-methylpyrimidin-2-yl)ethan-1-one (1.6 g, 54.8% yield) as a yellow oil. 1 H NMR: (500 MHz, CDCl3) δ: ppm 7.51 - 7.49 (m, 2H), 7.40 - 7.36 (m, 3H), 5.57 (s, 2H), 2.71 (s, 3H), 2.54 (d, J = 3.2 Hz, 3H).

[0173] Preparation 20 1-(2-Chloro-6-methylpyrimidin-4-yl)ethan-1-one [Chemical Structure] MeMgBr (3 M, 1.76 mL, 5.28 mmol) was added to a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (985 mg, 5.28 mmol) in THF (10 mL) at 0 °C under a N2 atmosphere and stirred for 5 h. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried (Na2SO4), evaporated to dryness, and the residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to give 1-(2-chloro-6-methylpyrimidin-4-yl)ethan-1-one as a white solid (147 mg, 16%). 1 H NMR (400 MHz, CDCl3) δ: 7.69 (s, 1H), 2.70 (s, 3H), 2.63 (s, 3H).

[0174] Preparation 21 2,4-Dichloro-6-(1,1-difluoroethyl)pyridine

Chemical formula

[0175] Preparations 22 - 26 The following table of compounds was prepared from the corresponding ketones and DAST using a procedure similar to that described in Preparation 21.

Table 1-1

Table 1-2

[0176] Preparation 27 2-Bromo-6-(1,1-difluoroethyl)-4-methoxypyridine

Chem.

[0177] Preparation 28 2-Chloro-4-(1,1-difluoroethyl)-6-methoxypyrimidine

Chem.

[0178] Preparation 29 2-(1,1-Difluoroethyl)pyrimidine-4,6-diol

Chem.

[0179] Preparation 30 4,6-Dichloro-2-(1,1-difluoroethyl)pyrimidine

Chem.

[0180] Preparation 31 4-Chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine

Chem.

[0181] Preparation 32 4-((1r,3r)-3-(Benzyloxy)cyclobutoxy)-2-chloro-6-(1,1-difluoroethyl)pyridine

Chem.

[0182] Preparation 33 (1r,3r)-3-((2-chloro-6-(1,1-difluoroethyl)pyridin-4-yl)oxy)cyclobutan-1-ol

Chemical Structure

[0183] Preparation 34 2-Chloro-6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine

Chemical Structure

[0184] Preparation 35 2-(1,1-Difluoroethyl)-5-fluoro-6-methylpyrimidin-4-ol [Chemical formula] A solution of 4-(benzyloxy)-2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidine (Preparation 25, 1.6 g, 5.53 mmol) in TFA (3 mL) was stirred at 25 °C for 16 h and then at 100 °C for 3 h. The mixture was concentrated under reduced pressure and purified by chromatography on silica gel (PE / EtOAc 15 / 1 to 3 / 1) to give 2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidin-4-ol (780 mg, 73.4% yield) as a colorless oil. 1 1H NMR: (500 MHz, CDCl3) δ: ppm 2.40 (d, J = 3.5 Hz, 3H), 2.02 (t, J = 18.5 Hz, 3H).

[0185] Preparation 36 4-Chloro-2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidine [Chemical formula] A solution of 2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidin-4-ol (Preparation 35, 3.1 g, 16.2 mmol) in POCl3 (39.5 g, 257 mmol) was stirred at 100 °C for 30 min. The mixture was concentrated under reduced pressure to give a residue, which was added to H2O (15 mL) and extracted with DCM (3 mL × 10). The combined organic phases were dried over Na2SO4, filtered, concentrated, and purified by column chromatography on silica gel (PE / EtOAc 15 / 1 to 3 / 1) to give 4-chloro-2-(1,1-difluoroethyl)-5-fluoro-6-methylpyrimidine (3.1 g, 90.7% yield) as a colorless oil. LCMS m / z = 211.0 [M+H] + .

[0186] Preparation 37 Methyl 4-(benzyloxy)-6-methylpyrimidine-2-carboxylate [Chemical formula] Methyl 4-(benzyloxy)-6-methylpyrimidine-2-carboxylate was obtained as a green oil (2.8 g, 56%) from 4-(benzyloxy)-2-chloro-6-methylpyrimidine according to the procedure similar to that described in Preparation 18. 1 H NMR(500 MHz,MeOH-d4)δ:7.53-7.28(m,5H),6.94(s,1H),5.50(s,2H),4.00(s,3H),2.50(s,3H).

[0187] Preparation 38 1-(4-(Benzyloxy)-6-methylpyrimidin-2-yl)ethan-1-one

Chem.

[0188] Preparation 39 4-(Benzyloxy)-2-(1,1-difluoroethyl)-6-methylpyrimidine

Chem.

[0189] Preparation 40 2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-ol

Chem.

[0190] Preparation 41 4-Chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine

Chemical formula

[0191] Preparation 42 4-(Benzyloxy)-2-chloro-5-fluoropyrimidine

Chemical formula

[0192] Preparation 43 Methyl 4-(benzyloxy)-5-fluoropyrimidine-2-carboxylate

Chemical formula

[0193] Preparation 44 1-(4-(Benzyloxy)-5-fluoropyrimidin-2-yl)ethan-1-one

Chemical formula

[0194] Preparation 45 4-(Benzyloxy)-2-(1,1-difluoroethyl)-5-fluoropyrimidine

Chemical formula

[0195] Preparation 46 2-(1,1-Difluoroethyl)-5-fluoropyrimidin-4-ol

Chemical formula

[0196] Preparation 47 4-Chloro-2-(1,1-difluoroethyl)-5-fluoropyrimidine

Chemical formula

[0197] Preparation 48 2-Bromo-6-(oxetan-3-yl)pyridine

Chemical formula

[0198] Preparation 49 3-(4-chloropyrimidin-2-yl)oxetan-3-ol

Chemical formula

[0199] Preparation 50 O-(3-(4-chloropyrimidin-2-yl)oxetan-3-yl) S-methyl carbonodithioate

Chemical formula

[0200] Preparation 51 4-Chloro-2-(oxetan-3-yl)pyrimidine

Chem.

[0201] Preparation 52 3-(6-Bromopyridin-2-yl)oxetan-3-ol

Chem.

[0202] Preparation 53 2-Bromo-6-(3-hydroxyoxolan-3-yl)-4-methyl-pyridine

Chemical formula

[0203] Preparation 54 2-Bromo-6-(3-methyloxetan-3-yl)pyridine

Chemical formula

[0204] Preparation 55 2-Fluoro-6-(3-methoxytetrahydrofuran-3-yl)pyridine

Chemical formula

[0205] Preparation 56 2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methyl-pyridine

Chemical formula

[0206] Preparation 57 2-Bromo-6-(3-fluorooxetan-3-yl)pyridine

Chem.

[0207] Preparation 58 6’-Chloro-1’-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]

Chem.

[0208] Preparations 59 - 66 The compounds in the following table were prepared from 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4) and the appropriate heterocycle according to a procedure similar to that described in Preparation 58.

Table 2-1

Table 2-2

Table 2-3

[0209] Preparation 67 6'-Chloro-1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical formula] A mixture of 6'-chloro-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 14, 40 mg, 192 μmol), 4-chloro-2-(1,1-difluoroethyl)pyrimidine (41 mg, 230 μmol), Xantphos Pd G4 (18 mg, 19 μmol), and Cs2CO3 (125 mg, 383 μmol) in dioxane (2 mL) was heated at 100 °C for 2 h under N2. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by chromatography on silica gel (0 - 80% EtOAc in heptane) to give 6'-chloro-1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-c]pyridine] (38 mg, 56% yield) as a white powder. LCMS m / z = 351.1 [M+H] + .

[0210] Preparation 68 tert-Butyl 6'-chloro-1'-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-carboxylate [Chemical formula] A mixture of tert-butyl 6'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-carboxylate (200 mg, 618 μmol), 2-chloro-4-(1,1-difluoroethyl)pyrimidine (132 mg, 741 μmol), Cs2CO3 (402 mg, 1.24 mmol), and Xantphos Pd G4 (59 mg, 62 μmol) in dioxane (6 mL) was heated at 110 °C for 1 h under N2. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by chromatography on silica gel (0 - 80% EtOAc in heptane) to give tert-butyl 6'-chloro-1'-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-carboxylate (116 mg, 40% yield) as a white powder. LCMS m / z = 466.2 [M+H] + .

[0211] Preparation 69 tert-butyl 6'-chloro-1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-carboxylate [Chemical formula] tert-butyl 6'-chloro-1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-carboxylate was prepared from tert-butyl 6'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-carboxylate and 4-chloro-2-(1,1-difluoroethyl)pyrimidine in a manner similar to the method described in Preparation 68. LCMS m / z = 466.2 [M+H] + .

[0212] Preparation 70 tert-Butyl 6'-chloro-1'-(6-(1,1-difluoroethyl)pyridin-2-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-carboxylate

Chem.

[0213] Preparation 71 6'-Chloro-1'-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

Chem.

[0214] Preparation 72 6-Chloro-1-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine

Chemical Structure

[0215] Preparation 73 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

Chem.

[0216] Preparation 74 6'-Chloro-1'-(4-(1,1-difluoroethyl)-6-methoxypyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

Chem.

[0217] Preparation 75 6'-Chloro-1'-(4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

Chemical Structure

[0218] Preparation 76 6'-Chloro-1'-(6-(3-methyloxetan-3-yl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical formula] To a mixture of 2-bromo-6-(3-methyloxetan-3-yl)pyridine (Preparation 54, 100 mg, 0.55 mmol) and 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4, 162 mg, 0.66 mmol) in dioxane (3 mL), CuI (21.1 mg, 0.11 mmol), K2CO3 (153 mg, 1.11 mmol) and N,N'-dimethylethane-1,2-diamine (19.5 mg, 0.22 mmol) were added. The reaction mixture was stirred at 100 °C for 3 h under N2. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (PE / EtOAc 3 / 1) to give 6'-chloro-1'-(6-(3-methyloxetan-3-yl)pyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (175.2 mg, 92.0% yield) as a white solid. 1 1H NMR: (400 MHz, CDCl3) δ: ppm 8.28 (s, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.06 (d, J = 6.8 Hz, 2H), 4.96 (d, J = 6.8 Hz, 2H), 4.14 (s, 2H), 3.31 (s, 3H), 1.22 - 1.18 (m, 4H).

[0219] Preparations 77 - 83 The compounds in the following table were prepared from the appropriate pyrrolo[3,2-c]pyridines and appropriate heterocycles listed below according to a procedure similar to the procedure described in Preparation 76. Heterocycle 1: 2-Bromo-6-(1,1-difluoroethyl)pyridine Heterocycle 2: 2-Bromo-6-(tetrahydrofuran-3-yl)pyridine [Table 3-1] [Table 3-2] [Table 3-3]

[0220] Preparation 84 6-Chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine [Chemical formula] A mixture of 6-chloro-3,3-dimethyl-1,2-dihydropyrrolo[3,2-c]pyridine (100 mg, 547.5 μmol), 2-bromo-6-(1,1-difluoroethyl)pyridine (146 mg, 657 μmol), K2CO3 (151 mg, 1.09 mmol), N,N’-dimethylethane-1,2-diamine (9.6 mg, 109 μmol) and CuI (10.4 mg, 54.8 μmol) in dioxane (4 mL) was purged with N2 and then the reaction mixture was heated at 110 °C for 1 h. The reaction mixture was cooled, filtered, the filtrate was diluted with EtOAc and washed with brine. The organic layer was separated, dried and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0 - 80% EtOAc in heptane) to give 6-chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (79 mg, 22% yield) as a white powder. LCMS m / z = 324.0 [M+H] + .

[0221] Preparation 85 6’-Chloro-1’-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]

Chemical Structure

[0222] Preparation 86 - 99 The compounds in the following table were prepared from 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4) and the appropriate heterocycles listed below according to a procedure similar to that described in Preparation 85. Heterocycle 3: 2-Chloro-4-(1,1-difluoroethyl)pyrimidine Heterocycle 4: 4-Chloro-2-(2-fluoropropan-2-yl)pyrimidine Heterocycle 5: 2-Fluoro-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Preparation 57) Heterocycle 6: 3-(6-Fluoropyridin-2-yl)tetrahydrofuran-3-ol (commercially available)

Table 4-1

Table 4-2

Table 4-3

Table 4-4

Table 4-5

[0223] Preparation 100 2-(6’-Chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)thiazole

Chem.

[0224] Preparation 101 6’-Chloro-1’-(6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]

Chem.

[0225] Preparations 102 to 120 The compounds in the following table were prepared from 6’-chloro-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] (Preparation 4) and the appropriate heterocycles according to the method described in Preparation 101.

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

[0226] Preparation 121 6’-Chloro-1’-(6-methyl-2-(methylthio)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]

Chemical Structure

[0227] Preparation 122 2-(6’-chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-5-methylthiazole

Chemical formula

[0228] Preparation 123 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-4-(1,1-difluoroethyl)thiazole

Chemical formula

[0229] Preparation 124 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-4,5-dimethylthiazole

Chemical formula

[0230] Preparation 125 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)-4-(tetrahydro-2H-pyran-3-yl)thiazole [Chemical formula] According to the procedure described in Preparation 122, 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)-4-(tetrahydro-2H-pyran-3-yl)thiazole was prepared from 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4) and 2-bromo-4-(tetrahydro-2H-pyran-3-yl)thiazole (commercially available). LCMS m / z = 348 [M+H] + .

[0231] Preparation 126 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)-5-methyl-4-(tetrahydrofuran-3-yl)thiazole [Chemical formula] According to the procedure described in Preparation 122, 2-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)-5-methyl-4-(tetrahydrofuran-3-yl)thiazole was prepared from 6'-chloro-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 4) and 2-bromo-5-methyl-4-(tetrahydrofuran-3-yl)thiazole. LCMS m / z = 348 [M+H] + .

[0232] Preparation 127 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical formula] A solution of 6'-chloro-1'-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 71, 100 mg, 0.280 mmol), 2-methoxyethanol (25.6 mg, 0.336 mmol) and Cs2CO3 (274 mg, 0.84 mmol) in DMF (5 mL) was stirred at 50 °C for 3 h. The mixture was treated with H2O (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with H2O (20 mL × 3) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc 1 / 0~1 / 1) to give 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-(2-methoxyethoxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine (60.0 mg, 54.0% yield) as a white solid. 11H NMR: (400 MHz, CDCl3) δ: ppm 8.30 (s, 1H), 7.58 (s, 1H), 6.0 (s, 1H), 4.61 - 4.59 (m, 2H), 4.01 (s, 2H), 3.76 - 3.73 (m, 2H), 3.44 (s, 3H), 2.05 (t, J = 18.5 Hz, 3H), 1.25 - 1.22 (m, 2H), 1.21 - 1.17 (m, 2H).

[0233] Preparation 128 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(3-methoxycyclobutoxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical Structure] Following a procedure similar to that described in Preparation 127, 6'-chloro-1'-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 71) and 3-methoxycyclobutan-1-ol were used to obtain 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-(3-methoxycyclobutoxy)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] as a white solid (80.0 mg, 52.0% yield). LCMS m / z = 423.1 [M + H] + .

[0234] Preparation 129 6'-Chloro-1'-(6-methyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical Structure] Following a procedure similar to that described in Preparation 127, 6’-chloro-1’-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] (Preparation 71) and cyclopropanol were used to obtain 6’-chloro-1’-(6-cyclopropoxy-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] as a white solid (80.0 mg, 68.6% yield). 1 1H NMR: (400 MHz, CDCl3) δ: ppm 8.36 (s, 1H), 7.62 (s, 1H), 5.99 (s, 1H), 4.39 - 4.34 (m, 1H), 4.07 (s, 2H), 2.10 (t, J = 18.4 Hz, 3H), 1.29 - 1.27 (m, 2H), 1.24 - 1.22 (m, 2H), 0.88 - 0.86 (m, 2H), 0.86 - 0.84 (m, 2H).

[0235] Preparation 130 6-(6’-chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridin]-1’(2’H)-yl)-2-(1,1-difluoroethyl)-N,N-dimethylpyrimidin-4-amine

Chemical Structure

[0236] Formulation 131 6-(6'-Chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-2-(1,1-difluoroethyl)-N-methylpyrimidin-4-amine [Chemical Formula] A mixture of 6'-chloro-1'-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 71, 50 mg, 139.98 μmol) and methanamine (2 M, 2.0 mL) was stirred at room temperature overnight. The solvent was removed, the crude product was diluted with EtOAc, washed with water and then brine. The organic layer was dried, filtered and evaporated under reduced pressure to give 6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-2-(1,1-difluoroethyl)-N-methylpyrimidin-4-amine as a white powder. LCMS m / z = 352.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.57 (s, 1H), 5.42 (s, 1H), 5.40 - 5.20 (m, 1H), 4.06 (s, 2H), 2.97 (d, 3H, J = 5.0 Hz), 2.05 (t, 3H, J = 18.6 Hz), 1.30 - 1.20 (m, 4H).

[0237] Preparations 132 - 135 The following compounds in the table were prepared from 6'-chloro-1'-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 71) and the appropriate amine according to the procedure described in Preparation 131. [Table 6-1] [Table 6-2]

[0238] Preparation 136 6'-Chloro-1'-(6-(1,1-difluoroethyl)-5-fluoropyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

Chem.

[0239] Preparation 137 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

Chem.

[0240] Preparation 138 6’-Chloro-1’-(2-(1,1-difluoroethyl)-6-isopropylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]

Chemical Structure

[0241] Preparation 139 6'-chloro-1'-(6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical formula] 6'-chloro-1'-(6-cyclopropyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] was prepared from 6'-chloro-1'-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 71) and cyclopropylzinc bromide using a similar method as described in Preparation 137. LCMS m / z = 363.1 [M+H] + .

[0242] Preparation 140 6'-chloro-1'-(6-cyclobutyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical formula] 6’-Chloro-1’-(6-cyclobutyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] was prepared from 6’-chloro-1’-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] (Preparation 71) and cyclobutylzinc bromide using a similar method as described in Preparation 137. LCMS m / z = 377.2 [M+H] + .

[0243] Preparation 141 6’-Chloro-1’-(2-(1,1-difluoroethyl)-6-(oxetan-3-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] [Chemical formula] 6'-Chloro-1'-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 71, 100 mg, 280 μmol), 3-bromooxetane (38 mg, 280 μmol), tris(trimethylsilyl)silane (69.6 mg, 280 μmol), and LiOH (13.4 mg, 560 μmol) were combined, and DME (2 mL) was added under N2. In a separate vial, DME (2 mL) was added to dtbbpy (7.5 mg, 28 μmol) and Ir[dF(CF3)ppy]2(dtbpy)PF6 (3.1 mg, 2.8 μmol) under N2. The catalyst mixture was sonicated and added to the reaction vial. The reaction mixture was stirred and irradiated with a blue LED at room temperature overnight. The mixture was concentrated under vacuum, diluted with water, and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried, and filtered. The filtrate was concentrated under reduced pressure and purified by chromatography on silica gel (0 - 80% EtOAc in heptane) to afford 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-(oxetan-3-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (11 mg, 10.4% yield). LCMS m / z = 379.2 [M+H] + .

[0244] Preparations 142 - 144 The compounds in the following table were prepared from 6'-chloro-1'-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 73) and the corresponding halide according to a procedure similar to that described in Preparation 147.

Table 7

[0245] Preparation 145 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(tetrahydrofuran-2-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

Chem.

[0246] Preparation 146 2-(6-(6'-Chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)cyclopropane-1-carbonitrile

Chem.

[0247] Preparation 147 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-(methylsulfonyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical Structure] A solution of 6'-chloro-1'-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 71, 200 mg, 560 μmol) in THF (3 mL) was added with an aqueous solution of sodium methanethiolate (2.14 M, 785 μL, 90% purity, 15% w / w) at 0 °C. The reaction mixture was stirred from 0 °C to room temperature for 4 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried, concentrated under reduced pressure and used without further purification. LCMS m / z = 369.1 [M+H] + .

[0248] The crude product was dissolved in DCM (3 mL) and cooled to 0 °C. MCPBA (251 mg, 1.12 mmol, 77% purity) was added. The reaction mixture was stirred at room temperature for 16 h and then saturated Na2S2O3. The mixture was extracted with DCM, washed with saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 - 80% EtOAc in heptane) to give 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-(methylsulfonyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (32 mg, 14% yield) as a white powder. LCMS m / z = 401.1 [M+H] + .

[0249] Preparation 148 6-chloro-1-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine

Chemical Structure

[0250] Preparation 149 6-(6-Chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-(1,1-difluoroethyl)-N-methylpyrimidin-4-amine [Chemical Structure] A mixture of 6-chloro-1-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (Preparation 72, 50 mg, 151 μmol) and methylamine (2 M in THF, 2 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by chromatography on silica gel (0 - 70% EtOAc - EtOH 3:1 (containing 2% NH4OH) in heptane) to give 6-(6-chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-(1,1-difluoroethyl)-N-methylpyrimidin-4-amine (15 mg, 30% yield). LCMS m / z = 326.1 [M+H] + .

[0251] Preparation 150 tert-Butyl 6’-acetamido-1’-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-1-carboxylate [Chemical formula] tert-Butyl 6’-acetamido-1’-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-1-carboxylate was prepared from tert-butyl 6’-chloro-1’-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-1-carboxylate (Preparation 68) and acetamide using a method similar to the method described in Example 12. LCMS m / z = 489.2 [M+H] + .

[0252] Preparation 151 tert-Butyl 6’-acetamido-1’-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-1-carboxylate [Chemical formula] tert-Butyl 6’-acetamido-1’-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-1-carboxylate was prepared from tert-butyl 6’-chloro-1’-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-1-carboxylate (Preparation 69) and acetamide using a method similar to the method described in Example 12. LCMS m / z = 489.2 [M+H] + .

[0253] Preparation 152 tert-Butyl 6’-acetamido-1’-(6-(1,1-difluoroethyl)pyridin-2-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[3,2-c]pyridine]-1-carboxylate

Chem.

[0254] Preparations 153 and 154 N-(1’-(2-Chloro-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide and N-(1’-(4-chloro-6-methylpyrimidin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide

Chem.

[0255] Preparation 153: N-(1’-(2-chloro-6-methylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridin]-6’-yl)acetamide (2.03 g, 62% yield). LCMS m / z = 330.0 [M+H] + 1 1H NMR (DMSO-d6, 400 MHz) δ 10.30 (s, 1H), 8.94 (s, 1H), 7.70 (s, 1H), 6.74 (s, 1H), 4.12 (s, 2H), 2.39 (s, 3H), 2.07 (s, 3H), 1.20 - 1.10 (m, 4H). Preparation 154: N-(1’-(4-Ethyl-6-methylpyrimidin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide. (71 mg, 2% yield). LCMS m / z = 330.0 [M+H] + 1 H NMR (DMSO-d6, 400 MHz) δ 10.27 (s, 1H), 9.05 (br s, 1H), 7.65 (s, 1H), 7.09 (s, 1H), 4.19 (s, 2H), 2.45 (s, 3H), 2.07 (s, 3H), 1.20 - 1.10 (m, 4H).

[0256] Preparation 155 N-(1’-(6-Chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide

Chemical formula

[0257] Preparation 156 N-(1'-(2-(1,1-Difluoroethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide

Chem.

[0258] Preparation 157 N-(1'-(6-Bromo-4-methylpyrimidin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide

Chem.

[0259] Preparation 158 Ethyl 2-(4-chloro-6-methylpyrimidin-2-yl)-2,2-difluoroacetate

Chemical Structure

[0260] Preparation 159 Ethyl 2-(6-chloro-4-methylpyridin-2-yl)-2,2-difluoroacetate

Chem.

[0261] Preparation 160 2-(6-chloro-4-methylpyridin-2-yl)-2,2-difluoroethan-1-ol

Chem.

[0262] Preparation 161 2-chloro-6-(1,1-difluoro-2-methoxyethyl)-4-methylpyridine

Chem.

[0263] Preparation 162 2-Chloro-4-methyl-6-(1,1,2-trifluoroethyl)pyridine

Chem.

[0264] Preparation 163 2-(1,1-Difluoropropyl)pyrimidine-4,6-diol

Chem.

[0265] Preparation 164 4,6-Dichloro-2-(1,1-difluoropropyl)pyrimidine

Chemical formula

[0266] Preparation 165 1,3-Dioxoisoindolin-2-yl 1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylate

Chemical formula

[0267] Preparation 166 1,3-Dioxoisoindolin-2-yl 1-fluorocyclopropane-1-carboxylate

Chemical formula

[0268] Preparation 167 6'-Chloro-1'-(6-methyl-2-(oxetan-3-yl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical formula] A solution of 6'-chloro-1'-(6-methylpyrimidin-4-yl)-1',2'-dihydros piro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 101, 200 mg, 0.733 mmol), concentrated H2SO4 (144 mg, 1.47 mmol), 3-iodooxetane (270 mg, 1.47 mmol), and ferrous sulfate heptahydrate (61 mg, 0.22 mmol) in DMSO (7 mL) was heated at 60 °C. Hydrogen peroxide (74.8 mg, 2.20 mmol) was added dropwise, and after 2 minutes, another portion of ferrous sulfate heptahydrate and hydrogen peroxide (74.8 mg, 2.20 mmol) was added, and the reaction mixture was stirred at 60 °C for 1 hour. The cooled mixture was poured into 0.2 M NaOH (saturated with NaCl) and extracted with EtOAc (2×). The combined organics were dried and concentrated, and the residue was purified by chromatography on silica gel (0 - 80% [(3:1 EtOAc / EtOH) + 2% NH4OH] / heptane) to give 6'-chloro-1'-(6-methyl-2-(oxetan-3-yl)pyrimidin-4-yl)-1',2'-dihydros piro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (24 mg, 10%). LCMS m / z = 329 [M+H] + .

[0269] Preparation 168 1'-(2-Bromopyrimidin-4-yl)-6'-chloro-1',2'-dihydros piro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical formula] A solution of 6’-chloro-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] (Preparation 4, 600 mg, 3.32 mmol) in THF (24 mL) was added with potassium tert-butoxide (2 M in THF, 3.32 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc and washed with brine. The combined organics were dried, concentrated, and the residue was purified by chromatography on silica gel (0 - 80% in heptane (3:1 EtOAc / EtOH + 2% NH4OH)) to afford 1’-(2-bromopyrimidin-4-yl)-6’-chloro-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] (121 mg, 11%). LCMS m / z = 337 / 339 [M+H] + .

[0270] Preparation 169 Ethyl 2-(4-(6’-chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)pyrimidin-2-yl)-2,2-difluoroacetate

Chemical Structure

[0271] Preparation 170 2-(4-(6'-Chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)pyrimidin-2-yl)-2,2-difluoroethan-1-ol [Chemical formula] Sodium borohydride (36 mg, 0.945 mmol) was added to a solution of ethyl 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)pyrimidin-2-yl)-2,2-difluoroacetate (Preparation 169, 90 mg, 0.236 mmol) in EtOH (5 mL) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with 2 M HCl and concentrated to remove volatiles. The residue was diluted with NaHCO3 / brine and extracted with EtOAc (3×). The combined organics were dried and concentrated to give 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)pyrimidin-2-yl)-2,2-difluoroethan-1-ol as a white solid (78 mg, crude product) which was used without further purification. LCMS m / z = 339 [M+H] + .

[0272] Preparation 171 6'-Chloro-1'-(2-(1,1-difluoro-2-methoxyethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical formula] NaH (17.71 mg, 0.443 mmol, 60% in mineral oil) was added to a mixture of 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)pyrimidin-2-yl)-2,2-difluoroethan-1-ol (Preparation 170, 75 mg, 0.221 mmol) and MeI (314 mg, 2.21 mmol) in THF (3 mL), and the mixture was stirred at room temperature overnight. The solid was removed by filtration, and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica gel (0 - 100% EtOAc / heptane) to give 6'-chloro-1'-(2-(1,1-difluoro-2-methoxyethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] as a white solid (46 mg, 59%). LCMS m / z = 353 [M+H] + .

[0273] Preparation 172 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(1-ethoxyvinyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical Structure] To a mixture of 6'-chloro-1'-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 71, 2 g, 5.60 mmol) and Pd(PPh3)4Cl2 (393 mg, 0.56 mmol) in DMF (20 mL) was added tributyl(1-ethoxyvinyl)stannane (2.22 g, 6.16 mmol) at room temperature. The reaction mixture was purged with N2 and then heated at 70 °C for 2 h. After cooling, the reaction was quenched with saturated aqueous KF and diluted with EtOAc. The precipitate was filtered off, the filtrate was collected and washed with water (3×) and brine. The organic layer was dried and concentrated. The white solid was diluted with EtOAc, filtered, rinsed with heptane and dried to give 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-(1-ethoxyvinyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (1.9 g, 77% yield). LCMS m / z = 393 [M+H] + .

[0274] Preparation 173 Ethyl 6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidine-4-carboxylate [Chemical Structure] A mixture of 6’-chloro-1’-(2-(1,1-difluoroethyl)-6-(1-ethoxyvinyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] (Preparation 172, 600 mg, 1.53 mmol), NaIO4 (1.31 g, 6.11 mmol), KMnO4 (96 mg, 0.611 mmol) and water (8 mL) was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc, the organic layer was separated, washed with water and brine, then dried and concentrated. The crude product was purified by chromatography on silica gel (0 - 60% EtOAc in heptane) to give ethyl 6-(6’-chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-2-(1,1-difluoroethyl)pyrimidine-4-carboxylate (122 mg, 20% yield). LCMS m / z = 395 [M+H] + .

[0275] Preparation 174 (6-(6’-Chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)methanol [Chemical Structure] To a solution of ethyl 6-(6’-chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-2-(1,1-difluoroethyl)pyrimidine-4-carboxylate (Preparation 173, 120 mg, 0.304 mmol) in EtOH (3 mL) was added NaBH4 (35 mg, 0.912 mmol), and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo, the residue was diluted with EtOAc and washed with brine. The organic layer was separated, dried and concentrated to give (6-(6’-chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)methanol (106 mg, 98% yield), which was used in the next step without further purification. LCMS m / z = 353 [M+H]+ .

[0276] Preparation 175 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(methoxymethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] [Chemical Structure] To a solution of (6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)methanol (Preparation 174, 90 mg, 0.255 mmol) in DMF (2 mL) were added Cs2CO3 (166 mg, 0.510 mmol) and MeI (217 mg, 1.53 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water (3×) and brine. The combined organics were dried and evaporated to dryness, and the residue was purified by chromatography on silica gel (0 - 60% EtOAc / heptane) to give 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-(methoxymethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (15 mg, 16%). LCMS m / z = 367 [M+H] + .

[0277] Preparation 176 1-(6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)ethan-1-one [Chemical Structure] To a solution of 6’-chloro-1’-(2-(1,1-difluoroethyl)-6-(1-ethoxyvinyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] (Preparation 172, 500 mg, 1.27 mmol) in acetone (8 mL) was added aqueous HCl solution (2 M, 1.91 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, the residue was diluted with ether, the formed solid was filtered, washed with ether and then dried under vacuum to give 1-(6-(6’-chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)ethan-1-one (304 mg, 65% yield). LCMS m / z = 365 [M+H] + .

[0278] Preparation 177 2-(6-(6’-chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)propan-2-ol

Chemical formula

[0279] Preparation 178 6’-Chloro-1’-(2-(1,1-difluoroethyl)-6-(2-fluoropropan-2-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] [Chemical formula] A solution of 2-(6-(6’-chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)propan-2-ol (Preparation 177, 100 mg, 0.263 mmol) in DCM (3 mL) was cooled to -78 °C, DAST (64 mg, 0.394 mmol) was added under N2, followed by the addition of N,N-triethylamine trihydrofluoride (42 mg, 0.263 mmol). The reaction mixture was stirred at 0 °C for 1 hour. The reaction was quenched with aqueous NaHCO3, and the mixture was extracted with EtOAc. The combined organics were dried and evaporated to dryness. The crude product was purified by chromatography on silica gel (0 - 80% EtOAc / heptane) to give 6’-chloro-1’-(2-(-1,1-difluoroethyl)-6-(2-fluoropropan-2-yl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine (67 mg, 66%). LCMS m / z = 383 [M+H] + .

[0280] Preparation 179 1-(6-(6’-chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)ethan-1-ol [Chemical formula] 1-(6-(6'-Chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)ethan-1-ol (226 mg, 82%) was prepared from 1-(6-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)ethan-1-one (Preparation 176) using a similar method as described in Preparation 174. LCMS m / z = 367 [M+H] + .

[0281] Preparation 180 6'-Chloro-1'-(2-(1,1-difluoroethyl)-6-(1-fluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

Chemical Structure

[0282] Preparation 181 Ethyl 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-6-methylpyrimidin-2-yl)-2,2-difluoroacetate

Chemical Structure

[0283] Preparation 182 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-6-methylpyrimidin-2-yl)-2,2-difluoroethan-1-ol [Chemical formula] Sodium borohydride (53.7 mg, 1.42 mmol) was added to a solution of ethyl 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-6-methylpyrimidin-2-yl)-2,2-difluoroacetate (Preparation 181, 140 mg, 0.355 mmol) in EtOH (3 mL), and the mixture was stirred at room temperature for 1 h. The reaction was quenched with 2 M HCl and concentrated to remove volatiles. The residue was diluted with saturated aqueous NaHCO3 and brine and extracted with EtOAc (2×). The combined organics were dried and evaporated to dryness to give 2-(4-(6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-1'(2'H)-yl)-6-methylpyrimidin-2-yl)-2,2-difluoroethan-1-ol as a white solid (66 mg, 53%). LCMS m / z = 353.0 [M+H] + .

[0284] Preparation 183 6'-Chloro-1'-(2-(1,1-difluoro-2-methoxyethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]

Chemical Structure

[0285] Preparation 184 N-(1'-(6-fluoro-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridin]-6'-yl)acetamide

Chemical Structure

[0286] Preparation 185 Ethyl 2-(6-(6’-acetamidospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridin]-1’(2’H)-yl)-4-methylpyrimidin-2-yl)-2,2-difluoroacetate

Chemical Structure

[0287] Preparation 186 N-(1’-(6-Chloro-2-(1,1-difluoropropyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide

Chem.

[0288] Preparation 187 N-(1’-(2-(1,1-Difluoroethyl)-6-(1-ethoxyvinyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide

Chem.

[0289] Preparation 188 N-(1’-(6-acetyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide [Chemical formula] To a solution of N-(1'-(2-(1,1-difluoroethyl)-6-(1-ethoxyvinyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide (Preparation 187, 110 mg, 0.265 mmol) in acetone (2 mL) was added HCl (2 M, 0.4 mL), and the mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated to dryness under reduced pressure, the residue was diluted with EtOAc, and Na2CO3. The organic matter was dried and evaporated to dryness, and the residue was purified by chromatography on silica gel (0 - 80% (3:1 EtOAc / EtOH) / heptane (+2% NH4OH)) to give N-(1'-(6-acetyl-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide (37 mg, 36%). LCMS m / z = 388 [M+H] + .

[0290] Preparation 189 N-(1'-(6-(Chloromethyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide [Chemical formula] A solution of N-(1’-(2-(1,1-difluoroethyl)-6-(hydroxymethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide (Example 292, 70 mg, 0.186 mmol) in DCM (2 mL) was treated with SOCl2 (222 mg, 1.86 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in EtOAc, followed by NaHCO3. The combined organics were dried and concentrated to afford N-(1’-(6-(chloromethyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide (67 mg, 91%). LCMS m / z = 394 [M+H] + .

[0291] Preparation 190 Ethyl 2-(6-(6’-acetamidospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-2-cyanoacetate [Chemical formula] A solution of N-(1’-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridin]-6’-yl)acetamide (Preparation 155, 200 mg, 0.527 mmol) and ethyl 2-cyanoacetate (119 mg, 1.05 mmol) in DMF (4 mL) was added with sodium tert-butoxide (101 mg, 1.05 mmol) at room temperature, and the mixture was heated at 80 °C for 1 h. Most of the volatiles were removed under reduced pressure, the residue was diluted with EtOAc and washed with water (3×). The organic layer was separated, dried and concentrated to give ethyl 2-(6-(6’-acetamidospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridin]-1’(2’H)-yl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-2-cyanoacetate (145 mg, 60%). LCMS m / z = 457 [M+H] + .

[0292] Preparation 191 1-Methyl-2-oxabicyclo[2.1.1]hexane-4-carboxamide [Chemical Structure] To a solution of 1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid (1 g, 7.03 mmol) in DCM (10 mL) was added oxalyl chloride (2 M in DCM, 4.2 mL) and DMF (54 μL) under N2, and the solution was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in DCM (10 mL), and the solution was cooled to 0 °C. Ammonia (7 M in methanol, 20 mL) was added slowly, and the mixture was stirred at room temperature for 2 h. The formed solid was filtered off and washed with MeOH. The filtrate was concentrated, diluted with MeCN, and the formed solid was collected by filtration and washed with MeCN to give 1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxamide (741 mg, 74% yield) as a white solid. LCMS m / z = 142 [M+H] + .

[0293] Preparation 192 6-Methyl-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)pyrimidin-4(3H)-one

Chem.

[0294] Preparation 193 4-Chloro-6-methyl-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)pyrimidine

Chem.

[0295] Preparation 194 2-oxabicyclo[2.1.1]hexane-4-carboxamide [Chemical formula] 2-oxabicyclo[2.1.1]hexane-4-carboxamide was obtained as a white solid (1.86 g, 93.7%) from 2-oxabicyclo[2.1.1]hexane-4-carboxylic acid according to a method similar to the method described in Preparation 191. 1H NMR (MeOD-d4, 400 MHz) δ 4.50 (t, 1H, J = 1.1 Hz), 3.81 (s, 2H), 2.12 (td, 2H, J = 1.3, 4.9 Hz), 1.90 - 1.70 (m, 2H).

[0296] Preparation 195 2-(2-oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4(3H)-one [Chemical formula] 2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-methylpyrimidin-4(3H)-one was obtained as a solid from 2-oxabicyclo[2.1.1]hexane-4-carboxamide and methyl (E)-3-aminobut-2-enoate according to a method similar to the method described in Preparation 192. LCMS m / z = 193 [M+H] + .

[0297] Preparation 196 2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-4-chloro-6-methylpyrimidine

Chem.

[0298] Preparation 197 2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-6-ethylpyrimidin-4(3H)-one

Chem.

[0299] Preparation 196 2-(2-Oxabicyclo[2.1.1]hexan-4-yl)-4-chloro-6-ethylpyrimidine

Chem.

[0300] Example 1 N-(1’-(2-(1,1-Difluoroethyl)-6-methoxypyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide [Chemical formula] A solution of 6’-chloro-1’-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] (Preparation 58, 150 mg, 0.425 mmol), acetamide (50.2 mg, 0.850 mmol) and Cs2CO3 (416 mg, 1.28 mmol) in dioxane (5 mL) was added BrettPhos Pd G3 (38.6 mg, 0.425 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 1 h under N2. The mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*25mm*5um; conditions: water (formic acid)-MeCN; start B: 17; end B: 37; gradient time (min): 22; flow rate (ml / min): 25) to give N-(1’-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide (29.5 mg, 18.5% yield) as a white solid. LCMS m / z = 376.1 [M+H] + . 1 1H NMR: (500 MHz, DMSO-d6) δ: ppm 10.88 (s, 1H), 8.71 (s, 1H), 7.70 (s, 1H), 6.29 (s, 1H), 4.17 (s, 2H), 3.99 (s, 3H), 2.20 - 2.11 (m, 6H), 1.22 - 1.20 (m, 4H).

[0301] Examples 2 - 9 The compounds in the following table were prepared from the appropriate pyrrolo[3,2-c]pyridine and acetamide according to a procedure similar to that described in Preparation 1. The crude material was purified by preparative HPLC (column: Boston Prime C18 150*25mm*5um; conditions: water (NH3 . H2O + NH4HCO3)-MeCN, gradient time (min): 10; flow rate (ml / min): 25) using an appropriate gradient.

Table 8-1

Table 8-2

Table 8-3

Table 8-4

[0302] Example 10 N-(1’-(2-(1,1-Difluoroethyl)-6-(methylamino)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide

Chem.

[0303] Example 11 N-(1’-(2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide

Chemical Structure

[0304] Example 12 N-(1’-(6-(1,1-Difluoroethyl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide [Chemical Structure] A mixture of 6-chloro-1’-(6-(1,1-difluoroethyl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine] (Preparation 77, 70 mg, 217 μmol), acetamide (64 mg, 1.1 mmol), Cs2CO3 (142 mg, 435 μmol), and BrettPhos Pd G3 (9.9 mg, 11 μmol) in dioxane (2 mL) was purged with N2 and then heated at 110 °C for 1 hour in a sealed tube. The cooled mixture was filtered, and the crude product was purified by chromatography on silica gel (0 - 80% EtOAc - EtOH 3:1 (containing 2% NH4OH) in heptane) to give N-[1-[6-(1,1-difluoroethyl)-2-pyridyl]spiro[2H-pyrrolo[3,2-c]pyridine-3,1’-cyclopropane]-6-yl)acetamide (37 mg, 49% yield) as a white powder. LCMS m / z = 345.1 [M+H] + . 1H NMR (CDCl3, 400 MHz) δ 8.86 (s, 1H), 8.05 (br s, 1H), 7.78 (t, 1H, J = 7.9 Hz), 7.45 (s, 1H), 7.29 (d, 1H, J = 7.5 Hz), 6.90 - 6.80 (m, 1H), 4.14 (s, 2H), 2.30 - 2.10 (m, 6H), 1.20 - 1.10 (m, 4H).

[0305] Examples 13 - 71 The compounds in the following table were prepared from acetamide and the appropriate chloride according to a procedure similar to that described in Example 12. [Table 9-1]

Table 9-2

Table 9-3

Table 9-4

Table 9-5

Table 9-6

Table 9-7

Table 9-8

Table 9-9

Table 9-10

Table 9-11

Table 9-12

Table 9-13

Table 9-14

Table 9-15

Table 9-16

Table 9-17

Table 9-18

Table 9-19

Table 9-20

Table 9-21

Table 9-22

Table 9-23

Table 9-24

Table 9-25

Table 9-26

Table 9-27

Table 9-28

Table 9-29

[0306] Examples 72 and 73 trans-rac-N-(1’-(6-(2-cyanocyclopropyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridin]-6’-yl)acetamide and cis-rac-N-(1’-(6-(2-cyanocyclopropyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridin]-6’-yl)acetamide

Chemical formula

[0307] Isomer 1, trans-rac-N-(1'-(6-(2-cyanocyclopropyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide and cis-rac-N-(1'-(6-(2-cyanocyclopropyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide, 13 mg, LCMS m / z = 411.2 [M+H] + 。 1 H NMR: (400 MHz, CDCl3) δ: ppm 9.20 - 8.90 (m, 1H), 8.29 (br s, 1H), 7.52 (s, 1H), 6.73 (s, 1H), 4.20 - 4.10 (m, 2H), 2.61 (ddd, 1H, J = 4.3, 5.8, 8.7 Hz), 2.30 - 2.20 (m, 4H), 2.13 (t, 3H, J = 18.7 Hz), 1.85 (ddd, 1H, J = 4.8, 5.8, 9.0 Hz), 1.67 (ddd, 1H, J = 4.8, 6.0, 8.8 Hz), 1.22 (br d, 4H, J = 4.3 Hz).

[0308] Isomer 2, cis-rac-N-(1'-(6-(2-cyanocyclopropyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide and trans-rac-N-(1'-(6-(2-cyanocyclopropyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide (2 mg), LCMS m / z = 411.2 [M+H] + 。 1 H NMR: (400 MHz, CDCl3) δ: ppm 9.01 (br s, 1H), 8.60 - 8.10 (m, 1H), 7.50 - 7.49 (m, 1H), 6.90 - 6.70 (m, 1H), 4.21 - 4.20 (m, 2H), 2.70 - 2.60 (m, 1H), 2.24 (s, 3H), 2.20 - 2.10 (m, 4H), 2.02 - 2.00 (m, 1H), 1.63 (br dd, 1H, J = 3.4, 8.4 Hz), 1.21 (br s, 4H).

[0309] Examples 74 and 75 N-(1'-(6-((1s,3s)-3-cyanocyclobutyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide and N-(1'-(6-((1r,3r)-3-cyanocyclobutyl)-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide

Chemical formula

[0310] Example 76 N-(1-(6-(1,1-difluoroethyl)pyridin-2-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide trifluoroacetate

Chemical Structure

[0311] Example 77 N-(1'-(thiazol-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide trifluoroacetate [Chemical Structure] To a mixture of 2-(6’-chlorospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-1’(2’H)-yl)thiazole (Preparation 100, 69.2 mg, 262.37 μmol), acetamide (77.49 mg, 1.31 mmol), and Cs2CO3 (170.97 mg, 524.75 μmol) in dioxane (3.22 mL) was added BrettPhos Pd G3 (23.78 mg, 26.24 μmol). The mixture was purged with N2 and then stirred at 100 °C overnight. The cooled reaction was diluted with EtOAc and washed with NaHCO3, H2O, and brine. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The crude mixture was purified by reverse phase HPLC (Sunfire Prep C18 OBD 5um 30×50mm, gradient: 5 - 40% MeCN in water, modifier 0.1% TFA, flow rate: 50 ml / min) to afford N-(1’-(thiazol-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide trifluoroacetate (2.5 mg). LCMS m / z = 287 [M+H] + 。

[0312] Examples 78 - 82 The compounds in the following table were prepared from the appropriate chloro compounds and acetamides according to the procedure described in Example 77.

Table 10-1

Table 10-2

[0313] Example 83 N-(1’-(4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide

Chem.

[0314] Examples 84 - 87 The compounds in the following table were prepared from the appropriate chloro compounds and acetamides according to a procedure similar to that described in Preparation 83.

Table 11-1

Table 11-2

[0315] Example 88 N-(1'-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide [Chemical Structure] To a solution of 6'-chloro-1'-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 73, 2.15 g, 6.38 mmol), acetamide (1.9 g, 31.9 mmol) and Cs2CO3 (4.2 g, 12.8 mmol) in dioxane (20 mL) were added Pd2(dba)3 (1.2 g, 1.28 mmol) and Xantphos (1.5 g, 2.55 mmol). The reaction mixture was stirred at 120 °C for 12 h under N2. The mixture was poured into H2O (50 mL) and extracted with EtOAc (50 mL × 3). The organic phase was washed with brine (50 mL × 2), dried over Na2SO4, filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (PE / EtOAc = 20 / 1 - 0 / 1) to give the crude product, which was treated with PE (20 mL) and MeOH (5 mL) to afford N-(1'-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide (1.21 g, 52.7% yield) as a white solid. LCMS m / z = 360.2 [M+H] + . 1 1H NMR: (400 MHz, DMSO-d6) δ: ppm 10.30 (s, 1H), 9.01 (s, 1H), 7.69 (s, 1H), 6.80 (s, 1H), 4.14 (s, 2H), 2.46 (s, 3H), 2.15 (t, J = 19.2 Hz, 3H), 2.07 (s, 3H), 1.18 - 1.16 (m, 4H).

[0316] Example 89 N-(1'-(2-(1,1-Difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)propionamide [Chemical formula] A solution of 6'-chloro-1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine] (Preparation 85, 120 mg, 0.372 mmol), propionamide (27.2 mg, 0.372 mmol), and Cs2CO3 (363 mg, 1.12 mmol) in dioxane (10 mL) was added with BrettPhos Pd G3 (33.8 mg, 0.0372 mmol). The reaction mixture was stirred at 100 °C for 2 hours under N2. The mixture was treated with H2O (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5 µm; conditions: water (NH3 . H2O + NH4HCO3)-ACN; start B: 41; end B: 71; gradient time (min): 10; flow rate (ml / min): 25) to obtain N-(1'-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)propionamide (56 mg, 41.9% yield) as a white solid. LCMS m / z = 360.1 [M+H] + . 1 1H NMR: (500 MHz, CDCl3) δ: ppm 8.97 (s, 1H), 8.61 (d, J = 6.0 Hz, 1H), 7.86 (s, 1H), 7.53 (s, 1H), 6.82 (d, J = 5.5 Hz, 1H), 4.16 (s, 2H), 2.46 - 2.41 (m, 2H), 2.19 (t, J = 19.0 Hz, 3H), 1.27 (t, J = 7.5 Hz, 3H), 1.22 - 1.21 (m, 2H), 1.20 - 1.18 (m, 2H).

[0317] Example 90 N-(1’-(6-(1,1-Difluoroethyl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)propionamide

Chemical formula

[0318] Example 91 N-(1’-(2-(1,1-Difluoroethyl)pyrimidin-4-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)-3-methoxypropanamide

Chemical formula

[0319] Example 92 N-(1’-(6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide [Chemistry] To a solution of N-(1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridin]-6’-yl)acetamide (Preparation 7, 60.0 mg, 0.295 mmol) in dioxane (3 mL) were added 2-chloro-6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridine (Preparation 34, 98.4 mg, 0.354 mmol), Xantphos Pd G3 (28.4 mg, 0.0295 mmol), and Zn(OAc)2 (162 mg, 0.886 mmol). The reaction mixture was stirred at 100 °C for 1 h under N2. The mixture was concentrated and purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5um; conditions: water (10 mM NH4HCO3)-ACN; start B: 49; end B: 79; gradient time (min): 11; flow rate (ml / min): 25) to give N-(1’-(6-(1,1-difluoroethyl)-4-((1r,3r)-3-methoxycyclobutoxy)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridin]-6’-yl)acetamide (13.6 mg, 10.4% yield) as a white solid. LCMS m / z = 445.2 [M+H] + . 1 1H NMR: (500 MHz, CDCl3) δ: ppm 8.81 (s, 1H), 8.06 (s, 1H), 7.41 (s, 1H), 6.76 (s, 1H), 6.28 (s, 1H), 4.49 - 4.43 (m, 1H), 4.08 (s, 2H), 3.72 - 3.70 (m, 1H), 3.27 (s, 3H), 2.99 - 2.93 (m, 2H), 2.20 - 2.11 (m, 8H), 1.17 - 1.06 (m, 4H).

[0320] Example 93 N-(1’-(6-(methylsulfonyl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridin]-6’-yl)acetamide [Chemistry] A mixture of N-(1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide (Preparation 7, 60 mg, 0.295 mmol), 2-bromo-6-methylsulfonyl-pyridine (139 mg, 0.59 mmol), BrettPhos Pd G3 (26.8 mg, 0.030 mmol) and Cs2CO3 (192.38 mg, 0.59 mmol) was added with dioxane (2.5 mL), and the reaction mixture was heated at 90 °C for 1 hour and then stirred at room temperature overnight. The mixture was diluted with EtOAc and water, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were concentrated, dry loaded, and purified by chromatography on silica gel (20 - 100% EtOAc - EtOH 3:1 in heptane) to give N-(1’-(6-(methylsulfonyl)pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide (15 mg, 14.2% yield) as a white solid. LCMS m / z = 359.1 [M+H] + . 1 1H NMR (400 MHz, CDCl3): δ (ppm) 9.16 (s, 1H), 8.13 - 8.07 (m, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.25 - 7.19 (m, 2H), 4.36 (s, 2H), 3.47 (s, 3H), 2.37 (s, 3H), 1.40 - 1.35 (m, 2H), 1.31 - 1.26 (m, 2H).

[0321] Example 94 N-(1’-(Pyridin-2-yl)-1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[3,2-c]pyridine]-6’-yl)acetamide

Chemical formula

[0322] Example 95 N-(1'-(6-(3-Hydroxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-6'-yl)acetamide

Chemical Structure

Claims

1. Equation (I): 【Chemistry 1】 A compound of which, in the formula, Ring A is an aromatic ring or a heteroaromatic ring formed by condensation of ring B, which is a five-membered heterocyclic ring. X １ However, it is N or CH, Ring C represents a phenyl molecule, a 5-10 member monocyclic or bicyclic heteroaryl molecule, a 3-7 member monocyclic carbocyclyl molecule, or a 4-7 member monocyclic heterocyclyl molecule, each of which has one or more R groups. Ｃ It is arbitrarily replaced by, Each R Ｃ is independently halo, -CN, -NR Ｎ１ R Ｎ２ -, -NR Ｎ３ -C(O)-R ７ -, -C(O)-NR Ｎ３ R Ｎ４ -, -NR Ｎ４ -SO ２ -R ７ -, -C(O)-R ７ -, -C(O)-OH, -C(O)-OR ７ -, -SR ７ -, -SO ２ -R ７ -, -OR Ｏ１ C １～６ alkyl, C ２～６ alkenyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, or 4- to 9-membered monocyclic or bicyclic heterocyclic, where the C Ｃ alkyl, C １～６ alkenyl, the phenyl, the 5- to 6-membered heteroaryl, the 3- to 7-membered monocyclic carbocyclic, and the 4- to 9-membered monocyclic or bicyclic heterocyclic represented by R １～６ are each optionally substituted with one or more R Ｃ１ s, Each R Ｃ１ However, independently, halo, oxo, -CN, -OR Ｏ１ , -NR Ｎ３ R Ｎ４ , -C(O)-R ７ , -C(O)-OR Ｏ３ , -SO ２ -R ７ , C １～６ Alkyl, phenyl, 3-7 member monocyclic carbocyclyl, 5-6 member heteroaryl, or 4-7 member monocyclic heterocyclyl, where R Ｃ１ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered monocyclic heterocyclil are, respectively, halo, oxo, -CN, and -OR. Ｏ１ , -NR Ｎ３ R Ｎ４ , C １～６ Alkyl, C １～４ It is optionally substituted with one or more substituents independently selected from haloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-8 membered monocyclic heterocyclyl. R １ However, H, C １～６ Alkyl, -OR ２ , -NR ２ R ４ , a monocyclic carbocyclyl with 3 to 7 members, or a monocyclic heterocyclyl with 4 to 7 members, where R １ The C represented by １～６ Alkyl, the 3- to 7-membered monocyclic carbocyrill, and the 4- to 7-membered monocyclic heterocyclyl each contain one or more R ８ It is arbitrarily replaced by, R １Ａ is H or C １～３ Is it alkyl? Each R ２ and R ４ These are H and C, independently. １～４ Alkyl or 3-4 membered monocyclic carbocyclyl; Each R ３ These are independently H, halo, or C １～３ It is alkyl; Alternatively, two R's ３ These, together with the atoms to which they are bonded, form a 3- to 7-membered monocyclic carbocyclyl or a 4- to 9-membered monocyclic heterocyclyl, each of which contains one or more R ５ It is arbitrarily replaced with; Each R ５ However, independently, H, Hal, -CN, -OR Ｏ１ , -NR Ｎ３ R Ｎ４ , C １～３ Alkyl, -C(O)-R ７ , -C(O)-OR Ｏ３ , -C(O)-NR Ｎ１ R Ｎ２ , -NR Ｎ３ -C(O)-R ７ 、 SO ２ -R ７ , phenyl, 5-6 membered heteroaryl, or 3-7 membered monocyclic carbocyrill, or 4-7 membered monocyclic heterocycline, where R ５ The C represented by １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, and 4-7 member monocyclic heterocyclyl are each represented as halo, oxo, -CN, and -OR, respectively. Ｏ１ , -NR Ｎ１ R Ｎ２ , C １～６ Alkyl, C １～４ It is optionally substituted with one or more substituents independently selected from haloalkyl groups, 3- to 7-membered monocyclic carbocyclils, and 4- to 7-membered monocyclic heterocyclils. Each R ７ However, independently, C １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, or 4-7 member monocyclic heterocycline, where R ７ The C represented by １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, and 4-7 member monocyclic heterocyclyl are each represented as halo, oxo, -CN, and -OR, respectively. Ｏ１ , -NR Ｎ３ R Ｎ４ , C １～６ Alkyl, C １～４ It is optionally substituted with one or more substituents independently selected from haloalkyl groups, 3- to 7-membered monocyclic carbocyclils, and 4- to 7-membered monocyclic heterocyclils. Each R ８ is, independently, halo, oxo, -CN, -OR Ｏ１ , -NR Ｎ１ R Ｎ２ , C １～６ alkyl, C １～４ haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, or 4- to 7-membered monocyclic heterocyclic, and Each R Ｏ１ is independently H, C １～６ alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, or 4- to 8-membered monocyclic or bicyclic heterocyclic, where the C Ｏ１ alkyl, the phenyl, the 5- to 6-membered heteroaryl, 3- to 8-membered monocyclic carbocyclic, and 4- to 7-membered monocyclic or bicyclic heterocyclic represented by R １～６ are each optionally substituted by one or more R Ｏ２ and, Each R Ｏ２ However, independently, Halo, OH, -CN, C １～４ Alkoxy, C １～４ Alkyl, C １～４ Alkyl-C １～４ Alkoxy, C １～４ The member is a haloalkyl, phenyl, a 5-6 member heteroaryl, a 3-7 member monocyclic carbosilyl, or a 4-7 member monocyclic or bicyclic heterocyclil, wherein the 4-7 member monocyclic or bicyclic heterocyclil is C １～４ Alkyl or C １～４ It is arbitrarily substituted with alkoxy, Each R Ｏ３ However, independently, H, C １～６ Alkyl, C １～４ A haloalkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, or 4-7 member monocyclic heterocyclyl, where R Ｏ３ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-7 membered monocyclic heterocyclyl each contain one or more R Ｏ２ It is arbitrarily replaced by, R Ｎ１ and R Ｎ２ However, each is independent of H or C １～６ It is alkyl, and here, R Ｎ１ and R Ｎ２ The C represented by １～６ Alkyl is, respectively, Halo and C １～４ Alkoxy, or -NR Ｎ３ R Ｎ４ It is arbitrarily replaced by, or R Ｎ１ However, H or C １～３ It is alkyl, R Ｎ２ However, ring D or -C １～３ It is an alkylene ring D, Ring D is a 3-7 member monocyclic or bicyclic carbocyclyl, or a 4-7 member monocyclic heterocyclyl, where the 3-7 member monocyclic carbocyclyl and the 4-7 member monocyclic heterocyclyl represented by ring D are, respectively, halo and C. １～６ Alkyl and C １～４ It is optionally substituted with one or two substituents independently selected from the alkoxy, Each R Ｎ３ H or C １～６ It is alkyl, Each R Ｎ４ H or C １～６ It is alkyl. The above-mentioned compound, or a pharmaceutically acceptable salt thereof.

2. Ring A is an aromatic ring or a heteroaromatic ring formed by condensation of ring B, which is a five-membered heterocyclic ring. X １ However, it is N or CH, Ring C represents a phenyl molecule, a 5-10 member monocyclic or bicyclic heteroaryl molecule, a 3-7 member monocyclic carbocyclyl molecule, or a 4-7 member monocyclic heterocyclyl molecule, each of which has one or more R groups. Ｃ It is arbitrarily replaced by, Each R Ｃ However, independently, Halo, -CN, -NR Ｎ１ R Ｎ２ , -NR Ｎ３ -C(O)-R ７ , -C(O)-NR Ｎ３ R Ｎ４ , -NR Ｎ４ -SO ２ -R ７ , -C(O)-R ７ , -SR ７ , -SO ２ -R ７ , -OR Ｏ１ , C １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, or 4-9 member monocyclic or bicyclic heterocyclyl, where R Ｃ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-9 membered monocyclic or bicyclic heterocyclyl each contain one or more R Ｃ１ It is arbitrarily replaced with, Each R Ｃ１ However, independently, halo, oxo, -CN, -OR Ｏ１ , -NR Ｎ３ R Ｎ４ , -C(O)-R ７ , -C(O)-OR Ｏ３ , -SO ２ -R ７ , C １～６ Alkyl, phenyl, 3-7 member monocyclic carbocyclyl, 5-6 member heteroaryl, or 4-7 member monocyclic heterocyclyl, where R Ｃ１ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered monocyclic heterocyclil are, respectively, halo, oxo, -CN, and -OR. Ｏ１ , -NR Ｎ３ R Ｎ４ , C １～６ Alkyl, C １～４ It is optionally substituted with one or more substituents independently selected from haloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-8 membered monocyclic heterocyclyl. R １ However, H, C １～６ Alkyl, -OR ２ , -NR ２ R ４ , a monocyclic carbocyclyl with 3 to 7 members, or a monocyclic heterocyclyl with 4 to 7 members, where R １ The C represented by １～６ Alkyl, the 3- to 7-membered monocyclic carbocyrill, and the 4- to 7-membered monocyclic heterocyclyl each contain one or more R ８ It is arbitrarily replaced by, R １Ａ is H or C １～３ Is it alkyl? Each R ２ and R ４ These are H and C, independently. １～４ Alkyl or 3-4 membered monocyclic carbocyclyl; Each R ３ These are independently H, halo, or C １～３ It is alkyl; Alternatively, two R's ３ These, together with the atoms to which they are bonded, form a 3- to 7-membered monocyclic carbocyclyl or a 4- to 9-membered monocyclic heterocyclyl, each of which contains one or more R ５ It is arbitrarily replaced with; Each R ５ However, independently, H, Hal, -CN, -OR Ｏ１ , -NR Ｎ３ R Ｎ４ , C １～３ Alkyl, -C(O)-R ７ , -C(O)-OR Ｏ３ , -C(O)-NR Ｎ１ R Ｎ２ , -NR Ｎ３ -C(O)-R ７ 、 SO ２ -R ７ , phenyl, 5-6 membered heteroaryl, or 3-7 membered monocyclic carbocyrill, or 4-7 membered monocyclic heterocycline, where R ５ The C represented by １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, and 4-7 member monocyclic heterocyclyl are each represented as halo, oxo, -CN, and -OR, respectively. Ｏ１ , -NR Ｎ１ R Ｎ２ , C １～６ Alkyl, C １～４ It is optionally substituted with one or more substituents independently selected from haloalkyl groups, 3- to 7-membered monocyclic carbocyclils, and 4- to 7-membered monocyclic heterocyclils. Each R ７ However, independently, C １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, or 4-7 member monocyclic heterocycline, where R ７ The C represented by １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, and 4-7 member monocyclic heterocyclyl are each represented as halo, oxo, -CN, and -OR, respectively. Ｏ１ , -NR Ｎ３ R Ｎ４ , C １～６ Alkyl, C １～４ It is optionally substituted with one or more substituents independently selected from haloalkyl groups, 3- to 7-membered monocyclic carbocyclils, and 4- to 7-membered monocyclic heterocyclils. Each R ８ However, independently, halo, oxo, -CN, -OR Ｏ１ , -NR Ｎ１ R Ｎ２ , C １～６ Alkyl, C １～４ The haloalkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, or 4-7 member monocyclic heterocyclyl, Each R Ｏ１ However, independently, H, C １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, or 4-7 member monocyclic or bicyclic heterocyclyl, where R Ｏ１ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-7 membered monocyclic or bicyclic heterocyclyl each contain one or more R Ｏ２ It is arbitrarily replaced by, Each R Ｏ２ However, independently, Halo, OH, -CN, C １～４ Alkoxy, C １～４ The haloalkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, or 4-7 member monocyclic heterocyclyl, Each R Ｏ３ However, independently, H, C １～６ Alkyl, C １～４ A haloalkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, or 4-7 member monocyclic heterocyclyl, where R Ｏ３ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-7 membered monocyclic heterocyclyl each contain one or more R Ｏ２ It is arbitrarily replaced by, R Ｎ１ and R Ｎ２ However, each is independent of H or C １～６ It is alkyl, and here, R Ｎ１ and R Ｎ２ The C represented by １～６ Alkyl is, respectively, Halo and C １～４ Alkoxy, or -NR Ｎ３ R Ｎ４ It is arbitrarily replaced by, or R Ｎ１ However, H or C １～３ It is alkyl, R Ｎ２ However, ring D or -C １～３ It is an alkylene ring D, Ring D is a 3-7 member monocyclic or bicyclic carbocyclyl, or a 4-7 member monocyclic heterocyclyl, where the 3-7 member monocyclic carbocyclyl and the 4-7 member monocyclic heterocyclyl represented by ring D are, respectively, halo and C. １～６ Alkyl and C １～４ It is optionally substituted with one or two substituents independently selected from the alkoxy, Each R Ｎ３ H or C １～６ It is alkyl, Each R Ｎ４ H or C １～６ It is alkyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R １Ａ However, H or -CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. Each R ３ However, independently, H or -CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. (i) Two R ３ However, together with the atoms to which they are bonded, C ３～６ They form cycloalkyl or 5-6 membered monocyclic heterocyclines, each of which has 1-3 R ５ It is arbitrarily replaced by (ii) Two R ３ However, together with the atoms to which they are bonded, they form cyclopropane, cyclobutane, cyclopentane, tetrahydropyran, or piperidine, each of which contains 1 to 3 R ５ It is arbitrarily replaced by, (iii) Two R ３ However, together with the atoms to which they are bonded, 【Chemistry 2】 The formula is formed where m is 0, 1, 2, or 3. 【Transformation 3】 - represents a bond within ring B. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. The compound is of formula (III), (IV), (V), (VI), (VII), (VIII), or (IX): 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by [the specified formula].

7. Each R ５ However, independently, H, -CN, or CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. (i) Ring C has 1 to 3 R Ｃ It is a 5- to 9-member monocyclic or bicyclic heteroaryl that is optionally substituted by, or (ii) Ring C is pyrazine, pyrozolo[1,5-a]pyrimidine, pyridine, pyrimidine, pyrimidinone, or thiazole, each of which has one or three R Ｃ It is arbitrarily replaced by, (iii) Ring C is 【Transformation 5】 Selected from, in the formula, 【Transformation 6】 - represents a bond to ring B, where n is 0, 1, 2, or 3, or (iv) Ring C is 【Transformation 7】 Selected from, in the formula, 【Transformation 8】 The - indicates a bond to ring B, and 1 to 3 R in ring C. Ｃ The base may be the same or different. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. Each R Ｃ However, it became independent, Halo, -NR Ｎ１ R Ｎ２ , -OR Ｏ１ , -SR ７ , -SO ２ -R ７ , -C(O)-NR Ｎ３ R Ｎ４ , -C(O)-R ７ , -C(O)H, -C(O)OH, -C(O)OR ７ , C １～６ Alkyl, C ２～４ Alkenil, C ３～６ A cycloalkyl, a 4- to 9-membered monocyclic or bicyclic heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl, where R Ｃ The C represented by １～６ alkyl, the C ２～４ Alkenyl, the C ３～６ Each of the cycloalkyl group, the 4-9 member monocyclic or bicyclic heterocyclil, the phenyl group, and the 5-6 member heteroaryl group each contains 1-3 R groups. Ｃ１ It is arbitrarily replaced with, R ７ However, C １～３ It is alkyl, R Ｏ１ However, H, C １～４ Alkyl, C １～４ Alkyl, C ３～６ Cycloalkyl, 4-8 membered monocyclic or bicyclic heterocyclyl, 5-6 membered heteroaryl, where R Ｏ１ The C represented by １～４ Alkyl is halo, OH, CN, C １～３ Alkoxy, C ３～６ Cycloalkyl, and C １～３ Alkyl or C １～３ Optionally substituted with 1 to 3 substituents independently selected from 4 to 6-membered monocyclic heterocyclines optionally substituted with alkoxys, R Ｏ１ The C represented by ３～６ Cycloalkyls, the 4-8 membered monocyclic or bicyclic heterocyclines, and the 5-6 membered heteroaryls are, respectively, halo and C. １～３ Alkyl, C １～３ Alkyl-C １～３ Alkoxy, CN, OH, and C １～３ It is optionally substituted with one or two substituents independently selected from the alkoxy, R Ｎ１ and R Ｎ２ However, each is independent of H or C １～６ It is alkyl, and here, R Ｎ１ and R Ｎ２ The C represented by １～６ Alkyl is, respectively, Halo and C １～４ Alkoxy, or -NR Ｎ３ R Ｎ４ It is arbitrarily replaced by, or R Ｎ１ However, H or C １～３ It is alkyl, R Ｎ２ However, ring D or -C １～３ It is an alkylene ring D, Ring D is a 3-7 member monocyclic or bicyclic carbocyclyl, or a 4-7 member monocyclic heterocyclyl, where the 3-7 member monocyclic carbocyclyl and the 4-7 member monocyclic heterocyclyl represented by ring D are, respectively, halo and C. １～６ Alkyl and -C １～４ Optionally substituted with one or two substituents independently selected from the alkoxy, R Ｎ１ and R Ｎ２ However, each is independent of H or C １～４ It is alkyl, and here, R Ｎ１ and R Ｎ２ The C represented by １～４ Alkyl is, respectively, Halo and C １～３ Alkoxy, or -NR Ｎ３ R Ｎ４ It is arbitrarily replaced by, or Each R Ｎ３ However, independently, H or C １～３ It is alkyl, Each R Ｎ４ However, independently, H or C １～３ It is alkyl, and optionally, (i) Ring D is cyclobutane, cyclopropane, bicyclo[1.1.1]pentane, spiro[2.2]pentane, azetidine, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, or thietan, each of which is a halo, C １～２ Alkyl and C １～２ It is optionally substituted with one or two substituents independently selected from the alkoxy, preferably, Ring D is as follows: 【Chemistry 9】 It is one of these, and each of these is F, -CH ３ , and -OCH ３ Optionally substituted with one or two substituents independently selected from and (ii) R Ｏ１ The aforementioned 4-8 member monocyclic or bicyclic heterocyclil, or R Ｏ１ The C represented by １～４ The alkyl substituent is oxetane, azetinidine, pyrrolidine, 2-oxaspiro[3.3]heptanyl, or tetrahydrofuran, each of which is C １～３ Alkyl, Halo, CN, OH, C １～３ Alkyl-C １～３ Alkoxy, or C １～３ R is optionally substituted with one or two substituents independently selected from alkoxy groups. Ｏ１ The 5-6 member heteroaryl represented by is a pyrazole, triazole, pyridine, pyrazine, pyrimidine, or pyridazine, and each of these is C １～３ Alkyl, halo, CN, OH, or C １～３ It is arbitrarily substituted with one or two substituents that can be independently selected as alkoxys. The compound according to claim 8, or a pharmaceutically acceptable salt thereof.

10. Each R Ｃ However, it became independent, Halo, -NR Ｎ１ R Ｎ２ , -OR Ｏ１ , -SR ７ , -SO ２ -R ７ , -C(O)-NR Ｎ３ R Ｎ４ , -C(O)-R ７ , C １～３ Alkyl, C ３～６ A cycloalkyl, a 4- to 9-membered monocyclic or bicyclic heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl, where R Ｃ The C represented by １～３ alkyl, the C ３－６ Each of the cycloalkyl group, the 4-9 member monocyclic or bicyclic heterocyclil, the phenyl group, and the 5-6 member heteroaryl group each contains 1-3 R groups. Ｃ１ It is arbitrarily replaced with, R ７ However, C １～３ It is alkyl, R Ｏ１ H, C １～４ Alkyl, C １～４ Alkyl, C ３～６ Cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered heteroaryl, R Ｏ１ C represented by １～４ Alkyl molecules are independently halos, CNs, and C. １～３ Alkoxy, C ３～６ One to three substituents selected from cycloalkyls and 4- to 6-membered monocyclic heterocyclines, where C ３～６ Cycloalkyl groups, 4-6 member monocyclic heterocyclines, and 5-6 member R groups Ｏ１ Each of the heteroaryls represented by these terms can be arbitrarily named Halo, C １～３ Alkyl, CN, OH, and C １～３ It is substituted with one or two substituents independently selected from the alkoxy; R Ｎ１ However, H or C １～３ It is alkyl, R Ｎ２ However, ring D or -C １～３ It is an alkylene ring D, Ring D is a 3- to 7-membered monocyclic or bicyclic carbocyclyl, or a 4- to 7-membered monocyclic heterocyclyl, and the 3- to 7-membered monocyclic carbocyclyl and the 4- to 7-membered monocyclic heterocyclyl represented by ring D are, respectively, halo and C. １～６ Alkyl and -C １～４ Optionally substituted with one or two substituents independently selected from the alkoxy, R Ｎ１ and R Ｎ２ However, each is independent of H or C １～４ It is alkyl, and here, C １～４ Alkyl, R Ｎ１ and R Ｎ２ Represented by, Each R Ｎ３ However, independently, H or C １～３ It is alkyl, Each R Ｎ４ However, independently, H or C １～３ It is alkyl, and optionally, R Ｏ１ A 4-6 member monocyclic heterocycline represented by, or R Ｏ１ The C represented by １～４ The alkyl substituent is oxetane, azetinidine, or tetrahydrofuran, and each of these is C １～３ Alkyl, halo, CN, OH, or C １～３ R is optionally substituted with one or two substituents independently selected from alkoxy groups. Ｏ１ The 5-6 member heteroaryl represented by is a pyrazole, triazole, pyridine, pyrazine, pyrimidine, or pyridazine, and each of these is C １～３ Alkyl, halo, CN, OH, or C １～３ It is optionally substituted with one or two substituents independently selected by an alkoxy, preferably, The aforementioned 4-6 member monocyclic heterocycline, 【Chemistry 10】 And each of these is F, -CN, -CH ３ ien-CH ２ CH ３ ,OH,-CH ２ OCH ３ , and -OCH ３ It is optionally substituted with one or two substituents independently selected from the original compound. The 5-6 member heteroaryl is 【Chemistry 11】 And each of these is F, -CN, -CH ３ ien-CH ２ CH ３ OH, and -OCH ３ Optionally substituted with one or two substituents independently selected from, The compound according to claim 8, or a pharmaceutically acceptable salt thereof.

11. (i) Each R Ｃ is F, -Cl, -CH ３ , -CHF ２ , -CF ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH ２ CH ２ CH ２ CH ３ , -CF ２ CH ３ , -CF ２ CFH ２ , -CFHCFH ２ , -CF ２ CH ２ CH ３ , -CF ２ CH ２ OH, -CF ２ CH ２ OCH ３ , -CH(CH ３ ) ２ , -CF(CH ３ ) ２ , -C(CH ３ ) ３ , -CF ２ C(O)OCH ２ CH ３ , -CH ２ OH, -CH(OH)CH ３ , -CH ２ OCH ３ , -CH ２ CH ２ CH ２ OH, -CH ２ CH ２ OCH ２ CH ３ , -CH ２ CH ２ CH ２ OCH ３ , -CH ２ CH ２ C(CH ３ )(OH)CH ２ CH ３ 、-CH ２ CH ２ CH ２ OC(H) ３ ) ３ 、-CH ２ CH ２ C(CH) ３ ) ２ OH、-EH(EH ３ )OCH ３ 、-C(CH ３ ) ２ OCH ３ 、-CH ２ OCH ２ CH ３ 、-CH ２ -シクロローピル、-CH(CH ３ )-ES ２ CH ３ 、-CH ２ CH ２ -ES ２ CH ３ 、-CH ２ NHCH ３ 、-CH ２ CN、-EH(EH ３ )CN、-EH=E-OEH ２ CH ３ 、OH、-OCH ３ 、-OCH ２ CH ３ ,-OCH(CH ３ ) ２ ,-OCH ２ CF ３ ,-OCH ２ CF ２ CH ３ ,-OCH ２ CH ２ OCH ３ ,-OCH ２ CH ２ F、-OCH ２ CH ２ CH ２ OCH ３ ,-OCH ２ CH ２ N(CH) ３ ) ２ ,-OCH(CH ３ )CH ２ OCH ３ ,-OCH(CH ３ )CN、-OCH ２ C(CH) ３ ) ２ OH、-OCH ２ C(CH) ３ ) ２ OCH ３ 、-OCH(シクロローピル)(CN),-C(O)NH ２ 、-C(O)NHCH ３ 、-C(O)N(CH ３ ) ２ 、-C(O)H、-C(O)CH ３ ,-C(O)OH,-C(O)OCH ２ CH ３ 、-NH ２ 、-NHCH ３ 、-NHCH ２ CH ３ 、-NHCH ２ CH ２ CH ３ ,-NHCH(CH ３ ) ２ 、-N(CH ３ ) ２ 、-N(CH ３ )CH(CH ３ ) ２ 、-NHCH ２ CH ２ CH ２ F、-NHCH ２ CHF ２ 、-NHCH ２ C(F)CH ３ 、-NHCH ２ CH ２ OCH ３ ,-NHCH(CH ３ )CH ２ OCH ３ 、-NHCH ２ HH(H) ３ )N(CH ３ ) ２ 、-NHCH ２ C(CH) ３ ) ２ OCH ３ 、-NHCH ２ CH ２ C(F)CH ３ 、-NHCH ２ HH(H) ３ )OCH ３ ,-NHCH(CH ３ )CH(CH ３ )OCH ３ 、-N(CH ３ )CH ２ CH ２ OCH ３ 、-NHC(O)CH ３ 、-SCH ３ 、-SO ２ CH ３ 、 【Chemistry 12】 Selected independently of, (ii) Each R Ｃ is F, -CH ３ -CHF ２ -CF ３ -CH ２ CH ３ -CH ２ CH ２ CH ３ -CH ２ CH ２ CH ２ CH ３ -CF ２ CH ３ -CF ２ CFH ２ -CFHCFH ２ -CH(CH ３ ) ２ -CF(CH ３ ) ２ -C(CH ３ ) ３ -CH ２ OH, -CH ２ OCH ３ -CH ２ CH ２ CH ２ OCH ３ -CH(CH ３ ) OCH ３ -C(CH ３ ) ２ OCH ３ -CH ２ OCH ２ CH ３ -CH ２ -cyclopropyl, -CH(CH ３ ) -SO ２ CH ３ OH, -OCH ３ -OCH ２ CH ２ OCH ３ -OCH ２ CH ２ CH ２ OCH ３ -OCH ２ CH ２ N(CH ３ ) ２ -OCH(CH ３ ) CH ２ OCH ３ -OCH(CH ３ )CN、-C(O)NH ２ 、-C(O)NXCH ３ 、-C(O)N(CH ３ ) ２ 、-C(O)H,-C(O)CH ３ 、-NH ２ 、-NXCH ３ 、-NXCH ２ CH ３ 、-NXCH ２ CH ２ CH ３ 、-NHCH(CH ３ ) ２ 、-N(CH ３ ) ２ 、-N(CH ３ )CH (CH ３ ) ２ 、-NXCH ２ CH ２ CH ２ F-NXCH ２ CHF ２ 、-NXCH ２ C(F) CH ３ 、-NXCH ２ CH ２ OCH ３ 、-NXCH ２ CH (CH ３ )N (CH ３ ) ２ 、-NXCH ２ C(CH ３ ) ２ OCH ３ 、-NXCH ２ CH ２ C(F) CH ３ 、-NXCH ２ CH (CH ３ )OCH ３ 、-NHCH(CH ３ )CH (CH ３ )OCH ３ 、-N(CH ３ )CH ２ CH ２ OCH ３ 、-NHC(O)CH ３ 、-SCH ３ 、-SO ２ CH ３ 、 【Chemistry 13】 Selected independently of The compound according to claim 10, or a pharmaceutically acceptable salt thereof.

12. (i) R Ｃ Each C represented by ３－６ The cycloalkyl group is selected from cyclobutane, cyclopentane, and cyclopropane. R Ｃ Each 4- to 9-membered monocyclic or bicyclic heterocyclil represented by is independently selected from azetidine, morpholine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, oxazaspiro[3.5]nonane, oxabicyclo[2.1.1]hexane, oxabicyclo[2.2.1]heptane, oxetane, piperidine, piperazine, pyrrolidine, dihydrofuran, tetrahydrofuran, tetrahydrothiophene dioxide, and tetrahydropyran. R Ｃ Each of the 5-6 membered heteroaryls represented by is independently selected from oxazoles, pyrazoles, pyridines, pyrimidines, triazoles, and thiazoles. C ３～６ Each of the cycloalkyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered heteroaryl has 1 to 3 R Ｃ１ It can be optionally replaced with, (ii) R Ｃ Each C represented by ３～６ The cycloalkyl group is selected from cyclobutane, cyclopentane, and cyclopropane. R Ｃ Each 4- to 9-membered monocyclic or bicyclic heterocyclil represented by is independently selected from azetidine, morpholine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, oxazaspiro[3.5]nonane, oxabicyclo[2.2.1]heptane, oxetane, piperidine, piperazine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene dioxide, and tetrahydropyran. R Ｃ Each of the 5-6 membered heteroaryls represented by is independently selected from oxazoles, pyrazoles, pyridines, pyrimidines, and thiazoles. C ３～６ Each of the cycloalkyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered heteroaryl has 1 to 3 R Ｃ１ It can be optionally replaced with, (iii) R Ｃ The C represented by ３～６ Each of the cycloalkyl groups is 【Chemistry 14】 Selected independently from, R Ｃ Each of the 4- to 9-member monocyclic heterocyclines represented by the above is, 【Chemistry 15】 Selected independently from, R Ｃ Each of the phenyls represented by the above is, 【Chemistry 16】 And, R Ｃ Each of the 5-6 member heteroaryls represented by can independently 【Chemistry 17】 Selected independently from, in the formula, [Chemistry 18] - represents a bond to ring C, and n is 0, 1, 2, or 3, as long as the valence allows, or (iv)R Ｃ The C represented by ３～６ Each of the cycloalkyl groups is 【Chemistry 19】 Selected independently from, R Ｃ Each of the 4- to 9-member monocyclic heterocyclines represented by the above is, 【Chemistry 20】 R Ｃ Each of the phenyls represented by the above is, 【Chemistry 21】 And, R Ｃ Each of the 5-6 member heteroaryls represented by can independently 【Chemistry 22】 Selected independently from, in the formula, 【Chemistry 23】 - represents a bond to ring C, and n is 0, 1, 2, or 3, as long as the valence allows, or (v) R Ｃ The C represented by ３～６ Each of the cycloalkyl groups is 【Chemistry 24】 Selected independently from, R Ｃ Each of the 4-6 member monocyclic heterocyclines represented by is 【Chemistry 25】 Selected independently from, R Ｃ Each of the phenyls represented by the above is, 【Chemistry 26】 Selected independently from, R Ｃ Each of the 5-6 member heteroaryls represented by can independently 【Chemistry 27】 Selected independently from, During the ceremony, 【Chemistry 28】 - represents the bonding ring C, or (vi)R Ｃ The C represented by ３～６ Each of the cycloalkyl groups is 【Chemistry 29】 Selected independently from, R Ｃ Each of the 4-6 member monocyclic heterocyclines represented by is 【Transformation 30】 Selected independently from, R Ｃ Each of the phenyls represented by the above is, 【Chemistry 31】 Selected independently from, R Ｃ Each of the 5-6 member heteroaryls represented by can independently 【Chemistry 32】 Selected independently from, During the ceremony, 【Transformation 33】 - represents the bonding ring C. The compound according to claim 10, or a pharmaceutically acceptable salt thereof.

13. (i) Each R Ｃ１ However, halo, OH, -NR Ｎ３ R Ｎ４ , -CN, -C(O)-R ７ , -SO ２ -R ７ , C １～３ Alkoxy, C １～３ Haloalkoxy, C ３～６ Cycloalkyls, 4-6 membered monocyclic heterocyclines, and C １～４ Selected independently of alkyl, where C １～４ The C represented by １～４ Alkyl is C ３～５ Cycloalkyl, 4-8 membered monocyclic heterocyclyl, C １～３ Alkoxy, OH, CN, -NR Ｎ３ R Ｎ４ , and optionally substituted with 1 to 3 substituents independently selected from the halo, R Ｃ１ The C represented by Ｃ１ Alkoxy, C １～３ It is optionally substituted with 1 to 3 substituents independently selected from alkoxys and halos, optionally, Each R Ｃ１ is F, -CN, -C(O)CH ３ -C(O)-cyclopropyl, -SO ２ -CH ３ , -SO ２ -CH ２ CH ３ ,OH,-OCH ３ , -OCH ２ CH ２ OCH ３ , -OCHF ２ , -N(CH ３ ) ２ ien-CH ２ CH ２ N(CH ３ ) ２ ien-CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ CH (CH ３ ) ２ ien-CH ２ CH ２ OH, -CH ２ CH ２ OCH ３ ien-CH ２ OCH ３ ien-CH ２ -Cyclopropyl, -CH ２ F, -CHF ２ , -CF ３ ien-CH ２ CF ３ , -CF(CH ３ ) ２ , -C(OH)(CH ３ ) ２ ien-CH ２ CN, -CHFCH ３ , -CF ２ CH ２ OCH ３ , cyclobutyl, cyclopropyl, 【Transformation 34】 Selected independently of, (ii) Each R Ｃ１ However, halo, OH, -NR Ｎ３ R Ｎ４ , -CN, -C(O)-R ７ , -SO ２ -R ７ , C １～３ Alkoxy, C １～３ Haloalkoxy, C ３～６ Cycloalkyls, 4-6 membered monocyclic heterocyclines, and C １～４ Selected independently of alkyl, where R Ｃ１ The C represented by １～４ Alkyl is C ３～５ Cycloalkyl, C １～３ R is optionally substituted with 1 to 3 substituents independently selected from alkoxy, OH, and halo. Ｃ１ The C represented by １～３ Alkoxy, C １～３ It is optionally substituted with 1 to 3 substituents independently selected from alkoxys and halos, optionally, Each R Ｃ１ is F, -CN, -C(O)CH ３ -C(O)-cyclopropyl, -SO ２ -CH ３ , -SO ２ -CH ２ CH ３ ,OH,-OCH ３ , -OCH ２ CH ２ OCH ３ , -OCHF ２ , -N(CH ３ ) ２ ien-CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ CH ２ OH, -CH ２ CH ２ OCH ３ ien-CH ２ -Cyclopropyl, -CH ２ F, -CHF ２ , -CF ３ , cyclobutyl, cyclopropyl, 【Chemistry 35】 Selected independently of The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. (i) R １ However, Halo, -CN, -NR ２ R ４ , C １～３ Alkoxy, C １～３ Alkyl and C １～３ One to three R molecules independently selected from haloalkyl groups. ８ C arbitrarily substituted by １～４ It is alkyl, R ２ and R ４ However, each is independent of H or C １～３ Alkyl, or (ii) R １ However, halo, -CN, C １～３ Alkoxy, C １～３ Alkyl and C １～３ One to three R molecules independently selected from haloalkyl groups. ８ C arbitrarily substituted by １～４ Alkyl, or (iii) R １ However, -CH ３ ien-CH ２ CH ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , -OCH ３ , or -CH ２ CH ２ OCH ３ is, or (iv)R １ However, -CH ３ ien-CH ２ CH ３ , or -CH ２ CH ２ OCH ３ That is, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. (i) Each R Ｏ１ However, independently, H, C １～３ Alkyl, or C ３～６ It is a cycloalkyl, and here, R Ｏ１ The C represented by １～３ Alkyl and the C ３～６ Cycloalkyl, C １～３ It is arbitrarily substituted with alkoxy, arbitrarily, Each R Ｏ１ is independently H, -CH ３ , -CH ２ -CH ２ -OCH ３ , 【Transformation 36】 is, and (ii) R Ｎ１ and R Ｎ２ However, each is independent of H or C １～３ C arbitrarily substituted with alkoxy １～３ Represents alkyl, optionally, R Ｎ１ and R Ｎ２ are each independently H, -CH ３ or -CH ２ -CH ２ -OCH ３ to represent, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. The aforementioned compound is of formula (X) or (XI): 【Chemistry 37】 It is a compound represented by the formula, in which, n is 1, 2, or 3; Each R Ｃ However, independently, -NR Ｎ１ R Ｎ２ , -OR Ｏ１ , or C １～６ It is an alkyl, 4-6 membered monocyclic heterocycline, where R Ｃ The C represented by １～６ The alkyl group and the 4-6 member monocyclic heterocycline each have 1-3 R Ｃ１ It is arbitrarily replaced with, Each R Ｃ１ However, it became independent and is Haro, R １ is C １～３ It is alkyl, R Ｏ１ R Ｏ２ C is arbitrarily replaced by ３～４ It is a cycloalkyl, R Ｏ２ C １～３ It is an alkoxy, and R Ｎ１ and R Ｎ２ Each of these is independently either H or C １～３ C arbitrarily substituted with alkoxy １～３ It is alkyl, and optionally, The aforementioned compound is of the formula (XA), (XIA), (XIB), (XIC), or (XID): 【Transformation 38】 Represented by, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. (i) Each R Ｃ However, it became independent, - NHCH ３ , - NHCH ２ CH ２ OCH ３ ien-CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ , -CF ２ CH ３ , -CF(CH ３ ) ２ , 【Chemistry 39】 And, R １ However, CH ３ is, or (ii) R Ｃ However, these are 4-6 member monocyclic heterocyclines independently selected from tetrahydrofuran and tetrahydropyran, each of which has 1-3 R Ｃ１ It is arbitrarily replaced with R Ｃ１ is F, or (iii) R Ｃ but, 【Chemistry 40】 Selected independently from, 【Chemistry 41】 - represents a bond to ring C, and optionally, R Ｃ１ is F, or (iv)R Ｃ but, 【Chemistry 42】 Selected independently from, 【Chemistry 43】 The - represents a bond to ring C. The compound according to claim 16, or a pharmaceutically acceptable salt thereof.

18. The aforementioned compound is of formula (XII): 【Chemistry 44】 It is a compound represented by the formula, in which, Each R Ｃ However, independently, C １～３ Alkyl, C １～３ Haloalkyl or -NR Ｎ１ R Ｎ２ And, arbitrarily, each R Ｃ However, independently, -CH ３ ien-CH ２ CH ３ , -CF ２ CH ３ , or -NHCH ３ And, R Ｎ１ and R Ｎ２ However, each is independent of H or C １～３ It is alkyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition according to claim 19 for treating a disease or disorder responsive to inhibition of tyrosine kinase 2 (TYK2), wherein the disease or disorder is optionally inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, cutaneous 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 The above-mentioned pharmaceutical composition is for intestinal diseases, 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, systemic sclerosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis, or sunburn.

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